Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): A Phase 1 Study

Abstract Background: Most adults with AML or high-risk MDS will ultimately require salvage therapy. However, the likelihood of achieving a complete remission (CR) with standard salvage regimens is often 15-20% or less. Emerging data suggest that pre-treatment (“priming”) with a hypomethylating agent such as decitabine can sensitize AML cells to chemotherapeutics, prompting a dose-escalation study of MEC preceded by decitabine-priming in relapsed/refractory AML and high-risk MDS. Methods: This single arm study aimed to estimate the maximum tolerated dose (MTD) of decitabine-primed MEC in adults ≥18 years with relapsed/refractory high-risk MDS (>10% blasts) or AML requiring first or subsequent salvage therapy. Previous treatment with hypomethylating agents or MEC (but not the combination) was acceptable. Trial participation required a treatment-related mortality (TRM) score of <9.2, corresponding to an expected TRM of 4% with standard induction chemotherapy. Patients with post-transplant relapse were eligible if graft-versus host disease was well controlled. Excluded were patients with concomitant illness with expected survival <1 year, and active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 3 total dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days) after a break of 5 days. In the case of persistent leukemia, patients were eligible for re-induction provided all non-hematologic toxicities had resolved to grade <2. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 additional cycles of decitabine-MEC given at doses identical to those used during induction. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 30 patients, median age 55 (range: 19-72) years, with primary refractory disease (n=13), first relapse (n=16), or second relapse (n=1) with median duration of prior CR of 4 (range: 1-19) months were enrolled and received a median of 1 (range: 1-3) cycles of therapy. During dose escalation, 1 DLT occurred at each the 2nd and 3rd tested dose level after cycle 1 (septic shock with multi-organ failure in both), identifying a 10-day course of decitabine together with standard dose MEC as the MTD. A total of 12 patients received therapy at the MTD level. 9/30 patients achieved a CR (30%). This CR rate compared favorably relative to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Blood 1996; 88:756), with an observed/expected CR ratio of 1.9. 5 additional patients achieved a CRp, and 1 achieved a CR with incomplete count recovery (CRi) for an overall response rate of 15/30 (50%). Furthermore, 4 patients achieved a morphologic leukemia-free state, 8 had refractory disease, and 3 died before a response was assessed. Of the 15 patients who achieved a remission, 3 remain on study, 9 were taken off protocol to pursue further intensive consolidation therapy including hematopoietic cell transplantation, and 3 have died after a median CR duration of 68 days. In the 15 responders, the median response duration was 68 days (range 0-437), with 6 of these responses ongoing. Overall survival of these 15 patients was longer (median of 211 [range: 59-484] days) than that for patients who failed to achieve remission but lived at least 29 days (i.e. did not experience TRM) (median of 110 [range: 30-303] days). Six patients died within 28 days of treatment initiation for a TRM rate of 20%: 4 from infection, 1 from intracranial hemorrhage, and 1 from unknown cause. Besides grade 3-4 cytopenias, cough, fatigue, nausea and infection/neutropenic fever were the most common adverse events. Conclusion: Decitabine-primed MEC is feasible, well tolerated, and has anti-leukemic activity in relapsed/refractory AML and high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Off Label Use: Off-label use of some of the study drugs for either AML or high-risk MDS.

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Phase I-II Study of Fludarabine, Cytarabine and Oxaliplatin In Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v118.21.4274.4274 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4274-4274

Author(s):

Apostolia Maria Tsimberidou ◽

Michael J Keating ◽

Elihu H. Estey ◽

Elias Jabbour ◽

Patrick Zweidler-McKay ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Phase Ii ◽

Myeloid Leukemia ◽

Off Label Use ◽

Off Label ◽

Grade 3 ◽

Acute Myeloid ◽

Refractory Aml

Abstract Abstract 4274 Introduction: The prognosis of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) is dismal. We designed a Phase I-II combination therapy of fludarabine, cytarabine and oxaliplatin (FAO) for patients with relapsed/refractory AML or high-risk MDS, hypothesizing that a mechanistic interaction of these agents combined would increase the leukemic cell death. Patients and Method: FAO consisted of fludarabine 30mg/m2 IV (Days 2–6); cytarabine 500mg/m2 IV continuous infusion (Days 2–6); and escalating doses of oxaliplatin (20, 25, 30 or 35mg/m2/day IV) (Days 1–4) (phase I). Patients received antibacterial, antiviral, antinausea and tumor lysis prophylaxis. Treatment was given every 28 days. Dose limited toxicity (DLT) was defined as any ≥ grade 3 non-hematological toxicity lasting ≥ 3 days involving a major organ system (brain, heart, kidney, liver, or lung). The maximum tolerated dose of oxaliplatin was used in the phase II portion of the study. The study was conducted based on an outcome-adaptive Bayesian procedure (Thall and Cook) and using the program “efficacy toxicity dose finding” (MD Anderson, Department of Biostatistics website). Results: Twenty-seven patients were treated: phase I, n=12 (3 patients per oxaliplatin dose level); and phase II, n=15. The median age was 58 years (range, 6–71). Six patients were ≥ 65 years. There were 11 men and 16 women. Six patients had performance status (PS) 0, 16 had 1 and 5 patients had PS 2. Twenty-one patients had complex cytogenetics (CG), 3 normal and 3 hyperdiploid. All patients were pretreated, including 11 patients who had prior allogeneic stem cell transplantation (SCT). DLTs were Grade 3 transaminitis; Grade 3 hyperbilirubinemia; and Grade 3 renal insufficiency and were all noted at the 35mg/m2/d oxaliplatin dose level. Therefore, the phase II recommended dose of oxaliplatin was 30 mg/m2/day. No DLT was noted in 18 patients treated at oxaliplatin 30 mg/m2/day dose level. Grade 3–4 non-hematologic toxicity was noted as follows: diarrhea (4 of 27 patients), hyperbilirubinemia (3 of 27 patients) and transaminitis (3 of 27 patients). Five of 27 (18.5%) patients responded to FAO (CR, n=3; CRp, n=2). Three of the 5 responders had prior SCT. Characteristics and clinical outcomes of responders are shown in Table: Conclusion: The Phase II recommended dose of FAO was fludarabine 30mg/m2 IV (Days 2–6); cytarabine 500mg/m2 IV continuous infusion (Days 2–6); and oxaliplatin 30mg/m2/day IV (Days 1–4) and it was well tolerated. FAO had significant antitumor activity in selected patients with heavily pretreated relapsed or refractory poor-risk AML and warrants further investigation. Disclosures: Tsimberidou: Sanofi: Research Funding. Off Label Use: Oxaliplatin - off-label use in a Phase I-II clinical trial (combined with fludarabine and cytarabine) for patients with relapsed/refractory AML or high-risk MDS.

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Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.423.423 ◽

2011 ◽

Vol 118 (21) ◽

pp. 423-423 ◽

Cited By ~ 2

Author(s):

Richard F. Schlenk ◽

Jürgen Krauter ◽

Markus Schaich ◽

Didier Bouscary ◽

Hervé Dombret ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Salvage Therapy ◽

Myeloid Leukemia ◽

Maximum Tolerated Dose ◽

Refractory Acute Myeloid Leukemia ◽

Grade 3 ◽

Acute Myeloid ◽

Refractory Aml

Abstract Abstract 423 BACKGROUND: Relapsed/refractory acute myeloid leukemia (AML) is characterized by poor prognosis, with low complete remission (CR) rates after salvage therapy and low overall survival. A major challenge is to improve the CR rate, thereby increasing allogeneic hematopoietic stem cell transplantation (alloHSCT) rates. Panobinostat is a pan-deacetylase inhibitor that increases acetylation of proteins involved in cancer. Preclinical studies in AML demonstrated that panobinostat potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in vitro. Single-agent panobinostat has induced CR in patients (pts) with AML. The addition of panobinostat to an active chemotherapeutic regimen in pts with relapsed/refractory AML has the potential to improve therapeutic outcomes in this setting. AIMS: This phase Ib, multicenter, open-label dose-escalation study was designed to determine the maximum tolerated dose (MTD) of panobinostat in combination with a fixed dose of ara-C and mitoxantrone in pts with relapsed/refractory AML. The secondary objectives were to characterize safety and tolerability during the dose-escalation phase and at the MTD and to evaluate anti-leukemic activity. METHODS: Successive cohorts of at least 3 pts with confirmed relapsed or refractory AML were treated with oral panobinostat (starting with 20 mg, escalated in 10-mg steps) thrice weekly on days 1, 3, 5, 8, 10, and 12, in combination with intravenous ara-C (1 g/m2) on days 1–6 and mitoxantrone (5 mg/m2) on days 1–5 of a 28-day cycle. The MTD was determined on the basis of the observed dose-limiting toxicities (DLTs), safety assessment, and tolerability during the first 28 days after starting panobinostat. A DLT was defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications with the following criteria: neutropenia lasting > 28 days after cycle 1 for hematologic DLTs; grade 4 AST/ALT or grade 3 AST/ALT for > 7 days; grade 3/4 bilirubin, vomiting, diarrhea, or any non-hematologic toxicity for non-hematologic DLTs. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of AEs according to CTCAE v3.0. The adaptive Bayesian logistic regression model was used to guide dose escalation with overdose control. RESULTS: Of 5 dose levels, 40 pts (median age, 55 years; range, 19–73 years) were treated at panobinostat dosages of 20 to 60 mg, with 5 pts at 20 mg, 8 at 30 mg, 10 at 40 mg, 11 at 50 mg, and 6 at 60 mg. Of 6 DLTs observed, 1 was at 40 mg (sepsis and tachyarrhythmia), 2 were at 50 mg (vomiting/nausea; diarrhea), and 3 were at 60 mg (neutropenic colitis; 2 hypokalemic events). Frequent AEs of all grades, regardless of causality, included nausea (32 [80%]), diarrhea (31 [78%]), vomiting (26 [65%]), hypokalemia (25 [63%]), thrombocytopenia (24 [60%]), abdominal pain (22 [55%]), decreased appetite, and febrile neutropenia (21 each [53%]). The most frequent grade 3/4 treatment-related AEs were thrombocytopenia (20 [50%]), anemia (9 [23%]), leukopenia, and neutropenia (7 each [18%]). Serious AEs, regardless of causality, were reported in 23 pts, with febrile neutropenia (12 [30%]) being the most common. The MTD was determined to be 50 mg of panobinostat on the basis of observed DLTs and safety and tolerability in cycle 1 of the dose-escalation phase. Clinical responses were observed in 22 pts (55%), including 13 CR, 5 morphological CR, and 4 partial remissions. In pts receiving 40- and 50-mg doses of panobinostat, the preliminary efficacy was promising, with a response in 11 of 21 pts (52%). An alloHSCT was performed in 8 pts after the start of salvage therapy. CONCLUSIONS: The combination of panobinostat, ara-C, and mitoxantrone showed no unexpected toxicities and promising anti-leukemic activity in pts with relapsed/refractory AML. The MTD was determined to be 50 mg of panobinostat; enrollment at this dose is ongoing for the dose-expansion phase to further assess safety, tolerability, and activity. Thrombocytopenia and anemia were the principal treatment-related hematologic AEs. Treatment-related non-hematologic AEs were primarily gastrointestinal toxicities and fatigue. Disclosures: Krauter: Novartis: Consultancy, Honoraria. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Squier:Novartis Corporation: Employment. Zahlten:Novartis AG: Employment. Wang:Novartis Corporation: Employment. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

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Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.3983.3983 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3983-3983 ◽

Cited By ~ 2

Author(s):

Beth A Christian ◽

John G. Kuruvilla ◽

Sonali M. Smith ◽

Pierluigi Porcu ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Disease Progression ◽

Dose Level ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Off Label ◽

Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

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Phase 1 Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v126.23.1339.1339 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1339-1339

Author(s):

Asma Anwar ◽

Anna B. Halpern ◽

Megan Othus ◽

Bart L. Scott ◽

Paul C. Hendrie ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Phase 1 ◽

Early Death ◽

Hematologic Toxicity ◽

Phase 2 ◽

Persistent Disease ◽

Phase 2 Study ◽

Grade 3 ◽

Refractory Aml

Abstract Background: Although some adults with AML or high-risk MDS will experience long-term disease-free survival after initiation of curative-intent therapy, most patient will require therapy re-induction therapy either for primary induction failure of disease recurrence after an initial complete remission (CR) was achieved. The outcomes with standard regimens for relapsed/refractory AML are generally poor, with CR rates often not exceeding 15-20%. Data from a large single arm phase 2 study in poor-risk relapsed/refractory AML suggested tolerability and encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (G-CLAM). Given recent data suggesting benefit of escalated doses of anthracyclines in AML, the goal of our phase 1 study was to determine the maximum tolerated dose (MTD) of mitoxantrone within G-CLAM in adults with relapsed/refractory AML or high-risk MDS and estimate the efficacy of this regimen. Patients and Methods: Adults ≥18 years of age with relapsed or refractory AML (APL excluded) or high-risk MDS (>10% blasts) were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a risk of early death with standard induction chemotherapy of ≤3%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal). Excluded were patients with concomitant illness with expected survival <1 year and those with active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day on days 1-3, as compared to 10 mg/m2/day used in standard-dose G-CLAM). Other drug doses were G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). A second identical course of G-CLAM was given in the case of persistent disease. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia or infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 26 patients (14M, 12F), median age 57 (range: 37-77) years, median TRM score 1.73 (range: 0.29-3.92) with relapsed/refractory AML (n=23), or high-risk MDS (n=3) and cytogenetically favorable (n=2), intermediate (n=13), and adverse (n=11) disease characteristics were enrolled. One DLT occurred at dose level 1 (nausea) and 2 at dose level 4 (encephalitis and cardiogenic shock), establishing G-CLAM with mitoxantrone at 16 mg/m2/day as the MTD in our study. 2 patients (8% [95% exact confidence interval: 1-25%]) died within 28 days of treatment initiation from sepsis and cardiogenic shock, respectively. Overall, 13/26 patients (50% [30-70%]) achieved a CR (n=8) (31% [14-52%]), CRp (n=1) (4% [0-20%]), or CRi (n=4) (15% [4-35%]) with 1-2 cycles of re-induction therapy; one patient each achieved a leukemia-free state and partial remission (in a patient presenting with myeloid sarcomas); nine patients (35% [17-56%]) had persistent disease. We were unable to assess response in 2 patients due to early death (n=1) and refusal for marrow re-assessment (n=1). 7/13 responders (54%) had no evidence of residual disease by flow cytometry at best response. Among responders, median times to an absolute neutrophil count ≥500/µL and a platelet count of 50,000/µL were 33 (range: 17-51) and 31 (range: 18-54) days, respectively. Besides infections and neutropenic fever, nausea, hypoxia (fluid overload/infection-related), and maculopapular rash were the most common grade ≥3 adverse events. Conclusion G-CLAM with mitoxantrone up to 16 mg/m2/day is feasible, well tolerated, and effective in relapsed/ refractory AML/high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Scott: Celgene Corporation: Consultancy, Speakers Bureau. Becker:Igenica: Research Funding. Walter:Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy.

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Activity of Combined Flavopiridol and Lenalidomide in Patients with Cytogenetically High Risk Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase I Trial,

Blood ◽

10.1182/blood.v118.21.3910.3910 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3910-3910

Author(s):

Kristie A. Blum ◽

Lai Wei ◽

Jeffrey A. Jones ◽

Leslie A Andritsos ◽

Joseph M. Flynn ◽

...

Keyword(s):

High Risk ◽

Combination Therapy ◽

Phase I ◽

Dose Escalation ◽

Phase I Trial ◽

Single Agent ◽

Significant Activity ◽

Upper Respiratory Tract ◽

Off Label ◽

Grade 3

Abstract Abstract 3910 Background: The cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are active in heavily pre-treated CLL patients (pts) with bulky adenopathy and adverse cytogenetics, although dose escalation of these two agents has been limited by tumor lysis syndrome (TLS) and tumor flare. Furthermore, these agents do not deplete T-cells, and combination therapy may result in greater efficacy and less infectious toxicity than observed with fludarabine or alemtuzumab combinations. Methods: We conducted a phase I trial of combined flavopiridol and lenalidomide in pts with CLL relapsed after at least 1 prior therapy, WBC < 150,000/mm3, ANC > 1000/mm3, platelets > 30,000/mm3, and creatinine < 1.5 mg/dL. Treatment consisted of flavopiridol alone, 30 mg/m2 bolus + 30–50 mg/m2 4-hour continuous IV infusion (CIVI) days 1, 8, and 15 of cycle 1. Starting in cycle 2, flavopiridol 30 mg/m2 bolus + 30–50 mg/m2 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 35 days. All pts received 20 and 4 mg of dexamethasone 30 minutes prior to and 24 hours after flavopiridol, respectively, to minimize cytokine release symptoms. Pegfilgrastim was administered on day 18 of cycles 2–8. Results : Thirty pts (18 males) with a median age of 60 (range 42–74) previously treated with a median of 3 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine and 40% were fludarabine refractory. Seventy-three percent of patients were Rai stages III-IV, 60% pts had bulky adenopathy > 5 cm, 60% pts had del(17p13.1), 37% pts had del(11q22.3), and 83% pts had a complex karotype. Twenty-five pts completed two or more cycles of therapy (median 3.5, range 1–8). Five pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=2), and grade 4 thrombocytopenia (n=1). Pts received 2.5 mg (n=6), 5.0 mg (n=7), 7.5 mg (n=4), and 10 mg (n=3) of lenalidomide with 30 mg/m2 bolus + 30 mg/m2 4-hour CIVI flavopiridol and 5 patients have received 10 mg of lenalidomide with 30 mg/m2 bolus + 50 mg/m2 4-hour CIVI flavopiridol. DLT consisting of grade 3–4 transaminitis persisting > 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of thrombocytopenia (60%), diarrhea (57%), transient transaminitis (47%), neutropenia (47%), hyperglycemia (47%), infection (43%, pneumonia in 5 pts, upper respiratory tract infection in 2 pts, cellulitis in 1 pt, herpes simplex stomatitis in 1 pt, oral candidiasis in 1 pt, catheter-associated in 1 pt, and febrile neutropenia without a source in 2 pts), hypokalemia (37%), anemia (33%), hypophosphatemia (33%), hypocalcemia (17%), hyperkalemia (17%), TLS requiring dialysis (7%), tumor flare (3%), and rash (3%). In 23 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 13 pts (57%), including 7 pts with del(17p13.1), 6 pts with del(11q22.3), 9 pts with complex cytogenetics, 5 fludarabine-refractory pts, and 6 pts with bulky lymphadenopathy. Six pts were able to proceed to allogeneic transplant after 1–3 cycles, and 4 of these pts remain in remission. Median PFS and OS are 7 months (range 0–24 months; 95% CI 5, 11) and 23 months (range 0–27 months; 95% CI 13, 27), respectively. No significant differences have been observed in the single agent and combination PK parameters (AUC, Cmax, T ½, and Clearance) of lenalidomide and flavopiridol. Conclusions: Combined flavopiridol and lenalidomide is well tolerated without increased risks of TLS or tumor flare, with significant activity in pts with bulky, cytogenetically high-risk CLL. This combination regimen could be utilized to de-bulk high risk pts prior to stem cell transplantation or prior to other oral therapies. The MTD has not been reached and dose escalation continues at a lenalidomide dose that exceeds the single agent MTD in CLL of 5 mg (Maddocks et al, Blood 114: abstract 3445, 2009). Future evaluation of continued maintenance lenalidomide after initial combination therapy is planned. This trial is supported by NCI 1R21 CA133875, NCI P50-CA140158, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080–06, and the D. Warren Brown Foundation. Disclosures: Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.

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Phase I Study Of The Combination Of Midostaurin, Bortezomib and Chemotherapy In Relapsed/Refractory Acute Myeloid Leukemia (AML): Targeting Aberrant Tyrosine Kinase Activity

Blood ◽

10.1182/blood.v122.21.3966.3966 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3966-3966

Author(s):

Alison R Walker ◽

Hongyan Wang ◽

Rebecca Klisovic ◽

Katherine Walsh ◽

Sumithira Vasu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Genetic Risk ◽

Progressive Disease ◽

Kinase Activity ◽

Off Label Use ◽

Tyrosine Kinase Activity ◽

Off Label ◽

Grade 3 ◽

Relapsed Disease ◽

Refractory Aml

Abstract Background We have shown that the proteasome inhibitor bortezomib is able to disrupt the physical interaction between the transcription factor Sp1 and NF-kB(p65), inhibiting Sp1 DNA-binding activity in myeloid blasts. (Liu, Blood 2008) We have also observed that both KIT and FLT3 promoters harbor Sp1 binding sites and that Sp1 induces transcription of these genes. We hypothesize that the Sp1/NF-kB pathway is a modulator of tyrosine kinase (TK) activity, and that administration of bortezomib with the tyrosine kinase inhibitor midostaurin will down regulate TKs at the transcription level and inhibit kinase activity in AML. The expectation is that two fold molecular targeting in combination with chemotherapy will result in a greater antileukemic effect. Methods Adults with relapsed or refractory AML by WHO criteria and preserved organ function with ECOG ≤ 2 were eligible. Patients enrolled at dose levels (DL) 1 and 2 received midostaurin 50mg po BID d 1-14, bortezomib was dose escalated – DL 1: 1.0mg/m2 IV d 1,4,8,11; DL 2: 1.3mg/m2 IV d 1,4,8,11. Cycles were repeated every 28 d or until achievement of morphologic complete remission (CR) or CR with incomplete count recovery (CRi), for up to 3 cycles. Patients enrolled at DL 3 received mitoxantrone 4mg/m2, etoposide 40mg/m2, cytarabine 1g/m2 d1-6 (MEC) followed by midostaurin 50mg bid d 8-21 and bortezomib 1.3mg/m2 IV d 8,11,15,18. Due to the development of grade 3 peripheral neuropathy (PN) that was a dose limiting toxicity (DLT) in two patients treated at DL 3, bortezomib administration was changed from IV to subcutaneous (SQ) and the dose and schedule was changed to 1.0mg/m2 on d 8 and 15 on (DL 3A) - doses of midostaurin and MEC remained constant. Patients enrolled at DL 3 or 3A received one cycle of treatment, but were able to continue with maintenance bortezomib and midostaurin only for up to three cycles if they did not proceed to allogeneic stem cell transplantation (SCT). Responses were graded by International Working Group criteria for AML (Cheson, JCO 2013). Results 11 patients enrolled to DL 1 and 2; 7 had relapsed disease (5 with CR1< 1 year) and 4 were primary refractory. The median age was 67 (range, 64-76) and 4 patients were FLT3-ITD or FLT3-TKD positive. According to European LeukemiaNet (ELN) genetic risk groups, 6, 3, and 2 patients had intermediate I, intermediate II and adverse risk disease, respectively. 2 patients received more than one cycle of chemotherapy (range, 1-2), all developed progressive disease and were removed from study. There were no DLTs at DL 1 or 2. 13 patients enrolled to DL 3 and 3A, 8 had relapsed disease (3 with CR1< 1 year) and 5 were primary refractory. The median age was 53 (range, 19-70) and 4 patients were FLT3-ITD positive. According to ELN genetic risk, 2, 7, 1 and 3 patients had favorable, intermediate I, intermediate II, and adverse risk, respectively. Of the first 3 patients treated at DL 3, one developed grade 3 PN which was a DLT. 3 additional patients were enrolled and 1 patient with a history of anthracycline exposure had a grade 3 decrease in EF. An additional 3 patients were treated, 1 developed grade 3 diarrhea and 1 developed grade 3 PN, both DLT. Given that 8/9 (88%) patients treated at DL 3 achieved a CR or CRi, we chose to further explore the regimen, however, given the concerns for PN, the dose of bortezomib only was modified (DL 3A). 4 additional patients were treated at DL 3A, 2 achieved CR, 1 achieved CRi. No patients have developed PN and there were no DLTs at this dose level. Death within 8 weeks occurred in 8 patients (34.7 %) due to sepsis (1), pneumonia (1), enterococcus bacteremia (1), or progressive disease (5). Overall the objective response rate was 47.8% (11/23), however the CR/CRi response in those who received bortezomib, midostaurin and chemotherapy was 84.6% (11/13). The CR/CRi rate in those with a FLT3 mutation was 75% (3/4). 7 patients have gone on to receive an allogeneic SCT. Conclusions The combination of bortezomib, midostaurin and intensive chemotherapy was active in this group of patients with relapsed/refractory AML. DLT of PN was observed, however with a decrease in dose and frequency of bortezomib this has not recurred. Correlative studies to evaluate bortezomib and midostaurin in modulating tyrosine kinase activity are ongoing. Off label use Bortezomib in AML Disclosures: Off Label Use: Bortezomib in AML.

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Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): Final Results from a Phase 1/2 Study

Blood ◽

10.1182/blood.v128.22.1064.1064 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1064-1064

Author(s):

Anna B. Halpern ◽

Sarah A. Buckley ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Response Rate ◽

Phase 1 ◽

Hematologic Toxicity ◽

Hypomethylating Agents ◽

Refractory Acute Myeloid Leukemia ◽

Pre Treatment ◽

Grade 3 ◽

Refractory Aml

Abstract Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (>10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of <9.2 (corresponding to an expected TRM of <9.2% with standard induction chemotherapy). Prior treatment with hypomethylating agents or MEC (but not combined) was allowed. Patients with prior hematopoietic stem cell transplant (HCT) were eligible. Excluded were patients with concomitant illness with expected survival <1 year and uncontrolled infection. In phase 1, cohorts of 6-12 patients were assigned to 1 of 3 dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed 5 days later by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days). Patients with persistent AML were eligible for re-induction. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 more cycles of similarly dosed d/MEC. Dose-limiting toxicity (DLT) was defined as: 1) a grade 3 non-hematologic toxicity lasting >48 hours resulting in a >7-day delay of the subsequent treatment cycle; 2) a grade ≥4 non-hematologic toxicity, if recovery to grade ≤2 within 14 days. Both excluded febrile neutropenia/infection and constitutional symptoms. During phase 2, a Simon minimax 2-stage design was used to monitor whether a response rate of 0.25 was reached, with 80% power and a 1-sided alpha of 7%, assuming a historical CR rate of 10-15%. Results: Fifty-two patients, median age 55 (range: 19-72) years, with primary refractory (n=19) or relapsed disease (n=33; median duration of prior CR: 5 [1-19] months) and a median TRM score of 3.15 (range: 0.07-9.05) were enrolled. They received a median of 2 (1-7) prior therapies; 14 had prior HCT. During dose escalation, 1 DLT occurred at each the 2nd and 3rd dose level, identifying a 10-day course of decitabine with MEC as MTD. Since no differences in response rates were noted between the 7 and 10-day course of decitabine, a 7-day course of decitabine was used in phase 2 for logistical reasons. Overall, 11/51 evaluable patients achieved a CR (21.6%; 95% confidence interval [CI]: 11.3-35.3%) of whom 9 had no measurable residual disease (MRD) by flow cytometry. This CR rate compared favorably to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Estey et al. Blood 1996; 88:756), with an observed/expected CR ratio of 1.77. Seven further patients achieved a CRp, and 2 had a CR with incomplete count recovery (CRi) for an overall response rate (ORR) of 20/51 (39.2%; 95% CI: 25.8-53.9%). Among the 45 evaluable patients treated with a 7 or 10-day course of d/MEC, the ORR was 37.8% (95% CI: 23.8-53.5%). Five patients achieved a morphologic leukemia-free state, 21 had resistant disease, and 5 died before response assessment. Median response duration (CR, CRi or CRp) was 130 (15-1,229) days, with 3 of these responses ongoing. Overall survival of these 20 patients was longer (median of 332 [62-1,000 days]) than that for patients who failed to achieve remission but did not experience TRM (median 119 [45-530] days). Inclusion of 6 eligible patients that were treated with this regimen outside the clinical trial did not change these results. Nine patients died within 28 days of treatment initiation for a TRM rate of 17.6% due to infection/septic shock (5), intracranial hemorrhage (1), respiratory failure (2), and progressive disease (1). Besides grade 3-4 cytopenias, infection/neutropenic fever, nausea, and mucositis were the most common adverse events. Conclusion: D/MEC is feasible and has anti-leukemic activity in heavily pretreated relapsed/refractory AML and high-risk MDS. A comparative analysis of these results with other contemporary intensive salvage regimens is ongoing. A follow-up study is also being done to explore the relative value of pre-treatment vs. concomitant use of decitabine with intensive salvage chemotherapy. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk or Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma (AFT-08)

Blood ◽

10.1182/blood-2018-99-114438 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2964-2964 ◽

Cited By ~ 1

Author(s):

Peter Martin ◽

Nancy L. Bartlett ◽

Julio C. Chavez ◽

John L. Reagan ◽

Sonali M. Smith ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Background: For patients with diffuse large B-cell lymphoma (DLBCL), resistance to standard R-CHOP immunochemotherapy remains an urgent and unmet clinical challenge. Aberrant DNA methylation likely contributes to chemoresistance and may represent a therapeutic target.In a phase I study of R-CHOP plus subcutaneous azacitidine, a DNA methyltransferase inhibitor, complete responses (CRs) were achieved in 10/11 high-risk DLBCL patients (Clozel et al. Cancer Discovery 2013), providing the rationale for this study of oral azacytidine (CC-486) plus R-CHOP. Previously reported data from the dose escalation phase of this study demonstrated promising response rates in patients with high-risk DLBCL (Martin et al. Blood 2017). Here, we present results from both the dose escalation and expansion phases after substantially longer follow-up. Methods: CC-486-DLBCL-001 (NCT02343536) is a phase I, open-label, multicenter study of CC-486 plus standard R-CHOP in patients with previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed FL. Eligible patients were aged ≥18-80 years with no active viral hepatitis, had an International Prognostic Index (IPI) score ≥2 or DLBCL double-positive for BCL2 and c-MYC, an Eastern Cooperative Oncology Group performance status ≤2, and Ann Arbor stage II-IV disease. Patients in the dose escalation phase were enrolled sequentially into 4 dose cohorts of CC-486 (100, 150, 200, and 300 mg) using the time-to-event continual reassessment method. Additional patients were enrolled in the expansion phase to evaluate preliminary efficacy. Patients received up to six 21-day cycles. CC-486 was administered for 7 days before initiation of R-CHOP and on days 8-21 of cycles 1-5. Granulocyte-colony stimulating factor was mandated by protocol and anti-emetics were standard treatment. The primary objectives were to determine safety (per NCI CTCAE v4.03) and the recommended phase 2 dose (RP2D) of CC-486 in combination with standard R-CHOP. Secondary endpoints included pharmacokinetics and preliminary efficacy per the International Working Group criteria (Cheson et al.J Clin Oncol 2014). Results: Fifty-nine patients were enrolled as of May 31, 2018, including 40 treated at the RP2D of CC-486 300 mg. The median age in the overall population was 66 years (range, 25-80), 76% were aged >60 years, 59% were male, and 59% had an IPI score ≥3. Fifty-four patients (92%) completed all 6 planned cycles of study treatment. Thirteen patients (22%) had CC-486 dose reductions because of adverse events (AEs). Two patients discontinued CC-486 due to AEs: febrile neutropenia (n=1; 150 mg) and sepsis (n=1; 300 mg). The most common AEs were gastrointestinal, which were mainly grade 1/2; hematologic AEs were the most common grade 3/4 toxicity (Table 1). Grade 3/4 AEs related to CC-486 occurred in 36 (61%) patients, most commonly neutropenia (41%) and febrile neutropenia (20%). Febrile neutropenia was more common among older patients (9/15 patients with this AE were aged >70 years) and those with IPI scores ≥3 versus ≤2 (31% vs 17%) but was not correlated with CC-486 dose. One patient died during the study (acute respiratory failure possibly related to study treatment). All patients were evaluable for response. The overall response rate was 95%, with 52 patients (88%) achieving a CR; response rates were generally similar in patients with IPI scores ≥3 and ≤2 and in patients treated at the RP2D (Table 2). Median progression-free survival (PFS) was not reached (median follow-up of 12 months); estimated 1-year PFS rates were similar in the overall population (86%) and in patients with IPI scores ≥3 (84%) and ≤2 (89%). Conclusions: Epigenetic priming with CC-486 before R-CHOP demonstrated promising clinical activity in patients with high-risk, previously untreated DLBCL, transformed FL, or grade 3B FL. AEs were generally consistent with the known safety profile of azacitidine and toxicities associated with R-CHOP. These results support further investigation of oral azacitidine (CC-486) in combination with R-CHOP, including patients with high-risk disease. Disclosures Martin: Gilead: Consultancy; Janssen: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; Seattle Genetics: Consultancy; Bayer: Consultancy. Bartlett:Astra Zeneca: Research Funding; Forty Seven: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Research Funding; Immune Design: Research Funding. Chavez:Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Humanigen: Consultancy. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding. Smith:Portola: Honoraria; BMS: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau. Jones:Celgene: Employment, Equity Ownership. Drew:Celgene Corp.: Employment. Wu:Celgene: Employment, Equity Ownership. Cerchietti:Celgene: Research Funding; Weill Cornell Medicine: Employment. Leonard:ADC Therapeutics: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; BMS: Consultancy; Juno: Consultancy; Celgene: Consultancy; Biotest: Consultancy; Novartis: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Sutro: Consultancy; United Therapeutics: Consultancy.

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Ofatumumab Based Chemoimmunotherapy (CIT) for Patients with Previously Untreated CLL,

Blood ◽

10.1182/blood.v118.21.3898.3898 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3898-3898

Author(s):

Tait D. Shanafelt ◽

Mark C Lanasa ◽

Clive S. Zent ◽

Jose F. Leis ◽

Timothy G Call ◽

...

Keyword(s):

Flow Cytometry ◽

Board Of Directors ◽

Research Funding ◽

Previous Experience ◽

Stage Iii ◽

Hematologic Toxicity ◽

Off Label Use ◽

Advisory Committees ◽

Off Label ◽

Grade 3

Abstract Abstract 3898 Background: Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 4050 of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a humanized anti-CD20 monoclonal antibody that is approved for patients with relapsed CLL refractory to fludarabine and alemtuzumab. The single agent activity of ofatumumab in patients with refractory CLL suggests it may have greater efficacy than rituximab in patients with CLL. To explore the efficacy of ofatumumab based CIT, we initiated a clinical trial studying the effect of ofatumumab in combination with pentostatin and cyclophosphamide (PCO) for patients with previously untreated CLL. METHODS: Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). The treatment schema included 6 cycles of ofatumuamb (300 mg on day 1 of cycle 1;1000 mg on day 2 of cycle 1 and day 1 of cycles 26) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) administered every 21 days. All patients underwent complete response evaluation including evaluation for MRD using sensitive flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 33 patients were enrolled at Mayo Clinic and Duke University between 3/2010 and 9/2010. All patients were eligible for treatment and have completed active treatment. Clinical characteristics included: 76 male, median age 63 (range: 5083); intermediate Rai risk 27; and high Rai risk 73. On prognostic testing 33 were CD38, 48 Zap-70 , 58 IGHV unmutated, and 6 had high risk FISH (del 17p13; del 11q22). 26 of 33 eligible patients (79) completed all 6 cycles of PCO induction. Seven patients went off treatment early (toxicity: n5; refusal: n1; progression: n1). Adverse events deemed at least possibly related to PCO induction included 8 (24) patients with grade 3 hematologic toxicity and 5 (15) with grade 3 non-hematologic toxicity. The overall response rate to PCO induction was 94 (31/33) with 15 (45) CR/CRi, 5 (15) CCR, 9 (27) nPR, and 2 (6) PR. 2/10 (20) patients with CR's tested for MRD were also MRD negative by 6 color flow cytometry analysis. Finally, we compared this cohort of patients treated with ofatumuamb-based CIT to our prior 108 patient cohort of patients treated with rituximab-based CIT both of which used an identical chemotherapy backbone (pentostatin and cyclophosphamide). Although the age, gender, ALC, and prognostic profile (CD38, ZAP-70, and IGHV mutation status) of treated patients were similar (all p0.3), the ofatumumab cohort included more advanced stage patients (Rai stage III/IV: 73 vs. 41 p0.002). Ofatumumab-based CIT appeared to be better tolerated than our previous experience with rituximab-based CIT (grade 3 hematologic toxicity ofatumumab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{8$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT51 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{55$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.009; grade 3 non-hematologic toxicity ofatumumab-CIT 15 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{5$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{26$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.34). Despite a higher proportion of Rai Stage III/IV patients in the ofatumumab cohort, the efficacy of ofatumumab-based CIT also compared favorably to our previous experience with rituximab based CIT (Table). CONCLUSION: Front-line ofatumumab-based CIT appears to be well-tolerated in patients with CLL. Compared to our historic experience with rituximab based CIT, ofatumumab-based CIT appeared to have less hematologic toxicity and improved efficacy. This trial has been expanded to provide a larger experience with ofatumumab-based CIT. Disclosures: Shanafelt: Hospira: Research Funding; Glaxo-Smith-Kine: Research Funding; Genentech: Research Funding. Off Label Use: Off label use of pentostatin and Ofatumumab. Lanasa:GlaxoSmithKline: Consultancy, Speakers Bureau. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

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A Single-Arm, Open-Label, Multi-Center Phase I/II Study Of The Combination Of Panobinostat and Carfilzomib In Patients (pts) With Relapsed Or Relapse/Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v122.21.1937.1937 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1937-1937 ◽

Cited By ~ 5

Author(s):

Jesus Berdeja ◽

Michael Savona ◽

Joseph R Mace ◽

Lowell Hart ◽

James Essell ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Escalation ◽

Off Label Use ◽

Expansion Phase ◽

Off Label ◽

Refractory Multiple Myeloma ◽

Grade 3 ◽

Dose Levels ◽

Experienced Grade ◽

Dose Reductions

Abstract Background Proteasome inhibitors (PI) such as bortezomib and carfilzomib (CFZ) have improved the treatment of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Preclinical studies demonstrate synergistic anti-MM activity of the combination of HDACi with PI through dual inhibition of the proteasome and aggresome pathways. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs in clinical studies. In this study, we evaluate the safety and efficacy of the PAN/CFZ combination in pts with relapsed and relapsed/refractory MM. Here we present the updated results of this ongoing trial. Methods Patients with MM who had relapsed after at least one prior treatment were eligible to participate. In the dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of 4 planned dose levels with the combination of CFZ and PAN. PAN was administered orally three times weekly during weeks 1 and 3 of each cycle (Days 1, 3, 5, 15, 17, 19). CFZ was administered IV over 30 min on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The 4 dose levels tested were DL 1, defined as 20 mg PAN and 20/27 mg/m2 CFZ; DL 2, defined as 20 mg PAN and 20/36 mg/m2 CFZ; DL 3, defined as 20 mg PAN and 20/45 mg/m2 CFZ; and DL 4, defined as 30 mg PAN and 20/45 mg/m2 CFZ. Treatment was continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse Events (AEs) were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). The MPD (maximum planned dose) was further explored in the expansion phase. Results 10 patients were treated in the dose escalation portion of the study. No DLTs were observed. DL 4 was further explored and 31 patients were enrolled in the expansion phase of the study. As of the data cutoff of 5/31/2013, 44 pts were accrued to the trial, including 34 pts on the eventual expanded DL 4. The median age of pts was 66 (41-83); most patients were ISS stages 2 and 3; 38% of pts had adverse prognostic cytogenetics or FISH, including 23% with del 17p. The median number of prior therapies was 3 (1-6) including 89% with prior bortezomib, 89% with prior immune modulating drugs (IMiDs), 34% with prior stem cell transplants. Thirty six percent of pts were refractory to bortezomib, 30% were refractory to IMiDs, 14% were refractory to both bortezomib and IMiDs, and 43% were refractory to their last treatment regimen. Twenty seven (61%) pts remain on active treatment. Forty five percent of pts experienced ≥ grade 3 hematologic-related AEs, the most common being G3 thrombocytopenia (30%) and neutropenia (20% G3 and 2% G4). Thirty four percent of pts experienced ≥ grade 3 non-hematologic AEs, the most common being fatigue (11% G3) and nausea/vomiting (9% G3). The most salient of all grade AEs were nausea/vomiting (39% G1, 20% G2, 9% G3, 0 G4) and thrombocytopenia (14% G1, 27% G2, 30% G3, 0 G4). Peripheral neuropathy was rare (5% G1, 2% G2, 0 G3/4). In pts treated on DL 4 (30 mg PAN and 20/45 mg/m2 CFZ), late cycle dose reductions for PAN were common (59% of pts) and the median PAN dose delivered was 23.4 mg. CFZ dose reductions were rare (18% of pts) and the median CFZ dose was 40.8 mg/m2. The ORR was 64% with 31% ≥VGPR and 30% PR. In addition, there were 5% MR, 26% SD and 5% PD. The ORR for bortezomib exposed pts, bortezomib refractory pts and dual bortezomib and IMiD refractory pts was 60%, 67% and 66%, respectively. With a median follow up of 6.3 months, the PFS at 6 and 12 months was 63% and 41% respectively. The OS was 83% at both 6 and 12 months and the median TTP was 8.6 months. Conclusions The combination of PAN and CFZ is feasible and effective in this relapsed/refractory MM population. Due to dose reductions required for PAN and no MTD reached, 2 further dose levels will be explored with plans to do a parallel dose expansion if tolerated. Disclosures: Off Label Use: Off-label use of the combo Panobinostat and Carfilomib in the treatment of relapsed/refractory Multiple Myeloma.

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