An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
Author(s):  
Noopur Raje ◽  
Paul Richardson ◽  
Parameswaran N Hari ◽  
Anuj Mahindra ◽  
Sarah Kaster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Oral Steroid ◽  
High Dose ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

Updated Results of a Phase I Study of RAD001 In Combination with Lenalidomide In Patients with Relapsed or Refractory Multiple Myeloma with Pharmacodynamic and Pharmacokinetic Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3051-3051 ◽  
Author(s):  
Anuj Mahindra ◽  
Paul G Richardson ◽  
Parameswaran Hari ◽  
Aliyah R. Sohani ◽  
Jacob P. Laubach ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
T Cell Subsets ◽  
Oral Steroid ◽  
Pharmacokinetic Analysis ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3051 Background: Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an mTOR inhibitor has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Informed by our previous studies demonstrating synergistic anti-MM activity of mTOR inhibitors when combined with Len, we studied this combination to evaluate its safety and activity as a non-steroid containing oral regimen in advanced MM. Methods: Patients with relapsed and refractory MM were assigned to Len and RAD001 to be taken for 21 days of a 28 day cycle (NCT00729638) in a standard 3+3 design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity and were required to receive concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Peripheral blood and bone marrow samples were collected before and after treatment for pharmacokinetic and pharmacodynamic studies. Results: Twenty-eight patients were registered on the trial between December 2008-December 2009. Two patients were inevaluable because of either rapidly progressive disease or failure to meet eligibility criteria on day 1. Data on 26 patients are therefore available. Pts had received a median of 4 prior lines of treatment.14 pts had received Len previously of which 11 pts had relapsed disease and 3 pts had relapsed/refractory disease. Both cohort 1 (Len: 10mg/day and RAD001: 5mg/every other day ×21 days of 28 day cycle) and 2 (Len: 15mg/day and RAD001: 5mg daily ×21 days of 28 day cycle) required expansion because of grade 3 neutropenia and grade 4 thrombocytopenia. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg × 21 days). The maximum tolerated dose (MTD) was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Most common (≥10%) Grade 1/2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which proved manageable with supportive care. One patient developed RAD related non-infectious pneumonitis requiring therapy discontinuation. Grade 3/4 adverse events (≥ 5%) included thrombocytopenia (11%) and neutropenia (22%). Nineteen patients completed 2 cycles and were evaluable for response. Median follow up is currently 8.7 months and median PFS is 4.3 months, with 12 patients receiving treatment at MTD. Overall response rate was 68% (13/19) (90% CI: [30-76%]) including CR(1) PR(2), MR(8) and SD(2). Four patients continue on the combination at 13, 14, 15 and 17 months respectively. Pharmacokinetic and pharmacodynamic data including immunohistochemistry for phosphorylated AKT, cytokine profiles, T cell subsets and transcription profile on MM cell pre and post treatment as well as correlation of response with pharmacodynamic studies will be presented. Conclusions: The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population with advanced MM. This combination thus provides an oral steroid free combination treatment strategy which warrants future evaluation in phase II studies. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: 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. Adams:Novartis: Employment. Makrides:Celgene: Employment. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide and RAD 001 for treatment of relapsed and refractory multiple myeloma.

A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 74-74 ◽  
Author(s):  
Jatin J. Shah ◽  
Edward A. Stadtmauer ◽  
Rafat Abonour ◽  
Adam D Cohen ◽  
William I. Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 74 Background: Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an immunomodulatory agent (IMiD), have both demonstrated promising activity as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma. IMiD+PI combinations including lenalidomide, bortezomib, dexamethasone and lenalidomide, carfilzomib, dexamethasone have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly active in patients with relapsed/refractory multiple myeloma. Here, we report the first findings from the Phase I dose-escalation and expansion portions of the first phase I/II trial of Car-Pom-d in patients with relapsed/refractory multiple myeloma (NCT01464034). Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pom-d. Secondary objectives included determination of overall response rate, time to progression, progression free survival, and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have been relapsed/refractory to their most recent therapy. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1–21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22. Dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Carfilzomib was initiated at 20 mg/m2for Cycle 1, days 1–2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results: In the Phase I dose-escalation portion of the trial, a total of 12 patients were enrolled from 6 centers. The median age was 61 years (range 44–78), 67% were male. The median number of prior regimens was 6 (range 2–15), and median time from diagnosis was 5.1 years. Four (33%) patients had prior stem cell transplant, 11 (92%) had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 5 patients with del(17p), 2 patients with t(4;14), and 1 patient each with del(13), t(11;14), and t(14;16). In these first 12 patients, drug-related AEs occurring in >20% of patients included fatigue (42%), anemia (33%), pneumonia (33%), dyspnea (25%), and thrombocytopenia (25%). Six (50%) patients experienced grade ≥3 AEs including 2 incidence each of neutropenia and febrile neutropenia. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). At this dose, 1 of 6 patients experienced a protocol-defined DLT of febrile neutropenia. At dose level 2 (carfilzomib 20/36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg), 2 of 6 patients experienced DLTs, consisting of grade 4 thrombocytopenia and grade 3 rash. All 12 patients were response evaluable with 2 very good partial response (VGPR), 4 partial response (PR), 2 minor response (MR), 2 stable disease (SD), and 2 progressive disease (PD) for a ≥ MR rate of 67%. The 6 month progression free survival was 70% (95% CI: 37 to 90%). Of the 5 patients with del(17p), 1 achieved VGPR, 2 achieved PR, 1 achieved SD. We then enrolled an expansion cohort of 20 patients from 8 centers resulting in a total study population of 32 patients, with 25 still receiving treatment. Three patients have died, all from progressive multiple myeloma. Early response assessments in 27 out of 32 patients show 2 VGPR, 7 PR, 6 MR, 8 SD, and 4 PD for a ≥MR rate of 56%. Conclusions: The Car-Pom-d regimen is well tolerated and achieves a high response rate in a heavily pre-treated, lenalidomide-refractory population with prior bortezomib exposure. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p). We are beginning enrollment in a larger phase 2 cohort, and updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Array: Consultancy. Stadtmauer:Celgene: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau. Abonour:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Cohen:Celgene: 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; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:Onyx: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaufman:Millenium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Lentzsch:Celgene: Consultancy, Research Funding. Vogl:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Research Funding; Otsuka: Consultancy; Acetylon: Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Durie:Onyx: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Amgen: Consultancy.

scholarly journals A Phase I-II Study of the Combination of Bendamustine and Pomalidomide with Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1857-1857 ◽  
Author(s):  
Cristina Gasparetto ◽  
Michael Green ◽  
Anandgopal Srinivasan ◽  
Yubin Kang ◽  
David A. Rizzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Response ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Background Bendamustine, a bifunctional mechlorethamine derivative with alkylating properties and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). Bendamustine in combination with lenalidomide, thalidomide, and bortezomib have had high response rates and good tolerability. We combined bendamustine and pomalidomide with dexamethasone (Ben-Pom-d) and hypothesized that this regimen would be highly effective in patients with RRMM. Dose-escalation started with 120mg/m2 bendamustine/3mg pomalidomide [or 4mg in the cohort 2]/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD was 120mg/m2 bendamustine/3mg pomalidomide/40 mg dexamethasone. Here, we report our findings to date from the phase I/II trial of Ben-Pom-d in patients with RRMM (NCT01754402). Methods The primary objective of the phase I portion was to determine the MTD. Data for overall response, progression free survival, and overall survival, includes all patients treated on the phase I and II portions of the study. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Patients had to be pomalidomide naïve. Treatment consisted of oral pomalidomide once daily on days 1-21, intravenous (IV) bendamustine given over 30 minutes on day 1 and dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results A total of 9 patients were enrolled in the phase I portion. The MTD was the starting dose level (bendamustine 120 mg/m2, pomalidomide 3mg, dexamethasone 40 mg). In Phase II we enrolled an additional 16 patients resulting in a total study population of 25 patients evaluable for toxicity and 22 for efficacy, with 6 still receiving treatment. The median age was 65 years (range 43-81), 46% were male. The median number of prior regimens was 3 (range 2-6), median time from diagnosis is 3.9 years (range 1.1-9.10 years), 88% of patients had a prior stem cell transplant, 100% had prior bortezomib, 20% had prior carfilzomib and all were lenalidomide-refractory. Fifteen patients had high risk cytogenetic, including 8 patients with del17. Patients received a median of 6 cycles of therapy (range 1-18 cycles). Best response assessments in 22 evaluable patients for efficacy, showed 5 (23%) VGPR, 12 (55%) PR, 3 (14%) MR, and 2 (9%) SD, for an ORR of 77% and a ≥MR rate of 91%. The median follow-up of survivors is 10 months (range: 2-19+ months). Median PFS and OS were 4.5 months (range 1-15+ months) and 9.5 months (range 2-19+ months), respectively, for the entire cohort with 13 of 22 still alive in follow-up. The Median PFS for patient with del 17 is 5.5 months (range 2-15 months) with >MR rate of 88%. During the first cycle, 3 patients of all 25 evaluable enrolled experienced a DLT at the different doses, including 1 nausea/vomiting [cohort 1], and 2 with rash and fever in cohort 2. The therapy was tolerated well, but toxicities reported at any point while on therapy included 32% grade 4 neutropenia, 16% grade 4 thrombocytopenia, and half the patients requiring delay of subsequent cycles due to cytopenias and 17 of 22 (77%) had a dose reduction of pomalidomide per protocol guidelines at some point in the continuation cycles. The major non-hematologic Grade ≥3 drug-related AEs that occurred included febrile neutropenia in 12%, grade 3 mucositis in 8%, grade 3 pneumonia 16% and grade 4%, and grade 4 sepsis 4%. Conclusions The Ben-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 77%; ≥MR rate of 91%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure. Therapy is ongoing for many and longer follow-up is needed to better assess the true durability of this approach. Disclosures Gasparetto: Onyx: Honoraria, Other: Advisory Board; Millennium/takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; teva: Other: spouse-ad board and speaker bureau. Off Label Use: Bendamustine-pomalidomide-dexa for treatment of relapsed myeloma. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Rao:novartis: Other: ad board; amgen: Other: ad board; Boehringer-Ingelheim: Other: Advisory Board. Tuchman:celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium/takeda: Honoraria, Research Funding, Speakers Bureau.

A Phase I Study of Vorinostat, Lenalidomide, and Dexamethasone In Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Excellent Tolerability and Promising Activity In a Heavily Pretreated Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1951-1951 ◽  
Author(s):  
Paul Richardson ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Meletios A. Dimopoulos ◽  
Jean-Luc Harousseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
Response Rate ◽  
Advisory Board ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1951 Background: Although novel treatment combinations for multiple myeloma (MM) have improved outcomes, the disease remains incurable and new drug combinations are urgently needed. Vorinostat is an oral histone deacetylase inhibitor approved in the United States for treatment of patients (pts) with advanced cutaneous T-cell lymphoma who failed prior therapies. Vorinostat alters gene expression and protein activity, promoting MM cell death through multiple pathways, and has been shown in preclinical studies to synergistically enhance the anti-MM activity of bortezomib and immunomodulatory drugs, including lenalidomide, with or without dexamethasone. Aims: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of vorinostat plus lenalidomide and dexamethasone in pts with relapsed or relapsed and refractory MM. Secondary objectives included overall safety, tolerability, response rate, duration of response, and time to progression (TTP). Methods: Pts in this Phase I multicenter open-label study were sequentially enrolled into 1 of 5 escalating doses of the combination regimen using a standard 3 + 3 design for ≤8 cycles. Pts who tolerated treatment and experienced clinical benefit were eligible for enrollment in an extension phase. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria (version 3.0). Response was assessed using the modified European Group for Blood and Marrow Transplantation criteria and International Myeloma Working Group Uniform Criteria. Safety and efficacy data were analyzed using summary statistics, except for TTP, which was estimated by the Kaplan-Meier method. Results: As of July 15, 2010, 31 pts were treated and evaluable for toxicity; 4 pts remain on study. Most pts had received prior thalidomide (n=22; 71%), bortezomib (n=20; 65%), or lenalidomide (n=14; 45%), with a median of 4 prior therapies (range, 1–10). The patient population contained both high-risk and low-risk pts, based on cytogenetic and/or fluorescence in situ hybridization analyses. Most adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 treatment-related AEs, experienced by 19 (61%) pts, were neutropenia (26%), thrombocytopenia (16%), diarrhea (13%), anemia (10%), and fatigue (10%); 8 pts discontinued due to toxicity. One dose-limiting toxicity (grade 3 diarrhea lasting >48 h) was observed at the maximum assessed dose (level 5), but MTD was not reached (Table) and there were no treatment-related deaths. Among 30 pts evaluable for response, the median TTP was 32 weeks (5 mo), and 4 pts remain on study as of the data cutoff date; 26 of 30 pts (87%) have achieved at least stable disease (SD). Best single responses included 2 complete responses, 3 very good partial responses (VGPR), 11 partial responses (PR), and 5 minimal responses (MR), with 5 pts achieving SD and 4 developing progressive disease, resulting in an overall response rate (ORR; PR or better) of 53%. Of 13 evaluable pts who had previously received lenalidomide, a best single response of SD or better was observed in 9 (69%; 2 VGPR, 3 PR, 1 MR, 3 SD), resulting in a 38% ORR. Notably, SD or better (2 PR, 1 MR, 3 SD) was observed in 60% of 10 evaluable pts who were relapsed, refractory, or intolerant to previous lenalidomide-containing regimens. Conclusions: Preliminary data from this Phase I study suggest that vorinostat plus lenalidomide and dexamethasone is a convenient and generally well-tolerated regimen with promising activity for relapsed or relapsed and refractory MM. The MTD for this combination was not reached. Importantly, responses were observed in pts who had received prior lenalidomide, bortezomib, and thalidomide. Further evaluation of this regimen is planned in future trials. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat, Lenalidomide, and Dexamethasone for treatment in Multiple Myeloma. Weber:Novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; Celgene- none for at least 2 years: Honoraria; Millenium-none for 2 years: Honoraria; Celgene, Millenium, Merck: Research Funding. Mitsiades:Millennium: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck & Co.: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis: Research Funding; Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding. Dimopoulos:MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Houp:Merck Research Laboratories: Employment. Graef:Merck Research Laboratories: Employment. Gause:Merck Research Laboratories: Employment. Byrne:Celgene Corporation: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board.

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 302-302 ◽  
Author(s):  
Luhua Wang ◽  
David Siegel ◽  
Jonathan L. Kaufman ◽  
A. Keith Stewart ◽  
Andrzej J Jakubowiak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Impaired Renal Function ◽  
Single Agent ◽  
Advisory Committees ◽  
Ortho Biotech ◽  
The Mean ◽  
Grade 3 ◽  
Dose Modifications

Abstract Abstract 302 Background: Carfilzomib (CFZ) is a proteasome inhibitor with unique target selectivity and an irreversible binding mechanism that results in sustained proteasome inhibition. In preclinical studies, CFZ lacks non-proteasome off-target activities associated with bortezomib (BTZ) (Kapur et al, Blood 2008). This may account for observed differences in tolerability with CFZ (e.g. minimal neuropathy and myelosuppression), permitting consecutive day dosing and treatment over an extended period of time. We previously observed higher response rates in multiple myeloma (MM) patients without prior BTZ exposure (BTZ-naïve) compared to those with relapsed disease following BTZ therapy (BTZ-treated). Here we present updated data on the BTZ-naïve cohort from PX-171-004, an ongoing Phase 2 study of single-agent CFZ in MM patients with relapsed or refractory disease following 1–3 prior therapies. Methods: Patients with relapsed or refractory (e.g, < 25% response or disease progression during last treatment) MM were enrolled and stratified into two cohorts: BTZ-naïve and BTZ-treated. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate [≥ Partial Response (PR)] per International Uniform Response Criteria for Multiple Myeloma. Secondary endpoints included Clinical Benefit Response [CBR = ORR + Minor Reponse (MR)] and safety. Results: Fifty-seven BTZ-naive patients have been enrolled and 56 subjects have received at least one dose of CFZ. Prior therapies included alkylators (81%), stem cell transplant (SCT) (77%), thalidomide (THAL) (67%), lenalidomide (LEN) (42%), and anthracyclines (23%). Ten (18%) patients had received both LEN and THAL and 18 (32%) patients were refractory to their most recent regimen prior to study entry. At baseline, 30 (53%) patients had an ECOG score ≥ 1, 21 (37%) had neuropathy Grade ≥ 1, 12 (21%) had impaired renal function (CrCl < 60 mL/min) and 10 (18%) had diabetes. The mean time from diagnosis was 4 years (range 0.7–24). To date, the mean number of CFZ doses administered was 29.2 (∼5 four-week cycles; range 2–72 doses, 1–12 cycles). Fifty-one patients initiated therapy and were evaluable for response per protocol. The ORR was 45% (23/51 patients) and included 1 CR, 4 VGPR and 18 PR. An additional 9 (18%) patients had MR and 10 (20%) had stable disease (SD) for ≥ 6 weeks. The most common (>25%) adverse events (AEs) were fatigue (59%), nausea (41%), dyspnea (36%), and anemia (29%), and were primarily ≤ Grade 2. Grade 3/4 AEs occurring in ≥ 5% of patients were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%) and hyperglycemia (5%). One (1.7%) patient had febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) of any grade was infrequent (7 patients, 12%) with a single case of Grade 3 PN (2%) in a pt with a history of THAL-induced PN that lasted 41 days. The CFZ dose was reduced and the event resolved to Grade 1 while on CFZ and prior to study discontinuation. Of the12 patients with impaired renal function at baseline, none required dose modifications due to renal AE. Overall, 5 patients have completed the full 12-cycle protocol and another 5 (9%) have completed ≥ 9 cycles; 17 patients (30%) are continuing on study. Conclusions: The 45% ORR (CBR 63%) is noteworthy for a single-agent regimen in patients with tumor progression despite therapy with novel combinations. CFZ can be safely administered to patients with significant comorbidities (e.g. peripheral neuropathy, leukopenia, renal dysfunction, diabetes) when other anti-myeloma agents may not be well tolerated. Enrollment to PX-171-004 is continuing and, based on the safety profile, subjects are now permitted to dose escalate to 27 mg/m2. Disclosures: Wang: Proteolix: Honoraria, Research Funding. Off Label Use: testing testing. 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. 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. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Le:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Kunkel:Proteolix: Consultancy, Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Cardiac Safety of One Versus Four Hour Romidepsin (Istodax®) Infusion In the Setting of a Phase I/II Trial of Romidepsin, Dexamethasone and Bortezomib for Relapsed or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5037-5037
Author(s):  
Sam A Ruell ◽  
Miles Prince ◽  
Hang Quach ◽  
Emma Link ◽  
Joanne Dean ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Histone Deacetylase Inhibitors ◽  
Treatment Time ◽  
Safety Data ◽  
Advisory Committees ◽  
Overall Treatment Time ◽  
Refractory Multiple Myeloma

Abstract Abstract 5037 Various bortezomib (Bz)-based combinations are being examined in the context of relapsed and/ or refractory Multiple Myeloma (MM). Histone Deacetylase Inhibitors (HDACIs) are a novel group of agents that effect a variety of cellular and intracellular processes by enhancing the acetylation of histone and non-histone targets. Romidepsin (Romi), a cyclic tetrapeptide, is a class 1 HDACi. Initial reports suggested that various HDACi induced QTc prolongation as a class effect, although subsequently it has been shown that careful electrolyte management prevent this from being a clinical problem. 32 patients (pts) have been enrolled in a Phase I/II Trial of Romi, Bz and dexamethasone (Dex) in relapsed or refractory MM. The maximum tolerated dose (Romi 10mg/m2, Bz 1.3mg/m2 and Dex 20mg) was determined in the first 6 pts with Romi given on day 1, 8 & 15, Bz on D1, 4, 8 and 11 and Dex D1, 2, 4, 5, 8, 9, 11 and 12 of a 28 day cycle (n=25). In an ongoing expanded Phase IIb cohort Romi is only given on day 1 & 8 of a 21 day cycle (n=7/15). Romidepsin was initially given as the standard 4 hour infusion. However animal and clinical safety data support the use of 1hr Romi infusions. In the expansion cohort, the duration of Romi infusions was reduced to 1 hour from cycle 2. To monitor safety (specifically QT interval), ECGs were mandatory pre and post the 4 hour infusions in cycle one and the 1 hour infusions in cycle 2 and reviewed prior to the continuation of the 1 hour infusion from cycle 3. Prolongation of QTc was defined as an increase of 33%, or 60 msec, or QTc 3500 msec. The maintenance of serum potassium > 4.0 mmol/L and magnesium >0.85 mmol/L prior to Romi infusion was mandated. Any patients in the initial cohort remaining on study and still receiving Romi were eligible to move to 1 hour Romi infusions with ECG monitoring during the first cycle. 32 patients have received 598 Romi infusions. 525 infusions have been given over 4 hours and 73 over 1 hour. 19 pts only received 4 hour infusions and 13 pts received at least one 1 hour infusion of Romi. The phase I/II cohort (n=25, median lines of therapy 2 (range1-3)) received 4 hour infusions, the overall response (CR+PR+MR) by modified EBMT criteria was 76% in 21 assessable patients. 2pts had CR (10%), 13 PR (62%), 1 MR (4%), 4 pts had SD, and 1PD. The Phase IIb cohort (n=7, median lines of therapy 2 (range 1–4)) received 1 hour infusions and 6 pts are currently assessable for response with 3 PR and 3 MR. In the first 25 pts receiving the 4 hour infusions, 2 patients experienced arrhythmias during their first cycle, grade 2 atrial flutter possibly related to drug and sinus tachycardia definitely not related. 1pt developed severe ischaemic heart disease and 1pt has died, likely from a PE. Since the introduction of 1hr Romi infusions, only one patient has experienced a Grade 1 cardiac event of asymptomatic lateral T wave flattening and mild ST depression on ECG. This occurred in cycle one, with 4 hour infusions. Full cardiac assessment reveled no clinically significant abnormality. This patient went on to receive the 1 hour infusions without incident. The implementation of the 1 hour infusions has successfully reduced the overall treatment time with Romi/ Bz/ Dex without increase in toxicity. Although numbers are small the response rates appear similar to those using the 4 hour infusions. Disclosures: Off Label Use: Romidepsin and Velcade in combination for the treatment of relapsed/refractory myeloma. Prince:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase I Trial of Everolimus and Rituximab or Everolimus, Bortezomib and Rituximab in Relapsed or Relapsed/Refractory Waldenstrom's Macroglobulinemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2705-2705 ◽  
Author(s):  
Irene M. Ghobrial ◽  
Erica N Boswell ◽  
Ranjit Banwait ◽  
Tiffany Poon ◽  
Amanda Donovan ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Recommended Dose ◽  
Synergistic Activity ◽  
Advisory Committees ◽  
Overall Response ◽  
Risk Patients ◽  
Grade 3

Abstract Abstract 2705 INTRODUCTION: This study aimed to determine the safety and maximum tolerated dose of the combination of everolimus and rituximab, or everolimus, bortezomib, and rituximab in relapsed and/or relapsed/refractory Waldenstrom Macroglobulinemia. This trial was based on our preclinical studies that demonstrated synergistic activity of everolimus and bortezomib with rituximab in WM cell lines, and based on our favorable clinical experience with everolimus as single agent in the treatment of WM. METHODS: Eligibility criteria include: 1) patients with relapsed or relapsed/refractory WM with any number of prior lines of therapy, including everolimus and bortezomib 2) not completely refractory to rituximab 3) measurable disease by monoclonal IgM protein in the serum and lymphoplasmacytic cells in the bone marrow, 4) Not receiving chemotherapy > 3 weeks, or biological/novel therapy for WM > 2 weeks. A cycle is 28 days and a total of 6 cycles are given, followed by everolimus maintenance for 2 years. Two stages with a total of four dose levels were planned. In stage A, patients received everolimus at the recommended dose orally daily for 28 days and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. In stage B, patients received everolimus at the recommended dose orally daily for 28 days, bortezomib at the recommended dose IV on days 1, 8, 15 every 28 days, and rituximab at the recommended dose IV on days 1, 8, 15, and 22 every 28 days at cycle 1 and 4 only. Patients were assessed for response after every cycle. Subjects who had a response continued on therapy for a total of 6 cycles, and then continued on to maintenance therapy with everolimus alone until progression (or for a maximum of 24 months). Because of the potential of an IgM flare after rituximab, patients who showed an increase in IgM after rituximab in the first 3 months were not deemed as having progressive disease unless they showed evidence of clinical progression. To examine the in vivo effect of everolimus, bortezomib, and rituximab, peripheral blood samples were obtained from patients on days 1, 8, 15, and 22 at cycle 1; and on day 1 only at all subsequent cycles. RESULTS: Twenty-three patients were enrolled in this phase I clinical trial from April 2009 to July 2011. The median age is 61 (range, 52–73) yrs and the median lines of prior therapy is 2 (range, 1–8) with all patients receiving prior rituximab and 12 (52%) receiving prior bortezomib. The median number of cycles on therapy was 3.5 (range, 0–15). Overall, this combination therapy is very well tolerated. Grade 4 toxicities included: neutropenia (8.7%), leukopenia (4.3%), thrombocytopenia (17.4%), lymphopenia (4.3%) and hypertriglyceridemia (4.3%). Grade 3 toxicities included: neutropenia (21.7%), leukopenia (26.1%), anemia (13%), lymphopenia (17.4%), pneumonitis (4.3%), SGPT (4.3%), neuropathy (4.3%), Herpes zoster reactivation (4.3%), hyperglycemia (4.3%) and hypernatremia (4.3%). 1 patient discontinued therapy due to grade 3 anemia. Nineteen patients are currently evaluable for response, including 1 (5%) very good partial response (VGPR) and 9 (47%) minimal response (MR), for an overall response rate including MR of 10/19 (53%) in this relapsed/refractory population. Furthermore, overall response including MR in stage A (everolimus/rituximab) was 2/6 (33%) and 8/13 (62%) in stage B (everolimus/bortezomib/rituximab). Additionally, 9 (39%) patients achieved stable disease, and 4 (17%) are early on therapy and not been yet assessed. CONCLUSIONS: The combination of everolimus, bortezomib, and rituximab is generally well tolerated, and importantly no grade 3/4 neuropathy was seen. Moreover, no dose limiting toxicities were observed even at the maximum dose evaluated. The responses observed to date in this relapsed/refractory population are encouraging. Based on the safety of this phase I study, the phase II study of two arms, everolimus/rituximab for low risk patients and everolimus/bortezomib/rituximab for intermediate and high risk patients is underway. Disclosures: Ghobrial: Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib and everolimus in WM. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: 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. Treon:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4081-4081 ◽  
Author(s):  
Jatin J. Shah ◽  
Sheeba K. Thomas ◽  
Donna M. Weber ◽  
Michael Wang ◽  
Raymond Alexanian ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Committees ◽  
Overall Response ◽  
Elevated Creatinine

Abstract Abstract 4081 Background: Carfilzomib, a novel irreversible proteasome inhibitor (PI), has demonstrated single agent activity in, and was recently FDA approved for relapsed and refractory myeloma. Panobinostat, a potent histone deacetylase inhibitor (HDACi), has been studied as a single agent and in combination with bortezomib, demonstrating promising response rates and a favorable safety profile in bortezomib-refractory patients. Our hypothesis proposed that the combination of carfilzomib and panobinostat (Car-Pan) would also be highly active, and we therefore aimed to combine these two agents for the first time. We report the initial findings from the phase I dose-escalation and expansion portions of our phase I/II trial of this novel combination regimen. Methods: The primary objectives were to determine the maximum tolerated dose (MTD) and the safety/tolerability of Car-Pan in patients with relapsed or refractory multiple myeloma. Secondary objectives included determination of the overall response rate, time to progression, progression free survival, and time to next therapy. Panobinostat was administered orally on days 1, 3, 5, 8, 10, 12 of every 28-day cycle, while carfilzomib was given intravenously over 30 minutes on days 1, 2, 8, 9, 15, and 16. Dose level 1 started carfilzomib at 20 mg/m2 with 15 mg of panobinostat, and escalated from there using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. An amendment was later introduced to allow carfilzomib to be given at 20 mg/m2for days 1 and 2 of cycle 1, followed by an increase to the full dose level for that cohort. Adverse events (AEs) were graded using the NCI-CTCAE v4, and responses were assessed with the modified International Uniform Response Criteria. Results: To date, 20 patients have been enrolled, 3 of whom are still in their first cycle, leaving 17 evaluable patients who are described herein, who have received a median of 4 cycles (range 1–8). The median age was 62 years (range 46–73), 11/17 (70%) were male, and the median number of prior regimens was 5 (range 2–15). Patients were very heavily pretreated, with 16/17 (94%) having undergone stem cell transplantation, 16/17 (94%) having prior bortezomib, including 8/17 (47%) who were bortezomib-refractory, and 17/17 (100%) having prior lenalidomide, including 12/17 (70%) who were lenalidomide-refractory. Cytogenetic abnormalities were common, including: 4 with del(17p), 4 with t(4;14), 2 with t(11;14), 9 with del(13), of whom 7 had additional mutations. Grade 1–4 AEs regardless of causality occurring in >20% of patients included anemia (14/17), thrombocytopenia (17/17), neutropenia (8/17), diarrhea (9/17), nausea/emesis (7/17), fatigue (10/17), elevated creatinine (8/17), and pneumonia (5/17). Grade ≥3 AEs regardless of causality included anemia (7/17), thrombocytopenia (10/17), neutropenia (6/17), diarrhea (2/17), nausea/emesis (1/17), fatigue (4/17), elevated creatinine (2/17), and pneumonia (4/17). An MTD has not been established, and dosing is ongoing in cohort 4, with Carfilzomib at 45mg/m2and 20 mg of Panobinostat. Of the 17 evaluable patients, the overall response rate was 35% (6/17) who achieved at least a partial response (PR); including 2 with very good PR (VGPR). In addition, one patient had a minor response, and 65% overall achieved stable disease or better. Conclusions: The combination of Carfilzomib + Panobinostat is well tolerated with a manageable side effect profile. Importantly, the combination achieves a promising response rate in a very heavily pre-treated, lenalidomide/bortezomib/high dose melphalan-refractory population, with an overall response (≥PR) rate of 35%. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about panobinostat, which is not yet approved for use in patients with multiple myeloma. Thomas:Celgene: Research Funding; Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. Wang:Onyx Pharmaceuticals: Honoraria, Research Funding. Orlowski:Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase II Study Of The c-MET Inhibitor ARQ 197 (Tivantinib) In Patients With Relapsed Or Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1953-1953
Author(s):  
Robert Z. Orlowski ◽  
Shadia Zaman ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Jatin J. Shah ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Phase Ii Study ◽  
Single Agent ◽  
Advisory Committees ◽  
Arq 197 ◽  
Met Inhibitor ◽  
Grade 3

Abstract Background c-MET receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-MET ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma. Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-MET and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-MET signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tivantinib-mediated cytotoxic response was observed at concentrations of less than 5 µM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-MET signaling axis could be a rational strategy against RRMM. Methods In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-MET RTK, was studied in patients with RRMM. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients who had received one to four prior lines of therapy, and to define the toxicities in this population. A Simon’s Minimax 2-stage design was used for the study. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma levels of ARQ 197 were 7 µM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study was supported by CTEP, as well as the MD Anderson Cancer Center SPORE in Multiple Myeloma. Results A total of 16 patients were enrolled and treated to date, including 9 men and 7 women, who had received a median of 1 prior line of therapy (range 1-3), including stem cell transplant in ten. The mean patient age was 66 (range 49-76), with ethnicity including 13 Caucasian Americans, 2 African Americans, and 1 Asian American. Patients have received a median of 3 cycles of therapy to date (1-11) with one patient continuing on study, and all were evaluable for toxicity, while 11 were evaluable for response based on having completed two treatment cycles. The most common adverse events (AEs) of any grade seen in at least 25% of patients and felt to be at least possibly drug related included fatigue or decreased neutrophils (94% each), pain (81%), myalgias (56%), diarrhea (38%), memory impairment, respiratory disorders, and rash (31% each), and hypertension (25%), and these were predominantly grade 1 or 2. Grade 3 or 4 AEs included neutropenia (31% and 25%, respectively), syncope, infection, pain (13% of each, all grade 3), and anal fissure, cough, fatigue, hypertension, and pulmonary embolism (6% each, all grade 3). Stable disease (SD) has been seen as the best response in 4/11 (36%) evaluable patients, which was maintained for up to 11 cycles, while the remaining patients showed evidence of disease progression. Conclusion Single-agent tivantinib has been well tolerated in patients with RRMM, and the ability to achieve stable disease in patients with previously progressing myeloma does support the possibility that targeting c-MET has some promise. Future studies with rationally designed combination regimens incorporating a c-MET inhibitor and other novel agents may better define the role of this class of drugs in our armamentarium against myeloma. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

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