Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10

Abstract Background: The randomized phase-2 trial SAKK 35/10 was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) to compare the activity of single-agent rituximab versus rituximab plus lenalidomide in the first-line treatment of symptomatic follicular lymphoma (FL). The results of primary endpoint (complete remission [CR/CRu] at week 23) assessment were previously reported, showing that addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate at the expected cost of increased but manageable toxicity (Kimby et al. Blood 2014.124 (21):799; Zucca et al. Hematol Oncol 2015. 33(s1): 105). Here we report the first analysis of secondary endpoints, progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), CR duration, as well as CR/CRu rate at 30 months (CR30). Methods: 154 patients (pts) with grade 1 to 3a FL, untreated and in need of systemic therapy, were randomized to receive either rituximab (375mg/m2 at week 1, 2, 3, 4, 12, 13, 14 and 15) or rituximab (same schedule) plus lenalidomide (15 mg daily, from 14 days before the first until 14 days after the last rituximab administration). The sample size was calculated to allow the detection of a 20% increase of the CR/Cru rate with 90% power and type I error 0.10; a one-sided Z-test for proportions was used to compare the two arms. Treatment was discontinued in pts who did not achieve at least a 25% reduction in the sum of products of tumor diameters at week 10. Primary and secondary endpoints were defined according to the NCI international standardized criteria (Cheson et al 1999). Results: 77 pts (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were allocated in the single-agent rituximab arm and 77 (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) in the combination arm. A higher CR/CRu rate in the combination arm was documented both by the investigator assessment (36% vs 25%) and by the independent response reviewers of CT scans (61% vs. 36%). Adverse events of grade ≥3 were more common (56% vs 22% of pts) in the combination arm, including neutropenia (23% vs 7%). At a median follow up of 3.1 years, a longer CR duration was seen for the pts in the combination arm (median not reached vs 2.3 years) as well as a longer PFS (median not reached vs. 2.3 years), these differences were not statistically significant. The CR30, recently identified as a reliable surrogate of PFS (Sargent et al. Hematol Oncol 2015. 33(s1): 166), was significantly improved by the addition of lenalidomide to rituximab (42% vs 19%, p=0.001). Moreover, TTNT was significantly longer with the combination (median not reached vs 2.1 years, p=0.02) [Figure1]. Overall survival rates at 3 years were 93% and 92%, respectively. Conclusions: The SAKK 35/10 randomized trial confirmed that lenalidomide plus rituximab is an active and feasible initial treatment for FL pts in need of therapy. Addition of lenalidomide significantly increased the CR/CRu rate at week 23 (primary endpoint) and was maintained throughout 30 months. Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better TTNT and a trend towards prolonged PFS and CR duration was seen in the combination arm. The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored. Figure 1. Time to next anti-lymphoma therapy by treatment arm Figure 1. Time to next anti-lymphoma therapy by treatment arm Disclosures Kimby: Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings; Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead. Mey:roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Wahlin:Roche: Consultancy. Hernberg:Roche: Consultancy, Honoraria. de Nully Brown:Roche: Research Funding. Ferreri:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10

Blood ◽

10.1182/blood.v124.21.799.799 ◽

2014 ◽

Vol 124 (21) ◽

pp. 799-799 ◽

Cited By ~ 5

Author(s):

Eva Kimby ◽

Giovanni Martinelli ◽

Bjorn Ostenstad ◽

Ulrich JM Mey ◽

Daniel Rauch ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Single Agent ◽

Stage Iv ◽

Phase 2 ◽

Advisory Committees ◽

Grade 3 ◽

Intent To Treat

Abstract Background: Previous trials from the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) showed that therapy with single-agent rituximab can produce long-term remissions in a sizeable subset of follicular lymphoma (FL) patients, with overall survival not inferior to chemo-immunotherapy, providing the rationale for the development of chemotherapy-free treatment strategies. Promising results have also been reported with the combination of rituximab and lenalidomide. The SAKK 35/10 phase-2 study was developed and conducted by the SAKK in cooperation with the NLG to compare the activity of rituximab plus lenalidomide versus single-agent rituximab in the first-line FL therapy. Methods: Patients with histologically confirmed untreated FL, grade 1, 2, 3a and in need of systemic therapy, were randomized either to rituximab monotherapy (R) (8 infusions of 375mg/m2 at day 1 of weeks 1, 2, 3, 4, and repeated at day 1 of weeks 12, 13, 14 and 15) or to rituximab (given at the same schedule) in combination with lenalidomide (RL) (lenalidomide given orally, 15 mg daily, starting 14 days before the first rituximab administration and continuously until 14 days after the last). The primary endpoint was the complete response (CR/CRu) assessed at week 23, defined according to the NCI standardized criteria (Cheson et al 1999). The study sample size was calculated to allow the detection of a 20% increase of the CR/CRu rate with RL over R, with 90% power and a type I error of 0.10. The 2 arms were compared using a one-sided Z-test with unpooled variance for proportions. Trial treatment was discontinued in patients who at week 10 did not achieve at least a minimal response, defined as reduction of more than 25% in the sum of product of tumor diameters (SPD), and rescue chemotherapy was given at the discretion of the treating physician. Results: In total, 154 patients were randomized; 77 (40 women and 37 men; median age 63yrs, range 29-85; 52% with stage IV and 47% with poor-risk FLIPI score) were allocated to arm R and 77 (42 women and 35 men; median age 61yrs, range 26-80; 48% with stage IV and 47% with poor-risk FLIPI score) to arm RL. Treatment was discontinued by 21 (28%) patients in arm R, in 16 due to lack of response at week 10 and in 1 due to toxicity, and by 19 (25%) patients in arm RL, in 3 due to lack of response at week 10 and in 13 due to toxicity. Adverse events of any grade were reported in 91% of patients in arm R and 100% in arm RL and adverse events of grade ≥3 were more common in arm RL than in arm R (51% vs 18% of patients). Grade 3-4 neutropenia was observed in 5% of patients in arm R and 19% in arm RL. The primary endpoint analysis (using the response assessment from the local investigators, reviewed by the study chairs) showed a significantly higher CR/CRu rate in patients treated with RL in comparison with those receiving R. This difference was observed both in the intent-to-treat (CR/CRu rate, 36% vs. 25%, respectively; p=0.056) and the per-protocol population (CR/CRu rate, 42% vs. 28%, respectively; p=0.049). Conclusions: The addition of lenalidomide to rituximab results in a significantly better CR/CRu at the cost of an expected increased toxicity. Further follow-up is needed to ascertain whether the response improvement will translate into prolonged time to next treatment and superior progression-free and overall survival rates. TableInvestigators’ assessment of the response at week 23 in the intent-to-treat (ITT) population Rituximab (N=77) Rituximab+Lenalidomide (N=77)Response category n (%)[95% C.I.]n (%)[95% C.I.]CR/CRu19 (25) [16-36%]28 (36)[26-48%] PR28 (36) [26-48%]35 (45)[34-57%]SD6 (8) [3-16%]4 (5)[1.4-13%]PD/relapse2 (3) [0.3-9%]3 (4)[0.8-11%]Not evaluable*22 (29) [19-40%]7 (9)[4-18%]*Patients with no assessment at week 23, including patients not achieving at least a minimal response at week 10. Disclosures Kimby: Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide, not approved for follicular lymphoma. Mey:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferreri:Celgene: Research Funding. Bargetzi:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Krasniqi:Roche, Takeda: Membership on an entity's Board of Directors or advisory committees. Zucca:Roche, Mundivarma, Novartis: Consultancy, Honoraria, Research Funding.

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Alkaline Phosphatase (ALP) Variation During Carfilzomib Treatment Is Associated to Best Response in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2865.2865 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2865-2865 ◽

Cited By ~ 2

Author(s):

Maurizio Zangari ◽

Latha Polavaram ◽

Fenghuang Zhan ◽

Guido J. Tricot ◽

Ravi Vij ◽

...

Keyword(s):

Retrospective Analysis ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Proteasome Inhibitors ◽

Phase 2 ◽

Two Phase ◽

Advisory Committees ◽

Best Response ◽

Ortho Biotech

Abstract Abstract 2865 Poster Board II-841 BACKGROUND: The ubiquitin-proteasome pathway, which has been shown to be an essential cellular degradative system in myeloma cells, can also regulate bone formation through its effects on osteoblast differentiation. Retrospective analysis of variation of ALP during treatment with bortezomib indicates a close correlation between myeloma response and serum ALP levels which multiple studies have shown to be of bone origin. To determine if this effect is a class effect of proteasome inhibitors (PIs), this retrospective study analyzed variation of ALP in relationship to myeloma response during treatment with carfilzomib, the first in a new class of selective epoxyketone PIs that has demonstrated encouraging safety and efficacy in two phase 2 studies of relapsed or refractory myeloma patients. METHODS: Retrospective analysis of serum ALP was performed on relapsed or refractory myeloma patients enrolled on two phase 2 studies (PX-171-003 and PX- 171-004) evaluating the safety and efficacy of single agent carfilzomib. We analyzed data from 38 patients in the first cohort of the PX-171-003 study, a relapsed and refractory myeloma trial for patients who have received ≥ 3 prior therapies including bortezomib and an IMiD and 29 patients in PX-171-004, a relapsed or refractory myeloma trial that included bortezomib naïve patients. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. RESULTS: Seventy-seven patients were enrolled. The median age was 63 years with a median time since diagnosis of 4.6 years, 52% were male, 84.% had relapsed after autologous transplants, 82.% were previously exposed to bortezomib, and 92% were previously exposed to an IMiD. Sixty seven patients with ALP data were evaluable for response. In PX-171-003 the ORR (≥PR) was 18% and the clinical benefit response (CBR; ≥MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline, which was most evident during the second cycle of treatment, was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In all patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline An ALP increase over the same period of time was seen in 26 %, 13%, and 11% of patients achieving PR, MR, and SD, respectively. None of the patients with progressive disease exhibited a similar increase. Our study indicates that response first assessed on Day 15 of Cycle 1 parallels the ALP elevation which returned to baseline levels at the end of Cycle 3. CONCLUSIONS: This retrospective analysis on a subset of patients in these ongoing phase 2 studies of single agent carfilzomib in relapsed or refractory multiple myeloma suggests that elevation in ALP may be associated with best response. Taken with previous publications describing bortezomib treatment, these results suggest that this specific anabolic bone phenomenon could be a class effect of proteasome inhibitors. These phase 2 studies are ongoing with a higher dose of carfilzomib (27 mg/m2) being evaluated. The data from this small subset analysis suggests that further exploration of this relationship is warranted. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Vij:Proteolix: Consultancy, Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Millennium: Consultancy, Research Funding; Proteolix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria. Wang:Proteolix: Honoraria, Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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The Novel KSP Inhibitor ARRY-520 Is Active Both with and without Low-Dose Dexamethasone in Patients with Multiple Myeloma Refractory to Bortezomib and Lenalidomide: Results From a Phase 2 Study

Blood ◽

10.1182/blood.v120.21.449.449 ◽

2012 ◽

Vol 120 (21) ◽

pp. 449-449 ◽

Cited By ~ 8

Author(s):

Jatin J. Shah ◽

Jeffrey A. Zonder ◽

Adam Cohen ◽

William Bensinger ◽

Jonathan L. Kaufman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Treatment Time ◽

Single Agent ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Heavily Pretreated ◽

Ksp Inhibitor

Abstract Abstract 449 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that arrests cells in mitosis and induces apoptosis due to degradation of the BCL2 family survival protein MCL-1. As previously reported, ARRY-520 has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM). In preclinical myeloma models, the addition of dexamethasone (Dex) increases the activity of ARRY-520, supporting clinical investigation of ARRY-520 combined with low-dose Dex (LoDex). Here, the efficacy and safety of ARRY-520 is compared in 2 Phase 2 cohorts in RRMM: as a single agent (Cohort 1) and in combination with LoDex (Cohort 2). Methods Both cohorts were designed as 2-stage single-arm Phase 2 studies. Cohort 1 evaluated the efficacy and safety of 1.5 mg/m2/d ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with prophylactic granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had RRMM with 2 prior lines of therapy that included both bortezomib (BTZ) and an immunomodulatory agent (IMiD), unless refusing or ineligible for this therapy. Cohort 2 is evaluating the efficacy and safety of the same dose and schedule of ARRY-520 and G-CSF with LoDex (40 mg PO weekly). Eligible patients had RRMM with 2 prior lines of therapy, and had disease refractory to (progressed on or ≤ 60 days of treatment) their last line of therapy and that was refractory to BTZ, lenalidomide (Len) and dexamethasone. Data from Cohort 1 and the first stage of Cohort 2 are reported. Results At the time of data cutoff, a total of 32 patients were enrolled into Cohort 1 with a median age of 65 years (range 51–82) and a median of 6 prior regimens (range 2–19). All patients received prior IMiD, 90% received prior BTZ and 78% had prior autologous stem cell transplant (ASCT). The defined first stage of Cohort 2 has been enrolled with 18 evaluable patients. These patients had a median age of 67 years (range 53–78) and were more heavily pretreated, with a median of 10 prior therapies (range 5–13). Safety was similar for both cohorts. A possible trend for more infections in Cohort 2 was noted. The most commonly reported (20% of patients) treatment-related adverse events (AEs) in both cohorts included thrombocytopenia, anemia, neutropenia and fatigue. No treatment-related events of neuropathy were observed in either cohort. The most common Gr 3/4 AEs (in Cohort 1, Cohort 2) included neutropenia (38%, 33%), thrombocytopenia (44%, 44%) anemia (28%, 50%), pneumonia (3%, 17%) and fatigue (16%, 11%). Treatment discontinuations due to AEs were infrequent (9%, 11%). Of 32 patients in Cohort 1, confirmed responses (≥ Minor Response (MR)) were observed in 6 patients (19%) with 5 Partial responses (PR) (16%) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria. The median treatment time was 2.1 months. In the subset of patients with disease refractory to both BTZ and Len, a 15% overall response rate (ORR ≥ MR) was observed. Among the 18 evaluable patients in Cohort 2, the ORR (≥ MR) was 28% (5/18), with 4 patients ≥ PR (22%). At the time of data cutoff, the median treatment time was 3.9 months. Summary Patients with RRMM refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months1. New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with Dex in RRMM. Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% ORR (≥ MR), with a manageable safety profile. These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients. Both the median time on study and ORR in Cohort 2 were greater than the activity seen for Cohort 1, despite the more advanced stage of these patients and the fact that they were heavily pretreated with Dex, suggesting that LoDex may enhance ARRY-520 activity. Based on this evidence of activity, further development of ARRY-520 + LoDex is warranted in patients who have exhausted other therapeutic options. Disclosures: Shah: Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: ARRY-520. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kaufman:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walker:Array BioPharma: Employment. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Dose Escalation Phase 2 Trial of Carfilzomib Combined with Thalidomide and Low-Dose Dexamethason in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. a Trial of the European Myeloma Network

Blood ◽

10.1182/blood.v124.21.2118.2118 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2118-2118 ◽

Cited By ~ 1

Author(s):

Pieter Sonneveld ◽

Emilie Asselbergs ◽

Bronno Van der Holt ◽

Sonja Zweegman ◽

Marie jose Kerstens ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Phase 2 Trial ◽

High Dose Melphalan ◽

Dose Levels

Abstract Background: Carfilzomib has significant activity in newly diagnosed Multiple Myeloma (MM). We present an update of a Phase 2 trial of dose-escalated Carfilzomib combined with Thalidomide and Dexamethasone (CTd). Introduction: This investigator sponsored, dose escalation phase 2 trial was designed to evaluate the clinical efficacy of standard dose Carfilzomib (C) (20/27 mg/m2) combined with Thalidomide (T) and Dexamethasone (D) (CTd) as induction therapy followed by high-dose Melphalan and autologous stem cell transplantation (ASCT), followed by consolidation therapy with CTd in transplant eligible patients with newly diagnosed symptomatic MM,. The second objective was to establish the maximum tolerated dose of Carfilzomib in this combination. Fifty patients were included in the first part who received 4 cycles of C at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, T 200 mg p.o. days 1 through 28 of a 28 day cycle and D 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In the second part 3 cohorts of 20 patients each were treated with escalated dose of C at 20/36 mg/m2,20/45 mg/m2 and 20/56mg/m2, respectively with T and D at the same dose. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and ASCT, followed by consolidation therapy consisting of 4 cycles CTd with C 27 mg/m2 (part1, n=50) or 36 mg/m2 or 45 mg/m2 or 56 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, respectively, combined with T 50 mg days 1-28 of a 28 day cycle and D 20 mg days 1, 8, 15, 22 of a 28 day cycle. Thrombosis prophylaxis was prescribed. The primary endpoint was very good partial response (VGPR) after 4 CTd cycles: secondary endpoints were complete response (CR), stringent CR (sCR) and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results: 111 patients were included as of 1st July 2014. We here report the response of all cohorts with a median follow-up of 34, 19, 12 and 6 months, respectively. Median age was 58 yr and ISS stages II and III were 40% and 27%, respectively. The CTd regimen was well tolerated. Fifteen patients discontinued treatment because of non-eligibility (n=3), refusal (n=2), toxicity (n=7) or progression (n=3). Safety analysis was available for all treatments in cohorts 27mg/m2 through 45mg/m2 and for induction cycles in cohort 56mg/m2. Non-hematological SAEs for the two lower dose levels were infections (n=8), polyneuropathy gr 2 (n=5), cardiac (n=3) and tumor lysis syndrome (n=2) (ASH 2013). Non-hematological SAEs for dose level 45mg/m2 (n=22) included thrombosis (n=1), reversible gastrointestinal event (n=2) and infections (n=5). At dose level 56mg/m2 SAEs were thrombosis (n=2), infections (n=3), reversible cardiac event (n=1). In 111 patients 4 cardiac events were observed (2 grade 2, 2 grade 3) 3 of which resolved completely. Two patients discontinued therapy because of thrombosis (n=1) and pneumonia (n=1). Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 85/85 patients and HDM/ASCT was performed with complete hematologic recovery in 77/78 patients. The primary endpoint ≥VGPR and CR was achieved in 94% and 56% (27mg/m2), 75% and 65% (36mg/m2), 91% and 55% (45mg/m2), 75% and 20% (56mg/m2, induction only). Of 25 CRs in dose levels 36mg/m2 and 45mg/m2, 9 (36%) were stringent CR with no clonal plasma cells in bone marrow and negative serum-free lite. VGPR + CR increased from 63% after induction to 73% after HDM/ASCT and 86% after consolidation, respectively. For CR these figures were 18%, 34% and 58%, respectively. Overall response and CR were not significantly different between dose cohorts. Responses did not differ between poor risk (gain 1q or t(4;14) or del17p) and standard risk FISH. At a median follow-up of 21 months for dose levels 27mg/m2, 36mg/m2 and 45mg/m2 ,78% of patients are alive without progression or relapse. PFS at 18 months is 88 %. Three patients died of myeloma. There were 2 second primary malignancies. Analyses for revised ISS and molecular subgroups will be presented. Conclusion: C combined with T and D is a safe and effective regimen for newly diagnosed MM. Dosing of Carfilzomib up to 56mg/m2 was well tolerated. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals, an Amgen subsidiary. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millenium: Honoraria, Research Funding. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Palumbo:Bristol-Myers Squibb: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria.

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Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.639.639 ◽

2016 ◽

Vol 128 (22) ◽

pp. 639-639 ◽

Cited By ~ 21

Author(s):

Jeffrey A. Jones ◽

Jennifer Woyach ◽

Farrukh T. Awan ◽

Kami J. Maddocks ◽

Thomas Whitlow ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Response Assessment ◽

Phase 2 ◽

Advisory Committees ◽

Once Daily ◽

Phase 1B

Abstract BACKGROUND Venetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination. METHODS Patients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14. RESULTS Twelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200). CONCLUSIONS G, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. Table. Table. Disclosures Jones: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

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A Randomized Phase 2 Trial Comparing Carfilzomib-Dexamethasone Vs Observation As Maintenance after Induction with Carfilzomib-Cyclophosphamide-Dexamethasone in Salvage ASCT in Multiple Myeloma: A Trial By the Nordic Myeloma Study Group

Blood ◽

10.1182/blood-2019-122141 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 601-601 ◽

Cited By ~ 1

Author(s):

Henrik Gregersen ◽

Valdas Peceliunas ◽

Kari Remes ◽

Fredrik H. Schjesvold ◽

Niels Abildgaard ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Observation Group ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Trial ◽

First Relapse ◽

Maintenance Group

Background: Salvage autologous stem cell transplantation (ASCT) is used in selected patients with relapsed multiple myeloma after up-front ASCT. However, there are limited data on the optimal induction therapy before salvage ASCT. There is strong support for the use of maintenance therapy after upfront ASCT in newly diagnosed multiple myeloma whereas data on maintenance therapy after salvage ASCT are sparse. The Nordic Myeloma Study Group (NMSG) initiated the CARFI trial (NCT02572492), an open randomized phase II study, to investigate the efficacy and safety of carfilzomib as part of induction and conditioning in salvage ASCT and to evaluate the role of carfilzomib/dexamethasone maintenance after salvage ASCT. Methods: Patients with first relapse after up-front ASCT were treated with an induction regime containing four cycles of CAR-CY-DEX (iv carfilzomib 20 mg/sqm → 36 mg/sqm on days 1, 2, 8, 9, 15 and 16, tablet cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and tablet dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28-days cycle). The subsequent conditioning regimen contained iv carfilzomib 27 mg/sqm on day -2 and -1, and iv melphalan 200 mg/sqm on day -2. The patients had not received any maintenance therapy after upfront ASCT. Two months after ASCT patients were randomized (1:1) to observation or maintenance therapy with iv carfilzomib 27 mg/sqm → 56 mg/sqm every second week and tablet dexamethasone 20 mg every second week. The randomization was stratified according to relapse 1 - 2 year or > 2 years after up-front ASCT, ISS stage and standard versus high-risk cytogenetics. Primary endpoint was comparison of time to progression (TTP) after up-front ASCT and TTP after salvage ASCT with CAR-CY-DEX induction. Another primary endpoint was to compare TTP between carfilzomib-dexamethasone maintenance and observation in patients treated with salvage ASCT. Results: 200 patients were enrolled in the study and 32 of these went off study during the induction and after ASCT. The remaining 168 patients were randomized to carfilzomib-dexamethasone (82 patients) or observation (86 patients). The median age was 62 (interquartile range: 56; 66) years and the median follow-up from time of inclusion was 20.1 (14.1 - 27.6) months. The median TTP after up-front ASCT was 33.2 (31.0-37.8) months compared with 28.1 (24.9-31.5) months after salvage ASCT. The two groups randomised to maintenance therapy or observation were balanced regarding age, time from myeloma diagnosis, treatment at diagnosis, performance status, ISS stage and high-risk cytogenetics (Table 1). The median TTP from randomisation was 28.8 (95% CI: 24.4-NR) months in the maintenance group and 18.5 (95% CI: 14.3-22.0) months in the observation group (hazard ratio 0.42 (95% CI: 0.26-0.68, P = 0.0003)) (Figure I). For the maintenance group TTP from inclusion was 35.4 (30.9-NR) months compared with TTP of 31.3 (29.4-37.8) months (P = 0.71) after up-front ASCT for these patients. A total of 53 serious adverse events (SAE) were reported in 25 patients on carfilzomib-dexamethasone maintenance and 33 SAEs in 21 patients in the observation group. The majority of the SAEs were infections; 39 in the maintenance group and 25 in the observation group, divided into viral infection (10 versus 3), septicemia (2 versus 0) and pneumonia (12 versus 7). Three SAEs classified as cardiac-pulmonary were observed in the maintenance group (syncope, atrial fibrillation and pulmonary embolism) in contrast to three in the observation group (atrial fibrillation and dyspnea(2)). Conclusion: In this randomized phase 2 trial, maintenance therapy with carfilzomib and dexamethasone prolonged median TTP with approximately 10 months following salvage ASCT in multiple myeloma. The difference between TTP after upfront ASCT and TTP after salvage ASCT with carfilzomib based induction therapy was small which supports the use of salvage ASCT followed by maintenance in selected patients at first relapse. Disclosures Remes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Amgen: Other: Congress Support; Celgene: Other: Congress Support; Sanofi: Other: Congress Support. Schjesvold:Janssen: 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; Novartis: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SkyliteDX: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Abildgaard:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Blimark:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM); Updated Results From the Bortezomib-Treated Cohort.

Blood ◽

10.1182/blood.v114.22.303.303 ◽

2009 ◽

Vol 114 (22) ◽

pp. 303-303 ◽

Cited By ~ 14

Author(s):

David Siegel ◽

Luhua Wang ◽

Robert Z Orlowski ◽

Jonathan L. Kaufman ◽

A. Keith Stewart ◽

...

Keyword(s):

Renal Insufficiency ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Cell Transplant ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Ortho Biotech ◽

Grade 3

Abstract Abstract 303 Background: Carfilzomib (CFZ) is a novel proteasome inhibitor that binds its target selectively and irreversibly, resulting in greater and more sustained proteasomal inhibition compared to BTZ (Demo et al, Cancer Res 2007). CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007) and in a previous Phase 2 study (PX-171-003), single-agent CFZ achieved durable responses and maintained disease control [e.g. ≥ Stable Disease (SD)] in patients with progressive multiple myeloma (MM) despite treatment with essentially all available agents. PX-171-004 is an ongoing Phase 2 study of CFZ monotherapy in MM patients with relapsed or refractory disease following 1–3 prior therapies. Here we report updated data for the BTZ-treated cohort. Methods: Patients with relapsed or refractory (defined as < 25% response or disease progression during therapy) MM were enrolled and stratified based on prior BTZ exposure (e.g. BTZ-naïve and BTZ-treated). For the BTZ-treated cohort, tolerability and response to prior BTZ [≥ Minor Response (MR)] was not required. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate (ORR) [≥ Partial Response (PR)] by IMWG criteria. Secondary endpoints included Clinical Benefit Response (CBR = ORR + MR) and safety. Results: Thirty-five BTZ-treated patients were enrolled. Six (17%) patients had previously received BTZ exclusively as a single agent, 15 (43%) received BTZ as part of a chemotherapy combination and 10 (29%) received BTZ as part of a stem cell transplant (SCT) regimen. An additional 4 (11%) received BTZ in a chemotherapy combination as well as part of a separate transplant regimen. Other prior therapies included alkylators (89%), SCT (81%), thalidomide (69%), lenalidomide (37%), and anthracyclines (31%). Six (17%) patients had disease refractory to BTZ and 9 (26%) additional patients had discontinued BTZ due to toxicities. At baseline, 19 (54 %) patients had an ECOG score ≥ 1, 17 (49%) patients had neuropathy of Grade ≥ 1, 9 (26%) patients had impaired renal function (CrCl <60 mL/min) and 9 (26%) had diabetes. The median time since diagnosis was 3.6 years (range 1.2–13.2). To date, the mean number of CFZ doses administered was 29.3 (∼5 four-week cycles; range 4–72 doses, 0.7–12 cycles). Thirty-three patients who initiated therapy were evaluable for response per protocol. The ORR was 18% (6/33), including 1 CR and 5 PRs. An additional 4 (12%) patients had MR (CBR= 30%) and 13 (39%) had SD for ≥ 6 weeks. For evaluable patients who were either refractory or intolerant to their prior BTZ therapy, responses to CFZ included 1 PR and 1 MR and 8 SDs. The most common adverse events (AEs) (≥ 30% patients) were primarily Grades 1/2 and included fatigue (57%), nausea (54%), vomiting (37%), dyspnea (34%), diarrhea (34%), anemia (31%), increased creatinine (31%) and upper respiratory tract infection (31%). Grade 3/4 AEs occurring in ≥ 10% of patients were anemia (14.3%) and neutropenia (11.4%). There were no reports of febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) was uncommon (4 patients, 11%); only 1 patient had a Grade 3 event that lasted < 36 hours and did not result in missed doses or dose modification. None of the 9 patients with baseline renal impairment were discontinued for renal AEs. To date, 6 (17%) patients have completed the full 12-cycle protocol at the initial dose and schedule, 6 (17%) remain on study and 1 patient has received > 19 cycles on a recently initiated extended treatment protocol. Conclusions: In a BTZ-exposed population that includes BTZ treatment failures and significant comorbidities (e.g. diabetes, renal insufficiency, etc), the 18% ORR (CBR 30%) is notable for this steroid- and anthracycline-sparing regimen. Single-agent CFZ is well tolerated, even in patients with renal insufficiency, and both myelosuppression and PN are uncommon. These data support the continuing evaluation of CFZ as a safe and effective treatment option in MM. Disclosures: Siegel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Kukreti:Celgene: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Kunkel:Proteolix: Consultancy, Employment. Bennett:Proteolix: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

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The Speed of Response to Single-Agent Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma: An Exploratory Analysis of Results From 2 Multicenter Phase 2 Clinical Trials,

Blood ◽

10.1182/blood.v118.21.3969.3969 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3969-3969

Author(s):

Luhua Wang ◽

David S. Siegel ◽

Andrzej J Jakubowiak ◽

Alvin F. Wong ◽

Sandra Dixon ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Exploratory Analysis ◽

Phase 2 ◽

Open Label ◽

Advisory Committees ◽

Speed Of Response

Abstract Abstract 3969 Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. Phase 1 and 2 studies with carfilzomib have demonstrated durable single-agent antitumor activity with a favorable safety profile in patients with relapsed and/or refractory multiple myeloma (MM). Results from a phase 1 study of carfilzomib in patients with relapsed and/or refractory hematologic malignancies (Alsina et al. Blood. 2007;110: Abstract 411) as well as those from an independent study of carfilzomib in the frontline combination setting (Jakubowiak, et al. Haematologica. 2011;96(2): Abstract P-253) have suggested that initial responses occur rapidly and the depth of response improves with continued treatment. Based on these encouraging findings, we have performed an exploratory analysis to evaluate the time to initial response (or the speed of response) from the following 2 multicenter phase 2 clinical trials with carfilzomib: 1) PX-171-003-A1, an open-label, single-arm phase 2 trial that enrolled patients with relapsed and refractory MM following ≥2 prior regimens and 2) PX-171-004, an open-label phase 2 trial in bortezomib-naïve and bortezomib-treated patients with relapsed or refractory MM following 1–3 prior regimens. Methods: Patients in study PX-171-003-A1 received carfilzomib 20 mg/m2 in Cycle 1 on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 cycles. Patients enrolled in PX-171-004 either received 20 mg/m2 for all treatment cycles or a stepped-up, dose-escalating regimen of 20 mg/m2for Cycle 1 and 27 mg/m2for all treatment cycles thereafter. Responses and progression were determined according to the International Myeloma Working Group criteria modified to include minimal response (MR) per European Blood and Marrow Transplant Group criteria and were assessed and confirmed by an Independent Review Committee. Responses were assessed on Day 15 of Cycle 1 and Day 1 of Cycles 2 through 12 and at the end of study. Time to response, as presented here, is the time from the start of treatment to either 1) the first confirmed response of MR or better or 2) the first confirmed response of PR of better. Results: A total of 257 response-evaluable patients from PX-171-003-A1 and 162 response-evaluable patients from PX-171-004 were eligible for inclusion in this exploratory analysis. Patients from the 003-A1 study had received a median of 5 prior anti-MM regimens, while bortezomib-naïve patients from the 004 study and bortezomib-treated patients had received a median of 2 and 3 prior regimens, respectively. Of these, 95 patients from 003-A1 and 78 bortezomib-naïve (both dose cohorts combined) and 11 bortezomib-treated patients from 004 had minimal responses (MR) or better and were analyzed for time to response. The specific time to response data are presented in the table below and are separated by study and by prior bortezomib exposure (ie, BTZ-naïve or BTZ-treated) for the 004 study. Patients from all cohorts in both clinical trials responded relatively rapidly with similar median times to response in patients from the 003-A1 study and from the 004 study (both bortezomib-naïve and treated). At the same time, the depth of responses improved with continued carfilzomib treatment. An analysis of time to best response will be presented. Conclusions: Based on this exploratory analysis, the speed of response to single-agent carfilzomib was rapid (within a median of 0.5–1.0 months to achieve responses of MR or better) in patients with relapsed and refractory MM in 2 multicenter clinical trials. This preliminary analysis represents the first focused evaluation of the dynamics of response to carfilzomib and the results merit additional evaluation in the setting of ongoing and future clinical trials. Disclosures: Wang: Onyx Pharmaceuticals: Research Funding. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Dixon:Onyx Pharmaceuticals: Employment. Renau:Onyx Pharmaceuticals: Employment. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau.

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Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.947.947 ◽

2012 ◽

Vol 120 (21) ◽

pp. 947-947 ◽

Cited By ~ 4

Author(s):

Nikoletta Lendvai ◽

Heather Landau ◽

Alexander Lesokhin ◽

Ioanna Tsakos ◽

Guenther Koehne ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Cell Transplant ◽

Phase 2 ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Higher Doses

Abstract Abstract 947 Background: Carfilzomib (CFZ) is a selective, irreversible epoxyketone inhibitor of the chymotrypsin-like activity of both the constitutive proteasome and the immunoproteasome. In patients with multiple myeloma single-agent CFZ is active and well tolerated at doses up to 27 mg/m2 when administered intravenously over 2–10 minutes. Based on preclinical safety data showing that a slower infusion was better tolerated and permitted administration of higher doses than a 2–10 minute infusion, the phase1b/2 PX-171-007 (NCT00531284) study evaluated the administration of CFZ as a 30-minute infusion. That study found the maximally tolerated dose of CFZ given as a 30 minutes infusion to be 56mg/m2. We designed a single institution, phase 2 study of high dose, infusional CFZ in patients with relapsed and/or refractory multiple myeloma. Methods: CFZ was given as a 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle1 Day1–2 doses were 20 mg/m2, followed by escalation to 56mg/m2. Dexamethasone 8 mg was given prior to infusion as premedication to mitigate infusion-related reactions. Patients who did not achieve a partial response (PR) after two cycles of CFZ or initially responded to single agent CFZ, but later showed evidence of progression of disease (POD) had dexamethasone (40mg/week) added to their regimen. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Subjects were evaluated for adverse events according to the Common Terminology Criteria for Adverse Events v 4.0. Results: Thirty-four patients have been enrolled. Patients had received a median of 5 (range 1–11) prior treatment regimens and included 7 patients who relapsed following allogeneic stem cell transplant. Seventy eight percent of patients were bortezomib-refractory. ORR among patients who completed 4 cycles of therapy or experienced POD prior to completing 4 cycles of therapy was 58% with 1 CR, 7 VGPRs, and 6 PRs. ORR after 4 cycles of therapy was 57% in bortezomib-refractory patients. By intention to treat analysis the ORR in all comers was 50%. Median progression free survival was 4.6 months, median overall survival has not been reached with a median follow-up among survivors of 9.6 months (range: 0.3–14.3 months). The average time to best response was two cycles. Three out of the 11 patients that had dexamethasone 40mg/week added to their regimen obtained an improved response. Twelve patients (35%) were dose reduced. Treatment emergent, non-hematologic Grade 3/4 adverse events for which contribution of CFZ cannot be excluded were: HTN (n = 7), lung infection (n = 6), pulmonary edema (n = 3), reduced ejection fraction (n=1), sepsis (n=2), febrile neutropenia (n=1), bacteremia (n = 1), protothecosis (n = 1), fatigue (n=1), neuropathy (n=1), microangiopathic hemolytic anemia(n=1), nausea/vomiting/+/− diarrhea (n = 2), gastrointestinal bleed in the setting of Grade 4 thrombocytopenia (n = 1), hyperkalemia (n = 1). Conclusions: The 20/56 mg/m2 dose for CFZ administered as a 30-minute IV infusion was associated with 58% ORR, in a heavily pretreated patient population, including 21% of patients w/ prior allogeneic transplant, where the majority of patients were bortezomib-refractory. The ORR from this study is consistent with the one previously reported at the similar dose. Higher doses of carfilzomib continue to be explored in ongoing Phase 2 and Phase 3 studies. Disclosures: Landau: Onyx: Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Onyx: 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, Research Funding; Milleneum: Membership on an entity's Board of Directors or advisory committees.

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