Ibrutinib Vs Temsirolimus: Results from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL)

Abstract Introduction MCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy. Methods Patients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety. Results Overall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p < 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm. Conclusions Ibrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. Disclosures Rule: Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Download Full-text

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

Author(s):

Luhua Wang ◽

Luis Fayad ◽

Fredrick B. Hagemeister ◽

Sattva Neelapu ◽

Felipe Samaniego ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Progression Free Survival ◽

Phase 2 ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Fostamatinib, a Spleen Tyrosine Kinase Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia: Initial Results of the Multicenter, Open-Label Extension Period of the Soar Phase 2 Study

Blood ◽

10.1182/blood-2018-99-110483 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3612-3612 ◽

Cited By ~ 2

Author(s):

David J. Kuter ◽

Richy Agajanian ◽

Donald M. Arnold ◽

Michael Boxer ◽

Catherine Broome ◽

...

Keyword(s):

Treatment Period ◽

Research Funding ◽

Rescue Therapy ◽

Primary Efficacy ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Antiglobulin Test ◽

Equity Ownership ◽

Extension Period

Abstract Background: Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare and often serious disease characterized by antibody-mediated destruction of red blood cells (RBCs). Activation of Fc receptors on macrophages in turn activates spleen tyrosine kinase (SYK), which triggers a signaling cascade leading to phagocytosis of the antibody-bearing cells. Fostamatinib, a SYK inhibitor, markedly improved Hgb levels in 9 of 17 (53%) patients with wAIHA during a phase 2, open-label, multicenter study. This abstract reports the results of ongoing fostamatinib treatment as of 2 July 2018 in patients who completed the 24-week treatment period and rolled over into the extension period of the study. Methods: Eligible adult patients had primary or secondary wAIHA and had failed more than one prior treatment for wAIHA. Patients had to have hemoglobin (Hgb) <10 g/dL, an IgG-positive direct antiglobulin test, haptoglobin <10 mg/dL, and lactate dehydrogenase (LDH) >ULN. In order to enter the extension period of the study, patients had to have [1] met the primary efficacy endpoint (Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion) OR have shown a beneficial trend during the 24-week treatment period and [2] tolerated study drug. Fostamatinib 150mg BID (or the dose taken at the end of the 24-week treatment period, if a dose reduction had occurred) was taken orally with no food restriction, and patients were seen every 6 weeks during the extension period. Results: Six patients have entered the extension period including 5 who had met the primary efficacy endpoint and 1 who showed a beneficial trend at Week 24 (and had a response at Week 30). One patient had lymphoproliferative disease. Prior AIHA treatment included splenectomy (1), steroids (6), and rituximab (2). The median duration of disease was 1.9 years (range 0.4-15.7). The mean age was 58.7 years (range 30-86), 5 were female, all were white, and 4 were Hispanic or Latino. At baseline the median Hgb was 9.1 g/dL (range: 8.6-9.5); the median lactate dehydrogenase was 273 U/L (range 233-781); the median reticulocyte count was 252.2 x109/L (range 7.8-350.0); and the median haptoglobin was 7.0 mg/dL (range 7.0-9.0). The direct antiglobulin test was positive for IgG in 5 patients at screening. Median Hgb levels increased over the course of the study. See figure. Four of 6 patients had an ongoing response as of the data cutoff date, and none has had rescue therapy or an RBC transfusion. All 6 patients had ≥1 adverse event (AE) during the study, including noninfectious diarrhea in 1 (treatment-related), hepatic disorders in 3 (treatment-related in 2; treatment interrupted in 1), and hypertension in 1 (not related). One patient had a serious AE (inappropriate antidiuretic hormone secretion), which was not related to fostamatinib. To date, no new safety signals have been detected. Summary/Conclusion: Patients with wAIHA continued to display markedly improved Hgb levels during the extension period of the study. Side effects were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure. Figure. Disclosures Kuter: ONO: Consultancy; Protalex: Research Funding; Rigel: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen Inc.: Consultancy; Principia: Research Funding; Bioverativ: Consultancy, Research Funding; Argenx: Consultancy; Syntimmune: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arnold:Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boxer:Incyte: Speakers Bureau; Rigel: Speakers Bureau; AbbVie: Speakers Bureau. Broome:Bioverativ: Honoraria; Alexion: Honoraria. Field:Prolong: Research Funding; Ironwood: Consultancy, Research Funding; Incyte: Research Funding. Lowe:Rigel: Consultancy. Tong:Rigel: Employment, Equity Ownership. Zayed:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership.

Download Full-text

Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽

10.1182/blood-2018-99-110388 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 690-690 ◽

Cited By ~ 12

Author(s):

Srdan Verstovsek ◽

Alessandro M. Vannucchi ◽

Alessandro Rambaldi ◽

Jason R. Gotlib ◽

Adam J. Mead ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Phosphate Binders ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Lymphoid Neoplasms ◽

Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

Download Full-text

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.

Download Full-text

The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Blood ◽

10.1182/blood.v118.21.442.442 ◽

2011 ◽

Vol 118 (21) ◽

pp. 442-442 ◽

Cited By ~ 12

Author(s):

Luhua Wang ◽

Peter Martin ◽

Kristie A. Blum ◽

Brad S. Kahl ◽

Lauren S. Maeda ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Research Funding ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Single Agent ◽

Employment Equity ◽

Mantle Cell ◽

Previously Treated ◽

Equity Ownership

Abstract Abstract 442 Introduction: Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL. Methods and Patients: Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria. Results: A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62–72). The median number of prior treatment regimens is 2 (1–5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1). Conclusions: Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned. Disclosures: Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial. Martin:Pharmacyclics: Research Funding. Blum:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Maeda:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. Williams:Pharmacyclics: Research Funding. Rule:Pharmacyclics: Research Funding. Rodriguez:Pharmacyclics: Employment, Equity Ownership. Pang:Pharmacyclics: Consultancy. Hedrick:Pharmacyclics: Employment, Equity Ownership. Goy:Pharmacyclics: Research Funding.

Download Full-text

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously Treated Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.lba-6.lba-6 ◽

2013 ◽

Vol 122 (21) ◽

pp. LBA-6-LBA-6 ◽

Cited By ~ 3

Author(s):

Richard R. Furman ◽

Jeff P. Sharman ◽

Steven E. Coutre ◽

Bruce D. Cheson ◽

John M. Pagel ◽

...

Keyword(s):

Odds Ratio ◽

Research Funding ◽

Single Agent ◽

Efficacy And Safety ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Heavily Pretreated ◽

Previously Treated ◽

Equity Ownership

Abstract Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression <24 mos since the completion of last therapy. Pts were considered unfit to receive cytotoxic therapy because of comorbidities (defined as a Cumulative Illness Rating Score [CIRS] > 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Download Full-text

Phase 3, Placebo-Controlled, ASPIRE Study (TRC114968) of Eltrombopag (EPAG) Treatment of Thrombocytopenia (TCP) in Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML): Assessment of Clinical Benefit, Safety, and Tolerability

Blood ◽

10.1182/blood.v126.23.1661.1661 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1661-1661 ◽

Cited By ~ 1

Author(s):

Moshe Mittelman ◽

Uwe Platzbecker ◽

Boris V Afanasyev ◽

Sebastian Grosicki ◽

Raymond SM Wong ◽

...

Keyword(s):

Platelet Count ◽

Adverse Events ◽

Research Funding ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Once Daily ◽

Thrombopoietin Receptor ◽

Open Label Extension ◽

Equity Ownership

Abstract Introduction: Thrombocytopenia (TCP) is a serious and life-threatening complication of advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Eltrombopag (EPAG), an oral thrombopoietin-receptor agonist, is approved for treatment of chronic immune thrombocytopenic purpura and severe aplastic anemia. Preclinical studies showed that EPAG has potential antileukemic effects. A phase 1 study in advanced MDS/AML demonstrated an acceptable safety profile at doses up to 300 mg, with no worsening of leukemia, and it also showed a trend towards efficacy. Eltrombopag as monotherapy in MDS/AML has not been studied in a randomized fashion. Methods: In Study TRC114968 (ASPIRE), after 8 weeks of open-label, dose-defining EPAG treatment (Study Part 1), patients with highly advanced MDS or AML were randomized 2:1 to EPAG 100-300 mg or placebo (PBO) once daily for 12 weeks (Part 2), then entered a 6-month, open-label extension (Part 3). Patients were stratified by baseline platelet count (<10 Gi/L vs ≥10 Gi/L), and by MDS vs AML. Eligibility included 10-50% baseline bone marrow blasts and a baseline platelet count of <25 Gi/L. The primary endpoint was improvement in the clinically relevant thrombocytopenic event (CRTE) rate during the 12-week double-blind period. CRTE was a composite of a platelet transfusion requirement, significant bleeding event, or platelet count <10 Gi/L. Part 1 results have been presented previously. Blinded results for patients randomized in Part 2 of the study are presented below. Analyses of results by treatment arm, including those for the primary endpoint of CRTE, are ongoing and will be presented at the meeting. Results: A total of 145 patients were enrolled and randomized. According to WHO criteria, 72 (50%) had MDS and 73 (50%) had AML. See Table 1 for baseline characteristics. The majority of patients (n=91, 63%) were escalated to 300 mg (150 mg for East Asians) once daily. 70 patients (48%) completed the randomized portion of the study, and 58 (40%) entered the open-label extension. Patient disposition is described in Table 2. Out of the 144 treated patients, 97 patients (67%) have died (67 patients in Part 2 and 30 patients in Part 3). The main reasons for withdrawal from the study were adverse events (49 patients, 34%) and progressive disease (39 patients, 27%). The most common adverse events in Part 2 were petechiae, epistaxis, fatigue, pyrexia, and diarrhea. The main serious adverse events in Part 2 were pneumonia, sepsis, and febrile neutropenia. Liver test abnormality occurred in 1 (<1%). The median number of platelet transfusions for both groups was 10. Conclusions: This is the first study to evaluate EPAG as monotherapy in a randomized fashion in patients with advanced MDS or AML and severe thrombocytopenia. Overall safety was as expected for this patient population with no unexpected adverse events. This study provides evidence for the safety of EPAG in this mostly heavily pretreated patient population. An Independent Response Committee (IRC) is currently assessing responses and disease progression centrally by arm, and final data will be presented at the meeting. Funding: This study was sponsored by GlaxoSmithKline; eltrombopag is an asset of Novartis AG as of March 2, 2015. Disclosures Mittelman: Celgene: Research Funding, Speakers Bureau; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Novartis Pharmaceuticals Corporation: Research Funding; Roche: Research Funding; Amgen: Research Funding. Off Label Use: Eltrombopag is a once daily oral thrombopoietin receptor agonist approved for treatment of chronic ITP, hepatitis C associated thrombocytopenia, severe aplastic anemia, and pediatric cITP. Data will be presented on use in myeloid malignancies for which eltrombopag is not approved.. Platzbecker:Novartis: Honoraria; Celgene: Honoraria; Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Wong:Johnson & Johnson: Research Funding; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Anagnostopoulos:GlaxoSmithKline: Research Funding. Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Mannino:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Stone:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Chan:Novartis Pharmaceuticals Corporation: Employment; GlaxoSmithKline: Employment, Equity Ownership. Mostafa Kamel:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership; GlaxoSmithKline: Employment, Equity Ownership. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

Improved Survival with Enzastaurin Treatment in Diffuse Large B-Cell Lymphoma Patients with the Novel Genetic Biomarker, DGM1

Blood ◽

10.1182/blood-2018-99-115807 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4207-4207

Author(s):

Wen Luo ◽

Hong Sun ◽

Jun Zhu ◽

Stephen D. Smith ◽

Isabel Han ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Phase 2 ◽

Newly Diagnosed ◽

Employment Equity ◽

Phase 3 ◽

Phase 2 Trial ◽

Phase 2 Study ◽

Biomarker Analysis ◽

Equity Ownership

Abstract Background Drugs that have benefited a subset of patients but discontinued for development may be rescued through identification of a biomarker predictive of response. Enzastaurin, a potent and selective inhibitor of protein kinase C-β, improved PFS in high-risk DLBCL patients in a randomized phase 2 trial when combined with RCHOP, but not when administered as maintenance therapy in DLBCL patients achieving CR. Using data from both trials, we identified a biomarker potentially predictive of enzastaurin benefit. Methods Biomarker discovery was conducted on Eli Lilly's (Lilly) PRELUDE study, a phase 3 maintenance trial that enrolled approximately 750 DLBCL patients who achieved a complete response to R-CHOP front-line therapy. Patients were randomized to enzastaurin or placebo maintenance for up to three years. A genome-wide screen was performed on DNA extracted from blood samples from patients participating in this study and results were evaluated for correlation to efficacy endpoints through bioinformatic analysis. Confirmation of the biomarker identified in the phase 3 study was performed by independent analysis of the biomarker in a separate completed Lilly enzastaurin study in patients with DLBCL. This study was a phase 2 trial in 101 newly diagnosed DLBCL patients randomized to treatment with R-CHOP or R-CHOP plus enzastaurin. Patients receiving R-CHOP plus enzastaurin and achieving a CR or PR after induction were eligible to continue with single agent enzastaurin for up to 3 years. Results Denovo Genomic Marker 1 (DGM1), a germline polymorphism on chromosome 8, was identified using Lilly's phase 3 samples as highly correlated and potentially predictive of response to enzastaurin. Although there was no difference in overall survival (OS) in the ITT population, biomarker analysis found that DGM1+ patients receiving enzastaurin had significantly improved OS compared to DGM1- patients receiving enzastaurin (HR 0.27, p=0.0002) in the PRELUDE trial (Figure 1). These findings were replicated in the phase 2 study biomarker analysis: DGM1+ patients receiving R-CHOP plus enzastaurin had significantly improved OS (HR 0.1, p-0.005) compared to DGM1- patients (Figure 2). The original analysis of the phase 2 study found a trend towards improved, but not statistically significant, OS in patients with high-risk DLBCL receiving R-CHOP plus enzastaurin. Biomarker analysis of this population demonstrated significant improvement in OS (HR 0.28, p=0.018) for high-risk DLBCL DGM1+ patients receiving R-CHOP plus enzastaurin compared to high-risk DLBCL DGM1+ patients receiving R-CHOP alone (Figure 3). DGM1+ status was not predictive of efficacy in the control (non-enzastaurin) arm (Figure 4). Conclusion These data are supportive of DGM1 as a potentially predictive biomarker for enzastaurin efficacy. The mechanism of DGM1 impact in DLBCL is under study. Based on this data, a biomarker driven phase 3 trial (ENGINE Trial) of R-CHOP plus enzastaurin versus R-CHOP in DGM1+ and DGM1- patients with newly diagnosed high-risk DLBCL is underway. Disclosures Luo: Denovo Biopharma LLC: Employment, Equity Ownership. Sun:Denovo Biopharma LLC: Employment, Equity Ownership. Smith:Portola: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding. Han:Denovo Biopharma LLC: Employment, Equity Ownership. Shazer:Denovo Biopharma LLC: Employment, Equity Ownership.

Download Full-text

Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-129893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1900-1900 ◽

Cited By ~ 4

Author(s):

Katja Weisel ◽

Thomas G Hopkins ◽

Doug Fecteau ◽

Weichao Bao ◽

Corinne Quigley ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Research Funding ◽

Standard Of Care ◽

Efficacy And Safety ◽

Open Label ◽

Employment Equity ◽

Phase 3 ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Download Full-text

Final Safety and Efficacy Results from the CPX-351 Early Access Program (EAP) for Older Patients with High-Risk/Secondary Acute Myeloid Leukemia (sAML)

Blood ◽

10.1182/blood-2018-99-111537 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1434-1434

Author(s):

Gail J. Roboz ◽

Melissa L. Larson ◽

S. Eric Rubenstein ◽

Scott R Solomon ◽

Gary J. Schiller ◽

...

Keyword(s):

High Risk ◽

Older Patients ◽

Research Funding ◽

De Novo ◽

Newly Diagnosed ◽

Open Label ◽

Employment Equity ◽

Phase 3 ◽

Equity Ownership ◽

De Novo Aml

Abstract Background: CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. In a large randomized, open-label, multicenter, phase 3 study of CPX-351 versus conventional cytarabine/daunorubicin chemotherapy (7+3 regimen) in adults aged 60-75 years with newly diagnosed high-risk/sAML, patients treated with CPX-351 had significantly longer survival times and higher remission rates (Lancet JE, et al. J Clin Oncol. 2018). Based on these results, CPX-351 was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC). This abstract reports the results of an EAP study that provided expanded access to CPX-351 for older patients who met the eligibility criteria for the phase 3 study and collected additional data on safety and efficacy. Methods: In this phase 4, single-arm, open-label EAP, patients were between 60-75 years of age and had confirmed high-risk/sAML (therapy-related AML [tAML], AML with a history of myelodysplasia [MDS] or chronic myelomonocytic leukemia [CMML], or de novo AML with MDS karyotype). Patients could receive up to 2 cycles of induction with CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) on Days 1, 3, and 5 (2nd induction: Days 1 and 3). Patients with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 4 cycles of consolidation with CPX-351 65 units/m2 (cytarabine 65 mg/m2 + daunorubicin 28.6 mg/m2) on Days 1 and 3. The primary endpoint was safety, and the secondary endpoint was the rate of CR+CRi. Results: Overall, 52 patients received ≥1 dose of CPX-351 and were included in the safety analysis. Among these patients, the median age was 70 years (range: 55-75) and 23% had an Eastern Cooperative Oncology Group score of 2. Median time since diagnosis was 0.30 months (range: 0.03-36.14) months. Patients with AML-MRC accounted for 77% of the safety analysis population, including those with antecedent MDS with prior hypomethylating agent (HMA) treatment (25%), antecedent MDS without prior HMA treatment (21%), antecedent CMML (8%), and de novo AML with MDS karyotype (23%); 23% of patients had tAML. All patients received 1 induction cycle and 25% received 2 induction cycles; 17%, 8%, 4%, and 2% of patients received 1, 2, 3, and 4 consolidation cycles, respectively. CR+CRi was achieved in 23 patients (44% [95% CI: 31%, 59%]), including 15 with CR (29% [95% CI: 17%, 43%]) and 8 with CRi (15% [95% CI: 7%, 28%]; Table). The median time to remission was 37 days (range: 15-72). At the end of the study, 47 (90%) of patients were still alive and 11 (21%) patients received transplant. All patients were alive at Day 30, and the mortality rate at Day 60 was 6%. The safety profile observed in this EAP study was consistent with that of the phase 3, randomized study (Table). Treatment-emergent adverse events (TEAEs) of any grade occurred in 96% of patients, including 44% of patients with an TEAE deemed related to treatment; the only treatment-related AE that occurred in >10% of patients was febrile neutropenia (31%). Only 2 patients (4%) discontinued treatment due to an AE (ejection fraction decrease and intercranial hemorrhage [n = 1 each]). Five patients (10%) had grade 5 AEs during the study, including disease progression, multiple organ dysfunction syndrome, acute respiratory distress syndrome, aspiration, and intracranial hemorrhage (n = 1 each). Conclusions: The data from this EAP study were consistent with results from the randomized, phase 3 study. The safety profile in the EAP study was similar to that observed in the phase 3 study and there was a similar CR+CRi rate (44% vs 48%, respectively) in this high-risk/sAML population. Disclosures Roboz: Sandoz: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Pfizer: Consultancy. Rubenstein:Alexion: Consultancy, Honoraria, Speakers Bureau; Cyclacel: Other: Travel support; Astex: Other: Travel support. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. An:Jazz Pharmaceuticals: Employment. Mancino:Jazz Pharmaceuticals: Employment. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Lin:Jazz Pharmaceuticals: Honoraria.

Download Full-text