Indatuximab Ravtansine (BT062) in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma: Clinical Activity in Patients Already Exposed to Lenalidomide and Bortezomib

Abstract Background: BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate (ADC), comprising the anti-CD138 chimerized MAb (nBT062) and the maytansinoid DM4 as a cytotoxic agent. It is designed to bind to CD138 on cancer cells, and then release DM4 after internalization to cause cell death. CD138 (Syndecan-1) is highly overexpressed on various solid tumors and in hematological malignancies, and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. BT062 was investigated as a single agent and found to have an acceptable tolerability profile and evidence of activity in patients with heavily pretreated relapsed and/or refractory MM (1). Preclinical studies showed enhanced anti-MM activity when BT062 was combined with lenalidomide and dexamethasone (Len/Dex). Based on these data, a Phase I/IIa study in MM was initiated to evaluate the safety and efficacy of BT062 in combination with Len/Dex. Objectives: To determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the recommended phase II dose (RPTD), pharmacokinetics (PK), and anti-MM activity of increasing doses of BT062 (days 1, 8, and 15, every 4 weeks) used in combination with Len (25 mg, daily on days 1-21) and low dose Dex (40 mg on days 1, 8, 15, and 22) in patients with relapsed and/or refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the RPTD cohort. Patients aged ≥18 years with relapsed and/or refractory MM who have failed at least one prior therapy were eligible to participate. Prior treatment with Len and/or Dex was allowed. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for additional treatment cycles. Patients were enrolled in cohorts of at least 3 at each dose level; DLT in the first cycle triggered cohort expansion. Toxicities were assessed by CTCAE v4 and clinical response was assessed according to International Myeloma Working Group criteria. Results: The maximum administered dose (MAD) was 120 mg/m². Two of six patients treated at this dose had a DLT: mucosal inflammation (CTC grade 3) and anemia (CTC grade 3). The MTD was defined as 100 mg/m² and selected as RPTD. Additional patients are being treated at this RPTD to further evaluate safety and efficacy. Enrollment into the study is ongoing. As of July 2014, a total of 45 patients had received BT062 at dose levels of 80 mg/m² (N=3), 100 mg/m² (N=36) or 120 mg/m² (N=6). Fifteen patients discontinued study treatment: 5 for disease progression, 7 for adverse events, 1 died (not treatment related) and 2 for withdrawal of consent. The other 30 patients remain on treatment. The median treatment duration was 123 days (range 1–597). The median number of prior therapies was 3 (range 1–11). 68% of patients had prior exposure to both Len and bortezomib, 73% of patients had prior Len exposure, and 30% were Len-refractory. According to preliminary data from this ongoing study, about 89% of reported Adverse Events (AEs) were CTC grade 1 or 2. The most common reported AEs were diarrhea, fatigue, nausea, and hypokalemia. Amongst the 36 patients across all dose levels currently evaluable for efficacy, the overall response rate (ORR) is 78%; including 1 stringent complete response, 2 complete responses, 10 very good partial responses, and 15 partial responses. Two patients achieved a minor response and 6 patients disease stabilization, resulting in a clinical benefit in 100% of the evaluable patients. The ORR was 83% among the 30 evaluable patients receiving the RPTD. Interestingly, the ORR was 70% among the 23 patients with prior exposure to Len and bortezomib, and among 10 patients refractory to prior treatment with Len. Conclusion: Preliminary data from this ongoing study indicate that BT062 is well tolerated in combination with Len/Dex at dose levels that induce responses in patients with relapsed and/or refractory multiple myeloma, including patients with prior exposure to both Len and bortezomib and patients refractory to prior treatment with Len. Updated results on safety and efficacy will be presented. References Heffner et al, BT062, an Antibody-Drug Conjugate Directed Against CD138, Given Weekly for 3 Weeks in Each 4 Week Cycle: Safety and Further Evidence of Clinical Activity. Blood. 2012; 120: Abstract 4042. Disclosures Kelly: Celgene: Speakers Bureau. Heffner:Amgen: Honoraria, Research Funding; Biotest: Research Funding; Dana Farber CI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Idera: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Research Funding; Spectrum: Research Funding; Talon Therapeutics: Research Funding. Somlo:Millennium: 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; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Munshi:Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Sanofi-Aventis: Consultancy; Ocopep: Consultancy, Equity Ownership, Patents & Royalties. Jagannath:Celgene: Consultancy; Millennium: Consultancy; Sanofi: Consultancy. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Ailawadhi:Millennium: Consultancy, Honoraria. Barmaki-Rad:Biotest AG: Employment. Chavan:Biotest Pharmaceuticals: Employment. Patel:Biotest Pharmaceuticals: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership; Acetylon: Equity Ownership.

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Indatuximab Ravtansine (BT062) in Combination with Low-Dose Dexamethasone and Lenalidomide or Pomalidomide: Clinical Activity in Patients with Relapsed / Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.4486.4486 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4486-4486 ◽

Cited By ~ 32

Author(s):

Kevin R. Kelly ◽

David S. Siegel ◽

Asher A. Chanan-Khan ◽

George Somlo ◽

Leonard T. Heffner ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Clinical Response ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Prior Exposure ◽

Tolerability Profile ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: 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.

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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 ◽

10.1182/blood.v116.21.1951.1951 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1951-1951 ◽

Cited By ~ 4

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.

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Indatuximab Ravtansine (BT062) In Combination With Lenalidomide and Low-Dose Dexamethasone In Patients With Relapsed and/Or Refractory Multiple Myeloma: Clinical Activity In Len/Dex-Refractory Patients

Blood ◽

10.1182/blood.v122.21.758.758 ◽

2013 ◽

Vol 122 (21) ◽

pp. 758-758 ◽

Cited By ~ 17

Author(s):

Kevin R. Kelly ◽

Asher Chanan-Khan ◽

George Somlo ◽

Leonard T Heffner ◽

David S Siegel ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Clinical Activity ◽

Antibody Drug Conjugate ◽

Advisory Committees ◽

Safety And Efficacy ◽

Dose Levels ◽

Antibody Drug

Abstract Background BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprising the anti-CD138 chimerized MAb (nBT062) and the maytansinoid DM4 as cytotoxic agent. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. CD138 (Syndecan-1) is highly overexpressed on various solid tumors and in hematological malignancies, and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. Data from two studies investigating BT062 as single agent demonstrated an acceptable tolerability profile and evidence of clinical activity in patients with heavily pretreated relapsed and/or refractory MM (1, 2). Preclinical studies showed enhanced anti-MM activity when BT062 was combined with lenalidomide and dexamethasone (Len/Dex). Based on these data, a Phase I/IIa study in MM was initiated to evaluate the safety and efficacy of BT062 in combination with Len/Dex. Objectives To determine the dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD), the recommended phase II dose (RPTD), pharmacokinetics (PK), and anti-MM activity of increasing doses of BT062 (days 1, 8, and 15, every 4 weeks) in combination with Len (25 mg, daily on days 1-21) and low dose Dex (40 mg on days 1, 8, 15, and 22) in patients with relapsed and/or refractory MM. Methods This is a prospective, open label, dose-escalation, multicenter Phase I/IIa study. The Phase I part includes dose escalation, and the Phase IIa the expansion of the MTD or RPTD cohort. Patients aged ≥18 years with relapsed and/or refractory MM who have failed at least one prior therapy were eligible to participate. Prior treatment with Len and/or Dex was allowed. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for additional treatment cycles. Patients were enrolled in cohorts of at least 3 at each dose level; DLT in the first cycle triggered cohort expansion. Toxicities were assessed by CTCAE v4 and clinical response was assessed according to International Myeloma Working Group criteria. Results As of July 2013, a total of 15 patients have received BT062 at dose levels of 80 mg/m2 (N=3), 100 mg/m2 (N=6) or 120 mg/m2 (N=6). Two patients at the highest dose level discontinued study due to toxicity (DLT), another patient withdrew consent. The other 12 patients remain on treatment; median duration 144 days (range 8–385). The median number of prior therapies was 4 (range 1–11), 87% of patients had prior Len exposure, and 50% were Len/Dex refractory. The maximum administered dose (MAD) has been reached at 120 mg/m2, with mucosal inflammation (CTC grade 3) as DLT in one, and anemia (CTC grade 3) in a second of the 6 patients treated at this dose level. About 85% of reported Adverse Events (AE) were of CTC grade 1 or 2. The most common reported AEs were fatigue, hypokalemia, and diarrhea. Amongst the 9 patients currently evaluable for efficacy, responses were observed across all dose levels with a overall response rate (ORR) of 78%; including 1 patient with complete response (120 mg/m2), 1 patient with very good partial response (80 mg/m2), and 5 patients with partial response (80 and 100 mg/m2). Two other patients achieved disease stabilization, resulting in a clinical benefit in 100% of the evaluated patients. Interestingly, partial response was observed in 3 patients refractory to prior treatment with Len/Dex. The MTD has been defined as 100 mg/m2 and is currently expanded to further evaluate the safety and efficacy of BT062 at the RPTD. Conclusion Preliminary data from this ongoing study indicate that BT062 is well tolerated in combination with Len/Dex at dose levels that induce responses in patients with relapsed and/or refractory multiple myeloma, including Len/Dex-refractory patients. Updated results on safety and efficacy will be presented. References 1. Jagannath et al, BT062, an Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma. Blood. 2011; 118: Abstract 305. 2. Heffner et al, BT062, an Antibody-Drug Conjugate Directed Against CD138, Given Weekly for 3 Weeks in Each 4 Week Cycle: Safety and Further Evidence of Clinical Activity. Blood. 2012; 120: Abstract 4042. Disclosures: Somlo: Celgene: Research Funding, Speakers Bureau; NIH: Research Funding; Millennium: Speakers Bureau. Heffner:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Siegel:Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: 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. Zimmerman:Celgene: Honoraria; Millennium: Honoraria; Onyx: Honoraria. Jagannath:Millennium: Honoraria; Celgene: Honoraria. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy. Ruehle:Biotest AG: Employment. Chavan:Biotest Pharmaceuticals: Employment. Patel:Biotest Pharmaceuticals: Employment. Rothenburger:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Gilead: Consultancy; Sanofi Aventis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Acetylon: Equity Ownership; Oncopep: Equity Ownership.

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Phase I Trial Of The Targeted Alpha-Particle Nano-Generator Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) In Combination With Low-Dose Cytarabine (LDAC) For Older Patients With Untreated Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.1460.1460 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1460-1460 ◽

Cited By ~ 16

Author(s):

Joseph G. Jurcic ◽

Farhad Ravandi ◽

John M. Pagel ◽

Jae H Park ◽

Dan Douer ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase I Trial ◽

Advisory Committees ◽

Molecular Abnormalities ◽

Equity Ownership ◽

Dose Levels

Abstract Background Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the isotope generator 225Ac (t½=10 days), which yields 4 α-particles, was conjugated to lintuzumab. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses ≤ 3 μCi/kg and has anti-leukemic activity across all dose levels studied (Jurcic et al. ASH, 2011). We are conducting a multicenter, phase I dose escalation trial to determine the maximum tolerated dose (MTD), toxicity, and biological activity of fractionated-dose 225Ac-lintuzumab in combination with LDAC. Patients and Methods Patients ≥ 60 yrs who had untreated AML with poor-prognostic factors, such as an antecedent hematologic disorder (AHD), unfavorable cytogenetic or molecular abnormalities, and significant comorbidities, were eligible. Patients received LDAC 20 mg bid for 10 days every 4-6 weeks. During cycle 1, beginning 4-7 days after LDAC, two doses of 225Ac-lintuzumab were given approximately one week apart. Results Seven patients (median age, 76 yrs; range, 72-80 yrs) were treated, all of whom had AHDs. Five (71%) had intermediate-risk cytogenetics, and two (29%) had unfavorable cytogenetics. The median CD33 expression was 76% (range, 69-95%). Prior therapy for myelodysplastic syndrome included hypomethylating agents (n=4) and allogeneic hematopoietic cell transplantation (n=1). Patients received 225Ac-lintuzumab at doses of 0.5 (n=3) or 1 (n=4) μCi/kg/fraction, two fractions per patient (total administered activity, 68-199 μCi). Dose-limiting toxicity was seen in one patient receiving 1 μCi/kg/fraction who had grade 4 thrombocytopenia in the setting of an aplastic bone marrow that persisted > 6 wks after completing the second fraction of 225Ac-lintuzumab. Other toxicities included grade 3 febrile neutropenia (n=5), bacteremia (n=1), pneumonia (n=1), cellulitis (n=1), transient increase in creatinine (n=1), and generalized weakness (n=1). Bone marrow blast reductions were seen in 4 of 6 evaluable patients (67%) after cycle 1 (mean blast reduction, 58%; range, 34-100%). No CRs, however, were observed. The median number of cycles administered was 2 (range, 1-4), and the median time to progression was 2.5 months (range, 2-7+ months). Conclusions Fractionated-dose 225Ac-linutuzmab in combination with LDAC is feasible, safe, and has anti-leukemic activity. Accrual continues to define the MTD, with planned dose levels up to 2 μCi/kg/fraction. Additional patients will be treated at the MTD in the phase II portion of this trial to determine response rate, progression-free survival, and overall survival. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees. Ravandi:Actinium Pharmaceuticals, Inc.: Research Funding. Pagel:Actinium Pharmaceuticals, Inc.: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Park:Actinium Pharmaceuticals, Inc.: Research Funding. Douer:Actinium Pharmaceuticals, Inc.: Research Funding. Estey:Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership. Scheinberg:Actinium Pharmaceuticals, Inc.: Ac-225-Lintuzumab, Ac-225-Lintuzumab Patents & Royalties, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees.

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Analysis of Pomalidomide Plus Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma with Vs without Moderate Renal Impairment

Blood ◽

10.1182/blood.v126.23.3031.3031 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3031-3031 ◽

Cited By ~ 3

Author(s):

David S Siegel ◽

Katja C. Weisel ◽

Meletios A. Dimopoulos ◽

Rachid Baz ◽

Paul G. Richardson ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Pooled Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership ◽

Support Research

Abstract Introduction: Renal impairment (RI) occurs in ≈ 20% to 40% of patients (pts) with multiple myeloma (MM; Kastritis et al, Haematologica, 2007) and is a major comorbidity with this disease (Korbet et al, J Am Soc Nephrol, 2006). Pts with MM who relapse on or become refractory to treatment (Tx) experience shortened overall survival (OS; Kumar et al, Leukemia, 2012). Pomalidomide + low-dose dexamethasone (POM + LoDEX) is approved for the Tx of relapsed/refractory MM (RRMM) in pts who have had Tx failure with lenalidomide and/or bortezomib. POM + LoDEX demonstrated safety and efficacy in pts with RRMM (MM-010; Dimopoulos et al, EHA 2015) as well as extended progression-free survival (PFS) and OS vs high-dose dexamethasone (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). Each trial included pts with moderate RI, and this pooled analysis examines the safety and efficacy of POM + LoDEX in pts with moderate RI. Patients and Methods: Pts from MM-002, MM-003, and MM-010 who had received POM + LoDEX were grouped by RI status (with moderate RI [creatinine clearance (CrCl) ≥ 30 to < 60 mL/min] and without RI [CrCl ≥ 60 mL/min]) and assessed for safety and efficacy. Results: Overall, from the 3 trials, data from 356 pts with moderate RI and 716 pts without RI were analyzed. Pts with moderate RI were slightly older (70 vs 63 yrs) and more commonly had International Staging System stage III disease (45.8% vs 25.4% in the 271 and 544 pts with available data). Median time from diagnosis was similar, 5.2 yrs (with moderate RI) vs 5.3 years (without RI); pts in both subgroups had a median of 5 prior Tx. The proportions of pts with moderate RI vs without RI who were refractory to LEN (95.5% vs 93.0%), BORT (82.0% vs 80.7%), and both LEN and BORT (78.4% vs 76.1%) were similar. The median Tx duration was slightly shorter for pts with moderate RI vs without RI (16.6 vs 20.4 weeks), but the median average daily dose (4.0 mg/day) and median relative dose intensity (0.9) were the same between renal subgroups. There were similar frequencies of discontinuations (7.4% vs 5.8%), dose reductions (22.7% vs 21.1%), and interruptions (63.1% vs 63.5%) due to adverse events (AEs) between subgroups of pts with moderate RI vs without RI. The most common grade 3/4 AEs for pts with moderate RI vs without RI were neutropenia (45.5% vs 48.3%), anemia (34.9% vs 27.5%), infections (31.3% vs 32.3%), and thrombocytopenia (21.3% vs 22.6%). The frequency of deep vein thrombosis/pulmonary embolism or peripheral neuropathy was ≤ 2% in both subgroups. The overall response rate (ORR) was 32.0% vs 33.0%, the median PFS was 18.1 weeks (95% CI, 15.6-20.9 weeks) vs 21.1 weeks (95% CI, 19.0-24.3 weeks), and median time to progression (TTP) was 20.3 weeks (95% CI, 17.3-24.1 weeks) vs 24.0 weeks (95% CI, 20.1-25.6 weeks) in pts with vs without moderate RI, respectively. Consistent with the poor prognosis associated with RI, median OS was shorter for pts with moderate RI (45.6 weeks [95% CI, 37.9-50.1 weeks]) vs those without RI (62.7 weeks [95% CI, 54.9-70.3 weeks]). Conclusions: In a pooled analysis of 3 trials of pts with RRMM treated with POM + LoDEX, ORR, PFS, TTP, and tolerability results appeared to be independent of the presence or absence of moderate RI. This analysis supports the use of POM + LoDEX as a standard of care in RRMM for pts with or without moderate RI. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy; BMS: Consultancy, Honoraria, Other: Travel Support. Dimopoulos:Genesis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Baz:Karyopharm: Research Funding; Millennium: Research Funding; Celgene Corporation: Research Funding; Sanofi: Research Funding. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. San Miguel: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: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Moreau:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: 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. Yu:Celgene Corporation: Employment, Equity Ownership. Hong:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

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Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-121805 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1869-1869 ◽

Cited By ~ 13

Author(s):

Noopur S. Raje ◽

Andrzej Jakubowiak ◽

Cristina Gasparetto ◽

Robert F. Cornell ◽

Heike I. Krupka ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Employment Equity ◽

Advisory Committees ◽

Best Response ◽

Equity Ownership ◽

Dose Levels

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent

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BT062, An Antibody-Drug Conjugate Directed Against CD138, Shows Clinical Activity in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.305.305 ◽

2011 ◽

Vol 118 (21) ◽

pp. 305-305 ◽

Cited By ~ 20

Author(s):

Sundar Jagannath ◽

Asher Chanan-Khan ◽

Leonard T. Heffner ◽

David Avigan ◽

Todd M. Zimmerman ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Clinical Activity ◽

Antibody Drug Conjugate ◽

Advisory Committees ◽

Dose Levels ◽

Antibody Drug

Abstract Abstract 305 Background: CD138 (Syndecan-1) is highly overexpressed in various solid tumors and hematological malignancies and represents one of the most specific target antigens for identification of multiple myeloma (MM) cells. BT062 (Biotest AG Dreieich, Germany) is an antibody-drug conjugate, comprised of the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent DM4. Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4, leading to target cell death. We performed the first in man study (969) to investigate safety and efficacy of BT062 in MM. Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in patients with relapsed and/or refractory MM. Methods: This is a prospective, open label, dose-escalation, multicenter phase I study. Patients aged ≥18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulatory agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients were enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Toxicities were assessed by CTCAE v3 and clinical response was assessed according to the international myeloma working group criteria. Results: A total of 32 patients have been treated with BT062, receiving one of 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has been defined at 200 mg/m2, with mucositis as the dose limiting toxicity (CTC grade III in 2 of the 3 patients in this cohort). Thirteen of 32 patients have been treated in an expanded MTD-cohort at 160 mg/m2. The most frequently reported adverse events to date are mild to moderate and cover primarily events expected for the underlying disease and patient group. A few adverse events have also been observed involving skin and/or mucosa (tissues of epithelial origin with CD138 expressing cells), as well as the eye. CTC grade II/III toxicity involving skin and/or mucosa (e.g. mucositis, stomatitis, hand/foot syndrome) has been observed mainly at the dose levels 160 mg/m2 or higher. Adverse events involving the eye (e.g. blurred vision, dry eye) have also been reported mainly in patients at the dose levels 160 mg/m2 or higher, all restricted to CTC grade I/II. Among the 27 evaluable patients, 3 patients responded including 1 partial response and 2 minor responses, with one patient (minor response) remaining on treatment for more than a year. Stabilization of disease was noted in an additional 11 patients, receiving a median of 5 cycles of therapy (range of 4–10). Thus stable disease or better was noted in 52% of patients. Most patients came off study due to disease progression. Conclusion: Preliminary data from this study demonstrate an acceptable toxicity profile of BT062. Even in this phase I patient population, evidence of clinical activity was observed. Based on the favourable safety profile, the pharmacokinetic data and early signs of clinical activity, a Phase I/IIa study in MM (975) is initiated to further evaluate the safety and anti-MM efficacy of BT062 in a more frequent dosing regimen. To date 13 patients have been treated with BT062 on the intensified multi-dose regimen, receiving one of the first four dose levels. Updated results on safety, PK and anti-MM efficacy of BT062 will be presented. Disclosures: Jagannath: Celgene: Honoraria; Millennium/Takeda Pharma: Honoraria; J&J Family: Honoraria; Onyx: Honoraria; Merck: Honoraria. Heffner:Millennium: Research Funding. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding; Curetec: Research Funding. Lutz:ImmunoGen, Inc.: Employment. Engling:Biotest AG: Employment. Uherek:Biotest AG: Employment. Osterroth:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Beelitz:Biotest Pharmaceuticals Corporation: Employment. Niemann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Merck: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Actelion: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munshi: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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Safety and Efficacy in the Stratus (MM-010) Trial, a Single-Arm Phase 3b Study Evaluating Pomalidomide + Low-Dose Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.80.80 ◽

2014 ◽

Vol 124 (21) ◽

pp. 80-80 ◽

Cited By ~ 1

Author(s):

Meletios A. Dimopoulos ◽

Antonio Palumbo ◽

Katja Weisel ◽

Enrique M. Ocio ◽

Michele Cavo ◽

...

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Advisory Committees ◽

Safety And Efficacy ◽

Equity Ownership

Abstract Background: Patients (pts) with multiple myeloma (MM) who have relapsed on or are refractory to treatment (Tx) with novel agents lenalidomide (LEN) and bortezomib (BORT) have few effective options for Tx and short overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a distinct oral IMiDs® immunomodulatory agent with direct antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia 2010; Mark, Leuk Res, 2014). POM has been approved in the United States and the European Union for the Tx of pts with ≥ 2 prior Tx, including LEN and BORT, and progressive disease (PD) on Tx (EU, in combination with low-dose dexamethasone [LoDEX]) or within 60 days of completion of the last line of Tx (US). Results from the pivotal phase 3 MM-003 trial demonstrated that POM + LoDEX significantly extended progression-free survival (PFS) and OS vs high-dose dexamethasone in this pt population (San Miguel, Lancet Oncol, 2013). STRATUS is a multicenter, single-arm, open-label phase 3b trial with > 85 sites across Europe designed to further evaluate safety and efficacy of POM + LoDEX in a large pt population (N = 456 at data cutoff). Methods: Eligible pts had refractory or relapsed and refractory disease (PD during or within 60 days of last line of Tx), previous BORT and LEN Tx failure, and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last prior line of Tx. Key exclusion criteria included absolute neutrophil count < 800/μL , platelet count < 75,000 or < 30,000/μL (for pts with < 50% or ≥ 50% of bone marrow nucleated cells as plasma cells, respectively), creatinine clearance < 45 mL/min, hemoglobin < 8 g/dL, and peripheral neuropathy ≥ grade (Gr) 2. POM was administered at 4 mg D1-21 of a 28-day cycle in combination with LoDEX 40 mg/day (20 mg for pts aged > 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent. The primary endpoint was safety, and key secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, OS, and cytogenetic analyses. STRATUS is registered with ClinicalTrials.gov (NCT01712789) and EudraCT (2012-001888-78). Results: As of March 17, 2014, 456 pts were enrolled and 452 had received POM + LoDEX; median age was 66 yrs (range, 37-88 yrs); median time since diagnosis was 4.9 yrs (range, 0.3-22.6 yrs). Pts were heavily pretreated with a median of 5 prior Tx (range, 2-18); 78% were refractory to BORT and LEN. Median follow-up was 6.8 mos with a median of 4 cycles received. Median PFS and OS were 4.3 mos and 10.9 mos, respectively (Figure 1). The ORR was 35%, with 6% of pts achieving ≥ very good partial response (VGPR); median DOR was 6.0 mos. Similar PFS (4.2 and 3.9 mos), OS (10.9 mos for each), and ORR (34% and 33%) were achieved in pts refractory to prior LEN (n = 427) or LEN and BORT (n = 356), respectively. In addition, PFS (4.3 and 3.9 mos), OS (11.5 mos and not estimable), and ORR (27% and 37%) were consistent in pts with LEN (N = 172) or BORT (N = 189) as last prior treatment, respectively. The most frequent Gr 3-4 treatment-emergent adverse events (TEAEs) were hematologic, including neutropenia (39%), anemia (27%), and thrombocytopenia (19%); Gr 3-4 non-hematological toxicities included pneumonia (11%), fatigue (5%), and hypercalcemia (4%). Gr 3-4 deep vein thrombosis was low (1%) with prophylaxis, and peripheral neuropathy was 1%. Dose reductions of either POM or LoDEX due to TEAEs were required in 28% of pts; discontinuations due to TEAEs were infrequent (9%). Conclusions: Results from STRATUS, the largest POM + LoDEX clinical trial thus far, were consistent with those observed in the pivotal MM-003 trial, and confirm that this regimen has an acceptable safety and efficacy profile and shows substantial improvements in PFS and OS benefits. Combination therapy with POM and LoDEX represents a new standard of therapy for pts with refractory or relapsed and refractory MM in whom LEN and BORT Tx failed. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria. Palumbo:Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Weisel:BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Ocio:Celgene Corporation: Honoraria, Research Funding. Cavo:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Doyen:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Simcock:Celgene Corporation: Employment. Miller:Celgene: Employment, Equity Ownership. Slaughter:Celgene: Employment. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Phase I/IIa Study of the CD38 Antibody MOR202 Alone and in Combination with Pomalidomide or Lenalidomide in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.1152.1152 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1152-1152 ◽

Cited By ~ 31

Author(s):

Marc S. Raab ◽

Manik Chatterjee ◽

Hartmut Goldschmidt ◽

Hermine Agis ◽

Igor Blau ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Prior Treatment ◽

Tumor Control ◽

Cell Transplant ◽

Advisory Committees ◽

Duration Of Response ◽

Dependent Cell

Abstract Introduction:CD38 is a type II transmembrane glycoprotein widely expressed in many hematological malignancies including multiple myeloma (MM). MOR202, a HuCAL-derived, human IgG1 CD38 monoclonal antibody, induces antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). MOR202 does not induce complement-dependent cytotoxicity, which is suspected to be a major contributor to infusion-related reactions (IRRs). Preclinical models of MM demonstrate high single-agent antitumor activity of MOR202 and synergy in combination with immunomodulatory drugs (IMiDs), lenalidomide (LEN) or pomalidomide (POM). Methods: This is an interim analysis of a multicenter, dose-escalation phase I/IIa study of MOR202 in relapsed or refractory (RR)MM. Preliminary safety and efficacy data from 3 patient cohorts treated with clinically relevant doses of MOR202 (administered as an IV 2-hour infusion), alone or in combination with an IMiD are presented: MOR202 4, 8 and 16 mg/kg weekly; MOR202 8 or 16 mg/kg weekly with either LEN or POM. All patients in these cohorts also received low dose dexamethasone. Primary objectives were to evaluate the safety, maximum tolerated dose (MTD) and recommended phase II dose of MOR202. Secondary objectives included an assessment of overall response rate, duration of response and progression-free survival. Results: As of July 12, 2016, a total of 66 patients had been treated; 31 in clinically relevant cohorts, including 18 patients receiving MOR202 alone, 8 receiving MOR202 + LEN and 5 receiving MOR202 + POM. Patients treated with MOR202 alone and MOR202 + POM had both received a median of 4 prior lines of therapy; 78% and 100% had been refractory to last prior treatment, respectively. Patients treated with MOR202 + LEN had received a median of 2 prior lines of therapy and 50% had been refractory to last prior treatment. Most of the patients had received bortezomib, LEN, cyclophosphamide, and melphalan alone or in combination with autologous stem cell transplant as part of their prior regimens. In this trial the MTD has not been reached yet. MOR202 alone or in combination with an IMiD was well tolerated, with mainly hematological toxicity reported. A 2-hour MOR202 infusion was feasible in all patients. In the clinically relevant cohorts only 1 patient discontinued due to an adverse event considered to be related to MOR202 (platelet count decreased) and no deaths related to any of the study drugs occurred. IRRs were seen in only 3/31 (10%) patients, all occurring during the first infusion. All IRRS were ≤ grade 2. So far, 28 patients were evaluable for response in the MOR202 clinically relevant cohorts. Of 16 evaluable patients in the MOR202 alone cohort, 3 partial responses (19%) and 2 very good partial responses (13%) were reported. In the MOR202 + LEN cohort 5/7 partial responses were seen, and 3/5 patients responded to MOR202 + POM treatment including 2 complete responses. Median time to response was 4 weeks, with responses tending to deepen over time. Most responses (10/13) are ongoing with the longest duration of response currently being 48 weeks. Preliminary analysis in 5 patients revealed preservation of high CD38 levels on MM cells under MOR202 therapy, with a mean decrease of only 10% from baseline to day 1 cycle 2 (4 weeks). Conclusions: In this analysis, a 2-hour infusion of MOR202 (up to 16 mg/kg) alone, or in combination with POM or LEN showed a very good safety profile, particularly an excellent infusion tolerability in heavily pretreated patients with RRMM. Promising preliminary efficacy and long-lasting tumor control was seen for MOR202 +/- IMiDs. The data suggest that CD38 expression on patient MM cells is preserved during treatment. Disclosures Raab: Novartis: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy, Research Funding. Goldschmidt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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, Research Funding; Chugai: Honoraria, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Agis:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau. Engelhardt:Amgen: Research Funding; Janssen: Research Funding; MSD: Research Funding; Celgene: Research Funding. Ferstl:Novartis: Other: Case report presentation; Bristol Myers Squibb: Other: Advisory Board. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Onyx: Consultancy; BMS: Consultancy, Honoraria; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Jarutat:MorphoSys AG: Employment. Weinelt:MorphoSys: Employment. Endell:MorphoSys AG: Employment, Patents & Royalties. Boxhammer:MorphoSys AG: Employment, Patents & Royalties. Peschel:MophoSys: Honoraria.

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Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-127350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3873-3873

Author(s):

Michael J. Burke ◽

David S. Ziegler ◽

Francisco José Bautista Sirvent ◽

Andishe Attarbaschi ◽

Lia Gore ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Salvage options for children with relapsed ALL remain sub-optimal, particularly for T-cell ALL patients, and relapse remains the leading cause of death. Achieving complete remission (CR) after relapse is the first critical step to cure. Combining the proteasome inhibitor (PI) bortezomib with chemotherapy has previously shown promising results in achieving CR in pediatric phase 2 studies in ALL (Messinger 2012, Horton 2013, Bertaina 2017). In this ongoing dose-escalation phase 1 study, the second generation PI carfilzomib was combined with chemotherapy in children with relapsed ALL. Subjects received one 4-week cycle of induction chemotherapy with either UKALLR3 (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine) or VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) plus carfilzomib administered intravenously on days 1, 2, 8, 9, 15, and 16. The primary endpoint was dose limiting toxicities (DLTs) occurring during induction (grade 4 neutropenia or thrombocytopenia extending past day 45 or grade 4 non-hematological toxicity). Efficacy endpoints included CR (with or without hematological recovery) based on bone marrow (BM) and LP on day 29 of induction and consolidation. Subjects < 21 years of age and diagnosed with first early BM relapse (<36 months from diagnosis), multiply relapsed ALL, or primary induction failure were eligible; subjects with T-cell disease with any BM relapse were eligible. Subjects achieving ≥ stable disease could receive a cycle of modified BFM consolidation therapy (6-MP, cyclophosphamide, cytarabine, PEG-asparaginase, IT chemotherapy) plus carfilzomib at the same dose level and schedule given in induction therapy. Dose escalation was based on an evaluation of DLT's using a Bayesian logistic regression model. Ten subjects with B (n=9) or T- (n=1) cell ALL were treated with UKALLR3 at 2 carfilzomib dose levels (20 or 27 mg/m2, 5 subjects each). Among DLT-evaluable subjects, 3 DLTs (meningoencephalitis, hemolytic uremic syndrome and neutropenia) were observed, 2 at 27 and 1 at 20 mg/m2 dose levels with an MTD of 27 mg/m2. The UKALLR3 regimen was considered too toxic by the protocol steering committee and was replaced with VXLD in January 2016. The VXLD cohort started at 27 mg/m2 and is currently in the 56 mg/m2 dose level. Fifteen subjects (7 B-cell and 8 T-cell) were treated with VXLD at carfilzomib dose levels of 27 (n=3), 36 (n=7), 45 (n=4), and 56 (n=1) mg/m2. One DLT of posterior reversible encephalopathy syndrome (PRES) occurred in the 36 mg/m2 cohort, with no further DLTs identified after expansion to 7 subjects. Table 2 lists the patient characteristics of the 15 subjects in the VXLD cohort. Grade 3-4 hematological AEs were nearly universal for both UKALLR3 and VXLD. Non-hematological > Grade 3 AE's of note are listed in Table 1. PRES occurred in 2 subjects in the VXLD cohort (both with prior allogeneic SCT) and rapidly reversed in both cases. Re-challenge with carfilzomib in one case was tolerated without PRES recurrence. Serious AE's (SAE) were reported in 50% and 56% of subjects receiving carfilzomib in combination with UKALLR3 or VXLD, respectively, with the most common SAE's among all subjects being sepsis (16%), pancreatitis and PRES (8% each). In the UKALLR3 cohort, 60% of subjects (n=6) achieved a remission, however only 30% proceeded to consolidation. In the VXLD cohort, 53% of evaluable subjects (n=8) achieved remission and 13% were non-evaluable due to hypocellular BM at day 29 of induction. All responding subjects recovered hematological counts by day 42 without evidence of progression. Eight subjects (53%) proceeded to consolidation, including 2 subjects with non-evaluable BM results and 1 with 8% BM blasts after induction. All subjects entering consolidation were in remission on day 29 post-consolidation. The overall remission rate with VXLD-carfilzomib was 67% at the end of consolidation. Detailed response data are listed in Table 3. Carfilzomib in combination with VXLD chemotherapy was tolerable in a predominantly T-cell ALL population, very early or post stem cell transplant relapse. Efficacy is promising in this small cohort of patients with carfilzomib dose escalation continuing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau. Bautista Sirvent:EusaPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending symposia; Takeda: Other: Support for attending symposia; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: Support for attending symposia; Amgen, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Brien:BMS: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; BTG: Research Funding. Obreja:Amgen, Inc.: Employment, Equity Ownership. Morris:Amgen, Inc.: Employment, Equity Ownership. Baruchel:Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bellicum: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: Kyprolis is a proteasomal inhibitor indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

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