scholarly journals PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 466-466 ◽  
Author(s):  
Aaron T. Gerds ◽  
Bart L Scott ◽  
Peter L Greenberg ◽  
Samer K. Khaled ◽  
Tara L Lin ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Single Agent ◽  
Early Termination ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) and those who fail to respond to or relapse/progress after treatment with hypomethylating agents (HMA) have limited therapeutic options and poor prognosis. PD-L1 expression is upregulated in HR-MDS pts (compared with lower-risk MDS pts) and in those who fail HMA therapy. Combining inhibition of the PD-L1/PD-1 pathway with azacitidine may improve outcomes in MDS. Methods: We conducted a Phase Ib trial of the anti-PD-L1 monoclonal antibody atezolizumab, with or without azacitidine, in HMA-failure and HMA-naive MDS pts (NCT02508870). The primary objective was to determine the safety and tolerability of atezolizumab as a single agent or in combination with azacitidine. An initial safety evaluation was performed in three cohorts. Cohort A1 (10 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab alone (1200mg IV q3w). Cohort B1 (11 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w) for 6 cycles, followed by atezolizumab maintenance alone (1200mg IV q3w). Cohort C1 (6 pts) consisted of HMA-naive HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w). If atezolizumab alone or in combination with azacitidine was deemed safe and tolerable in Cohorts A1 and B1, an additional 1:1 randomization into two cohorts of 30 pts each (Cohorts A2 and B2) was planned. If the combination of atezolizumab and azacitidine was found to be safe and tolerable in Cohort C1, an additional expansion cohort (Cohort C2) of 14 pts with HMA-naive HR-MDS was planned. Primary endpoints included determining the safety and tolerability of atezolizumab-based regimens in HR-MDS and defining the recommended Phase II dose for the combination. Results: As of January 2018, 42 HR-MDS pts had been treated with atezolizumab-based regimens: Cohort A, 10 pts; Cohort B, 11 pts; Cohort C, 21 pts. Median age for the entire pt cohort was 76 years (range: 63−89). Median treatment duration for Cohorts A, B, and C was 4.2, 5.5, and 5.8 months, respectively. The overall response rate for Cohorts A, B, and C was 0%, 9% (hematologic improvement [HI]: 9%), and 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%), respectively. All pts in Cohorts A and B have discontinued therapy, with a median overall survival (OS) of 5.9 months and 10.7 months, respectively. For pts in Cohort C, 8/21 pts remain on therapy, and median OS has not been reached. Grade 3−5 adverse events (AEs) in >10% of pts were primarily hematologic; grade 3−5 febrile neutropenia occurred in 29% of all pts and was particularly common in pts receiving the atezolizumab-azacitidine combination (Cohorts B [36%] and C [33%] compared with Cohort A [10%]; Table 1). In Cohort A, 70% (7/10) of pts died, as did 64% (7/11) of pts in Cohort B and 29% (6/21) of pts in Cohort C. Median time to death was 160 days (Cohort A), 299 days (Cohort B), and 53 days (Cohort C). Timing and causes of death were different in the three cohorts. Causes of death were more commonly from disease progression in Cohorts A and B, while serious AEs accounted for all deaths in Cohort C (Table 2). In addition, deaths within 3 months occurred in 10%, 18%, and 29% of pts in Cohorts A, B, and C, respectively. The high early death rate compared with historical controls observed in HMA-naive HR-MDS patients (Cohort C) led to early termination of the study prior to completing recruitment. Biomarker assessment demonstrated PD-L1 expression on variable proportions of AML blasts in samples from all pts analyzed. However, PD-L1 expression was not associated with clinical response (Figure). Conclusions: Combination of atezolizumab plus azacitidine in HMA-naive HR-MDS pts had an unfavorable safety profile, which led to early termination. Limited responses were observed with atezo-based regimens (with or without azacitidine) in HMA-failure HR-MDS pts, without excessive or unexpected toxicity. Better understanding of the reasons associated with the differential toxicity profile observed between HMA-naive versus HMA-failure HR-MDS pts will be crucial for potential future developments of this combination. Disclosures Gerds: Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy. Khaled:Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding. Lin:Jazz Pharmaceuticals: Honoraria. Pollyea:AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech: Employment. Ma:Genentech: Employment. Medeiros:Genentech: Employment, Equity Ownership. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Yan:Roche: Employment.

scholarly journals Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4471-4471 ◽  
Author(s):  
Michael Wang ◽  
Andre Goy ◽  
Peter Martin ◽  
Rod Ramchandren ◽  
Julia Alexeeva ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Complete Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Despite recent advances, mantle cell lymphoma (MCL) remains difficult to treat with frequent chemoresistance in the relapsed or refractory setting. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton’s tyrosine kinase, demonstrated durable single-agent efficacy in a previous phase 2 study of patients with MCL who had received 1 to 5 prior therapies (Wang M, et al. N Engl J Med. 2013;369:507-516). In that study, the investigator-assessed overall response rate was 68% (complete response rate, 21%). The current study reports on the efficacy and safety of single-agent ibrutinib specifically in patients with MCL who had received a rituximab-containing regimen and had progressed after at least 2 cycles of bortezomib therapy. Methods: In this phase 2, multicenter, single-arm study, patients received 560 mg/day oral ibrutinib continuously until progressive disease or unacceptable toxicity. The primary end point was the overall response rate (ORR) in response evaluable patients, as assessed by an Independent Review Committee (IRC). Secondary end points, also assessed by IRC, included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: 120 patients in this international multicenter study were enrolled. The median age was 67.5 years, ranging from 35 to 85 years with 62.5% ≥ 65 years. Most patients had stage IV disease at study entry (77.5%), and 9.2% were reported as blastoid variant (per investigator). 76.3% of patients had an intermediate or high risk simplified MIPI score, and 52.5% had bulky disease (longest diameter ≥ 5 cm). Forty two (35.0%), 67 (55.8%) and 11 patients (9.2%) had an ECOG score of 0, 1 and 2, respectively. The median number of prior lines of systemic therapy was 2 (range 1-8 lines) with almost half of the patients (47.5%) receiving 3 or more prior lines of therapy. Overall, 33% of patients had received prior stem cell transplantation. At the time of clinical cut-off for the primary analysis (29 April, 2014), median follow-up was 14.9 months with median treatment duration of 8 months (range: 0.5-20.9 months). The main reasons for treatment discontinuation were disease progression in 53 patients (44.2%) and an adverse event (AE) in 8 patients (6.7%). The ORR for response evaluable patients was 62.7% (95% confidence interval [CI]: 53.7%-71.8%) with a complete response rate of 20.9%. Subgroup analysis suggested that the ORR was independent of age, gender, geographic region, number of prior lines of therapies, baseline extranodal disease, simplified MIPI score, bulky disease, and stage of MCL. Median DoR by IRC was 14.9 months and the median time to first response was 2.1 months, ranging from 1.3 to 6.3 months. Median PFS was 10.5 months and 47% of the patients remained progression-free at 1 year. The OS rate at 18 months was 61%. The most common AEs were fatigue (any grade, 43.3%; grade 3 or 4, 3.3%) and diarrhea (any grade, 42.5%; grade 3 or 4, 2.5%). The most common grade 3 or higher AEs were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic events were reported in 45 patients (37.5%), including 3 (2.5%) with major hemorrhagic events. The median time to initial hemorrhagic event was 84 days (range 1-515 days), with a median duration of 22 days (95% CI: 8-31 days). Atrial fibrillation was reported in 13 patients (10.8%), which was grade 3 or 4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%). Conclusion: Single agent ibrutinib is highly efficacious and well tolerated, with an acceptable toxicity profile in patients with MCL who progressed after rituximab-containing chemotherapy and bortezomib therapy. These results are consistent with previous ibrutinib studies, with no new safety signals. Disclosures Wang: Pharmacyclics, Janssen, Celgene, Onyx, OnyPep, : Research Funding; Onyx, Janssen: Honoraria. Goy:Janssen/Pharmacyclics: Honoraria, Speakers Bureau; Clinical Trials through Institution: Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Martin:Janssen: Honoraria. Popat:Janssen: Honoraria. Advani:Seattle Genetics, Genetech, (Uncompensated): Membership on an entity's Board of Directors or advisory committees; Janssen, Pharmacyclics, Seattle Genetics: Research Funding. Le Gouill:Roche: Consultancy; Janssen: Consultancy. Yuan:Johnson & Johnson: Equity Ownership; Johnson & Johnson: Employment. Kranenburg:Johnson&Johnson: Equity Ownership; Janssen Biologics: Employment. Rizo:Janssen R&D: Employment, Equity Ownership. Zhuang:Johnson & Johnson: Employment, Equity Ownership. Deraedt:Johnson & Johnson: Employment, Equity Ownership. Rule:Pharmacyclics, J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3981-3981
Author(s):  
Stephen D. Smith ◽  
Javier Munoz ◽  
Don Stevens ◽  
Sonali M. Smith ◽  
Tatyana A. Feldman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Equity Ownership ◽  
Grade 3 ◽  
Anti Cd20 ◽  
Age Range

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in ≥5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens:Astellas: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Feldman:Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye:MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller:Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Preliminary Results from a Phase I Dose Escalation Trial of Ruxolitinib and the PI3Kδ Inhibitor TGR-1202 in Myelofibrosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Tamara K Moyo ◽  
Andrew Sochacki ◽  
Gregory D Ayers ◽  
Michael T. Byrne ◽  
Stephen A. Strickland ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Single Agent ◽  
Symptom Assessment ◽  
Akt Signaling ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib. Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patients Secondary Objectives: Hematologic response, symptom assessment Methods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1. Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1). Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: 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; Gilead: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of GS-4059 in Combination with Idelalisib in Subjects with B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2961-2961 ◽  
Author(s):  
Gilles A. Salles ◽  
Franck Morschhauser ◽  
Bruce Cheson ◽  
Simon A. Rule ◽  
Christopher Fegan ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Inhibitors of signaling downstream of the B-cell receptor have a demonstrated clinical benefit in a number of lymphoid malignancies but generally require chronic therapy with the potential for single mutations to lead to resistance. GS-4059 (ONO-4059) is a Bruton's tyrosine kinase (BTK) inhibitor. GS-4059 is safe and tolerable as a single agent at doses up to 480 mg in non-Hodgkin lymphoma and up to 600 mg in chronic lymphocytic leukemia (CLL). Idelalisib, a phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is approved for the treatment of CLL. Single-agent therapy leads to durable responses, but with limited depth of response; treatment with a combination of GS-4059 and idelalisib has the potential to lead to deeper and more durable responses at lower doses of individual agents than needed as monotherapy. Methods:This ongoing, phase 1b study (NCT02457598) is evaluating the safety and tolerability of GS-4059 in combination with idelalisib. Patients with previously treated CLL, FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), or non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) and no prior exposure to BTK or PI3Kd inhibitors eligible for enrollment. Patients are enrolled using a 3+3 dose escalation design with a fixed dose of idelalisib (50 mg BID) and increasing doses of GS-4059. Optional dose expansion cohorts of up to 30 patients can be enrolled to generate disease-specific data. Patients were observed for a 28-day period to identify dose-limiting toxicities (DLTs). Efficacy evaluation was performed at 6-week intervals for DLBCL, 24-week intervals for CLL, and 12-week intervals for all other indications. Results: As of June 1, 2016, 20 patients have enrolled; the median age was 64 (37-79) years and 65% were men. The disease subtypes enrolled were CLL (n = 8), FL (5), MZL (2), SLL (2), and 1 each with DLBCL, MCL, and WM. The median number of prior therapies is 2.5 (range 1-4). The median duration of treatment is 113 days (range 29-310) with 17 patients still on-treatment. Three patients discontinued all study treatment due to disease progression (FL, MZL, DLBCL). There has been 1 death on study following progressive disease. Two DLTs of neutropenia were observed at dose level 2B (GS-4059 20 mg BID/idelalisib 50 mg BID), prompting the decision to discontinue the evaluation of twice-daily administration of GS-4059 when combined with idelalisib. The maximum tolerated dose (MTD) was not reached in Arm A of the study (Table 1). Of the 20 patients enrolled, 95% reported a treatment-emergent AE (TEAE), of which 55.0% were ≥grade 3. The only ≥grade 3 TEAE that was present in more than 1 patient was neutropenia. The most common TEAEs are listed in Table 2. Grade 3 liver laboratory test abnormalities were observed in 1 patient after approximately 5 months of treatment; a liver biopsy revealed a lymphocytic infiltrate consistent with CLL. Dose interruption due to an AE was reported in 45% of patients. Aside from 2 patients who discontinued idelalisib due to neutropenia and restarted therapy on GS-4059 alone, all patients successfully re-initiated therapy with both agents after treatment interruption. Nine patients have been on study for ≥24 weeks with 7 patients evaluable for radiographic response; 3 patients have had a >50% decrease in lymphadenopathy (CLL, SLL, FL). Preliminary pharmacokinetic (PK) results indicate that idelalisib at the evaluated dose levels does not significantly alter the PK of GS-4059. Conclusion: Once-daily dosing of GS-4059 up to 80 mg in combination with idelalisib 50 mg BID was generally safe and well tolerated. Early results show efficacy at combination doses significantly below the MTD for either single agent. This data supports continued clinical evaluation of the combination of GS-4059 and idelalisib for the treatment of B-cell malignancies. Disclosures Salles: Mundipharma: Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Fegan:AbbVie: Honoraria; Roche: Honoraria; Gilead Sciences: Honoraria. Nelson:Gilead Sciences: Employment, Equity Ownership. Yang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Starodub:Bayer: Consultancy; BMS: Speakers Bureau; Sandoz: Consultancy. Dyer:Roche: Consultancy, Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Other: Travel funding, Research Funding, Speakers Bureau.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 814-814 ◽  
Author(s):  
Paul G. Richardson ◽  
Melissa Alsina ◽  
Donna M. Weber ◽  
Steven E. Coutre ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Treatment Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4070-4070 ◽  
Author(s):  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Paul G. Richardson ◽  
Sundar Jagannath ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Board ◽  
Prior Exposure ◽  
Employment Equity ◽  
Advisory Committees ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3

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

Long-Term Safety, Efficacy, and Survival Findings From Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 801-801 ◽  
Author(s):  
Francisco Cervantes ◽  
Jean-Jacques Kiladjian ◽  
Dietger Niederwieser ◽  
Andres Sirulnik ◽  
Viktoriya Stalbovskaya ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Extension Phase ◽  
Spleen Volume ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 801 Background: Ruxolitinib is a potent JAK1 & 2 inhibitor that has demonstrated superiority over traditional therapies for the treatment of MF. In the two phase 3 COMFORT studies, ruxolitinib demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life. COMFORT-II is a randomized, open-label study evaluating ruxolitinib versus BAT in patients (pts) with MF. The primary and key secondary endpoints were both met: the proportion of pts achieving a response (defined as a ≥ 35% reduction in spleen volume) at wk 48 (ruxolitinib, 28.5%; BAT, 0%; P < .0001) and 24 (31.9% and 0%; P < .0001), respectively. The present analyses update the efficacy and safety findings of COMFORT-II (median follow-up, 112 wk). Methods: In COMFORT-II, 219 pts with intermediate-2 or high-risk MF and splenomegaly were randomized (2:1) to receive ruxolitinib (15 or 20 mg bid, based on baseline platelet count [100-200 × 109/L or > 200 × 109/L, respectively]) or BAT. Efficacy results are based on an intention-to-treat analysis; a loss of spleen response was defined as a > 25% increase in spleen volume over on-study nadir that is no longer a ≥ 35% reduction from baseline. Overall survival was estimated using the Kaplan-Meier method. Results: The median follow-up was 112 wk (ruxolitinib, 113; BAT, 108), and the median duration of exposure 83.3 wk (ruxolitinib, 111.4 [randomized and extension phases]; BAT, 45.1 [randomized treatment only]). Because the core study has completed, all pts have either entered the extension phase or discontinued from the study. The primary reasons for discontinuation were adverse events (AEs; ruxolitinib, 11.6%; BAT, 6.8%), consent withdrawal (4.1% and 12.3%), and disease progression (2.7% and 5.5%). Overall, 72.6% of pts (106/146) in the ruxolitinib arm and 61.6% (45/73) in the BAT arm entered the extension phase to receive ruxolitinib, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis. The primary reasons for discontinuation from the extension phase were progressive disease (8.2%), AEs (2.1%), and other (4.1%). Overall, 70 pts (48.3%) treated with ruxolitinib achieved a ≥ 35% reduction from baseline in spleen volume at any time during the study, and 97.1% of pts (132/136) with postbaseline assessments experienced a clinical benefit with some degree of reduction in spleen volume. Spleen reductions of ≥ 35% were sustained with continued ruxolitinib therapy (median duration not yet reached); the probabilities of maintaining the spleen response at wk 48 and 84 are 75% (95% CI, 61%-84%) and 58% (95% CI, 35%-76%), respectively (Figure). Since the last report (median 61.1 wk), an additional 9 and 12 deaths were reported in the ruxolitinib and BAT arms, respectively, resulting in a total of 20 (14%) and 16 (22%) deaths overall. Although there was no inferential statistical testing at this unplanned analysis, pts randomized to ruxolitinib showed longer survival than those randomized to BAT (HR = 0.52; 95% CI, 0.27–1.00). As expected, given the mechanism of action of ruxolitinib as a JAK1 & 2 inhibitor, the most common new or worsened grade 3/4 hematologic abnormalities during randomized treatment were anemia (ruxolitinib, 40.4%; BAT, 23.3%), lymphopenia (22.6%; 31.5%), and thrombocytopenia (9.6%; 9.6%). In the ruxolitinib arm, mean hemoglobin levels decreased over the first 12 wk of treatment and then recovered to levels similar to BAT from wk 24 onward; there was no difference in the mean monthly red blood cell transfusion rate among the ruxolitinib and BAT groups (0.834 vs 0.956 units, respectively). Nonhematologic AEs were primarily grade 1/2. Including the extension phase, there were no new nonhematologic AEs in the ruxolitinib group that were not observed previously (in ≥ 10% of pts), and only 1 pt had a new grade 3/4 AE (epistaxis). Conclusion: In COMFORT-II, ruxolitinib provided rapid and durable reductions in splenomegaly; this analysis demonstrates that these reductions are sustained over 2 years of treatment in the majority of pts. Ruxolitinib-treated pts showed longer survival than those receiving BAT, consistent with the survival advantage observed in previous (Verstovsek et al. NEJM. 2012) and current analyses of COMFORT-I, as well as with the comparison of pts of the phase 1/2 study with matched historical controls (Verstovsek et al. Blood. 2012). Disclosures: Cervantes: Sanofi-Aventis: Advisory Board, Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Pfizer: Advisory Board, Advisory Board Other; Teva Pharmaceuticals: Advisory Board, Advisory Board Other; Bristol-Myers Squibb: Speakers Bureau; Novartis: AdvisoryBoard Other, Speakers Bureau. Kiladjian:Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment, Equity Ownership. Stalbovskaya:Novartis: Employment, Equity Ownership. McQuity:Novartis: Employment, Equity Ownership. Hunter:Incyte: Employment. Levy:Incyte: Employment, stock options Other. Passamonti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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. Barbui:Novartis: Honoraria. Gisslinger:AOP Orphan Pharma AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees. Knoops:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Harrison:Shire: Honoraria, Research Funding; Sanofi: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4679-4679 ◽  
Author(s):  
Jeff P. Sharman ◽  
Charles M. Farber ◽  
Daruka Mahadevan ◽  
Marshall T. Schreeder ◽  
Heather D. Brooks ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agent ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Highly Active ◽  
Efficacy Assessment ◽  
Equity Ownership ◽  
Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

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