Phase 1/2 Study of Oral MLN9708, A Novel, Investigational Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 479-479 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Paul G. Richardson ◽  
Sagar Lonial ◽  
Ruben Niesvizky ◽  
Ai-Min Hui ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Phase 1 ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Reductions

Abstract Abstract 479 Background: MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor, which immediately hydrolyzes to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 has shown faster proteasome dissociation and greater tissue penetration than bortezomib. Current phase 1 data indicate that oral administration of single-agent MLN9708 was generally well tolerated, with no grade ≥3 peripheral neuropathy, and showed signs of antitumor activity in some patients with relapsed and/or refractory MM. Bortezomib in combination with lenalidomide and dexamethasone demonstrated a 100% partial response or better (≥PR) rate in patients with previously untreated MM, providing the rationale for evaluating oral MLN9708 in place of bortezomib in this combination. Here we report phase 1 data from the first combination study of MLN9708 (ClinicalTrials.gov: NCT01217957). Methods: Primary phase 1 objectives were to determine the safety, tolerability, and maximum tolerated dose (MTD) of weekly MLN9708 in combination with lenalidomide and dexamethasone; secondary objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN9708, assessment of PK interaction and response. Adults aged ≥18 years with ECOG performance status of 0 to 2, and adequate renal, hepatic, and hematologic function were eligible. Patients with grade ≥2 peripheral neuropathy or prior/concurrent deep vein thrombosis (DVT)/pulmonary embolism were excluded. Patients received oral MLN9708 weekly on days 1, 8, and 15, lenalidomide 25 mg on days 1–21, and dexamethasone 40 mg on days 1, 8, 15, and 22, for up to twelve 28-day cycles. Patients received thromboprophylaxis with aspirin or low molecular weight heparin. Transplant-eligible patients could undergo stem cell transplant after six cycles. MLN9708 dose escalation, from a starting dose of 1.68 mg/m2, followed a 3+3 scheme based on the occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were evaluated according to NCI-CTCAE v4.0. Response was assessed according to modified EBMT criteria. Results: At data cut-off (June 29, 2011), 10 patients have been enrolled and treated: three each at 1.68, 2.23, and 2.97 mg/m2 and one at 3.95 mg/m2; median age was 66 years (range 59–77). Patients completed a median of 3 cycles (range 1–6), with three having received 6 cycles; treatment is ongoing in six patients. A DLT of grade 3 fainting was observed in a patient treated at 3.95 mg/m2. The MTD has not yet been reached; the current cohort is receiving 3.95 mg/m2. Drug-related AEs included rash in four patients (two maculopapular, two erythematous); vomiting and fatigue in three patients each; and diarrhea, constipation, and nausea in two patients each. Grade 1 treatment-related peripheral neuropathy was reported in one patient. Serious AEs were seen in four patients: one at 3.95 mg/m2 (DLT of grade 3 fainting), one at 2.23 mg/m2 (grade 3 DVT) unrelated to MLN9708, and two unrelated at 1.68 mg/m2 (grade 3 hypotension; grade 3 gastrointestinal hemorrhage resulting in discontinuation). Two patients required lenalidomide dose reductions to 15 mg due to erythematous rash; no dose reductions were required for MLN9708 or dexamethasone. There were no on-study deaths. Of nine response-evaluable patients, all nine achieved ≥PR, including three very good PR (VGPR) and one complete response. Time to response was rapid; all responders achieved a ≥50% decrease in M-protein in cycle 1, and best response was reached by the end of cycle 4. No patient has progressed to date. One patient with confirmed VGPR discontinued at cycle 6 to undergo stem cell transplant. Conclusions: MLN9708 administered weekly in combination with lenalidomide and dexamethasone appears to be generally well tolerated in previously untreated MM patients at the MLN9708 dose levels studied, with evidence of antitumor activity in the dose-escalation cohorts. Evaluation continues to determine the MTD of MLN9708 in this combination. Updated results, PK data, assessment of PK interaction, and PD data will be presented. Disclosures: Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding.

MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 731-731 ◽  
Author(s):  
Giampaolo Merlini ◽  
Vaishali Sanchorawala ◽  
Jeffrey A. Zonder ◽  
Vishal Kukreti ◽  
Stefan O Schonland ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Cardiac Biomarker ◽  
Hematologic Response ◽  
Major Organ ◽  
Organ Response ◽  
Grade 3

Abstract Abstract 731 Background: Treatment with bortezomib achieves high hematologic response rates and rapid and durable responses in AL patients (pts), providing the rationale for proteasome inhibition in this population. MLN9708 is an investigational, oral, potent, reversible, and specific 20S proteasome inhibitor (PI). In preclinical studies, MLN9708 has shown improved antitumor activity compared to bortezomib in a range of xenograft models. This phase 1 study (NCT01318902) assessed weekly doses of oral MLN9708 in pts with relapsed or refractory AL. Methods: Pts aged ≥18 years with relapsed or refractory AL after ≥1 prior therapy, cardiac biomarker stage I/II disease, and measurable major organ (heart/kidney) involvement, received increasing doses of oral MLN9708 (standard 3+3 dose escalation fixed doses of 4.0 and 5.5 mg), on days 1, 8, and 15 of 28-day cycles for up to 12 cycles. Pts with no major hematologic response (<PR) after 3 cycles received dexamethasone (dex; 40 mg, days 1–4). Two expansion cohorts of PI-naïve and PI-exposed pts were enrolled at the MTD. The primary objectives were to determine the safety, tolerability, and MTD. Secondary objectives included analysis of plasma pharmacokinetic (PK) and whole blood pharmacodynamic effects of MLN9708, and assessment of overall hematologic response rate, time to and duration of hematologic and organ response. Adverse events (AEs) were graded using NCI-CTCAE version 4.03. Blood samples were collected at multiple timepoints pre- and post-MLN9708 dosing for PK analysis during cycle 1. Hematologic response and amyloid-related organ assessments were performed according to standardized criteria. Results: At data cut-off (June 29, 2012) 16 pts had been enrolled and received ≥1 MLN9708 dose (safety population). The median age was 66.5 years (range 54–78) and 7 were male. Median number of prior therapies was 3 (range 1–7); 10 received prior transplant, 7 received prior bortezomib. Major organ involvement, defined by standard criteria, included heart, kidney, or both in 7/5/4 pts, respectively, with a median of 2 (range 1–5) involved organ systems, and Mayo cardiac biomarker risk stage was I, II, III in 6, 9, 1 pts. Five pts were treated in the 5.5 mg cohort and 11 pts were treated in the 4.0 mg (n=6 dose escalation; n=5 dose expansion) cohorts. Of the 11 pts treated at 4.0 mg, 4 were PI-naïve, 7 were PI-exposed. Pts received a median of 3 cycles (range 1–12); 5 pts received ≥5 cycles, and 8 pts remain on treatment. Dex was added in 4 pts (2 in each MLN9708 dose level). There were no on-study deaths. Pts discontinued due to disease progression (n=5), AE, withdrawal by pt, or unsatisfactory response (each n=1); 2 pts completed planned 1 year of therapy. One pt in the 4.0 mg cohort experienced a DLT of grade 3 thrombocytopenia. Two pts in the 5.5 mg dose cohort experienced DLTs: grade 3 diarrhea in 1 pt, and renal failure, respiratory failure (both grade 2), and cardiac arrest (grade 4) in another pt. The MTD was determined as 4.0 mg. AEs were reported in 14 pts. The most common drug-related AEs included nausea (n=5), diarrhea and thrombocytopenia (each n=4), abdominal pain and fatigue (each n=3). Grade ≥3 AEs (any cause) reported in >1 pt were thrombocytopenia (n=4), dyspnea (n=3), maculo-papular rash, dehydration, and abdominal pain (each n=2); all were grade 3. Preliminary response data are shown in the table. At data cut-off, one responder had progressed, and the median duration of hematologic response was 7.4 months (range 1.3–11.5+); 2 pts had cardiac organ response. Preliminary PK data showed that MLN9708 was rapidly absorbed, with a median Tmax of 1 hr (range 0.5–6). MLN9708 day 15 plasma Cmax was 73.6 ± 40.2 ng/mL (mean ± SD) and AUC0–168was 1250 ±530 ng*hr/mL (n=8 at 4.0 mg dose cohort). MLN9708 PK parameter values in this study appear similar to other MLN9708 studies in myeloma pts. Conclusions: These data suggest weekly oral administration of MLN9708 is feasible in pts with relapsed or refractory AL. The MLN9708 MTD was determined as 4.0 mg. Assessment is ongoing, with preliminary evidence of hematologic responses noted. A phase 3 study of MLN9708 plus dex versus physician's choice of treatment is planned (NCT01659658). Disclosures: Merlini: Millennium Pharmaceuticals, Inc.: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Sanchorawala:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Onyx: Research Funding. Zonder:Celgene: Research Funding; Millennium Pharmaceuticals, Inc: Consultancy, Research Funding. Kukreti:Roche: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria. Schonland:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Dispenzieri:Janssen Research & Development: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Celgene: Research Funding. Cohen:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Comenzo:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Carfilzomib (CFZ), a Novel Proteasome Inhibitor for Relapsed or Refractory Multiple Myeloma, Is Associated with Minimal Peripheral Neuropathic Effects.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 430-430 ◽  
Author(s):  
Ravi Vij ◽  
Luhua Wang ◽  
Robert Z Orlowski ◽  
A. Keith Stewart ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Class Effect ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
Grade 3

Abstract Abstract 430 Background: Peripheral neuropathy (PN) is a feature of multiple myeloma (MM) itself as well as a debilitating side effect and major dose-limiting toxicity of thalidomide (THAL) and bortezomib (BTZ) (Chaudry et al, J Peripher Nerv Syst. 2008). Although the mechanism of BTZ-induced PN (BIPN) is unknown, PN may not be a proteasome inhibitor class effect. Carfilzomib (CFZ) is a highly selective proteasome inhibitor with activity in relapsed or refractory MM. CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007), lacks the off-target activities of BTZ (Kapur et al, Blood 2008), and does not cause neurotoxicity in long-term chronic (e.g. up to 9 months) animal toxicology studies (Kirk et al, Blood 2008). In Phase I and 1b/2 trials (total n=138), CFZ was not associated with dose-limiting PN. Here we report on the experience of CFZ treatment from two ongoing Phase 2 trials in relapsed or refractory MM. Methods: Patients with relapsed or refractory MM received CFZ, 20 mg/m2 IV, Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles on studies PX-171-003 and PX-171-004. Neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) were collected at screening. Prospective neurological exams and subjective reporting of PN using the FACT-GOG/Ntx subscale v.4 questionnaire occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse Event (AE) data were also collected. AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' were included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: To date, baseline data are availabel for 136 patients. At screening, 73 (54%) patients had active PN, including 64 (47%) with Grade (G) 1 and 9 (7%) with G2. 111 (82%) patients had a history of PN which was attributed to prior chemotherapy, 86 cases of which were attributed to either THAL or BTZ. THAL was implicated in 57 cases, BTZ in 45 cases, and both THAL and BTZ in 17 cases. For 27 of these patients, PN was the primary reason for THAL or BTZ discontinuation. The mean number of CFZ doses was 27 (4.5 four-week cycles) and 27 (20%) patients completed at least 8 cycles. Peripheral neuropathy AEs (all grades) were reported in 21 (15%) patients; 12 (9%) cases were considered possibly related to CFZ. Grade ≥ 3 PN was reported in only 3 (2%) patients. In one patient, the Grade 3 neuropathy lasted from treatment days 2 to 3 (i.e., < 36 hours) and resolved; the patient continued on CFZ at full dose for 30 days before discontinuing study due to progressive MM. In a second patient, Grade 3 neuropathy occurred on study day 91. The dose was reduced from 20 mg/m2 to 15 mg/m2, at the same twice-weekly frequency; the PN resolved to G1 and the patient continued on therapy until day 133. The third patient had G3 PN that occurred from days 260-281 and resolved to G1 while still on full dose CFZ. This patient completed the full 12-cycle protocol (∼1 year CFZ treatment). Paraesthesias and dysesthesia were reported in 10 (7%) patients; all were G1 or 2. There were no missed doses or CFZ treatment discontinuations due to PN, paraesthesias or dysesthesias. Comparative FACT-GOG/Ntx subscale scores were availabel for 95 patients. There was no statistically significant change in FACT-GOG/NTx scores from baseline to the end of the study. Neurological exams did not identify any additional peripheral neuropathy beyond those reported as AEs. Conclusions: In MM patients receiving CFZ therapy, reports of PN, paraesthesias and dysesthesia are generally mild and do not result in missed doses or CFZ discontinuation, allowing long-term treatment and prolonged disease control. These data, along with the experience from other clinical trials, indicate that PN is not a class effect of proteasome inhibitors. Disclosures: Vij: Proteolix: Consultancy, Research Funding. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: 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. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Cruickshank:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Molineaux:Proteolix, Inc.: Employment, Equity Ownership. 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.

Results of a Phase 1 Dose-Escalation Study of Once-Weekly MLN9708, an Investigational Proteasome Inhibitor, in Patients with Relapsed/Refractory Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3646-3646 ◽  
Author(s):  
Sarit Assouline ◽  
Julie E. Chang ◽  
Bruce D. Cheson ◽  
Robert Rifkin ◽  
Solomon Hamburg ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Advisory Committees ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Abstract 3646 Background: The validity of proteasome inhibition as an effective therapeutic approach in lymphoma has been demonstrated by the first-in-class proteasome inhibitor bortezomib. MLN9708 is a reversible, orally bioavailable, specific investigational 20S proteasome inhibitor that immediately hydrolyzes in vivo to MLN2238, the biologically active form. In mouse models of lymphoma, MLN2238 was associated with greater tumor proteasome inhibition and enhanced antitumor activity versus bortezomib (Lee et al., Clin Cancer Res 2011). The primary objectives of this study of intravenous (IV) MLN9708 in patients with relapsed/refractory lymphoma (NCT00893464) were to determine the safety and maximum tolerated dose (MTD) of once-weekly MLN9708; secondary objectives included characterization of pharmacokinetics (PK) and pharmacodynamics, and assessment of preliminary antitumor activity. Methods: Patients aged ≥18 years with measurable relapsed/refractory lymphoma who had failed ≥2 prior lines of therapies received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Dose doubling proceeded from a starting dose of 0.125 mg/m2 with 1 patient per dose up to 1.0 mg/m2. Dose escalation then occurred in 26–40% increments using a standard 3+3 scheme based on occurrence of dose-limiting toxicities (DLTs) in cycle 1. Adverse events (AEs) were graded using NCI CTCAE v3.0. Blood samples were collected at multiple time points on days 1 and 15 of cycle 1, and day 1 of cycle 2 for PK analyses. Response was assessed using IWG criteria. Results: At data cut-off (June 29, 2012), 26 patients (16 male) had been enrolled: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, 6 at 2.34 mg/m2, and 5 at 3.11 mg/m2. Median age was 56.5 years (range 23–78). Median number of prior therapies was 5 (range 1–12); 31% had prior radiation therapy, 23% had a prior stem cell transplant. Eight patients had Ann Arbor stage IV, 3 had stage III, 6 had stage II, and 2 had stage I; staging was unknown in 4 patients and not applicable in 3. Histologies included follicular lymphoma (FL; n=8), diffuse large B-cell lymphoma (n=6), peripheral T-cell lymphoma (PTCL; n=4), mycosis fungoides (n=2), Hodgkin lymphoma (n=3), and others (n=3). Patients have received a median of 2 cycles of MLN9708 (range 1–29). Four DLTs were reported: 1 grade 4 neutropenia at 1.76 mg/m2, 1 grade 3 neutropenia at 2.34 mg/m2, and 2 grade 3 acute pre-renal failure due to GI toxicities and dehydration at 3.11 mg/m2. The MTD has been determined as 2.34 mg/m2. All patients experienced drug-related AEs, including fatigue (n=12), diarrhea (n=10), nausea, vomiting (each n=8), thrombocytopenia (n=6), pyrexia, neutropenia, decreased appetite, and headache (each n=5). Twelve patients (46%) had drug-related grade ≥3 AEs, including neutropenia (n=4), thrombocytopenia, and diarrhea (each n=3). Three patients discontinued due to AEs of drug-related grade 3 neutropenia (2.34 mg/m2), drug-related grade 3 asthenia and grade 3 acute pre-renal failure, and unrelated grade 3 thrombocytopenia (both 3.11 mg/m2). Three patients reported drug-related serious AEs. Four patients reported drug-related peripheral neuropathy, all were grade 1 or 2. There was 1 on-study death due to respiratory failure, considered unrelated to MLN9708. PK analyses showed a dose-proportional increase in plasma exposure with increasing dose from 0.5 to 2.34 mg/m2 and a terminal half-life of 5.5–9 days after multiple dosing. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Of 22 response-evaluable patients (as of August 7, 2012), one achieved a complete response (CR; FL at 1.76 mg/m2, initial partial response [PR] at cycle 4, improved to CR at cycle 20, ongoing at cycle 24), and 3 achieved a PR (1 FL at 1.4 mg/m2, achieved at cycle 10, ongoing at cycle 30; 1 FL at 3.11 mg/m2, recently achieved at cycle 2 and ongoing at cycle 3; 1 PTCL at 2.34 mg/m2, achieved at cycle 4 but progressed at cycle 8). A further 4 patients had stable disease of ≥ 4 cycles. Conclusions: These phase 1 data suggest that once-weekly IV MLN9708 is generally well tolerated, with infrequent peripheral neuropathy, and shows signs of clinical activity in heavily pretreated relapsed/refractory lymphoma patients, particularly FL patients. Enrollment continues at the MTD; phase 2 studies with oral MLN9708 are planned. Disclosures: Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory lymphoma. Chang:Genentech: Research Funding; Celgene: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc./Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONYX: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; INCYTE: Speakers Bureau; Amgen: Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Yu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc: Employment. Shou:Millennium Pharmaceuticals, Inc: Employment. Martin:Millennium Pharmaceuticals, Inc.: Speakers Bureau.

Nivolumab in Patients (Pts) with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Clinical Outcomes from Extended Follow-up of a Phase 1 Study (CA209-039)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 583-583 ◽  
Author(s):  
Stephen Ansell ◽  
Philippe Armand ◽  
John M. Timmerman ◽  
Margaret A. Shipp ◽  
M Brigid Bradley Garelik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Cell Transplant ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Overall Response ◽  
Duration Of Response ◽  
Grade 3

Abstract Introduction: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in solid tumors and hematologic malignancies. Nivolumab (Bristol-Myers Squibb, Ono Pharmaceutical) is a fully human IgG4 PD-1-blocking monoclonal antibody with demonstrated efficacy in a range of tumors. Results from an independent cohort of 23 pts with R/R cHL in a phase 1 study (CA209-039) showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87% (Ansell et al, N Engl J Med, 2015). This raises important questions including the necessary duration of treatment, the relevance of the depth of response (complete response [CR] vs partial response [PR]), the duration of response, and the feasibility of retreatment. Here, we present the clinical course and post-treatment outcomes from extended follow-up of these pts to shed some light on these questions. Methods: Pts with R/R cHL received nivolumab 3 mg/kg at weeks (wks) 1 and 4, and then every 2 wks for up to 2 years (yrs). Therapy was stopped earlier in pts with intolerance to treatment or progressive disease (PD) without evidence of clinical benefit. Pts who discontinued treatment due to toxicity were followed for up to 120 days after discontinuation; other pts were followed for 1 yr after discontinuation. Responding pts discontinued after confirmed CR or 16 wks after unconfirmed CR, or continued treatment for up to 2 yrs if they had PR or stable disease (SD). Pts who discontinued treatment with ongoing CR, PR, or SD could be retreated for confirmed PD occurring <1 yr after nivolumab discontinuation. Responses were evaluated using the Revised Response Criteria for Malignant Lymphoma (Cheson et al, J Clin Oncol, 2007). The primary endpoint was safety, and the key secondary endpoint was antitumor activity. Results: A total of 23 pts with R/R cHL were treated. The median follow-up observation time is now 86 wks (range: 32-107 wks). Of 20 responders (14 PR, 6 CR), 10 have had durable responses per protocol assessment; their treatment durations and response characteristics are shown in Table 1. Responses were maintained in 2 pts (#5 and #6) after discontinuing nivolumab for >40 wks and in 1 pt (#7) after stopping due to toxicity. Eight pts with durable responses have received nivolumab for >1 yr, including 7 pts who have been in response for >1.5 yrs. One pt (#2) with an initial CR experienced a relapse 43 wks after treatment was discontinued, and achieved a second response (CR) after retreatment with nivolumab. Of the 10 remaining responders, 4 eventually progressed (time to progression [TTP] range: 21.4-92 wks), 1 discontinued treatment due to toxicity with no PD within the 120-day follow-up period, and 5 discontinued nivolumab to undergo stem cell transplant (SCT; 4 allogeneic, 1 autologous) after achieving remission. Time to CR for all responders ranged from 3-88 wks after starting nivolumab, including 2 pts with initial PRs that converted to CRs with continued treatment. All 5 pts who proceeded to SCT had responded to nivolumab within 16 wks of starting treatment (4 PR, 1 CR). Three pts had a best overall response of SD (1 discontinued due to toxicity without documented PD within the 120-day follow-up period; 2 subsequently discontinued for PD [TTP: 15 and 15.3 wks, respectively]). Overall, 3 pts discontinued nivolumab due to adverse events (AEs; Grade 2 peripheral neuropathy, Grade 3 myelodysplastic syndrome, Grade 3 pancreatitis). Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 pts and resolved without treatment in 2 pts. The incidence of IR-AEs did not increase with time on treatment. Conclusions: In pts with R/R cHL, nivolumab was well tolerated and produced a high ORR. Responses occurred within 16 wks of nivolumab initiation in 15 of 20 pts. Early responses to nivolumab allowed 5 pts to proceed to SCT and lasted ≥1 yr in 7 of 10 pts who did not pursue SCT. One pt achieved CR again after retreatment with nivolumab when relapse occurred within 1 yr of discontinuing treatment following an initial CR. Table 1. Treatment and Response Parameters for Pts with Durable Ongoing Responses Pt # Best Response Duration of Response, wks Time to First Response, wks Time on Treatment, wks 1 PR 90.7 3.6 96+ 2 CR 82.1 7.1 91+ 3 PR 73.1 7.6 82.4+ 4 PR 71.4 14.9 88+ 5 CR 71.1 3.1 24.9 6 CR 65.1 7.1 22.9 7 PR 55.9 15.3 70.9 8 CR 48.3 39 87 9 CR 45.3 55 82.9 10 PR 41.7 38.7 82.1+ +Still on treatment Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding. Timmerman:Valor Biotherapeutics: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Bradley Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.

scholarly journals Safety and Clinical Activity of Atezolizumab (Anti-PDL1) in Combination with Obinutuzumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5104-5104 ◽  
Author(s):  
Brian G. Till ◽  
Steven I. Park ◽  
Leslie L. Popplewell ◽  
Andre Goy ◽  
Elicia Penuel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Autologous Stem Cell Transplant ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Grade 3

Abstract Introduction: Despite modern chemo-immunotherapy regimens, the outcomes for patients with relapsed or refractory diffuse-large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) remain poor, and more effective therapies are sorely needed. Immune checkpoint inhibitors (anti-PDL1 or anti-PD-1) represent a novel class of therapeutics with great promise. Atezolizumab (MPDL3280A) is a fully humanized IgG1 monoclonal antibody that blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, thereby preventing inhibition of T-cell activity. Clinical activity of atezolizumab has been seen in multiple tumor types, including NHL as monotherapy. Increased PD-L1 expression has been reported in DLBCL and FL on tumor cells, stromal cells and tumor-infiltrating immune cellsand may represent a mechanism of tumor escape from immune surveillance. Obinutuzumab is a next generation anti-CD20 monoclonal antibody with enhanced ADCC activity. The combination of atezolizumab and obinutuzumab has the potential to activate both innate and adaptive immunity to enhance anti-tumor responses in lymphoma. Methods: This multi-center, open-label, Phase Ib (NCT02220842) study is evaluating atezolizumab in combination with obinutuzumab in patients with relapsed or refractory DLBCL or FL. Primary endpoints were safety and tolerability, with secondary endpoints of PK and clinical activity. Key eligibility criteria included measurable disease and treatment with ≥ 1 prior chemo-immunotherapy regimen. Previous autologous stem cell transplant was allowed, but not allogeneic stem cell transplant. During cycle 1, patients received obinutuzumab alone on days 1 (100 mg), 2 (900 mg), 8 and 15 (1000 mg). From cycles 2-8, atezolizumab (1200 mg) and obinutuzumab (1000 mg) were administered on day 1 every 3 weeks. This was followed by atezolizumab consolidation (1200 mg q3 weeks) for an additional 6 months. ORR was assessed by IWG NHL criteria (Cheson et al, J Clin Oncol 2007). Pre-treatment biopsies and on-treatment samples are being collected to determine PD-L1 expression and other biomarkers of response and resistance. Results: As of July 28, 2015, all 6 patients (2 male, 4 female) evaluable for safety have completed at least 4 cycles of therapy. Median age was 68.5 years (range, 58-81 years). Three patients had FL, and 3 patients had DLBCL. The median number of prior therapies was 4 (range, 2-6). All patients have received at least one prior rituximab-containing chemo-immunotherapy regimen. One patient with DLBCL had received a prior autologous stem cell transplant, as well as CD19 CAR T-cell therapy. The median disease burden at baseline was 2717.4 mm2 (range, 990-7247 mm2). The median duration of therapy was 118 days (range, 64-212 days). One dose-limiting toxicity (Grade 3 thrombocytopenia) was observed. Three patients experienced 1 treatment-emergent Grade 3 AE each (thrombocytopenia, ileus, intestinal obstruction). No Grade ≥ 3 infusion-related reactions, Grade 4 or 5 AEs, treatment related deaths or discontinuations due to study treatment have been seen. Responses for 5 patients who have completed the first disease assessment time point are available. Preliminary efficacy evaluation (CT scan) after 4 cycles (3 months) of therapy are as follows: 2 PRs (up to 68.6% reduction; 1 pt with DLBCL and 1 pt with FL), 2 SDs and 1 PD. Three of 4 patients, experiencing SD or better have ongoing clinical benefit. Expansion cohorts in FL and DLBCL are currently enrolling, and updated safety and efficacy data will be presented. Biomarker data will also be discussed. Conclusions: Preliminary results indicate that the combination of atezolizumab and obinutuzumab appears well tolerated with early evidence of activity in patients with heavily pretreated relapsed or refractory DLBCL and FL. Disclosures Till: Roche-Genentech: Research Funding. Park:TEVA: Research Funding; Seattle Genetics: Research Funding; Jannsenn: Other: Travel. Goy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Penuel:Genentech, Inc.: Employment. Venstrom:Genentech: Employment. Liu:Genentech: Employment. Fingerle-Rowson:F.Hoffmann-LaRoche: Employment. Byon:Genentech: Employment. Woodard:Genentech: Employment.

scholarly journals CC-486 (Oral Azacitidine) in Patients with Hematological Malignancies Who Had Received Prior Treatment with Injectable Hypomethylating Agents (HMAs): Results from Phase 1/2 CC-486 Studies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 905-905 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Michael R. Savona ◽  
Steven D. Gore ◽  
Bart L. Scott ◽  
Christopher R. Cogle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Therapeutic Effects ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Injectable HMAs (azacitidine [AZA], decitabine) are the standard of care in higher-risk myelodysplastic syndromes (HR-MDS) (NCCN, 2016). When other treatment (Tx) options are no longer feasible, HMAs may be used to treat patients (pts) with lower-risk MDS (LR-MDS) and have demonstrated efficacy in older pts with newly diagnosed acute myeloid leukemia (AML) (Dombret, Blood, 2015; Kantarjian, JCO, 2012). Injectable HMAs induce hematologic response or improvement (HI) in ~50% of pts (Grinblatt, Haematologica, 2014; Lyons, JCO, 2009; Silverman, JCO, 2002), but responses may lack durability. There are no standard Tx options indicated for use after HMA failure; the mainstay of Tx in this setting for pts ineligible for stem cell transplant is a clinical trial or supportive care. CC-486, the oral formulation of AZA, was evaluated in 3 phase 1/2 studies that did not exclude pts who had received HMA Tx before study entry. Aim: Determine clinical outcomes for pts with MDS, chronic myelomonocytic leukemia (CMML), or AML, treated with CC-486 monotherapy who had previously failed injectable HMA Tx. Methods: Pts with MDS, CMML, or AML from 3 phase 1/2 CC-486 studies (2 of which included dose-finding periods) who had received HMA Tx before receiving CC-486 are included in these analyses. CC-486 Tx regimens were: 120-600mg x7 days (d) following a single SC AZA cycle (75mg/m2/d x7d), or 300mg QD or 200mg BID x14d or 21d (with no initial SC AZA cycle). All dosing regimens were administered in repeated 28d cycles. Overall response rate (ORR) included complete remission (CR), partial remission (PR), CR with incomplete hematologic recovery (CRi; AML pts only), HI, and transfusion independence (TI). Marrow CR (mCR) was assessed in MDS pts with ≥5% bone marrow blasts at baseline. Results: In all, 40 pts had received prior HMA Tx: 26 pts with MDS, 2 with CMML, and 12 with AML. In the MDS/CMML and AML groups, respectively, median ages were 75 years (range 55-84) and 71 years (60-93) and median times since diagnosis were 28 (2-140) and 4 (0-32) months (Table). Before receiving CC-486, 12 pts (30%) had failed >1 prior injectable HMA course. Most pts (58%) had previously received >4 HMA Tx cycles. Six pts with AML (50%) had received prior HMAs for Tx of antecedent MDS. Of 29 pts for whom outcomes with prior HMAs were known, 16 pts relapsed and 13 pts were refractory to the injectable HMA. The median number of CC-486 Tx cycles was 5 (range 1-52). For all pts treated with CC-486, ORR was 35%. ORR and rates of specific responses were similar between pts with MDS/CMML and pts with AML (Figure). Five of 13 pts (38%) who were refractory to prior HMAs responded, including 1 AML pt who attained CR with CC-486. Six of 16 pts (38%) who had relapsed during or after prior HMA Tx responded. During CC-486 Tx, 32% of pts attained any HI and 31% achieved RBC TI. Of pts who had received ≥6 cycles of prior HMA Tx (n=20), ORR was 35% (7/20). ORR was not statistically different between 7d (n=26) and extended (n=14) CC-486 dosing (P=0.288). The most frequent (≥10%) grade 3-4 hematologic TEAEs were anemia (33%), thrombocytopenia (23%), neutropenia (15%), and febrile neutropenia (10%); the most frequent grade 3-4 gastrointestinal TEAEs were diarrhea and vomiting (10% each). Conclusions: Among pts who were relapsed or refractory to prior HMA Tx, 35% had a hematologic response to CC-486, suggesting that prior HMA failure does not preclude future response to CC-486. Notably, the majority of pts had received >4 prior HMA Tx cycles; thus, prior failures to injectable HMAs were not likely due to inadequate duration of Tx. The ORR with CC-486 in pts who had received ≥6 cycles of the prior injectable HMA was the same as the ORR with CC-486 in all pts. Hypomethylating effects of HMAs are transient; unlike injectable HMAs, oral CC-486 can be administered over extended dosing periods (>7d) of the Tx cycle to produce sustained hypomethylating activity. There was no statistical difference in ORR between CC-486 7d and extended dosing in this small pt group. Nevertheless, given the short half-life and S-phase-restricted DNA incorporation of AZA (Li, Cancer Res, 1970), extending AZA exposure to >7d/cycle with CC-486 could increase the opportunity for cycling cells to incorporate AZA and expose more malignant progenitor cells to AZA, which may optimize therapeutic effects. Extended hypomethylation due to longer exposure to CC-486 may induce pts to respond to CC-486 who had failed prior injectable HMA Tx. Disclosures Savona: TG Therapeutics: Research Funding; 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; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Gore:Celgene: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Cogle:Celgene: Membership on an entity's Board of Directors or advisory committees. Conkling:USOncology Research: Research Funding; Amgen Inc.: Research Funding. Hetzer:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment, Equity Ownership. Kumar:Celgene: Employment, Equity Ownership. Ukrainskyj:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership.

scholarly journals Ixazomib with or without Rituximab Following Immunochemotherapy and Autologous Stem Cell Transplant in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-39
Author(s):  
Jason T. Romancik ◽  
Pamela B. Allen ◽  
Edmund K. Waller ◽  
Zhengjia Chen ◽  
Kelly Valla ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Mantle Cell ◽  
Grade 3 ◽  
Study Therapy

Background: Maintenance rituximab administered post autologous stem cell transplant (ASCT) in mantle cell lymphoma (MCL) is associated with improved overall survival (OS). Maintenance approaches with the proteasome inhibitor, bortezomib, are associated with improved progression-free survival (PFS), although its use is limited by peripheral neuropathy (Kaplan et al, 2020). We conducted a phase 1 study to evaluate the safety of maintenance therapy with ixazomib, an oral proteasome inhibitor, alone and in combination with rituximab for patients with MCL completing ASCT in first remission. Methods: Adult patients with MCL completing an ASCT in first partial or complete remission and who remained progression-free were enrolled between days 70-180 post-ASCT. Initially, patients received ixazomib monotherapy in cohorts of three using a standard 3+3 design. Patients self-administered ixazomib on days 1, 8, and 15 of each 28-day cycle at one of 3 dose levels: 2.3mg, 3mg, or 4mg. Patients continued therapy until disease progression, intolerance, or completion of 10 cycles. While we were enrolling to the 4mg dose level, the LYMA trial reported an OS benefit associated with maintenance rituximab (Le Gouill et al, 2017), so the protocol was amended to explore the combination of ixazomib and rituximab. Combination therapy consisted of ixazomib 4mg (given at the same schedule) and rituximab 375 mg/m2 given on day 1 of cycles 1, 3, 5, 7, and 9. The primary objective of the study was to evaluate the safety of this treatment and determine the maximum tolerated dose (MTD) while secondary objectives included efficacy. Results Twelve patients enrolled in the trial and received at least one dose of study therapy. Seven patients received ixazomib monotherapy (3mg = 3 patients, 4mg= 4 patients), and 5 patients received combination with rituximab and 4mg ixazomib. In all patients, the median age was 58 years (range 42-73 years) and 75% of the patients were male. Five patients had a high risk MIPI score. All patients entered the study in complete remission. Pre-transplant induction was R-HyperCVAD (n=6), VR-CAP/R-DHAP (n=2), NORDIC regimen (n=2), R-CHOP/R-DHAP (n=1), and R-DHAX (n=1). Transplant conditioning regimens were BEAM (n=7) or Bu/Cy/VP-16 (n=5). In the monotherapy group, 6 patients completed all 10 cycles of therapy. One patient experienced a dose limiting toxicity (DLT) which consisted of grade 3 neutropenia following cycle 1. In addition to the patient who experienced a DLT, one patient discontinued therapy early due to persistent abdominal pain that was ultimately determined to be unrelated to study therapy after an extensive evaluation. Two patients required dose reductions due to grade 3 hematologic toxicities. Two patients in the combination therapy group completed 10 cycles of therapy. Two patients experienced DLTs which consisted of grade 4 neutropenia, and 1 patient opted to discontinue therapy early due to persistent grade 2 peripheral neuropathy. In all patients, common adverse events (AEs) regardless of attribution were abdominal pain (n=6), leukopenia (n=5), nausea (n=4), thrombocytopenia (n=4), and peripheral neuropathy (n=3). Grade 3/4 AEs were thrombocytopenia (n=1) and neutropenia (n=4). No grade 3/4 peripheral neuropathy was observed. With a median follow up of 29.6 months, no patients experienced disease progression and all are alive. Due to the myelosuppression-related DLT's encountered in the combination arm, the study was closed to further accrual. Conclusions Our findings suggest adding rituximab to ixazomib at the evaluated dose and schedule as post-ASCT maintenance is associated with myelosuppression, and we would suggest future studies evaluate an alternative dose/schedule to mitigate this risk. The lack of early progressions is encouraging, confirming the findings from CALGB50403 that proteasome inhibition may provide therapeutic benefit in this setting. Further evaluation of rituximab-containing post-induction combination therapies may identify a safer dosing strategy while improving long-term remission rates. Disclosures Allen: Bayer: Consultancy, Other; Curio Sciences: Honoraria; Clinical Care Options: Speakers Bureau; Research to Practice: Speakers Bureau; Imbrium: Consultancy, Other. Waller:Verastem Oncology, Inc: Consultancy, Research Funding. Flowers:Bayer: Consultancy; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; OptumRx: Consultancy; Pharmacyclics/Janssen: Consultancy; Spectrum: Consultancy; Acerta: Research Funding; Millennium/Takeda: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Kite: Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy.

scholarly journals Alliance A061202. a Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib Versus Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Refractory to Lenalidomide and Proteasome Inhibitor Based Therapy: Phase I Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 375-375 ◽  
Author(s):  
Peter M. Voorhees ◽  
Flora Mulkey ◽  
Hani Hassoun ◽  
Claudia E. Paba-Prada ◽  
Yvonne A. Efebera ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Phase I ◽  
Board Of Directors ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Grade 3 ◽  
Experienced Grade

Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Lenalidomide, Bortezomib, and Dexamethasone (RVD) In Combination with Vorinostat as Front-Line Therapy for Patients with Multiple Myeloma (MM): Initial Results of a Phase 1 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3034-3034 ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Jatin J Shah ◽  
Jacob P. Laubach ◽  
Leonard Heffner ◽  
Dixil Francis ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Patient Choice ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Upfront Therapy ◽  
Grade 3

Abstract Abstract 3034 Background: The combination of lenalidomide (R), bortezomib (V), and dexamethasone (D) (RVD) in newly diagnosed MM patients is well tolerated and associated with a very high overall response rate. The goal of the current trial is to improve on the CR rate compared with RVD by adding a novel targeted agent. Preclinical studies have demonstrated that vorinostat (Vor), an HDAC inhibitor, is synergistic with bortezomib, immunomodulatory (IMiD®) compounds and dexamethasone. Clinical studies in the relapsed setting using either bortezomib or lenalidomide with vorinostat have yielded promising results with manageable toxicity. The aim of this study is to determine the tolerability and preliminary efficacy of the combination of RVD with vorinostat in newly diagnosed patients with symptomatic MM. Methods: Patients (Pts) received the current standard RVD regimen (lenalidomide 25 mg days 1–14, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 and dexamethasone 20/10 mg PO [cycles 1–4/5-8] days 1, 2, 4, 5, 8, 9, 11, 12 for up to 8 21 day cycles) combined with oral vorinostat (Vor), provided by Merck and Co. Inc., at 100, 200, 300 or 400 mg daily days 1 – 14 of each cycle. Pts were assigned to one of the four dosing cohorts according to the Bayesian Escalation with Overdose Control (EWOC) algorithm. DLT (≥ G3 non hematologic toxicity, G4 hematologic toxicities defined as G4 thrombocytopenia of any duration; failure of recovery of ANC to ≥1,000/μL or platelets to ≥50,000/μL within 14 days of the last treatment; or inability to receive Day 1 dose for Cycle 2 due to continued drug-related toxicity from cycle 1) was determined in the first cycle of therapy. Toxicities were assessed and graded for all cycles using the NCI CTCAE v 3.0. Responses were assessed by modified EBMT and Uniform criteria. Pts with PR or better could proceed to autologous transplant after ≥ 4 cycles. Results: Eleven pts (median age 54, 82% men, 54.5% ISS Stage II/III) have been enrolled to date with n=4 pts each in cohorts 1 (Vor 100mg) and 2 (Vor 200mg), and 3 pts in cohort 3 (Vor 300 mg). One patient has completed 8 cycles, 1 pt completed 4 cycles and proceeded to transplant, 6 pts remain on study treatment and 3 pts have discontinued therapy (1 for significant peripheral neuropathy {grade 3}, 1 for patient choice unrelated to toxicity and 1 for non adherence). Two DLTs have occurred: syncope (cohort 1) and asymptomatic grade 3 elevation of ALT (cohort 2) with none in cohort 3.The episode of syncope was not related to cardiac arrhythmia. One study related SAE has occurred (syncope). One other episode of grade 3 elevation of ALT occurred in a pt in cycle 3 in cohort 1. Both episodes of increased ALT resolved and patients remained on study with dose modification. One patient developed grade 3 diarrhea in cohort 1. No patients have developed a grade 4 toxicity. Treatment emergent peripheral neuropathy occurred in 6 patients (4 grade 1, 1 grade 2 and 1 grade 3). No episodes of study related grade 3 fatigue, nausea, or vomiting have occurred. The MTD has not been reached. Eight patients are evaluable for response. All have responded to study therapy with 3 CRs, 1 VGPR and 4 PRs. Three patients went on to stem cell collection after 4 cycles and all collected an adequate dose for transplant of >5 ×106 CD34+ cells/kg. Conclusion: The combination of RVD with vorinostat has been generally well tolerated to date. No unexpected toxicity has been noted with side effects commensurate with prior experience with each of the drugs and no additive toxicity seen to date. While asymptomatic elevation of ALT has been seen and will require ongoing monitoring, grade 3 ALT elevation was a DLT in the original RVD study and related to dexamethasone, so may not be related to the addition of vorinostat. Early efficacy data is promising with 50% of patients achieving a VGPR or higher. Accrual is ongoing to determine the MTD. Disclosures: Kaufman: Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Off Label Use: Use of lenalidomide as upfront therapy. Use of vorinostat as upfront therapy. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Novartis: Research Funding. Heffner:Millenium: Consultancy, Honoraria, Research Funding. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Orlowski:Celgene: Consultancy, Research Funding; Millenium: Consultancy, Research Funding. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau.

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.

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