Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 816-816 ◽  
Author(s):  
Shaji Kumar ◽  
William I Bensinger ◽  
Craig B. Reeder ◽  
Todd M. Zimmerman ◽  
James R. Berenson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Institutional Research ◽  
Advisory Committees ◽  
Investigational Agent

Abstract Abstract 816 Background: Proteasome inhibition is a very effective therapeutic strategy in multiple myeloma (MM). The investigational agent MLN9708 is an oral, specific, reversible inhibitor of the 20S proteasome that has shown antitumor activity in solid tumor and hematologic malignancy xenograft models. Phase 1 trials are evaluating both intravenous and oral formulations using different dosing schedules in a variety of tumor types. Here we report the findings from the dose-escalation portion of a phase 1 trial of once-weekly, orally administered MLN9708 in patients with relapsed and/or refractory MM (NCT00963820). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of MLN9708. Secondary objectives included determination of response rate, and characterization of the pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (PD, 20S proteasome inhibition in blood) of once-weekly oral MLN9708. Patients with MM who had received ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids, were eligible. Treatment consisted of MLN9708 administered orally on days 1, 8, and 15 of a 28-day cycle. Dose-escalation proceeded from 0.24 mg/m2 using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded by NCI-CTCAE v3. Response was assessed by modified EBMT/IMWG criteria. Blood samples were collected after dosing on days 1 and 15 of cycle 1 for PK and PD analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: A total of 28 patients have been enrolled to date (data cut-off: June 29, 2011), including 3 each at dose levels of 0.24, 0.48, 0.80, and 1.20, 4 at 1.68, 3 at 2.23, 4 at 2.97, and 5 at 3.95 mg/m2. The median age was 63.5 years (range 40–76); 54% were male. The median number of prior regimens was 5 (range 2–15), and median time from diagnosis was 4.6 years. Nineteen (68%) patients had prior stem cell transplant, and 16 (59%) were refractory to their last prior therapy, including 7 (26%) to bortezomib and 11 (41%) to lenalidomide or thalidomide. The MTD has not been reached; the current cohort is receiving 3.95 mg/m2. No DLTs have been observed among 21 DLT-evaluable patients. Patients have received a median of 2 treatment cycles (range 1–11; mean 2.8). Four patients remain on treatment; discontinuation was mainly due to progressive disease (71%). All 28 patients are evaluable for toxicity; 26 (93%) experienced at least one AE, including 22 (79%) who experienced at least one drug-related AE. Drug-related AEs occurring in >20% of patients included fatigue (39%), thrombocytopenia (36%), nausea (32%), and diarrhea (29%). Two (7%) patients had drug-related peripheral neuropathy (PN, both grade 2); both had grade 1 PN at baseline. Ten (36%) patients experienced grade ≥3 AEs, 4 (14%) had AEs resulting in MLN9708 dose reductions, and 3 (11%) discontinued due to AEs. No on-study deaths have occurred. In 16 response-evaluable patients, one partial response has been seen, in a patient treated at 2.97 mg/m2 (who had three prior lines of therapy, thalidomide–dexamethasone, lenalidomide–dexamethasone –perifosine, and bortezomib–dexamethasone, to which the patient responded and relapsed); duration of response is 3.7 months, and the patient remains in response at cycle 8. A further five patients had a best response of stable disease, durable for up to 9.5 months. PK analyses showed that MLN9708 was rapidly absorbed, with MLN2238 Tmax of 0.5–2.0 hours and a terminal half-life after multiple dosing of approximately 7 days based on limited data (n=5). MLN2238 exposure appeared to increase proportionally with increasing MLN9708 dose over the range 0.8–2.97 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that MLN9708 on a once-weekly schedule is generally well tolerated and has early signs of anti-tumor activity in this heavily pre-treated population with prior exposure to lenalidomide/thalidomide and bortezomib. To date, toxicity has been manageable, and no significant neuropathy signal has been observed. Updated data will be presented, with the MTD anticipated to be reached. Data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708 will also be presented. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding; Array: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding. Reeder:Celgene: Institutional research funding; Millennium Pharmaceuticals, Inc.: Institutional research funding; Novartis: Institutional research funding. Zimmerman:Novartis: Expert witness; Celgene: Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc: Honoraria, Speakers Bureau. Berenson:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Medtronic: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Research Funding; Genentech: Research Funding. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Niesvizky:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx Pharmaceuticals: Research Funding.

Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 301-301 ◽  
Author(s):  
Paul G. Richardson ◽  
Rachid Baz ◽  
Luhua Wang ◽  
Andrzej J Jakubowiak ◽  
Deborah Berg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Control ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
20S Proteasome ◽  
Advisory Committees ◽  
Investigational Agent

Abstract Abstract 301 Background: The investigational agent MLN9708 is the first oral proteasome inhibitor (PI) to enter clinical investigation in MM pts. MLN9708 has shown antitumor activity in solid tumor and hematologic malignancy xenograft models, including in vivo models of MM. The primary objectives of this study (NCT00932698) were to determine safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral MLN9708 in pts with relapsed and/or refractory MM. Secondary objectives included evaluation of response rate and characterization of pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (20S proteasome inhibition in blood). Methods: Pts aged ≥18 years with measurable disease and no grade ≥2 peripheral neuropathy (PN) were eligible. For the dose-escalation phase (3+3 design), pts required ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. Pts could have received other PIs. At the MTD, pts were enrolled to four expansion cohorts: relapsed and refractory cohort (progressive disease [PD] on therapy or <60 days after last dose of most recent prior therapy), bortezomib-relapsed cohort (relapsed after previous bortezomib but not refractory), PI-naïve cohort (relapsed after ≥1 therapy, including thalidomide or lenalidomide and corticosteroids), and prior carfilzomib cohort (last dose of carfilzomib 21–60 days prior to first dose of MLN9708). MLN9708 was administered orally on days 1, 4, 8, and 11 of 21-day cycles. Adverse events (AEs) were graded per NCI-CTCAE v3.0. Response was assessed per modified EBMT/IMWG uniform criteria. Blood samples were obtained at multiple time points on days 1 and 11, cycle 1, for PK and pharmacodynamic analyses; parameters were calculated using noncompartmental methods (WinNonlin software v5.3). Results: As of June 29 2011, 53 pts have been enrolled (53% male). Median age was 66 years (range 50–86), median time since initial MM diagnosis was 4.6 years (range 1.1–24.3), and median number of prior therapies was 4 (range 1–28); 55% of pts had received stem cell transplant, 92%, 80%, 56%, and 4% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively, and 47% were refractory to last therapy, including 28% who were bortezomib-refractory. During dose escalation, 27 pts received MLN9708 0.24–2.23 mg/m2; the MTD was determined as 2.0 mg/m2. To date, 32 pts have been enrolled to the expansion cohorts (including 6 from the dose-escalation phase): 17, 11, and 4 to the relapsed and refractory, bortezomib-relapsed, and PI-naïve cohorts, respectively. Overall, pts have received a median of 3 cycles (range 1–17), with 6 (11%) receiving ≥12 cycles. At data cut-off, 58% of pts had discontinued, mainly due to PD (36%). Safety profiles appeared similar between dose-escalation and expansion cohorts. Overall, 87% of pts experienced drug-related AEs, the most common being fatigue (45%), thrombocytopenia (30%), nausea (26%), diarrhea (25%), vomiting, and rash (each 23%). Only four (8%) pts had drug-related PN (three grade 1, one grade 2); all had grade 1 PN (n=3) or paresthesias (n=1) at baseline. Overall, 58% had grade ≥3 AEs, 21% had dose reductions, and 6% discontinued due to AEs (thrombocytopenia, arthralgia, hypoxia). Two pts died on study due to PD and a cardiac disorder, considered unrelated. To date, of 36 evaluable pts, six have achieved minimal response or better, including two with partial responses (in the 1.2 and 2.23 mg/m2 cohorts), with duration of disease control of up to 11.3 months; all 6 pts remain in response. Another 22 pts have achieved stable disease, which also proved durable with stabilization for up to 9.9 months. MLN9708 was rapidly absorbed with MLN2238 Tmax of 0.5–1.25 hours and terminal half-life of approximately 4–5 days after multiple MLN9708 dosing. MLN2238 plasma exposure appeared to increase proportionally with increasing MLN9708 dose from 0.8–2.23 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that single-agent MLN9708 may result in clinical activity in heavily pretreated relapsed and/or refractory MM pts, including durable disease control, and is generally well tolerated, with infrequent PN. Updated information for all cohorts, plus data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708, will be presented. Disclosures: Richardson: Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Baz:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Orthobiotech: Research Funding. Wang:Millennium Pharmaceuticals, Inc.: Research Funding. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

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.

scholarly journals Trial in Progress: Phase I Dose-Escalation and Dose-Expansion Trial of a Novel Glutaminase Inhibitor (CB-839 HCl) in Combination with Carfilzomib and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3160-3160
Author(s):  
Wilson I Gonsalves ◽  
Srinivas Devarakonda ◽  
Rachid Baz ◽  
Natalia Neparidze ◽  
Alex A Adjei ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Mitochondrial Respiration ◽  
Research Funding ◽  
Phase 1 ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Cellular Respiration ◽  
Advisory Committees

Background: c-MYC activation is an early event of myeloma pathogenesis. It upregulates the expression of the glutaminase 1 (GLS1) enzyme which converts glutamine to glutamate in the mitochondria. Glutamate is required for the biosynthesis of various molecules in the tricarboxylic acid (TCA) cycle (i.e., glutamine anaplerosis). CB-839 HCl is a first-in-class, orally available, selective, noncompetitive inhibitor of GLS1. This inactivation of GLS1 results in an increase of glutamine and a decrease of glutamate and several TCA cycle intermediates within cancer cells, leading to a decrease in their proliferation and/or an increase in cell death. In the phase 1 study, CX-839-002, the safety and tolerability of CB-839 HCl was evaluated in patients with hematological tumors (multiple myeloma (MM) and non-Hodgkin's lymphoma), either as monotherapy or in combination with pomalidomide and dexamethasone or with dexamethasone alone. It was determined to be well tolerated and the maximal tolerated dose (MTD) was not reached. Proteasome inhibitors (PI) are the cornerstone agents in the treatment of myeloma. They disrupt normal protein homeostasis causing an induction of cellular proteotoxic stress, thus, making it an effective strategy against myeloma plasma cells, which naturally mass-produce large quantities of immunoglobulin proteins. PI-resistant MM cells are associated with changes in cellular bioenergetics that favor the increased use of mitochondrial respiration for energy production. Given the increased reliance of PI-resistant MM cells on mitochondrial respiration, and the critical role of glutamine for cellular respiration, inhibition of glutamine metabolism is a rational molecular strategy for the treatment of PI-resistant MM. Furthermore, pre-clinical studies demonstrate the in vitro and ex vivo synergism of CB-839 HCl with carfilzomib (CFZ) in terms of its cytotoxicity and anti-proliferation capacity in various primary human myeloma cell lines and primary patient myeloma cells respectively. As a result, this novel combination of glutaminase inhibition with proteasome inhibition appears promising as a therapeutic combination in MM and warrants further clinical investigation. Methods: This study is a phase 1, multicenter clinical trial of CB-839 HCl in combination with carfilzomib and dexamethasone for patients with relapsed and/or refractory myeloma. Part A of this trial is a 3+3 dose escalation design and Part B is a dose expansion cohort at the RP2D determined in Part A. Up to a maximum of 42 patients will be enrolled at participating ETCTN sites. CFZ will be administered in its usual weekly dosing schedule of days 1, 8 and 15 of a 28 day schedule along with dexamethasone on days 1, 8, 15 and 22. CB-839 will be started at a dose level of 400 mg twice daily and will be investigated to a maximum dose of 800 mg twice daily. Prior to day 1 of Cycle 1, we will administer a 7 day lead in of CB-839 monotherapy before combining it with CFZ. Key inclusion criteria are having relapsed/refractory myeloma with at least 2 prior lines of therapy and prior exposure to PIs, immunomodulators and Anti-CD38 monoclonal antibodies, having measurable disease, adequate hematologic reserve, kidney function and liver function. Key exclusion criteria are being refractory or intolerant to CFZ, adverse cardiac history, central nervous system disease and AL amyloidosis. The primary objective of this trial is to determine the MTD or recommended phase II dosing (RP2D) of CB-839 HCl in combination with carfilzomib and dexamethasone. The secondary objective is to evaluate the safety and tolerability as well as the overall response rate (ORR) associated of CB-839 HCl in combination with carfilzomib and dexamethasone. Correlative objectives will evaluate plasma pharmacokinetic profiles of CB-839 HCl and carfilzomib when used in combination. They will also evaluate potential predictive and prognostic biomarkers as well as resistance mechanisms using genomic DNA, RNA, flow cytometry, immunohistochemistry and metabolomics-based assessment platforms. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT03798678. Disclosures Baz: Bristol-Myers Squibb: Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding. Neparidze:Janssen Scientific Affairs, LLC: Research Funding; Eidos Therapeutics: Other: Member of Independent Diagnostic Committee; MMRF/Synteract: Membership on an entity's Board of Directors or advisory committees. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

A Phase 1 Study Of ARRY-520 With Bortezomib (BTZ) and Dexamethasone (dex) In Relapsed Or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1938-1938 ◽  
Author(s):  
Ajai Chari ◽  
Myo Htut ◽  
Jeffrey Zonder ◽  
Joseph W. Fay ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Initial Dose ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Ksp Inhibitor

Abstract Background ARRY-520 is a novel KSP inhibitor with encouraging activity in patients (pts) with RRMM. In preclinical models, the activity of ARRY-520 is synergistic with BTZ, providing a rationale to combine these drugs in the clinic. Methods ARRAY-520-111 is a Phase 1 study to identify the maximum tolerated dose of ARRY-520, BTZ and dex. Eligible pts have RRMM with ≥ 2 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent. ARRY-520 is administered intravenously (IV) on Days 1, 2, 15 and 16 (Schedule 1) or on Days 1 and 15 (Schedule 2); BTZ is administered IV or subcutaneously (SC) on Days 1, 8 and 15; and 40 mg oral dex, if applicable, is taken on Days 1, 8 and 15 in a 28-day cycle. Results A total of 41 pts have been treated to date at various dose levels of ARRY-520 and BTZ. Patients had a median of 5 prior regimens (range 2-10). All pts received a prior PI, 39 pts received prior BTZ, and 25 pts received at least 2 prior PI- including regimens (range 1-6). In Schedule 1, the initial dose level of ARRY-520 (1.0 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was not tolerated, with dose-limiting toxicities (DLT) in 2/3 pts (pneumonia and pseudomonal sepsis). After a protocol amendment, dose escalation resumed at reduced doses of ARRY-520 (0.5 mg/m2/day) and BTZ (1.0 mg/m2/day) without dex. The addition of prophylactic filgrastim (G-CSF) enabled escalation to full dose ARRY-520 and BTZ (1.5 and 1.3 mg/m2/day, respectively). Only 1 DLT of pneumonia was observed during the further dose escalation, at 1.0 mg/m2/day ARRY-520 and 1.0 mg/m2/day BTZ. Dex has been added to the combination at 1.25 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ and this dose level has been well tolerated. Enrollment is ongoing in the final planned dose level. In Schedule 2, the initial dose level of ARRY-520 (2.25 mg/m2/day) with BTZ (1.3 mg/m2/day) and dex was well tolerated and enrollment is ongoing at 3.0 mg/m2/day ARRY-520 and 1.3 mg/m2/day BTZ + dex, the maximum planned dose of both drugs. The most commonly reported adverse events (AEs) (in ≥ 15% of pts) include anemia, diarrhea, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, neutropenia, constipation, headache, fatigue, hyperuricemia, nausea, vomiting, and dizziness. All Grade 3 – 4 non-hematologic AEs have an incidence of < 10%. Based on the laboratory data, Grade 4 neutropenia was observed in 15% of patients, Grade 4 thrombocytopenia was observed in 10%. Apart from the one pt described above with the DLT of pseudomonal sepsis, no other febrile neutropenic events were reported. Neuropathy (Grade 2) was observed in 1 pt. Monopolar spindles have been observed in a post-dose biopsy for a pt treated at 1.0 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, indicating that pharmacodynamic activity of ARRY-520 is maintained in the presence of full dose BTZ. Preliminary signs of efficacy have been observed in this ongoing dose-escalation study. To date, among the subset of 13 evaluable pts who received doses at ≥ 1.25 mg/m2/day ARRY-520 + 1.3 mg/m2/day BTZ, 4 (31%) partial responses (PR) and 1 minimal response (MR) have been observed. By contrast, in the 27 patients receiving lower doses of ARRY-520 and BTZ, only 1 MR has been reported. An additional 29 pts experienced stable disease (SD) on ARRY-520 + weekly BTZ without the use of steroids (dex), including 17 pts with disease refractory to BTZ. Conclusions ARRY-520 + BTZ with prophylactic G-CSF appears well tolerated with manageable non-hematologic AEs in this heavily pretreated pt population and has demonstrated preliminary evidence of activity, including PRs and SD in pts with disease refractory to BTZ. These data support further exploration of this novel KSP inhibitor in combination with BTZ in expansion cohorts. The authors would like to acknowledge the dedicated research staff and physicians at the participating centers of the Multiple Myeloma Research Consortium for their contribution to this study. Disclosures: Chari: Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Off Label Use: ARRY-520 is an investigational drug being combined with bortezomib in multiple myeloma. Zonder:Celgene Corporation: Consultancy; Onyx: Consultancy; Skyline Diagnostics: Consultancy. Jakubowiak:Millenuim: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Kaufman:Millenium: Consultancy; Merck: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy; Janssen: Consultancy.

Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 432-432 ◽  
Author(s):  
Sagar Lonial ◽  
Ravi Vij ◽  
Jean-Luc Harousseau ◽  
Thierry Facon ◽  
Jonathan Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Advisory Board ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Grade 3

Abstract Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.

Final Results of Phase 1 MMRC Trial of Selinexor, Carfilzomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 973-973 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Jagoda Jasielec ◽  
Cara A. Rosenbaum ◽  
Craig E. Cole ◽  
Ajai Chari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Advisory Committees ◽  
Treatment Regimens ◽  
Line Of Therapy

Abstract Background There are an increasing number of multiple myeloma (MM) patients (pts) refractory to currently available drugs, including the proteasome inhibitors bortezomib and carfilzomib (CFZ), necessitating development of novel therapeutics. Pre-clinical evaluation of selinexor (SEL), an orally available Selective Inhibitor of Nuclear Export (SINE) compound, demonstrated synergistic myeloma cell death with CFZ and mechanistic rationale for overcoming resistance to CFZ (Rosebeck et al., 2016), providing support for this phase 1 trial. Aims The primary objectives were to assess the maximum tolerated dose (MTD) of a SEL, CFZ and dexamethasone (DEX) combination and to obtain preliminary efficacy data for this novel regimen in RRMM pts. Methods Pts with RRMM who progressed after at least two prior treatment regimens of myeloma therapy were eligible for enrollment. Dose escalation followed the 3+3 design with pts receiving 30 mg/m2 - 40 mg/m2 SEL PO on days (D) 1, 3, 8, 10, 15, 17; 20 mg/m2 - 56 mg/m2 CFZ IV on D 1, 2, 8, 9, 15, 16, and DEX PO (20mg cycles 1-4/ 10mg cycles 5+) in 28-day cycles (C) in up to 5 dose levels. An expansion cohort has enrolled additional pts to a total of 12 CFZ-refractory pts treated at the recommended Phase 2 dose (RP2D). Dose Limiting Toxicities (DLTs) were evaluated through C2D1. Responses were assessed by IMWG criteria plus near complete response (nCR). Results As of July 1st, 2016, the study has completed dose escalation and enrolled a total of 18 pts; 5 at dose level 1 (30 mg/m2 SEL, 20/27 mg/m2 CFZ, 20/10 mg DEX), 3 at dose level 2a (30 mg/m2 SEL, 20/36 mg/m2 CFZ, 20/10 mg DEX), and a total of 10 (7 in dose escalation, 3 in cohort expansion) at dose level 2b (60mg flat dose SEL, 20/27 mg/m2 CFZ and 20/10 DEX). Pts age ranged between 55 to 74 years with a median of 63.5 years; and had a median of 4 prior treatment regimens (range 2-10). Sixteen pts were evaluable for response, all refractory to their last line of therapy. All 16 response evaluable pts were refractory to CFZ, of which 11 were refractory to CFZ combinations as their last line of therapy, including 8 to a KPd combination of CFZ, pomalidomide, and DEX. Fifteen pts were evaluable for DLT and 3 of 18 pts required replacement for DLT evaluation (1 had DEX reduced not due to DLT; 2 did not receive all scheduled C1 doses). In the dose escalation phase, there was one DLT of cardiac amyloidosis (CA) in a pt with history of prior congestive heart failure and CA at baseline. While the maximum tolerated dose (MTD) has not been reached, the RP2D was identified at dose level 2b based on tolerability. Grade 3/4 adverse events (AEs) included: thrombocytopenia (67%), neutropenia (33%), anemia (17%), fatigue (17%), and infections (11%). The most common all grade AEs included: gastrointestinal disorders (78%), thrombocytopenia (73%), fatigue (72%), anemia (47%), dyspnea (33%), and elevated liver and pancreatic enzymes (28%). There were 2 (11%) serious AEs, 1 upper respiratory infection and 1 lower gastrointestinal bleeding. All adverse events were manageable with concomitant medications. Response rates for all evaluable pts were 75% ≥MR (12 of 16), 63% ≥PR, and 25% ≥VGPR. Response rates in CFZ-refractory pts at last line of treatment were 73%, 64%, and 18% respectively. Responses occurred rapidly; after C1 with 75% ≥MR. As of the data cutoff date, 15 pts progressed (between 1 and 14 months on study) and 3 pts remained on treatment (1 - 4 months). Conclusions The combination of SEL, CFZ, and DEX demonstrates encouraging activity and safety in heavily pretreated, mostly CFZ-refractory myeloma. In addition, with 64% PR or better for pts progressing on CFZ, these results provide early clinical evidence that selinexor has the ability to overcome CFZ resistance, warranting further investigation of this regimen in RRMM. Disclosures Jakubowiak: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenbaum:Celgene: Speakers Bureau. Chari:Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Zonder:Pharmacyclics: Other: DSMC membership; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Prothena: Consultancy, Honoraria.

Phase 1 Clinical Trial of NPI-0052, a Novel Proteasome Inhibitor in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2770-2770 ◽  
Author(s):  
Paul Richardson ◽  
Craig C. Hofmeister ◽  
Todd M. Zimmerman ◽  
Asher Alban Chanan-Khan ◽  
Matthew A. Spear ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Significant Activity ◽  
Potential Clinical Benefit

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including multiple myeloma (MM) resistant to bortezomib and other agents (Chauhan et al, Blood 2006). Studies have therefore been initiated in patients with multiple myeloma, lymphoma, leukemia and solid tumors. Materials and Methods: This Phase 1 dose escalation study evaluated NPI-0052 monotherapy in patients with relapsed and relapsed/refractory MM, including those that have received bortezomib and/or lenalidomide. Patients were assessed for safety, pharmacodynamics (including ex vivo proteasome inhibition), plasma pharmacokinetics (PK), and clinical activity (with response assessed by modified EBMT criteria). Patients were treated with NPI-0052 administered as a weekly IV injection on Days 1, 8 and 15 every 4 weeks with concomitant hydration. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. Proteasome inhibition and PK were assayed after the 1st and 3rd dose and upon any intra-patient dose escalation. Proteasome inhibition was also assessed in CD138 positive cells isolated from bone marrow aspirates obtained at baseline and after the 3rd dose in a subset of patients. Preliminary Results: To date, 10 patients have been treated at doses ranging from 0.025 mg/m2 to 0.075 mg/m2 without reaching an MTD. One patient experienced reversible elevation in serum creatinine that responded to drug cessation and steroids; this event may have been related to progression of his underlying light chain nephropathy (as interval worsening of renal function was noted prior to enrollment). Drug-related adverse events have been otherwise unremarkable at all dose levels tested. PK data demonstrate a rapid elimination half life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L; no change in PK has been observed comparing the 1st and 3rd injection. Proteasome inhibition in whole blood suggests drug-dependent CT-L inhibition, with inhibition up to 28% observed (inhibition up to 100% at doses of up to 0.7 mg/m2 has been observed in other clinical trials with NPI-0052 without producing the profile of toxicity reported with standard doses of bortezomib). Whilst no responses have been confirmed, two patients with relapse/refractory MM remained on study for over 6 months and one year, respectively, with stable disease and no significant toxicity. Importantly, no peripheral neuropathy or myelosuppression has been seen in 41 treatment cycles in patients to date. Conclusions: In patients with relapsed and relapsed, refractory MM, NPI-0052 affects parameters relevant to pharmacodynamics, PK and demonstrated potential clinical benefit at doses well below the MTD anticipated from Phase 1 clinical trials with NPI-0052 in lymphoma and solid tumors. Drug administration to date has been well tolerated. Dose escalation continues to define DLT and MTD, and to recommend a phase 2 dose for further study in patients with advanced MM.

Phase 1 Dose-Escalation Study of Multiple Dosing Schedules of the Investigational Drug MLN4924, a Nedd8-Activating Enzyme Inhibitor, In Patients with Relapsed and/or Refractory Multiple Myeloma or Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2801-2801 ◽  
Author(s):  
Jatin J Shah ◽  
R. Donald Harvey ◽  
Owen A O'Connor ◽  
Andrzej J Jakubowiak ◽  
Mitchell R Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Peripheral Blood ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Advisory Committees ◽  
Dose Escalation Study

Abstract Abstract 2801 Background: MLN4924 is an investigational inhibitor of Nedd8-activating enzyme (NAE), which plays an essential role in regulating the activity of the cullin-RING E3 ligases (CRLs). NAE controls the neddylation cascade that results in Nedd8 conjugation to the CRLs, which is required for ligase activity. NAE inhibition thus inhibits ubiquitination and proteasomal degradation of CRL substrates, which include proteins involved in cell-cycle regulation (p27), signal transduction (pIκBα), DNA replication (Cdt-1), stress response (Nrf-2), and other processes important to tumor cell growth and survival. In lymphoma cells, NAE inhibition with MLN4924 has been shown to result in apoptosis either through increased Cdt-1 levels, S-phase accumulation, and DNA re-replication, or via pIκBα stabilization and consequent NF-κB pathway inhibition. In vivo, MLN4924 treatment resulted in tumor growth inhibition and regressions in lymphoma xenograft models. This phase 1 dose-escalation study is the first investigation of MLN4924 in multiple myeloma (MM) and lymphoma patients. We have previously reported (Shah et al, ASH 2009) that the maximum tolerated dose (MTD) of MLN4924 on Schedule A of this study (days 1, 2, 8, and 9 of 21-day cycles) was 110 mg/m2, with dose-limiting toxicities (DLTs) including muscle cramps and febrile neutropenia. Analyses of peripheral blood mononuclear cells and skin biopsies indicated MLN4924 exerted the predicted pharmacodynamic (PD) effects in peripheral blood and skin, including inhibition of neddylated cullins and induction of pIκBα, Cdt-1, and Nrf-2. Two additional schedules of MLN4924 administration are now being investigated with the aim of increasing tolerability and the deliverable dose. Methods: Patients aged ≥18 years with ECOG performance status 0–2 and relapsed and/or refractory MM or lymphoma, including any B- or T-cell non-Hodgkin's lymphoma (NHL) and Hodgkin lymphoma (HL), following ≥2 prior lines of therapy were eligible. Primary objectives were to determine the MTD and safety profile of MLN4924 on the different dosing schedules, describe the pharmacokinetics (PK) and PD of MLN4924 in blood, and investigate PD effects in skin and tumor. Secondary objectives included evaluation of disease response. Patients received MLN4924 via a 60-minute intravenous infusion on either days 1, 4, 8, and 11 (Schedule B) or days 1 and 8 (Schedule C) of 21-day cycles for up to 12 months. Doses of 25–147 mg/m2 were investigated on Schedule A; for Schedules B and C, dose escalation started at the MTD of Schedule A, 110 mg/m2, and proceeded in 1.33-fold increments using a Bayesian continual reassessment method based on the occurrence of DLTs in cycle 1. The MTD was defined as the dose level closest to that predicted to result in a DLT rate of 25%. Adverse events (AEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: To date, 7 patients (5 male, median age 60 years [range 48–68]) have been enrolled to Schedule B, 2 each at 110, 147, and 196, and 1 at 261 mg/m2; 2 have MM and 5 lymphoma (2 diffuse large B-cell lymphoma [DLBCL], 1 small lymphocytic lymphoma, 1 mantle cell lymphoma [MCL], 1 nodular sclerosis HL). Patients have received a median of 3 cycles (range 2–5) to date. A total of 7 patients (all male, median age 49 years [range 45–66]) have been enrolled to Schedule C, 2 each at 110 and 147, and 3 at 196 mg/m2; 4 have MM and 3 lymphoma (1 follicular lymphoma [FL], 1 MCL, 1 nodular sclerosis HL). Median number of cycles received is 4 (range 1–7). No DLTs and no grade ≥3 AEs have been reported on either schedule to date. On Schedule B, only grade 1 dyspnea and myalgia (both n=2) have been reported in >1 patient, with grade 1 diarrhea (n=3), constipation, fatigue, and nausea (each n=2) reported on Schedule C. PK data for the 110 mg/m2 cohorts of Schedules B and C are consistent with the lack of significant accumulation of MLN4924 in plasma shown on Schedule A. One patient with HL on Schedule A achieved a partial response; no responses have been reported to date on Schedules B and C though some heavily treated patients have demonstrated stable disease for 5 or more cycles (1 FL, 7 cycles; 1 DLBCL, 5 cycles; 1 MM, 5 cycles). Conclusion: Enrollment and dose escalation are proceeding on Schedules B and C (at doses above Schedule A MTD) to determine the MTD on each schedule; updated clinical data will be presented, together with data on the PK and PD of MLN4924, on these dosing schedules. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of multiple myeloma and lymphoma. O'Connor:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Smith:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding, Speakers Bureau. Orlowski:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding. Mulligan:Millennium Pharmaceuticals: Employment. Smith:Millennium Pharmaceuticals, Inc.: Employment. Pickard:Millennium Pharmaceuticals, Inc.: Employment. Dezube:Millennium Pharmaceuticals: Employment, Equity Ownership. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2672-2672 ◽  
Author(s):  
Sarit Assouline ◽  
Julie Chang ◽  
Robert Rifkin ◽  
Ai-Min Hui ◽  
Deborah Berg ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Follicular Lymphoma ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Advisory Committees ◽  
Refractory Lymphoma ◽  
Grade 3

Abstract Abstract 2672 Background: MLN9708 is an investigational, potent, reversible, and specific 20S proteasome inhibitor. It is immediately hydrolyzed in vivo to MLN2238, the biologically active dipeptidyl leucine boronic acid. In preclinical studies, MLN2238 showed faster proteasome dissociation and greater tissue penetration than bortezomib. In OCI-Ly10 and PHTX22L mouse models of lymphoma, prolonged tumor proteasome inhibition and enhanced antitumor activity was seen with MLN2238 compared with bortezomib. Both intravenous (IV) and oral formulations are in clinical development. Here we report data from the first phase 1 study of IV MLN9708 in patients with lymphoma (ClinicalTrials.gov: NCT00893464). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and safety of MLN9708. Other objectives included characterization of the pharmacokinetic (PK)/pharmacodynamic (PD) profile, and assessment of antitumor activity and tumor biomarkers. Adults with lymphoma who had failed at least 2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles for up to 12 cycles or until disease progression or unacceptable toxicity occurred. Patients had ECOG PS 0–2, adequate renal, hepatic, and hematologic function, and no grade ≥2 peripheral neuropathy. One patient was enrolled at the starting dose of 0.125 mg/m2; dose doubling proceeded with 1 patient at each dose level up to 1.0 mg/m2. Dose escalation then proceeded in ≤40% increments via a standard 3+3 scheme based on DLT occurrence in cycle 1. The MTD was defined as the highest dose resulting in DLT during cycle 1 in 0/3 or 1/6 patients. Adverse events (AEs) were graded using NCI-CTCAE v3.0. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analysis. PK and PD parameters were calculated using noncompartmental methods (WinNonlin v5.3). Archived tumor specimens were used for biomarker analysis. Response was assessed using International Working Group criteria for lymphoma. Results: At data cut-off (July 8, 2011), 17 patients had been enrolled and treated: 1 each at 0.125, 0.25, 0.5, and 1.0 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 2 at 2.34 mg/m2. The median age was 53 years (range 23–78). Histologies were follicular lymphoma (n=6), diffuse large B-cell lymphoma (n=3), Hodgkin lymphoma (n=3), T-cell lymphoma (n=3), and other (n=2). The median number of prior therapies was 5, including radiation and stem cell transplant in 29% of patients each; 47% had received ≥6. Patients received a median of 2 cycles (range 1–16); treatment is ongoing in 3 patients. Two DLTs were seen (1.76 mg/m2, grade 4 neutropenia; 2.34 mg/m2, grade 3 neutropenia delaying cycle 2 by >1 week); the MTD has not yet been reached. Drug-related AEs included fatigue (n=8), diarrhea (n=5), nausea (n=5) and vomiting, pyrexia, neutropenia, thrombocytopenia, and headache (n=4 each). Drug-related peripheral neuropathy was reported in 3 patients (one grade 1, two grade 2 in patients with peripheral neuropathy at baseline). Grade ≥3 drug-related AEs were seen in 8 patients, including neutropenia (n=4) and thrombocytopenia (n=3). Two patients treated at 1.4 mg/m2 had SAEs (grade 3 increased creatinine, grade 2 pyrexia). There were no on-study deaths. One patient treated at 2.34 mg/m2 discontinued due to drug-related grade 3 neutropenia. Three patients treated at 1.76 mg/m2 required dose reductions. Of 16 response-evaluable patients, 3 achieved partial response and continue to respond (2/6 with follicular lymphoma at 1.4 and 1.76 mg/m2, 1/3 with T-cell lymphoma at 2.34 mg/m2); duration of response is >9 months in a patient with follicular lymphoma. Stable disease, durable for up to 3.7 months, occurred in 4 patients. MLN2238 plasma concentration decreased by 90% within 4 hours post dose. After multiple dosing, the terminal half-life ranged from 4–8 days. Plasma exposure appeared to increase proportionally with increasing dose from 0.5–2.34 mg/m2. Whole blood 20S proteasome inhibition was immediate, and maximal inhibition correlated with maximum plasma concentration. Conclusions: These data suggest that once-weekly MLN9708 is generally well tolerated and has early signs of clinical activity in some patients with heavily treated lymphoma. Dose escalation continues to determine the MTD; a total of 16 patients will be evaluated at the MTD. Updated data and analyses of patient stratification biomarkers will be presented. Disclosures: Off Label Use: Use of investigational agent MLN9708 for the treatment of relapsed/refractory lymphoma. Rifkin:Amgen: Speakers Bureau; Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: 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, Speakers Bureau. Hui:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Xi:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Martin:Millennium Pharmaceuticals, Inc.: Research Funding, Speakers Bureau.

scholarly journals A First in Human Study Planned to Evaluate Hdp-101, an Anti-BCMA Amanitin Antibody-Drug Conjugate with a New Payload and a New Mode of Action, in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Andras Strassz ◽  
Marc S. Raab ◽  
Robert Z. Orlowski ◽  
Michael Kulke ◽  
Gudrun Schiedner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Rna Polymerase Ii ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Myeloma Cells

Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of hematologic malignancies. Most of these ADCs are based on only a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins that mainly impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as indolent lymphomas or multiple myeloma. Thus, new compounds with alternative toxicity mechanisms and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated. Del(17p) is a frequent deletion in tumor cells, identifying high-risk patients with poor prognosis. TP53, a well-known tumor suppressor gene, is located on the short arm of chromosome 17. The major subunit of the RNA Polymerase II POLR2A is frequently co-deleted with TP53 in del(17p) human cancers, which renders these tumors more vulnerable to amanitin-ADC treatment compared to wild-type tumor and healthy cells. HDP-101 is a new ADC targeting BCMA (B cell maturation antigen) carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma. Furthermore, the cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. On safe doses, hematology and clinical chemistry parameters were mainly unaffected except for a mild to moderate and transient increase of liver enzymes and lactate dehydrogenase predominantly after the first dose. Free payload was detectable at levels close to the lower limit of quantification only. GLP toxicity studies of the released payload in rodents revealed a NOAEL, which is well above concentrations observed in non-human primate studies after ADC administration as well as above the toxin doses administered by the ADC. This may be attributed to the hydrophilicity of the toxin, which cannot passively enter any antigen-negative cell and is rapidly cleared without further drug metabolism. Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. Patients whose myeloma cells harbor 17p deletion may have a specific therapeutic sensitivity towards HDP-101. HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial in setup phase with HDP-101 in patients with multiple myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. Patients in phase 2a will be stratified based on del(17p) status. An adaptive Bayesian logistic regression model with overdose control principle will be used to guide the dose escalation steps. The design of the study ensures a safe dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. The study is expected to enroll patients in early 2021. Disclosures Strassz: Heidelberg Pharma: Current Employment. Raab:Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kulke:Heidelberg Pharma: Current Employment, Current equity holder in publicly-traded company. Schiedner:Heidelberg Pharma: Current Employment. Pahl:Heidelberg Pharma: Current Employment, Current equity holder in publicly-traded company.

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