A Phase I Study of Vorinostat in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3705-3705 ◽  
Author(s):  
David Siegel ◽  
Donna Weber ◽  
Constantine S. Mitsiades ◽  
Syed Rizvi ◽  
Jose Garcia-Vargas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Therapeutic Potential ◽  
Hematologic Malignancy ◽  
Randomized Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Tumor Types

Abstract Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin’s lymphoma and despite recent advances in therapy, including the introduction of thalidomide, bortezomib, and lenalidomide, remains incurable. Vorinostat is an inhibitor of Class I and II histone deacetylases, which play key roles in the regulation of both transcriptional and post-transcriptional activity in a variety of tumor types, including MM. This histone deacetylase inhibitor has demonstrated anti-proliferative activity as monotherapy and synergistically with other agents in a variety of tumor types, including MM, where it was well tolerated in Phase I trials. Lenalidomide is a potent structural analog of thalidomide and demonstrates clinical efficacy in the treatment of MM as a single agent and to a larger degree, in combination with dexamethasone. Preclinical data suggest that the addition of vorinostat to lenalidomide and dexamethasone has at least additive, and possibly synergistic, therapeutic potential, with the anti-tumor mechanisms of vorinostat and dexamethasone being distinct from the immunomodulatory effects of lenalidomide. This Phase I, multicenter, open-label, non-randomized study assessed the safety and tolerability of vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary and exploratory objectives included: assessment of safety and tolerability; determination of clinical activity of the combination, and evaluation of in vivo molecular and biologic effects of the combination in patients with MM through analysis of gene expression. Patients aged ≥18 years with an established diagnosis of relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels (table). Patients received vorinostat daily, administered orally for 14 days with 7 days on (Days 1–7 and 15–21), combined with oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22; cycles were repeated every 28 days); use of concomitant prophylactic acetylsalicylic acid was recommended. Dose-limiting toxicities (DLTs) were assessed in the first treatment cycle. Barring DLT, dose escalation continued until the MTD was established. Response, safety, and tolerability were evaluated. Adverse events (AEs) were recorded throughout the study. Dosing Regimen Dose Level Vorinostat Dose (mg q.d.) 7 days on 7 days off (Days 1–7 and Days 15–21) in each 28-day cycle Lenalidomide Dose (mg q.d.) × 21 days (Day 1 through Day 21) in each 28-day cycle Dexamethasone Dose (mg q.d.) On Days 1, 8, 15, and 22 in each 28-day cycle 1 300 10 40 2 400 10 40 3 400 15 40 4 400 20 40 5 400 25 40 Results: Enrolment is ongoing and tolerability of treatment has been good so far. Of 7 patients assessed to date, 6 patients (86%) have reported ≥1 AE, and 3 patients’ (43%) AEs were considered drug-related. The most frequently reported AE was anemia (n=4, 57%). Serious AEs were reported by 2 patients (29%), none of which were considered drugrelated. No patients have discontinued due to AEs or SAEs, and no DLT has been observed to date. Of 6 evaluable patients, the best responses were: partial response in 1 patient, minimal response in 1 patient and stable disease in 2 patients and progressive disease in 2 patients. Currently, 4 patients remain on treatment and 3 patients have discontinued treatment due to progressive disease. Conclusion: Vorinostat with lenalidomide and dexamethasone represents a novel combination therapy for the treatment of relapsed or relapsed, refractory MM. Preliminary results suggest that the combination is well tolerated to date, is active and has the convenience of oral administration.

Dasatinib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1876-1876 ◽  
Author(s):  
Thierry Facon ◽  
Xavier Leleu ◽  
A. Keith Stewart ◽  
Andrew Spencer ◽  
Philip Rowlings ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Performance Status ◽  
Randomized Study ◽  
Single Agent ◽  
Open Label ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1876 Poster Board I-901 Background: Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells. Methods: The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria. Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose. Results: Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment). Conclusion: Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.

Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): Phase I safety and efficacy analyses.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4073-4073 ◽  
Author(s):  
Robin Kate Kelley ◽  
Ghassan K. Abou-Alfa ◽  
Johanna C. Bendell ◽  
Tae-You Kim ◽  
Mitesh J. Borad ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Progressive Disease ◽  
Hospice Care ◽  
Randomized Study ◽  
Immune Checkpoints ◽  
Clinical Activity ◽  
Open Label ◽  
Study Results ◽  
Grade 3

4073 Background: Durvalumab and tremelimumab, investigational monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, respectively, have shown efficacy in monotherapy and offer promise in combination for patients (pts) with HCC. This is a phase I/II, open-label, randomized study of durvalumab combined with tremelimumab in unresectable HCC. Methods: Phase I part of this study is a safety run-in cohort treated at the recommended phase II doses of the durvalumab/tremelimumab combination (20 and 1 mg/kg IV Q4W respectively for 4 doses followed by 20 mg/kg Q4W durvalumab alone) in pts with unresectable HCC with or without concomitant HBV or HCV infection who progress on, are intolerant to, or have refused sorafenib therapy. Secondary objectives include evaluation of antitumor activity. Here we present results of a preplanned analysis from the completed phase I part of the study. Results: As of 10 January 2017, 40 pts have been enrolled (11 HBV+, 9 HCV+, 20 uninfected). 30% had no prior systemic therapy; 93% were Child Pugh Class A. 24 (60%) had ≥1 treatment-related AE; 20% had ≥1 grade ≥3 related AE. Most common (≥15%) treatment-related AEs: fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). Most common grade ≥3 related AE was asymptomatic increased AST (10%). 24 pts have discontinued treatment: 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (pt entered hospice care). 40 pts were evaluable for response at ≥16 weeks follow-up. Conclusions: No unexpected safety signals with durvalumab and tremelimumab were seen in this unresectable HCC population. Clinical activity observed predominantly in uninfected pts though interpretation limited by small subsets. Enrollment to the phase II portion of the study is ongoing. Clinical trial information: NCT02519348. [Table: see text]

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

A Phase I Trial Of Anti-KIR Monoclonal Antibody IPH2101 and Lenalidomide For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3181-3181 ◽  
Author(s):  
Don M. Benson ◽  
Adam D Cohen ◽  
Craig C Hofmeister ◽  
Munshi C Nikhil ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Nk Cells ◽  
Nk Cell ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Low Grade ◽  
Dosing Interval ◽  
Infusion Reactions

Abstract Introduction Multiple myeloma (MM) remains an essentially incurable plasma cell malignancy. MM utilizes specific immunoevasive strategies to avoid natural killer (NK) cell immune surveillance and cytotoxicity. Immunomodulatory agents such as lenalidomide (LEN) may exert indirect anti-MM efficacy via expansion and activation of NK cells. However, these favorable effects may be diminished when LEN is co-administered with high doses of dexamethasone (DEX). IPH2101 is a monoclonal anti-inhibitory KIR antibody which prevents negative signaling in NK cells and enhances NK cell recognition and killing of MM cells. A single-agent, phase I study of IPH2101 demonstrated full KIR blockade with encouraging safety and tolerability, and 34% of heavily pre-treated patients achieved disease stabilization (Blood 2012;120:4324-33). Preclinical data demonstrate that LEN and IPH2101 exert anti-MM effects via complementary NK-cell immunomodulatory mechanisms (Blood 2011;118:6397-91). Herein, data are presented from the first clinical experience with IPH2101 and LEN in combination in patients with MM. Methods A 3+3 phase I dose-escalation trial was conducted. Patients (age 18-80) with measurable, progressive MM were enrolled having received one or two prior lines of therapy. Prior LEN exposure was permitted unless resistance or intolerance was observed. Patients must have had ECOG performance status ≤ 2, creatinine clearance ≥ 60 ml/min, platelets ≥ 75,000/uL (or ≥ 30,000/uL if > 50% bone marrow plasma cells), absolute neutrophil count ≥ 1,000/uL, bilirubin < 1.5 ULN, and ALT / AST < 3 ULN. Patients must have adhered to standard prescribing guidelines for LEN. Three dose levels included: IPH2101 0.2mg/kg IV q 28 days + LEN 10 mg PO days 1-21; IPH2101 0.2 mg/kg + LEN 25 mg, and IPH2101 1mg/kg + LEN 25 mg for 4 cycles. Responding patients were allowed to receive 4 additional cycles. Patients completing all 8 cycles were maintained on LEN thereafter. No administration of DEX or other systemic corticosteroids was permitted. Dose reductions of LEN were permitted per prescribing information. The primary objective was to determine the safety and tolerability of IPH2101 + LEN, the secondary objectives included pharmacokinetics (PK) and pharmacodynamics (PD) of IPH2101 and biologic correlates with LEN as well as to determine clinical activity by standard IMWG uniform response criteria. Results 15 patients (10 M, 5 F, median age 60) were enrolled, 8 in first relapse and 9 in second relapse. 9 had prior LEN exposure. Cohorts 1 and 3 were expanded to n=6 patients respectively due to occurrence of possible dose-limiting toxicity. In both cases, a patient experienced a similar, apparent infusion reaction on cycle 1, day 1, characterized by fever, chills, cytokine release, and leucopenia. Events resolved with supportive care and both patients continued on trial without recurrence. The protocol was amended to include premedication with anti-histamine and acetaminophen,and no further infusion reactions were observed. Most other observed adverse events were of low grade and generally investigator-attributed as possibly or probably related to LEN. IPH2101 PD were not affected by co-administration of LEN. Full KIR occupancy was achieved in cohort 3 across the dosing interval. Five patients achieved a response (2 VGPR, 3 PR) with a median duration of 15+ months (3-26+). Conclusion The combination of IPH2101 + LEN appears to be a safe and well tolerated, and steroid-free combination in MM patients. Infusion reactions have not been observed since the addition of premedication prior to IPH2101 dosing. IPH2101 PD do not appear to be altered by co-administration of LEN, and full KIR blockade over the dosing interval has been achieved. Although the study is small, response rate and response duration are encouraging. These findings support further investigation of antiKIR therapy with LEN as the first, steroid-sparing, dual immunotherapy for MM. Disclosures: Benson: Innate Pharma: Research Funding. Off Label Use: Lenalidomide without concomitant dexamethasone. Zerbib:Innate Pharma: Employment. Andre:Innate Pharma: Employment. Caligiuri:Innate Pharma: Membership on an entity’s Board of Directors or advisory committees.

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2140-2140 ◽  
Author(s):  
Peter M Voorhees ◽  
Robert L. Schlossman ◽  
Cristina J Gasparetto ◽  
Jesus G. Berdeja ◽  
John Morris ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Advisory Committees ◽  
Ras Pathway ◽  
Label Dose

Abstract Introduction: Overall survival for patients with multiple myeloma (MM) has improved, but most patients relapse and eventually succumb to complications of the disease. The development of new therapeutic agents to treat relapsed and relapsed/refractory MM is therefore vital. Proteins of the Ras family are frequently mutated in human cancers, including MM. However, direct, selective, potent inhibitors of mutant Ras proteins are not clinically available. Extensive efforts have been made to identify agents which are "synthetically active" against the activated Ras pathway which may not inhibit the Ras protein itself, but target other molecules selectively important for cells with, but not those without, Ras mutation. PRLX 93936, 3-(2-ethoxyphenyl)-2-[(1-piperazinyl)methyl]-4(3H)-quinazolinone, is an analog of such a "synthetically active" compound against the activated Ras pathway. The compound has demonstrated promising efficacy in preclinical laboratory studies and mouse models of MM with an improvement in survival and 30% suppression in tumor growth at the lowest tested dose. A phase 1, multi-center, open-label, dose escalation trial was conducted to determine the maximum tolerated dose (MTD), assess toxicities, and evaluate response to treatment with monotherapy of PRLX 93936 in patients with relapsed or relapsed/refractory MM. Methods: Patients (Pts) with relapsed or relapsed/refractory MM in whom at least two prior anti-myeloma regimens had failed (including a proteasome inhibitor and/or immunomodulatory drug) were considered. PRLX 93936 as a single agent was given intravenously 3 days/week for 3 weeks followed by a 9 day rest period constituting a 28-day treatment cycle. Sequential cohorts of at least three pts were treated with escalating doses of PRLX 93936 beginning at 10 mg/m2 and increasing the dose in increments of 5mg/m2 until the MTD was established. Pts received a minimum of 2 cycles of treatment at their assigned dose level for evaluation of anti-myeloma activity of PRLX 93936 and could receive up to 8 cycles followed by an option of maintenance therapy. Dexamethasone at a dose of 20 mg provided on each day of PRLX 93936 infusion could be added at the investigator’s discretion after a minimum of 2 cycles or after cycle 1 for patients with progressive disease. Adverse events were assessed according to version 4.0 of the CTC, and response per the International Myeloma Working Group uniform response criteria, incorporating the modified EBMT response criteria, were assessed with each cycle. Correlative studies from peripheral blood and bone marrow were collected. Results: To date, 14 pts (4 women, 10 men) enrolled in the trial and 13 have completed therapy. Mean age was 61 years (range, 48-81). Prior to enrollment, pts had received an average of 5 lines of therapy (median 4, range 2-9) including 6 who received stem cell transplantation (4 autologous, 2 allogeneic). The median time since diagnosis was 5 years (range 2-11.5). Of the 13 pts whom completed treatment, 11 completed at least one full 28 day cycle (range 1-15). This includes 3 pts at the 10mg/m2 dose, 3 pts at the 15mg/m2 dose, 5 pts at the 20 mg/m2 dose, and 2 pts at the 25mg/m2 dose. Of the 13 pts who completed study therapy, 7 experienced at least one serious adverse event (SAE). The most frequently reported SAEs (2 each) included sepsis and cellulitis. Four SAEs were considered related to PRLX 93936 by the investigator (thrombocytopenia, neutropenia, nausea, and vomiting). The MTD was determined to be 20 mg/m2. Dose limiting toxicities that occurred at the next higher level of 25mg/m2 included nausea, vomiting, and neutropenia (both pts) and thrombocytopenia, weakness, elevated AST, and elevated creatinine (1 pt). The best response among 11 evaluable pts was minimal response (MR) in 2 pts (18%). Stable disease (n=4) and progressive disease (n=5) was observed in the remaining pts. Analysis of the impact of dexamethasone is on-going, but no significant additive toxicity has been seen. Conclusions: PRLX 93936, a “synthetically active” compound against the activated Ras pathway, has demonstrated activity as a single agent in relapsed and refractory MM patients with MR in 18% of patients to date. Toxicity has proven manageable and the MTD has been defined at 20 mg/m2. Additional studies, including those involving PRLX 93936 as part of combination therapy and correlative studies to determine those pts most likely to benefit, are warranted. Disclosures Voorhees: Millennium: The Takeda Oncology Company : Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: PRLX 93936 is a non-FDA approved drug currently in phase 1 development in multiple myeloma. Gasparetto:Millenium: Honoraria; Celgene: Consultancy, Honoraria. Jacobstein:Prolexys Pharmaceuticals, Inc: Employment. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership. Mitsiades:Millennium: A Takeda Oncology Company: Consultancy; Celgene: Consultancy; Johnson & Johnson: Research Funding; Amgen: Research Funding. Laubach:Celgene: Research Funding; Novartis: Research Funding; Millennium: A Takeda Oncology Company: Research Funding; Onyx: Research Funding. Richardson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millennium: The Takeda Oncology Co.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8556-TPS8556 ◽  
Author(s):  
Saad Zafar Usmani ◽  
Evangelos Terpos ◽  
Wojt Janowski ◽  
Hang Quach ◽  
Sarah West ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Open Label

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

Replacement of ixazomib for relapsed/refractory multiple myeloma patients refractory to a bortezomib or carfilzomib-containing combination therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
James R. Berenson ◽  
Alexa Cohen ◽  
Tanya M. Spektor ◽  
Jacob D. Bitran ◽  
Gigi Qiqi Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
The Other ◽  
Clinical Activity ◽  
Combination Regimen ◽  
Open Label ◽  
Combination Regimens

8013 Background: The proteasome inhibitor (PI) ixazomib (Ixz) is the first orally administered PI approved for treating multiple myeloma (MM). It has shown clinical activity as a single agent and when used in other combinations. In this phase 1/2 trial, we evaluated Ixz as a replacement therapy for bortezomib or carfilzomib for MM patients who were refractory to a bortezomib- or carfilzomib-containing combination regimen. Methods: This was a phase 1/2, intra-patient, multicenter, open-label trial evaluating the replacement of ixazomib for bortezomib or carfilzomib for MM patients who were refractory in combination with the other agents that the patients had received and failed. Patients received Ixz on days 1, 8 and 15 on a 28-day schedule and the other drugs were administered using the same doses and schedules as they were receiving during their prior regimen. If the Ixz maximum tolerated dose (MTD) for a particular combination regimen was previously determined, then patients were enrolled directly into Phase 2 (PhII). If not, MTD was determined during the Phase 1 (PhI) portion of the trial. Results: To date, a total of 40 patients have been enrolled; 37 patients (21 were enrolled in PhI and 16 in PhII) had completed at least one cycle of this treatment. Patients received a median of 5 prior treatments (range, 1-22). The median follow-up time for all patients was 1.6 months (range, 0.1-10.7 months), whereas that of PhII was 2.2 months (range, 0.2-10.7 months). There was no clinical benefit (CBR; 0%) nor any overall response rate (ORR; 0%) for patients receiving Ixz 3 mg (PhI). Nine patients (43%) showed stable disease (SD) while 12 (57%) exhibited disease progression (PD). In PhII (4mg Ixz) portion of the trial, ORR and CBR were both 18.7% with 16 (43.2%) patients showing SD, and 18 (48.6%) patients displaying PD. Common ≥ Gr3 adverse events were anemia (11%), thrombocytopenia (5.4%), hyponatremia (5.4%), dehydration (5.4%) and neutropenia (2.7%). Conclusions: Replacement of bortezomib or carfilzomib with Ixz infrequently leads to responses among RRMM patient who have progressed while on proteasome inhibitor -containing combination regimens. Clinical trial information: NCT02206425.

Phase I Study of AVE1642 Anti IGF-1R Monoclonal Antibody in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1166-1166 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Hulin ◽  
Thierry Facon ◽  
Mario Boccadoro ◽  
Dominique Mery-Mignard ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Phase I ◽  
Phase I Study ◽  
Clinical Activity ◽  
Diabetic Patients ◽  
Human Antibody ◽  
Synergistic Activity ◽  
Open Label

Abstract Rationale: CD221 (IGF-1R) is aberrantly expressed in multiple myeloma (MM) and is associated with disease severity (Bataille et al, Haematologica2005;90:706). IGF-1R is thus an attractive therapeutic target in patients with advanced disease. Patients and methods: We have conducted an open-label dose escalation phase I study of AVE1642, anti IGF-1R monoclonal antibody, in patients with advanced MM. The primary objective was to determine the selected dose of AVE1642 administered every 3 weeks (q3w) based on pharmacokinetic (PK), pharmacodynamic (PD) parameters and dose limiting toxicities. The secondary objectives were to assess the safety profile, the biological activity (saturation of receptors) on peripheral granulocytes, the potential immunogenicity and preliminary clinical activity of AVE1642. Results: 14 patients have been treated with AVE1642 as IV infusion administered q3w (day 1 = day 22) at 3 different dose levels: 3 (n = 4), 6 (n = 6) and 12 mg/kg (n = 4). A median number of 2 infusions (1–8) were administered. AVE1642 was well tolerated, except reversible grade 3 hyperglycemia observed in 2 diabetic patients. No hypersensitivity during infusion was reported. No human antibody anti AVE1642 was detected. One patient with Bence-Jones MM experienced a decrease in proteinuria and relief of bone pain. Based on PK/PD results, the dose of 12 mg/kg of AVE1642 has been selected for further clinical evaluation in MM patients. Based on the in vitro synergistic activity of AVE1642 + bortezomib (Descamps et al, ASH2006, 845a), we have started a combination trial of AVE1642, 12 mg/kg q3w + bortezomib (1.3 mg/m2 at d1, d4, d8 and d11 q3w) in patients with advanced MM.

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