Health-Related Quality of Life Among Patients with Relapsed or Refractory Multiple Myeloma Who Received Pomalidomide, Bortezomib, and Low-Dose Dexamethasone Versus Bortezomib and Low-Dose Dexamethasone - Results from the Phase 3 Optimismm Study

Abstract Introduction : A diagnosis of multiple myeloma (MM) has a substantial impact on health-related quality of life (HRQoL) due to associated symptoms, such as bone pain, infection, and fatigue. Furthermore, HRQoL deteriorates with each subsequent line of therapy. The phase 3 OPTIMISMM study (NCT01734928) demonstrated that pomalidomide, bortezomib, and low-dose dexamethasone (PVd) resulted in a significantly longer progression-free survival (PFS) and greater overall response rate (ORR) compared with bortezomib and low-dose dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM), all of whom had received prior treatment with lenalidomide. Given that HRQoL in RRMM is an important consideration, we conducted this analysis to evaluate the effect of PVd versus Vd on HRQoL in patients enrolled in the OPTIMISMM study. Methods : The OPTIMISMM study was a phase 3, multicenter, randomized, open-label study that enrolled adult RRMM patients who had received 1 to 3 prior anti-myeloma regimens including lenalidomide. Patients (N=559) were randomly assigned to receive PVd (n=281) or Vd (n=278) per 21-day treatment cycle until progression or treatment discontinuation. HRQoL was assessed as an exploratory endpoint using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 (QLQ-C30) questionnaire at Day 1 of each 21-day cycle prior to treatment administration and at the end of treatment. The primary domain of interest was the Global Health Status/QoL domain of the QLQ-C30. Analyses were performed in the HRQoL-evaluable population, which included randomized patients who completed the QLQ-C30 assessment at baseline and at least one post-baseline visit. Key primary analyses of PVd versus Vd on the global QoL domain of the QLQ-C30 included a longitudinal assessment of change from baseline using a mixed-model repeated measure (MMRM) approach; an assessment of the proportion of patients experiencing clinically meaningful deterioration (i.e., ≥10 points worsening from baseline) at pre-selected post-baseline visits; and an analysis of time to first clinically meaningful deterioration. Results : The HRQoL-evaluable population consisted of 240 patients in the PVd group and 209 in the Vd group; baseline characteristics were well-balanced between the treatment groups. HRQoL compliance rates based on the number of patients expected to complete the QLQ-C30 at each given visit exceeded 80% for most visits among both groups. Mean (SD) baseline scores for the global QoL domain of the QLQ-C30 were similar between groups (61.0 [23.2] in the PVd group and 63.5 [21.3] in the Vd group); these scores were maintained over time for both treatment groups, with no clinically meaningful differences observed between the treatment groups at any cycle (Figure 1). The MMRM analyses showed no clinically meaningful difference in global QoL of patients between the PVd group and the Vd group. There was also no significant difference observed in the proportion of patients who experienced clinically meaningful worsening in the global QoL domain between the treatment groups throughout the pre-selected post-baseline visits. The median time to the first clinically meaningful worsening was also similar between treatment groups: 3.0 months for the PVd group and 3.4 months for the Vd group, respectively (hazard ratio: 1.20; 95% confidence interval: 0.9456, 1.5151; p=0.1351; Figure 2 for when death was considered as an event); similar results were observed when death was censored. Conclusions: The results from this analysis of the OPTIMISMM study showed that the triplet regimen of PVd, which consisted of pomalidomide added to the doublet regimen of Vd, did not compromise HRQoL in lenalidomide-treated patients with RRMM. Overall, there were no clinically meaningful differences in the Global Health Status/QoL domain of the QLQ-C30 between treatment groups. These results are meaningful and provide further evidence of the clinical benefits of the addition of pomalidomide to Vd, which include significant improvements in PFS and ORR. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Dimopoulos:Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Moreau:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Rodriguez Otero:Clínica Universidad de Navarra: Employment; Takeda: Consultancy; Bristol Myers Squibb: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Anttila:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hayden:Celgene: Honoraria; Jassen: Honoraria; Amgen: Honoraria. Krauth:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Guo:Celgene Corporation: Consultancy. Purnomo:Celgene: Employment. Yu:Celgene: Employment, Equity Ownership. Grote:Celgene: Employment. Biyukov:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sezary Syndrome: Results from a Multicenter Phase 1 Trial

Blood ◽

10.1182/blood-2018-99-118021 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 684-684 ◽

Cited By ~ 1

Author(s):

Martine Bagot ◽

Pierluigi Porcu ◽

Basem M. William ◽

Maxime Battistella ◽

Maarten Vermeer ◽

...

Keyword(s):

Quality Of Life ◽

Monoclonal Antibody ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Employment Equity ◽

Advisory Committees ◽

Multicenter Phase ◽

Equity Ownership

Abstract Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Venetoclax Improves Quality of Life for Patients with Elapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-117127 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4858-4858 ◽

Cited By ~ 1

Author(s):

Tara Cochrane ◽

Tatiana Chagorova ◽

Tadeusz Robak ◽

Su-Peng Yeh ◽

Evgeny Nikitin ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Eortc Qlq ◽

The Impact

Abstract INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.

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MM-005: A Phase 1 Trial Of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone (PVD) In Relapsed and/Or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v122.21.1969.1969 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1969-1969 ◽

Cited By ~ 10

Author(s):

Paul G. Richardson ◽

Craig C. Hofmeister ◽

David Siegel ◽

Sagar Lonial ◽

Jacob P. Laubach ◽

...

Keyword(s):

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

The Us ◽

Equity Ownership ◽

Grade 3

Abstract Background The combination of the immunomodulatory drug lenalidomide (LEN) with the proteasome inhibitor bortezomib (BORT) and dexamethasone (DEX) has demonstrated substantial preclinical and clinical activity in patients with MM (Richardson PG, et al. Blood. 2010; Kumar S, et al. Blood. 2012). Pomalidomide (POM), a distinct immunomodulatory agent, has been approved by the US FDA for patients with RRMM with ≥ 2 prior therapies, including LEN and BORT, and progressive disease (PD) on or within 60 days of completion of the last line of treatment (Tx). POM with low-dose DEX (LoDEX) has demonstrated efficacy in patients with RRMM treated with prior LEN and BORT (San Miguel, EHA 2013; Leleu X, et al. Blood. 2013; Richardson PG, et al. Blood 2013; Lacy MQ, et al. Blood. 2011). MM-005 was designed to identify the optimal dose of POM-BORT-DEX (PVD) combination Tx for a phase 3 trial comparing PVD vs BORT + LoDEX (VD) in patients with RRMM (MM-007). Methods Eligible patients had RRMM with 1-4 prior lines of Tx including ≥ 2 consecutive cycles of LEN and a proteasome inhibitor. Patients must have been refractory to LEN (PD during or within 60 days of LEN Tx) but not refractory to BORT (at 1.3 mg/m2 twice weekly). The maximum tolerated dose (MTD) was determined using a 3 + 3 design in 5 cohorts. Each cohort received 21-day cycles of POM (1-4 mg/day on days 1-14); intravenous BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11); and LoDEX (20 mg/day on days 1-2, 4-5, 8-9, and 11-12; patients aged > 75 years received 10 mg/day on days 1-2, 4-5, 8-9, 11-12). The study protocol was revised to include a 6-patient cohort receiving subcutaneous BORT. Thromboprophylaxis was given to all patients as either aspirin or low-molecular-weight heparin. Once established, an expansion cohort was enrolled at the MTD. Tx was continued until PD or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1. MTD was the primary endpoint; secondary endpoints included safety, overall response rate (ORR; ≥ partial response), duration of response, and time to response (TTR). Results A total of 28 patients across all Tx cohorts is planned. As of April 2013, 22 patients have been enrolled, 21 patients were evaluable for baseline characteristics and safety, and 20 patients were evaluable for response. The median age was 57 years (range, 36-75 years). The median number of prior Tx lines was 2 (range, 1-4). All patients were refractory to LEN and had received prior BORT. 67% of patients had progressed on LEN as their last prior Tx and an additional 2 patients never responded to LEN. At the time of analysis, 14 of 22 (64%) patients remain on study. The primary reason for discontinuation was PD (27%). No DLTs have been observed during cycle 1 at any dose level; thus, the MTD/maximum planned PVD dose is POM 4 mg (days 1-14); intravenous BORT 1.3 mg/m2 (days 1, 4, 8, and 11 for cycles 1-8; days 1 and 8 for cycles 9+); and LoDEX 20 mg/day (days 1-2, 4-5, 8-9, and 11-12 for cycles 1-8; days 1-2, 8-9 for cycles 9+). The most common grade 3/4 adverse events (AEs) were neutropenia (29%) and thrombocytopenia (19%). With thromboprophylaxis, no deep vein thrombosis was observed. Despite 62% of patients having a history of peripheral neuropathy (PN) at baseline, only 29% developed grade 1 and 14% developed grade 2 PN; no grade 3/4 PN was observed. Only 1 patient has discontinued due to AE (Tx-unrelated metastatic pancreatic cancer). Thus far, the ORR is 75% (15 of 20 evaluable), 30% achieving very good partial response (VGPR) or better (including 1 patient in stringent complete response). Responses were rapid (median TTR of 1 cycle [range 1-3]). Many responses are ongoing and may improve with longer follow-up. Responses were also observed in patients with adverse cytogenetics. Updated and pharmacokinetic data on all 28 patients are planned for presentation at the meeting. Conclusions PVD was generally well tolerated in this population of LEN-refractory and BORT-exposed patients with RRMM, with no DLTs and no discontinuations due to Tx-related AEs to date. PVD had promising activity in this population of LEN-refractory and BORT-exposed RRMM pts with an ORR of 75% and 30% ≥ VGPR. The maximum planned dose of POM 4 mg/day on days 1-14; BORT 1.3 mg/m2 on days 1, 4, 8, and 11; and LoDEX 20 mg on days 1-2, 4-5, 8-9, and 11-12 (21-day cycles) has been incorporated into the ongoing MM-007 randomized, prospective phase 3 trial comparing PVD with VD in patients with RRMM (N = 782). Disclosures: Richardson: Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: POM is approved in the US but not in Europe. Hofmeister:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Lonial:Sanofi: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Onyx: Consultancy. Vesole:Millennium: Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Raje:Millennium: Consultancy; Onyx: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding. Zaki:Celgene: Employment, Equity Ownership. Hua:Celgene: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene: Employment, Equity Ownership. Wang:Celgene: Employment, Equity Ownership. Anderson:Acetylon: Equity Ownership; Gilead: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Oncopop: Equity Ownership.

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Treatment Decision Making in AML: Factors of Importance to Clinicians, AML Patients and Their Family

Blood ◽

10.1182/blood-2019-124660 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3498-3498

Author(s):

Thomas W. LeBlanc ◽

Roland B. Walter ◽

Loriana Hernandez-Aldama ◽

Kate Sully ◽

Timothy J Bell ◽

...

Keyword(s):

Quality Of Life ◽

Decision Making ◽

Board Of Directors ◽

Research Funding ◽

Treatment Decision ◽

Employment Equity ◽

Advisory Committees ◽

Trade Offs ◽

Equity Ownership

INTRODUCTION: Acute myeloid leukemia (AML) is a rare hematologic cancer primarily affecting older people, with a median age at diagnosis of 67 years old (Almeida & Ramos, 2016). Heterogeneity in the presentation, functional status and presence of comorbidities among AML patients presents unique challenges for treatment. Intensive chemotherapy (IC), although the best option for prolonging survival, carries a risk of early death and other trade-offs, including significant time spent in the hospital. The toxicity of IC treatment and the requirement for prolonged hospitalizations may negatively affect patients' physical functioning and health-related quality of life (HRQoL). Novel, low-intensity treatments can be administered in the clinic and may pose less risk of immediate toxicities but may be associated with reduced efficacy. Each patient and family will approach these trade-offs differently, yet few studies examine the process of shared decision-making in AML. We aimed to better understand this process by eliciting patient/family and physician narratives about expectations and attitudes towards AML treatments. METHODS: Ten physicians in the US (n=4), UK (n=3) and Canada (n=3) and 12 AML patients (all US) and a member of their family took part in an individual, 60-minute qualitative telephone interview. Further interviews are scheduled and any additional data at the time of presentation will also be reported. The interviews followed a semi-structured guide comprising open-ended questions. The overarching aim of the interviews was to understand the value of living longer for AML patients who are not candidates for standard IC and to explore the treatment decision process from the patient, family and physician perspective. During the interviews, each participant (patient, family member or physician) completed a rating exercise in which they were asked to rate a list of pre-defined factors (9-10 factors) on a scale of 0 (not at all important) to 3 (very important) to determine their importance in AML treatment decisions. As well as providing a numerical rating for each factor, each participant was asked why they selected their rating and which three factors they would consider the most important. RESULTS: Across all three groups, relief in AML symptoms (namely fatigue and pain), longer survival and better QoL were equally considered the three most important factors when making a treatment decision. All three groups described the interaction between QoL and longer survival, explaining that any increase in survival would be important, but only if QoL (time spent with family, maintaining hobbies/interests) was maintained or improved. Physician's advice was also important to AML patients when making decisions regarding treatment. Other treatment-related factors within the rating task were rated as very important for at least a subset of patients, with no factors widely considered to be of limited importance. All participants noted that while relief of AML symptoms, longer survival and quality of life were all important, these had to be considered in light of treatment side effects and risk of infection. Likelihood of being hospitalized was important to family members, as they wanted to spend quality time at home with their loved ones, while patients and physicians considered hospitalization as an inevitable consequence of the disease and treatment. All participants reported that AML patients would consider taking any form of treatment if suitable and effective, regardless of the mode of administration. However, it was acknowledged that oral treatments would be more convenient and less invasive. The relative importance of location of care/treatment delivery was influenced by proximity to resources and whether the participant was based in an urban or rural setting. The ability to receive treatment at home was considered beneficial. CONCLUSIONS: The results from this rating exercise and qualitative interviews showed convergence across all stakeholders, indicating that AML patients, family and physicians have similar priorities regarding treatment decisions, prioritizing symptom relief, survival, and quality of life. The predominant treatment pathways in AML each require trade-offs in these factors, demonstrating the importance of shared decision making in ensuring the most appropriate treatment is selected for a given individual, in accordance with their values, goals, and preferences. Figure Disclosures LeBlanc: Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Heron: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Flatiron: Consultancy; NINR/NIH: Research Funding; Duke University: Research Funding; Astra Zeneca: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Celgene: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareVive: Consultancy. Walter:Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy. Hernandez-Aldama:Pfizer Inc: Consultancy. Sully:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Johnson:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Peloquin:Pfizer Inc: Employment, Equity Ownership. Gater:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Welch:Pfizer Inc: Employment, Equity Ownership. O'Hara:Adelphi Values Ltd: Employment; Pfizer Inc: Consultancy. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Horikoshi:Pfizer Inc: Consultancy. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Outcomes Based on Prior Treatment Exposure

Blood ◽

10.1182/blood.v120.21.4070.4070 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

Ravi Vij ◽

Craig C. Hofmeister ◽

Paul G. Richardson ◽

Sundar Jagannath ◽

David S. Siegel ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Advisory Board ◽

Prior Exposure ◽

Employment Equity ◽

Advisory Committees ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4070 Background: There are currently limited effective treatment options for patients (pts) with RRMM with prior exposure to lenalidomide (LEN), bortezomib (BORT) and chemotherapy. In a multicenter, randomized phase 2 study, POM with or without LoDEX (n=221) was active in RRMM pts who had received ≥2 prior therapies, including LEN and BORT (Richardson PG, et al. Blood 2011;118:abs 634); activity was also observed in those with disease refractory to LEN, BORT, or both (Vij R, et al. J Clin Oncol 2012;30:abs 8016). Here we characterize outcomes in the POM+LoDEX group (n=113) according to the prior treatment exposure. Methods: Pts with RRMM who had received ≥2 prior therapies, including LEN and BORT, and had progressive disease (PD) within 60 days of their last treatment were randomized (1:1 ratio) to POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDex, 40 mg/week) or POM alone. At randomization, pts were stratified by age, prior number of treatments, and prior thalidomide exposure. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. All pts received thromboprophylaxis (daily low-dose aspirin). The endpoints in this study were progression-free survival (PFS), response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, overall survival (OS), and safety. Response data according to prior therapy were assessed by investigator assessment. Results: All 113 pts assigned to POM+LoDEX had prior exposure to LEN (100%), BORT (100%), and steroids (100%). Most pts had also received prior alkylator therapy (93%), stem cell transplant (SCT) (73%), and thalidomide (THAL) (68%); 49% had received prior anthracyclines. Regimens immediately prior to study entry included BORT (50%), LEN (39%), cyclophosphamide (13%), THAL (8%), vorinostat (8%), carfilzomib (5%), and melphalan (5%). The median number of exposures to LEN and BORT in prior lines was once (range 1–4) and twice (range 1–6), respectively. The majority of pts (80%) had received >3 prior therapies. The overall response rate (ORR) was 48% and 30% in pts who had received ≤3 and >3 prior therapies, respectively. Of the pts who had ≤3 vs > 3 prior therapies, 9% vs 1% pts achieved complete response (CR), 39% vs 29% pts achieved partial response (PR), 9% vs 12% pts achieved minimal response (MR) and 44% vs 36 % pts achieved stable disease (SD), respectively. ORR was 34% and appeared similar regardless of prior exposure to alkylators (33%), anthracyclines (35%), SCT (35%), or THAL (35%). Median duration of response was also similar in pts who had received prior alkylators (8.4 mos), anthracyclines (10.1 mos), SCT (7.7 mos), and THAL (7.7 mos). Of the 69 pts who had a best response of SD or PD to their last prior antimyeloma therapy, 21 pts (12 SD and 9 PD) achieved a PR and 3 pts (1 SD and 2 PD) achieved a CR with POM+LoDEX treatment. Responding pts had longer time to progression (TTP; 11.1 mos) with POM+LoDex compared with the TTP (4.4 mos) observed with their last antimyeloma regimen prior to study. The most common grade 3–4 adverse events in the POM+LoDEX group were neutropenia (41%), anemia (22%), pneumonia (22%), thrombocytopenia (19%), and fatigue (14%). The incidence of at least 1 grade 3–4 adverse event was 100% in pts with ≤ 3 prior therapies, and 88% in pts with >3 therapies. Conclusions: The combination of POM+LoDEX has demonstrated an ORR of 34% in heavily pretreated pts with RRMM who have been previously exposed to LEN, BORT, steroids, and other treatments. Early treatment of POM+LoDEX (≤3 prior therapies) achieved better ORR (48%) compared with pts who received POM+LoDex later (>3 prior therapies; ORR, 30%). Disclosures: Vij: Onyx: Consultancy, Research Funding; Millennium Pharma: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory Board Other, Honoraria. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Jagannath:Onyx Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.3026.3026 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3026-3026 ◽

Cited By ~ 5

Author(s):

Jesús F. San-Miguel ◽

Vania T.M. Hungria ◽

Sung-Soo Yoon ◽

Meral Beksac ◽

Meletios A. Dimopoulos ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Final Analysis ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

Study Therapy

Abstract Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months]; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72]). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

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Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multi-Organ Dysfunction: Final Results from a Pivotal, Historically Controlled, Phase 3 Trial

Blood ◽

10.1182/blood.v126.23.737.737 ◽

2015 ◽

Vol 126 (23) ◽

pp. 737-737

Author(s):

Paul G. Richardson ◽

Marcie Riches ◽

Nancy A. Kernan ◽

Joel A. Brochstein ◽

Shin Mineishi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Final Analysis ◽

Occlusive Disease ◽

Sinusoidal Obstruction Syndrome ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of >80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/>16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4509.4509 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4509-4509 ◽

Cited By ~ 4

Author(s):

R. Frank Cornell ◽

Adriana C Rossi ◽

Rachid Baz ◽

Craig C Hofmeister ◽

Chaim Shustik ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Low Dose ◽

Phase 1 ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Blood ◽

10.1182/blood.v126.23.1087.1087 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1087-1087 ◽

Cited By ~ 3

Author(s):

K John Pasi ◽

David J Perry ◽

Johnny Mahlangu ◽

Barbara A Konkle ◽

Savita Rangarajan ◽

...

Keyword(s):

Treatment Group ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Groups ◽

Equity Ownership

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylactic treatment with conventional FVIII products usually requires frequent intravenous infusions (3-4 times/week). Recombinant FVIII Fc fusion protein (rFVIIIFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FVIII. The safety, efficacy and prolonged half-life of rFVIIIFc in adults and adolescents with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01027377, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in participants in these studies. Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the interim data cut, 6 January 2014) for subjects treated with ≥1 dose of rFVIIIFc (n=164). A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on day 1 and 50 IU/kg on day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment. Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or episodic treatment groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) treatment group. Subjects could change treatment groups at any point during ASPIRE. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 4 weeks), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic dose and dosing interval. Results: Of the 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE. At the time of the interim data cut, 140 subjects were ongoing in ASPIRE. Cumulatively, subjects had a median (IQR) of 25.5 (24.6, 26.7) months of rFVIIIFc treatment, and a median (IQR) of 183.0 (120.5, 232.5) rFVIIIFc exposure days (EDs). No inhibitors were reported. The estimated inhibitor incidence rate (95% CI) was 0.0% (0.0, 2.2) overall (N=164), and 0.0% (0.0, 2.7) in subjects with ≥100 rFVIIIFc EDs (n=136). The type and incidence of AEs observed were consistent with those expected for the general hemophilia population. 84.8% of subjects reported ≥1 AE on study, with the majority assessed by the investigator as mild and unrelated to rFVIIIFc treatment. 17.7% of subjects experienced at least 1 SAE; none were assessed by the investigator as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were generally lower with rFVIIIFc treatment compared with prestudy FVIII (Figure). In the IP treatment group, the year 1 and year 2 median spontaneous ABRs were 0.0. Overall, 89.1% of bleeding episodes were controlled with 1 infusion; 97.3% with 1 or 2 infusions. Among subjects treated with FVIII prophylaxis prior to entering A-LONG (n=79), 86% were dosed at least 3 times/week. With rFVIIIFc, 96% of these subjects extended their dosing interval compared with their prestudy product, while the median (IQR) total weekly prophylactic dose was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.2] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE demonstrate long-term safety, with no inhibitors observed in any subjects, and efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without an increase in median prophylactic factor consumption. Figure 1. Figure 1. Disclosures Pasi: Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Roche: Research Funding; Biotest: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Konkle:Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Consultancy, Other: IDMC chair; Pfizer: Other: IDMC member; Octapharma: Research Funding; Novo Nordisk: Consultancy. Rangarajan:Grifols, Pfizer, and Baxter: Research Funding; Grifols: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees; LFB: Other: Conference support. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Dong:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership.

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