Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Abstract Background: Poly (ADP-ribose) polymerase (PARP) enzymes are involved in repair of single-strand DNA breaks through base excision repair pathways. Inhibitors of PARP are approved for the treatment of BRCA1/2-mutant malignancies. We have previously demonstrated (Portwood et al, ASH 2019 abstract) that PARP inhibitors can synergistically enhance the activity of DNA-damaging agents in preclinical models of human acute myeloid leukemia (AML). Talazoparib (Tala) is a selective PARP inhibitor which exhibits potent inhibitory effects against multiple human AML cell lines. Gemtuzumab ozogamicin (GO) is an CD33 antibody drug conjugate approved for treatment of patients (pts) with AML. We hypothesized that the combination of Tala + GO would result in improved efficacy as compared with the historical response of GO monotherapy in pts with relapsed or refractory (R/R) AML. Study Design: This open-label multi-center phase 1b study evaluated the safety, tolerability, and preliminary response rates for Tala + GO in adult pts with CD33+ R/R AML. In the dose escalation portion, pts will be treated with Tala (dosed at 0.5, 0.75, or 1 mg orally daily) in combination with fixed dose GO (3 mg/m 2/day on days 1, 4, and 7, capped at one 4.5 mg vial) using a standard 3+3 design. The dose limiting toxicity (DLT) window is 28 days. After determination of DLTs and establishment of a recommended phase 2 dose, additional pts are planned for an expansion cohort. Results: This trial was activated in July 2020 and is registered at ClinicalTrials.gov (NCT04207190). As of August 2021, 6 pts have been enrolled, 3 each at Tala dose levels of 0.5 and 0.75 mg daily, respectively. Median age is 77 (range, 53-84) years with 3 (50%) women (Table 1). Median prior lines of therapy were 3 (range, 1-7), and 2 pts had received prior allogeneic transplant. Four pts had intermediate European LeukemiaNet risk disease at diagnosis. Five pts had next-generation sequencing at diagnosis (Table 1). One pt had p53 mutant AML (1/5, 20%), and two pts had FLT3 mutations (2/6,33%). To date, there have been no DLTs. The most common adverse events (AEs) of any grade included elevated alanine transaminase, hyperbilirubinemia, hypocalcemia, diarrhea, and oral thrush (83% each) (Table 2). Grade ³3 hematological AEs were common and related to Tala + GO. These consisted of neutropenia (n=4, 67%), anemia (n=1, 17%), and thrombocytopenia (n=1, 17%). The most frequent non-hematological grade ³3 AEs were bacteremia (67%), sepsis (67%), febrile neutropenia (50%), and pneumonia (50%). All were considered unrelated to Tala (Table 2). Three pts (50%) achieved a best response of complete response with incomplete count recovery (CRi) after 2 cycles. Two of these 3 pts were dosed at Tala 0.5 mg oral daily. All 6 pts are currently off protocol. Two had no response after 2 cycles, 1 died from persistent diease, 1 had persistently elevated AST, 1 was pt choice, and 1 died of pneumonia/respiratory failure. To date, a protocol defined maximally tolerated dose (MTD) has not been identified. Conclusion: This open-label multi-center phase 1b study is evaluating the safety, tolerability, and preliminary response rates of Tala + GO in adult pts with relapsed/refractory CD33+ AML. To date, 6 pts have been enrolled at the first two dose levels (Tala 0.5 mg po daily + GO, Tala 0.75 mg po daily +GO). No DLTs or MTD have been identified. The overall response rate after 2 cycles of therapy was 50% (n=3, CRi). A recent protocol amendment was enacted to shorten the duration of Tala treatment from continuous (28 out of 28 day) dosing to 21 out of 28 day dosing per cycle. Accrual is ongoing with plans to open this trial at two other centers in 2022. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Apellis Pharmaceuticals: Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Download Full-text

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2553.2553 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2553-2553

Author(s):

Daniel J. DeAngelo ◽

Alison R. Walker ◽

Richard F. Schlenk ◽

Jorge Sierra ◽

Bruno C. Medeiros ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Expansion Phase ◽

Phase 1B ◽

Grade 3 ◽

Advisory Role

Abstract Background: For patients (pts) with acute myeloid leukemia (AML) with poor prognostic indicators, such as unfavorable cytogenetics or secondary AML, overall and event-free survival (EFS) rates are much worse, highlighting the critical need for more effective therapeutic modalities. Increasing evidence implicates epigenetic processes in the development of AML. Panobinostat (PAN), a potent pan-deacetylase inhibitor, has been shown to augment the effects of standard chemotherapies (anthracyclines and Ara-C) in preclinical studies with AML cells. These preclinical results led to a phase 1b study of PAN in combination with idarubicin and Ara-C in pts with high-risk AML. Methods: The trial included younger pts (≥ 18 y and ≤ 65 y) with newly diagnosed high-risk AML, defined as: treatment-related AML, AML following previously diagnosed myelodysplasia or medical history of relevant hematologic disorders, and presence of unfavorable cytogenetics. The primary objective was determination of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of PAN when given in combination with idarubicin and Ara-C. Secondary objectives included safety, efficacy, and pharmacokinetics (PK). Exploratory endpoints included assessment of the relationship between efficacy and PK parameters and 1-year EFS. The study examined escalating doses (15-25 mg) of PAN given 3 times per wk for 2 wk starting on day 8 of a 28-day cycle (ie, D8, D10, D12, D15, D17, D19) in combination with standard induction doses of idarubicin (12 mg/m2/d; D1-D3) and Ara-C (100 mg/m2/d; C1, D1-D7). After 2 cycles, pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) moved to a consolidation phase with a combination of high-dose Ara-C and PAN at the dose received during induction. After determination of the RP2D, additional pts were enrolled in the expansion phase and treated at the RP2D dose. Results: A total of 46 pts with a median age of 55.5 y (range, 19-65 y) were enrolled in the study (34 in the dose-escalation phase [15 mg, n = 11; 20 mg, n = 15; 25 mg, n = 8] and 12 in the dose-expansion phase). Seven dose-limiting toxicities were observed in the escalation phase: 4 of 12 pts in the 20-mg group (left ventricular systolic dysfunction [n = 2], hepatosplenic candidiasis [n = 1], increased QTCF [n = 1]) and 3 of 7 pts in the 25-mg group (febrile neutropenia [n = 2], grade 3 diarrhea [n = 1]). Based upon the Bayesian linear regression model, the upper limit (≤ 25% probability of excessive toxicity in > 33% of pts) was not reached for determination of MTD. The RP2D of PAN was 20 mg. Among the 27 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic, including febrile neutropenia (59.3%), thrombocytopenia (48.1%), and anemia (40.7%). Although most pts experienced gastrointestinal AEs, they were largely grade ≤ 2 (all grades, 74.1%; grade 3/4, 11.1%). AEs led to discontinuation in 15% of pts treated at the RP2D. Four pts (3 of 46 during induction and 1 of 19 during consolidation) treated with RP2D died during treatment. Of the on-treatment deaths, 1 (grade 4 sepsis) was potentially related to study drug, whereas the remaining 3 (progressive AML, ischemic stroke, and cerebral hemorrhage) were determined to be unrelated. The geometric mean AUC0-24 of PAN after oral dosing increased with increasing PAN dose (42.5 hr•ng/mL [15 mg], 62.6 hr•ng/mL [20 mg], and 74.6 hr•ng/mL [25 mg]). However, AUC0-24 was higher in the expansion phase (92.7 hr•ng/mL) than at 25 mg in the escalation phase, with high variability (coefficient of variation, 32.3% [expansion]; 45.5% [25-mg escalation]). Among pts treated at the RP2D, 44.4% and 11.1% achieved CR and CRi, respectively (CR/CRi, 56%). In the subset of pts in the RP2D, no relationship was found between AUC0-24 and response rates. In the overall population, the 1-year EFS rate was 78.3%. Conclusions: The data from this study showed high variability in PAN PK and largely overlapping exposure between dose levels. Overall, these data demonstrate a safety profile consistent with those of single-agent PAN and the combination of Ara-C and idarubicin. Disclosures DeAngelo: Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sierra:Novartis: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Ocio:Novartis: Consultancy, Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Valera:Novartis: Employment. Wegener:Novartis: Employment. De:Novartis: Employment. Mu:Novartis: Employment. Binlich:Novartis: Employment. Stuart:Novartis: Research Funding.

Download Full-text

ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor, In Combination With Lenalidomide and Dexamethasone (dex), Is Well Tolerated Without Dose Limiting Toxicity (DLT) In Patients (Pts) With Multiple Myeloma (MM) At Doses Demonstrating Biologic Activity: Interim Results Of a Phase 1b Trial

Blood ◽

10.1182/blood.v122.21.3190.3190 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3190-3190 ◽

Cited By ~ 9

Author(s):

Andrew Yee ◽

Peter Vorhees ◽

William I. Bensinger ◽

Jesus Berdeja ◽

Jeffrey G Supko ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Employment Equity ◽

Advisory Committees ◽

Acetylated Tubulin ◽

Phase 1B ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Background ACY-1215 is the first selective HDAC6 inhibitor in clinical trials and is well-tolerated as monotherapy up to 360 mg/day, the maximum dose examined. Cmax ≥ 1µM was achieved at dose levels >80 mg. Unlike nonselective HDAC inhibitors, which are associated with severe fatigue, vomiting, diarrhea and myelosuppression, DLTs have not been observed with ACY-1215. ACY-1215 synergizes in in vitro with both lenalidomide and dex in MM cell lines providing the rationale to conduct a phase 1b trial of ACY-1215 in combination with these agents. Methods Relapsed and relapsed and refractory pts who have progressed on at least one prior treatment regimen, who have creatinine clearance >50 mg/mL/min, adequate bone marrow and hepatic function, and who gave informed consent were enrolled. In Part A, patients were treated with escalating doses of oral ACY-1215 on days 1-5 and 8-12 of a 28 day cycle with lenalidomide 25 mg d 1-21 and dex 40 mg weekly. In Part B, the schedule includes ACY-1215 on days 15-19. Subsequent cohorts will explore twice daily dosing based on emerging clinical, pharmacokinetic (PK) and pharmacodynamic (PD) data. Peripheral blood samples were obtained for PK and PD analysis. PD assessment measured the fold increase of acetylated tubulin (a marker of HDAC6 inhibition) and acetylated histones (a marker of class 1 HDAC inhibition) in peripheral blood mononuclear cells (PBMC). Results As of July 3, 2013, 15 pts who progressed after 1 to >3 prior therapies have been enrolled; 8 were relapsed and 7 were refractory to the most recent therapy. Patients were treated daily at up to 240 mg ACY-1215. Fourteen pts had received prior lenalidomide of which 6 were previously refractory as defined by having less than a minimal response (MR) to therapy (1) or progressive disease on either full dose or maintenance therapy (5). Pts have completed 0 to 11+ cycles of therapy with 10 pts continuing on therapy. Five pts have discontinued therapy due to progressive disease (PD) (3), travel difficulties (1), or missed doses of lenalidomide (1). The latter pt was replaced. The most common treatment emergent events were fatigue (43%), upper respiratory infection (36%), anemia and peripheral edema (21% each), neutropenia (29%) and muscle spasms (21%). Most were grade 1 and 2 and there was no dose relationship to ACY-1215. There were 9 grade 3-4 events in 6 pts, primarily hematologic, as well as fatigue and asymptomatic laboratory investigations. Only 1 event, grade 3 neutropenia, was considered possibly related to ACY-1215 by the investigator. PK and PD data is available from 12 pts up to 160 mg dose level. PK for ACY-1215 is similar to the analogous dose levels in phase 1a monotherapy suggesting coadministration of lenalidomide does not significantly impact the PK of ACY-1215. Maximal levels were ≥ 1µM at ≥ 80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones. Twelve pts, at doses up to 160 mg ACY-1215, are evaluable for response (after at least two cycles). In addition, 1 pt who discontinued therapy after one cycle had response data available. Nine patients (69%) have ≥ PR, including 1 CR, 4 VGPR, 3 PR, and 1 PRu. Two pts had MR and 2 had SD as the best response. Reponses are durable up to 11+ cycles of therapy. Of the 6 patients who were refractory to lenalidomide, best responses included 1 PR, 1 VGPR, 2 MR and 2 SD. Conclusions ACY-1215 at doses which have biological activity (as determined by PD data in PBMC) can be safely combined with lenalidomide and dex with favorable toxicity to date. Significant responses were observed in pts, and responses have been seen in pts previously refractory to lenalidomide. Future cohorts will explore longer duration of exposure as well as a twice daily dosing schedule for ACY-1215. Disclosures: Vorhees: Acetylon Pharmaceuticals, Inc: Research Funding; GlaxcoSmithKline: Consultancy, Research Funding; Millenium: Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys: Research Funding; Abbott: Consultancy. Bensinger:Celgene: Consultancy, Honoraria, Research Funding. Supko:Acetylon Pharmaceuticals, Inc: Research Funding. 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; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Patrick:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Raje:Acetylon Pharmaceuticals, Inc: Research Funding; Eli Lilly: Research Funding; Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy.

Download Full-text

An Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination with Backbone Regimens in Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.176.176 ◽

2014 ◽

Vol 124 (21) ◽

pp. 176-176 ◽

Cited By ~ 17

Author(s):

Philippe Moreau ◽

Maria-Victoria Mateos ◽

Joan Bladé ◽

Lotfi Benboubker ◽

Javier de la Rubia ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Newly Diagnosed ◽

Duration Of Treatment ◽

Open Label ◽

Advisory Committees ◽

Dependent Cell ◽

Phase 1B ◽

Grade 3

Abstract Multiple myeloma (MM) remains an incurable disease due to complex molecular abnormalities, lower sensitivity to chemotherapy of MM cells in the bone marrow microenvironment, and the emergence of drug resistance. Daratumumab (DARA) is a human IgG1κ MAb in clinical development for the treatment of MM. DARA binds to CD38 and elicits signaling cascade and immune effector function engagement leading to multiple direct and indirect mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis, and induction of apoptosis. DARA binding to CD38 also modulates vital cellular enzymatic activities associated with calcium mobilization and signaling, independent of its other activities. All of these activities, in concert, lead to elimination of plasma cells from bone marrow in MM patients. DARA has shown single agent efficacy and a manageable safety profile in patients relapsed or refractory (RR) to 2 prior lines of therapy including immunomodulatory agents (IMiDs) or proteasome inhibitors (PIs) (Lokhorst HM, et al. J Clin Oncol 2014;32 Suppl 1: 8513). DARA in combination with lenalidomide (LEN) and dexamethasone (D) has also shown encouraging early efficacy and tolerability in relapsed or RR MM (Plesner T, et al. J Clin Oncol2014;32 Suppl 1: 8533). The aim of this ongoing open-label, 4-arm, multicenter, phase 1b study was to evaluate the safety, tolerability and dose regimen of DARA in combination with other MM backbone treatments including bortezomib-dexamethasone (VD), bortezomib- thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP), and pomalidomide-dexamethasone (POM-D). Newly diagnosed patients were included in the VD, VTD arms irrespective of transplant eligibility. Patients in the VMP arm were newly diagnosed and transplant ineligible. Patients in the POM-D arm were RR to ≥2 lines of therapy including 2 consecutive cycles of LEN and V. Initially six patients in each arm were treated with DARA 16 mg/kg and the approved label or standard of care of each backbone treatment as follows. In the VD and VTD arms treatment was for 18 three-week cycles or until transplantation (DARA qw, 2 cycles; q3w, 16 cycles). In the VMP arm treatment was for 9 six-week cycles (DARA qw, 1 cycle; q3w, 8 cycles) and in the POM-D arm four-week cycles until disease progression (DARA qw, 2 cycles; q2w, 4 cycles; q4w remaining cycles). An independent data safety monitoring board will evaluate dose limiting toxicities (DLT) at the end of Cycles 1, 2 and 3. Combinations are considered safe and well-tolerated if a DLT is observed in ≤1 of the initial 6 patients treated with DARA 16 mg/kg for a given combination regimen and a further 6 patients will be enrolled in the VMP, VTD and POM-D cohorts. If ≥2 DLTs are observed the DARA dose is reduced for the remaining treatment cycles and additional patients may be enrolled at the reduced dose. Data from 17 subjects treated in the newly diagnosed cohorts (VD [n=5], VTD [n=6], and VMP [n=6]) are described with a median duration of treatment of 44 days (range 1 to 113 days). All subjects were treated with DARA 16 mg/kg. The median duration of treatment was 44 days (range 1 to 113 days). There was no additional toxicity when DARA was added to bortezomib-containing backbone therapy, other than infusion related reactions (IRR) specific to DARA. There were 4/17 subjects with IRRs and all events occurred on Cycle 1 Day 1, were grade 1 in severity, and resolved with supportive treatment allowing the subject to continue DARA treatment. All other AEs were consistent with those associated with the backbone agents. The most common AEs were hematologic toxicity, likely related to the backbone therapy (bortezomib, melphalan and/or thalidomide). There were three episodes of grade ≥3 neutropenia and one episode of grade 3 anemia. There were no grade ≥3 non-hematologic AEs. The most common (3 or more occurrences) grade 1 and 2 AEs included: peripheral sensory neuropathy, headache, asthenia, pyrexia, and constipation. Two episodes of rash were noted. One episode of bronchospasm, noted in a subject with a history of COPD, was classified as an IRR (VMP arm). In summary, the addition of DARA was well tolerated in all evaluable patients and did not result in significant additional toxicity. Patient enrollment and assessments of safety and efficacy are ongoing. Disclosures Moreau: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bladé:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Comenzo:Takeda Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Research Funding. Fay:BMS: Honoraria. Qin:Janssen Pharmaceutical Research & Development: Employment. Masterson:Janssen Pharmaceutical Research & Development: Employment. Schecter:Janssen Pharmaceutical Research & Development: Employment. Ahmadi:Janssen Pharmaceutical Research & Development: Employment. San Miguel:Millenium: 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; 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.

Download Full-text

Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽

10.1182/blood-2020-140584 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Geoffrey Fell ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Remission Rate ◽

Conventional Chemotherapy ◽

Advisory Committees ◽

Secondary Aml ◽

Grade 3 ◽

Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged >60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

Download Full-text

The Application of Machine Learning to Improve the Subclassification and Prognostication of Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-139013 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-28

Author(s):

Hassan Awada ◽

Arda Durmaz ◽

Carmel Gurnari ◽

Ashwin Kishtagari ◽

Manja Meggendorfer ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Somatic Mutations ◽

Cross Validation ◽

Steering Committee ◽

Advisory Board ◽

Advisory Committees ◽

Genomic Features ◽

Acute Myeloid

Genetic mutations (somatic or germline), cytogenetic abnormalities and their combinations contribute to the heterogeneity of acute myeloid leukemia (AML) phenotypes. To date, prototypic founder lesions [e.g., t(8;21), inv(16), t(15;17)] define only a fraction of AML subgroups with specific prognoses. Indeed, in a larger proportion of AML patients, somatic mutations or cytogenetic abnormalities potentially serve as driver lesions in combination with numerous acquired secondary hits. However, their combinatorial complexity can preclude the resolution of distinct genomic classifications and overlap across classical pathomorphologic AML subtypes, including de novo/primary (pAML) and secondary AML (sAML) evolving from an antecedent myeloid neoplasm (MN). These prognostically discrete AML subtypes are themselves nonspecific due to variable understanding of their pathogenetic links, especially in cases without overt dysplasia. Without dysplasia, reliance is mainly on anamnestic clinical information that might be unavailable or cannot be correctly assigned due to a short prodromal history of antecedent MN. We explored the potential of genomic markers to sub-classify AML objectively and provide unbiased personalized prognostication, irrespective of the clinicopathological information, and thus become a standard in AML assessment. We collected and analyzed genomic data from a multicenter cohort of 6788 AML patients using standard and machine learning (ML) methods. A total of 13,879 somatic mutations were identified and used to predict traditional pathomorphologic AML classifications. Logistic regression modeling (LRM) detected mutations in CEBPA (both monoallelic "CEBPAMo" and biallelic "CEBPABi"), DNMT3A, FLT3ITD, FLT3TKD, GATA2, IDH1, IDH2R140, NRAS, NPM1 and WT1 being enriched in pAML while mutations in ASXL1, RUNX1, SF3B1, SRSF2, U2AF1, -5/del(5q), -7/del(7q), -17/del(17P), del(20q), +8 and complex karyotype being prevalent in sAML. Despite these significant findings, the genomic profiles of pAML vs. sAML identified by LRM resulted in only 74% cross-validation accuracy of the predictive performance when used to re-assign them. Therefore, we applied Bayesian Latent Class Analysis that identified 4 unique genomic clusters of distinct prognoses [low risk (LR), intermediate-low risk (Int-Lo), intermediate-high risk (Int-Hi) and high risk (HR) of poor survival) that were validated by survival analysis. To link each prognostic group to pathogenetic features, we generated a random forest (RF) model that extracted invariant genomic features driving each group and resulted in 97% cross-validation accuracy when used for prognostication. The model's globally most important genomic features, quantified by mean decrease in accuracy, included NPM1MT, RUNX1MT, ASXL1MT, SRSF2MT, TP53MT, -5/del(5q), DNMT3AMT, -17/del(17p), BCOR/L1MT and others. The LR group was characterized by the highest prevalence of normal cytogenetics (88%) and NPM1MT (100%; 86% with VAF>20%) with co-occurring DNMT3AMT (52%), FLT3ITD-MT (27%; 91% with VAF <50%), IDH2R140-MT (16%, while absent IDH2R172-MT), and depletion or absence of ASXL1MT, EZH2MT, RUNX1MT, TP53MT and complex cytogenetics. Int-Lo had a higher percentage of abnormal cytogenetics cases than LR, the highest frequency of CEBPABi-MT (9%), IDH2R172K-MT (4%), FLT3ITD-MT (14%) and FLT3TKD-MT (6%) occurring without NPM1MT, while absence of NPM1MT, ASXL1MT, RUNX1MT and TP53MT. Int-Hi had the highest frequency of ASXL1MT (39%), BCOR/L1MT (16%), DNMT3AMT without NPM1MT (19%), EZH2MT (9%), RUNX1MT (52%), SF3B1MT (7%), SRSF2MT (38%) and U2AF1MT (12%). Finally, HR had the highest prevalence of abnormal cytogenetics (96%), -5/del(5q) (68%), -7del(7q) (35%), -17del(17p) (31%) and the highest odds of complex karyotype (76%) as well as TP53MT (70%). The model was then internally and externally validated using a cohort of 203 AML cases from the MD Anderson Cancer Center. The RF prognostication model and group-specific survival estimates will be available via a web-based open-access resource. In conclusion, the heterogeneity inherent in the genomic changes across nearly 7000 AML patients is too vast for traditional prediction methods. Using newer ML methods, however, we were able to decipher a set of prognostic subgroups predictive of survival, allowing us to move AML into the era of personalized medicine. Disclosures Advani: OBI: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Takeda: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding. Carraway:Novartis: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Jazz: Consultancy, Speakers Bureau. Saunthararajah:EpiDestiny: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kantarjian:Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Aptitute Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria. Kadia:Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; JAZZ: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Research Funding. Sekeres:Pfizer: 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; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Download Full-text

Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

Download Full-text

A Phase 1 Study of Sea-CD70 in Myeloid Malignancies

Blood ◽

10.1182/blood-2020-136203 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ahmed Aribi ◽

Anjali S Advani ◽

William Donnellan ◽

Amir T. Fathi ◽

Marcello Rotta ◽

...

Keyword(s):

Board Of Directors ◽

Immune Evasion ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Steering Committee ◽

Advisory Board ◽

Open Label ◽

Advisory Committees ◽

Myeloid Malignancies

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1856.1856 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1856-1856 ◽

Cited By ~ 1

Author(s):

Suzanne Lentzsch ◽

Amy O’Sullivan ◽

Silvana Lalo ◽

Carrie Kruppa ◽

Diane Gardner ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Advisory Board ◽

Clinical Activity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Download Full-text

A Phase 1/2 Multi-Center, Randomized, Open Label Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That Includes Lenalidomide and Bortezomib.

Blood ◽

10.1182/blood.v114.22.301.301 ◽

2009 ◽

Vol 114 (22) ◽

pp. 301-301 ◽

Cited By ~ 4

Author(s):

Paul Richardson ◽

David Siegel ◽

Rachid Baz ◽

Susan L. Kelley ◽

Nikhil C. Munshi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Maximum Tolerated Dose ◽

Open Label ◽

Advisory Committees ◽

Dose Escalation Study ◽

Safety And Efficacy ◽

Heavily Pretreated ◽

Grade 3 ◽

Dose Dependent Increase

Abstract Abstract 301 Background: Pomalidomide (POM) is an IMiD® derived from thalidomide with a modified chemical structure with improved potency in vitro and potential efficacy and safety benefits in vivo. Two phase (Ph) 1b, single-center, ascending dose, open-label studies in pts with relapsed/refractory multiple myeloma (MM; Schey et al, 2004, Streetly et al, 2008) identified maximum tolerated dose (MTD) as 2mg QD or 5mg on alternate days (28 of each 28-day cycle). High response rates of POM alone in heavily pretreated pts were encouraging. To evaluate the MTD, safety and efficacy of POM alone or with Dexamathasone (dex) on a 21/28 day schedule, a Ph 1/2, multicenter, randomized, open-label, 3×3 dose-escalation study was initiated in pts with relapsed/refractory MM after at least 2 prior regimens, including bortezomib and lenalidomide. Methods: The study has a Ph 1 POM MTD (n=32) portion, followed by Ph 2 open-label randomized POM+ dex vs POM alone (192 pts planned). Eligible pts had documented relapsed/refractory MM. All pts received low-dose prophylactic aspirin QD and monitored for venous thromboembolic events (VTE). In Ph 1, POM was given QD on Days 1–21 of 28-day cycle: 4 dose levels of POM (2, 3, 4, 5mg) were studied with option to add dex at 40 mg/wk after 4 cycles for lack of response or progressive disease (PD). Pts enrolled in Ph 1 and discontinued either for intolerance or PD could not be enrolled in Ph 2. Toxicities and responses were assessed using CTCAE v3 and modified European Group for Blood and Marrow Transplantation (EBMT) criteria. Results: Results from Ph 1 of the study are reported with 32 pts enrolled to date. Fifteen pts discontinued therapy and 17 pts are ongoing for both safety and efficacy analyses. Mean age is 66.6 yrs (range 38–84), with median number of prior regimens 7 (range 2–18). MTD has not yet been reached. There were 4 dose reductions due to POM (5mg [2-neutropenia, 1-rash]; 3mg [1-neutropenia]) after 108 completed cycles. Neutropenia and thrombocytopenia were the most common grade 3/4 toxicities, with no dose-dependent increase apparent so far: 12 serious adverse events (SAEs) occurred in 10 pts; drug related events included POM (VTE, syncope, 3rd degree AV block, asthenia, diarrhea, neutropenia, anemia, rash); dex (lung infection with neutropenia); POM + dex (sepsis with pharyngeal abscess). AEs such as somnolence (1) VTE (1) neuropathy (2), and constipation (4) were uncommon. There were 3 deaths on study not attributed to POM; 2 pts died of rapid PD, 1 pt died of gastrointestinal perforation due to amyloidosis. Responses were seen at each dose level (Table 1). In 20/21 (95%) evaluable pts, clinical activity (SD or better) was reported. During treatment with POM alone, overall response rate (ORR; 1 CR, 2 PR, 5 MR) was 38% (8/21), mean duration of response (DOR) was 11.1 (range 4–32) wks, mean time to progression (TTP) was 8.3 (range 2–36) wks. Median completed cycles of POM +/− dex overall was 4 (range 1–12), with 13/21 evaluable pts (62%) having dex added to their regimens at various different cycles (median cycle 3, range 2–9) for PD or lack of response. During treatment with POM+dex, ORR (2 PR, 3 MR) was 38%, mean DOR of 14.2 (range 4–32) wks, and mean TTP of 20 (range 4–52) wks. In addition, there were 9 stable diseases (SD) on POM alone with mean DOR of 7.1 (range 4–16) wks, and 6 SD on POM + dex with mean DOR of 10.7 (range 8–16) wks. In 5/13 pts (38%), responses improved after dex was added (2 PR, 2 MR, 1 SD). Conclusions: These preliminary results indicate that POM alone or in combination with dex is associated with 38% MR or better, while SD was achieved in 43% (POM alone) and 46% (POM + dex), amongst heavily pretreated pts with relapsed/refractory MM. The incidence of SAEs and discontinuations decreased with increased dose of POM with no dose-dependent increase in grade 3/4 hematological toxicities. The MTD has not been reached to date. Overall, these data indicate that POM has an acceptable safety profile and is a clinically active therapeutic option for advanced refractory MM, warranting further investigation in this patient population. Disclosures: Richardson: Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an anti-proliferative and immunomodulatory agent that is in clinical development for relapsed/refractory MM. Siegel:Celgene: Speakers Bureau; Millenium Pharmaceuticals: Speakers Bureau. Baz:Celgene: Research Funding. Munshi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Sullivan:Merck: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Merrion: Membership on an entity's Board of Directors or advisory committees. Doss:Celgene: Speakers Bureau. Larkins:Celgene: Employment, Equity Ownership. Jacques:Celgene: Employment. Donaldson:Celgene: Employment. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millenium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

Download Full-text

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.

Download Full-text