Single Institution Phase 1 Study on Combination Therapy of Midostaurin and Panobinostat in Acute Myeloid Leukemia - the Interim Report

Abstract Background: Midostaurin is a non-specific FLT3 inhibitor which showed anti-leukemic activity against both FLT3 mutated as well as unmutated acute myeloid leukemia (AML) in early phase studies. Panobinostat, a potent oral pandeacetylase inhibitor had also showed significant anti-leukemic signal in early phase studies. In the pre-clinical study, our group had previously reported synergistic anti-leukemic activity when a FLT3 inhibitor was used in combination with a HDAC inhibitor in vitro as well as in vivo animal study. The current study is our first bench-to-bedside study to further evaluate this combination therapy in AML patients. Method: Elderly AML who were either newly diagnosed and decline hypomethylating agent (HMA) or who failed HMA, MDS-RAEB-2, and relapsed refractory AML who were unfit for intensive chemotherapy or have no other treatment option were eligible regardless of FLT3 mutation status. The classical 3+3 dose escalation method was applied. Dose level 1 for Midostaurin was 50mg bd and Panobinostat was 10mg 3 times per week. Dose escalations were planned with only one drug escalation at a time on every level. Midostaurin was administered daily as continuous cycle while Panobinostat was given for the first 3 weeks of a 4 weeks cycle. Dose-limiting toxicities were defined as grade 3 or more non-haematologic toxicities occurring within the first cycle. Chronic toxicity is defined as recurrent or persistent adverse events that are possibly related to investigational products. Response assessments were done at post cycle 2 and cycle 4. Concomitant treatment with hydroxyurea was allowed up to cycle 1 day 14 to control leukocytosis if needed. Results: A total 7 patients have been recruited with a median age of 71 years old (range: 47 to 82). 2 patients had MDS-RAEB2, one with Acute myelomonocytic leukemia, 3 had AML with myelodysplasia-related changes (AML-MRC) and one with de novo FLT3-ITD AML. One of the AML-MRC had FLT3-ITD mutation and another had FLT3-TKD mutation. 4 out of 7 had prior HMA therapy, the remaining three were treatment naïve. 2 patients were not evaluable for DLT and response assessment due to progressive disease. 2 completed 2 cycles, the other 3 completed 4, 5 and 9 cycles respectively. No DLT was observed within cycle 1. Significant grade 1-2 treatment emerging adverse events were anorexia (4/5), fatigue (3/5), nausea (2/5), and dysgeusia (2/5). These toxicities persist beyond cycle 1 with increasing frequency. Grade 2 fatigue were observed in 4 patients, grade 2 anorexia in 4 patients, grade 1 dysgeusia in 4 patients, and grade 3 lipase elevation in one patient. 4 out of 5 patients developed severe grade 4 thrombocytopenia requiring regular platelet transfusion. Two had baseline grade 4 thrombocytopenia but the severity worsen after 1 cycle of treatment. These were thought to be chronic toxicities because the symptoms were largely resolved or improved during dose interruptions. In view of significant chronic toxicities, no further dose escalation was done and dose level 1 would be evaluated further in expansion cohort. 5 out 7 had post cycle 2 response assessment. One patient with FLT3-TKD achieved CRi, one AML-MRC showed 50% blast reduction, and the remaining 3 had stable disease. The one who achieved CRi eventually withdrew from study after completing 6 cycles due to fatigue, anorexia, severe grade 4 thrombocytopenia with gastrointestinal bleeding. As of report date, he remains alive and well after 9 months off study. His transfusion requirement has also reduced. One succumbed to intracranial bleeding during his cycle 10. He was in stable disease. The remaining 5 demised due to progressive disease. Conclusion: Even though no DLT was observed within cycle 1, significant chronic toxicities such as fatigue and anorexia were observed. Objective anti-leukemic activity was observed in 5 evaluable patients. Further expansion cohort would provide a clearer picture on the anti-leukemic effect as well as the chronic toxicities. Disclosures Chng: Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Merck: Research Funding; Aslan: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.

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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.

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Sunitinib and Intensive Chemotherapy in Patients with Acute Myeloid Leukemia and Activating FLT3 Mutations: Results of the AMLSG 10-07 Study (ClinicalTrials.gov No. NCT00783653)

Blood ◽

10.1182/blood.v120.21.1483.1483 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1483-1483 ◽

Cited By ~ 1

Author(s):

Walter Fiedler ◽

Sabine Kayser ◽

Maxim Kebenko ◽

Jürgen Krauter ◽

Helmut R. Salih ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Single Agent ◽

Intensive Chemotherapy ◽

Consolidation Therapy ◽

Flt3 Mutations ◽

Level 1 ◽

Acute Myeloid

Abstract Abstract 1483 Background: Activating FLT3 mutations including internal tandem duplications (FLT3-ITD) and tyrosine-kinase domain mutation (FLT3-TKD) occur in approximately one third of patients with acute myeloid leukemia (AML) and are particularly associated with a poor outcome in case of FLT3-ITD. Sunitinib is a multitargeted FLT3 inhibitor approved for the treatment of advanced/metastatic renal cancer and metastatic/unresectable malignant GIST after failure of imatinib. Sunitinib has been evaluated in refractory AML as single agent treatment resulting in transient blast count reduction and in several cases of partial response in AML with activating FLT3 mutations. Aims: To evaluate the feasibility of a standard induction and consolidation therapy in combination with orally administered sunitinib in elderly AML patients with activating FLT3 mutations. Methods: Patients aged 60 years or higher with AML with activating FLT3 mutations (FLT3-ITD, FLT3-TKD) and fit enough for intensive chemotherapy were eligible. Induction therapy included cytarabine 100 mg/m2 per continuous infusion on days 1–7 and daunorubicin 60 mg/m2 i.v. on days 1–3 (DA). A second course was allowed in responding patients, who did not achieve a complete remission (CR). In patients achieving a CR after induction therapy three consolidation cycles were intended (cytarabine 1 g/m2 i.v. bid, on days 1,3,5). A 3+3 dose escalation/de-escalation scheme was used to define the dose and scheduling of sunitinib. The first cohort of three patients received oral sunitinib continuously starting from day 1 in a dose of 25 mg/day (level 1). Dose escalation to level 2 with sunitinib 37.5 mg/day continuously or dose de-escalation to level −1 with 25 mg day 1 to 7 had been defined in the protocol. After definition of the maximally tolerated dose (MTD) an extension of the cohort at that dose was intended. Results: A total of twenty-two patients were enrolled between January 2009 and March 2011. The median age was 70 years (range 60–78), 13 were female. The type of AML was de novo in 16 pts., s-AMLin one patient and t-AML in 4 pts. Fifteen patients had a FLT3-ITD (68%) and 7 a FLT3-TKD (32%) mutation. A NPM1 mutation was present in 11 patients (50%), 15 patients exhibited a normal karyotype, 3 an intermediate-2 risk karyotype according to ELN guidelines and 2 a complex karyotype and 2 had no evaluable metaphases. In the first cohort 5 patients were treated and two experienced dose-limiting toxicity (DLT), i) prolonged hematological recovery beyond day 35 in a patient achieving a CR and ii) a hand-foot-syndrome grade III. Four of the 5 patients achieved a CR. According to the protocol the following patients received treatment at dose level −1 with sunitinib 25mg days 1 to 7. In this cohort only one DLT occurred, again prolonged hematological recovery. Thus the MTD was defined at dose level −1. Response to induction therapy in all patients was CR in 13 pts. (59%), partial remission in 1 pt. (4.5%), refractory disease in 5 pts. (23%), death in 3 pts. (13.5%). CR rate in AML with FLT3-ITD was 53% (8/15) and 71% (5/7) in those with FLT3-TKD. All 13 patients achieving CR received repetitive cycles of high-dose cytarabine consolidation therapy and 7 proceeded to single agent sunitinib maintenance therapy (median 11 months, range 1–24 months). In these patients relapse occurred in 10, one patient died due to severe colitis during consolidation therapy and two patients are in sustained CR. Two patients not achieving a CR after induction therapy underwent allogeneic stem cell transplantation form matched unrelated donors. Twelve of the 22 patients died leading to a median survival of 18.8 months and a 2 year survival of 36% (95%-CI, 19–70%). Median relapse-free survival was 11 months. Conclusion: Combination of intensive induction and consolidation therapy with oral sunitinib in AML with activating FLT3 mutations is feasible with 25 mg sunitinib given during intensive therapy on days 1 to 7 and continuously during maintenance. Disclosures: Fiedler: Novartis: Consultancy, Research Funding; Pfizer Inc.: Consultancy, Research Funding.

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Early Results Of a Phase I/II Trial Of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) For Patients (Pts) With Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v122.21.3949.3949 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3949-3949

Author(s):

Paolo Strati ◽

Hagop M Kantarjian ◽

Aziz Nazha ◽

Gautam Borthakur ◽

Naval G. Daver ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

Flt3 Mutations ◽

Flt3 Inhibitors ◽

Grade 3 ◽

Acute Myeloid

Abstract Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) affect primarily elderly pts. Their treatment with aggressive chemotherapy is frequently challenging. Moreover, pts with FLT3 mutations have very poor prognosis. We hypothesized that the combination of midostaurin, a FLT3 inhibitor, and 5-AZA, a hypomethylating agent, may be an effective and safe regimen. Methods Both untreated (8) and previously treated (36) pts with AML or MDS were eligible for this study, regardless of FLT3 mutation and prior exposure to FLT3 inhibitors. Pts received 5-AZA 75 mg/mq subcutaneously or intravenously on day 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter, for 12 cycles of 28 days duration. Cytogenetic risk was defined according to MRC criteria. Differences between categorical variables were compared by the chi2 test. CR duration (CRD) was calculated from the time of CR achievement until relapse and estimated by the Kaplan-Meier method and compared by the log-rank test. Results Fourty-four pts were enrolled, 13 included in Phase I and 31 in Phase II. Baseline pts’ characteristics are shown in the Table. Thirty-eight pts (86%) received 50 mg bid of midostaurin, and 6 (14%; Phase I) received 25 mg bid. The median number of administered cycles was 2 (1-9). Grade 3-4 hematological toxicities consisted of 95% neutropenia, 64% anemia and 93% thrombocytopenia. Grade 3-4 non-hematological toxicities consisted of 45% infections, 23% hypokalemia, 16% hyponatremia, 7% reduction in ejection fraction, 7% hyperuricemia, 4% hyperglycemia, 4% nausea/vomiting, 4% QTc prolongation, 4% hyperbilirubinemia, and 4% elevated AST. Eleven pts (25%) achieved a CR, 9 with incomplete platelet recovery (20%), after a median time of 13 (10-16) weeks from treatment start. Five (11%) of these pts relapsed after achieving CR. Two pts (5%) received an allogeneic stem cell transplant while on study, one in CR and one primary refractory (after a blast count drop from 27 to 7%), and they are both still in CR and alive. Among 26 pts with FLT3 ITD and no D835 mutation, 9 (35%) achieved CR/CRp. Six of 18 (33%) pts not previously exposed to FLT3 inhibitors responded. There was no significant correlation of dose with response (24% with 50 mg bid vs 33% with 25 mg bid, p=0.63). After a median follow-up of 15 (3-72) weeks, 20 pts (64%) died, 3 (7%) while on study (2 died of sepsis, 1 of unknown causes with progressive disease). The median CRD was 16 (9-23) months. Factors significantly associated with a longer CRD were male sex (p=0.04), age older than 65 years (0.03) and use of 50 mg bid of midostaurin (p=0.02). Conclusions The combination of midostaurin and 5-AZA is safe and well tolerated. Its efficacy is most noticeable among pts with FLT3 mutations. A longer response duration is observed using midostaurin at 50 mg bid dose and in elderly male pts. Disclosures: Ravandi: CELGENE: Honoraria; NOVARTIS: Honoraria. Cortes:ARIAD: Consultancy, Research Funding; ASTELLAS: Research Funding; AMBIT: Research Funding; AROG: Research Funding; NOVARTIS: Research Funding.

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Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽

10.1182/blood.v128.22.1611.1611 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1611-1611 ◽

Cited By ~ 3

Author(s):

Maro Ohanian ◽

Guillermo Garcia-Manero ◽

Elias J. Jabbour ◽

Naval Daver ◽

Gautam Borthakur ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Median Overall Survival ◽

Cell Transplant ◽

Overall Response ◽

Grade 3 ◽

Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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A Phase I Safety Study of Enzastaurin Plus Bortezomib in the Treatment of Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.1870.1870 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1870-1870

Author(s):

Irene M Ghobrial ◽

Nikhil C Munshi ◽

Brianna N Harris ◽

Zheng Yuan ◽

Nichole M Porter ◽

...

Keyword(s):

Board Of Directors ◽

Dose Level ◽

Phase Ii ◽

Research Funding ◽

Progressive Disease ◽

Loading Dose ◽

Advisory Committees ◽

Level 3 ◽

Level 1 ◽

Grade 3

Abstract Abstract 1870 Poster Board I-895 Background: Enzastaurin is an oral serine/threonine kinase inhibitor that targets the PKC and PI3K/AKT pathways. Enzastaurin has demonstrated activity in preclinical models of multiple myeloma (MM), and clinical studies suggest activity and a favorable safety profile in a variety of hematological cancers. Enzastaurin has also demonstrated in-vitro synergy with bortezomib. Objectives: This phase I, open-label, multicenter, dose-escalation study was initiated to identify the recommended doses of enzastaurin and bortezomib in combination for phase II studies in patients (pts) with previously treated MM. Secondary objectives included evaluations of safety and response. Patients and Methods: A conventional dose-escalation scheme was applied. In dose level 1, pts received enzastaurin as a loading dose of 500 mg (250 mg po BID) on day 1 followed by daily doses of 125 mg po BID plus bortezomib 1.0 mg/m2 IV on days 8, 11, 15, and 18 in cycle 1 and days 1, 4, 8, and 11 thereafter. In dose level 2, pts received the same enzastaurin dose but a higher bortezomib dose (1.3 mg/m2). In dose level 3, pts received enzastaurin as a loading dose of 1125 mg (375 mg po TID) on day 1 followed by daily doses of 250 mg po BID plus 1.3 mg/m2 bortezomib. All treated pts were evaluated for response using the International Uniform Response Criteria (IURC; Durie et al. 2006) and European Group for Blood and Bone Marrow Transplantation (EBMT) criteria (Blade et al. 1998). All adverse events (AEs) were graded according to Common Toxicity Criteria for Adverse Events (CTCAE) v3.0. Results: A total of 23 pts, 4 in dose level 1, 3 in dose level 2, and 16 in dose level 3, were enrolled in the study, which is now closed to enrollment. There were 8 women and 15 men, with a median age of 62 years (range, 37–78 years); 91% of the pts had an ECOG performance status of 1 or 0, and the median number of prior systemic therapies was 3 (range, 2–12), with 17 pts previously treated with bortezomib. The median number of cycles completed was 4 (range, 1–20). No dose-limiting toxicities (DLTs) were observed; thus, dose level 3 was the recommended phase II dose. The combination was well tolerated with few grade 3/4 AEs. CTCAE drug-related grade 3/4 laboratory toxicities included: thrombocytopenia in 5 (22%) pts, anemia in 2 (9%) pts, increased creatinine in 1 (4%) pt, and hyponatremia in 1 (4%) pt. Drug-related grade 3/4 non-laboratory toxicities included: sensory neuropathy, prolonged QTc interval, and renal/genitourinary in 1 (4%) pt each. Serious drug-related AEs were increased serum creatinine and renal tubular necrosis in 1 (4%) pt and thrombocytopenia in 1 (4%) pt. The thrombocytopenia was not considered a DLT as the baseline platelet count was low secondary to MM. Five (22%) pts were discontinued from the study due to drug-related toxicities: renal tubular necrosis (also a serious AE) in 1 (4%) pt, peripheral neuropathy in 2 (9%) pts, neuralgia in 1 (4%) pt, and pain in extremity in 1 (4%) pt. There were no deaths on therapy; 1 pt died within 30 days of treatment due to progressive disease. Of the 23 enrolled pts, objective responses based on IURC criteria included 1 (4%) pt with a very good partial response (dose level 1), 2 (9%) pts with a partial response (in dose levels 2 and 3), 9 (39%) pts with stable disease, and 3 (13%) pts with progressive disease; 2 pts had no post-baseline response assessment, and 6 pts had unconfirmed stable disease or progressive disease. Two (9%) pts had a minimal response based on EBMT criteria. Activity was seen in pts regardless of prior exposure to bortezomib. Conclusions: The recommended phase II dose in patients with MM is enzastaurin 250 mg po BID with a loading dose of 1125 mg (375 mg po TID) on day 1 plus 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 (days 8, 11, 15, and 18 in cycle 1 only). The combination was generally well tolerated, and responses were observed. Disclosures: Ghobrial: Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Millenium: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yuan:Eli Lilly and Company: Employment. Schlossman:Millenium: Speakers Bureau; Celgene: Speakers Bureau. Laubach:Novartis: Consultancy. Anderson:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria, Research Funding. Lin:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Analysis of in Vitro Activity of the Clinically-Active ABL/FLT3 Inhibitor Ponatinib (AP24534) Against AC220-Resistant FLT3-ITD Mutants

Blood ◽

10.1182/blood.v118.21.930.930 ◽

2011 ◽

Vol 118 (21) ◽

pp. 930-930 ◽

Cited By ~ 1

Author(s):

Catherine C. Smith ◽

Lauren E. Damon ◽

Xiaotian Zhu ◽

Sara Salerno ◽

Neil Shah

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Cross Resistance ◽

Activation Loop ◽

In Vitro Activity ◽

Flt3 Inhibitor ◽

T315i Mutation ◽

High Degree ◽

Acute Myeloid

Abstract Abstract 930 Background: Activating mutations in FLT3 are detected in approximately 30 percent of adult acute myeloid leukemia (AML) cases, most commonly in-tandem duplication (ITD) events. Ponatinib (AP24534) is a potent inhibitor of ABL and FLT3 that has shown clinical activity in CML as well as in a limited experience with FLT3-ITD-positive acute myeloid leukemia (AML) with 2/7 kinase inhibitor-naïve AML patients achieving CRi in a phase I study (Talpaz et al, ASCO 2011, abstract #6518). We recently reported that the FLT3 inhibitor AC220, which has achieved an interim composite CR rate of 43% in a phase II study in relapsed/refractory AML (Cortes, et al, EHA 2011, abstract #1019) is vulnerable to a limited number of resistance-conferring kinase domain mutations in vitro (Smith et al, AACR 2011, abstract #4737). Mutations at 2 of these residues, F691 and D835, have been identified in 9/9 FLT3-ITD+ patients who relapsed after achieving clearance of bone marrow blasts on AC220 (Smith et al, ASH 2011, submitted). Notably, AC220-resistant mutations were found to confer cross-resistance to sorafenib. Given that ponatinib retains activity against a wide range of TKI-resistant BCR-ABL mutants, we sought to test its activity against AC220-resistant mutants. Results: We assessed the activity of ponatinib against highly AC220-resistant FLT3-ITD mutations F691I/L, D835V/Y and Y842C/H. Ponatinib potently suppressed the growth of Ba/F3 cells transformed with native FLT3-ITD with an inhibitory concentration 50 (IC50) of 2 nM. Ba/F3 cells transformed with the “gatekeeper” F691I mutation retained sensitivity to ponatinib at a similar concentration (5 nM). This substitution is analogous to the BCR-ABL T315I mutation, which is clinically sensitive to ponatinib. The remaining AC220-resistant FLT3-ITD mutants, including the gatekeeper F691L substitution, conferred a substantial degree of relative cross-resistance to ponatinib. Mutations at the activation loop residue D835 confer the highest degree of resistance. In an effort to identify other substitutions in FLT3-ITD that are capable of conferring ponatinib resistance in vitro, we employed an in vitro mutagenesis strategy (Azam et al, Cell, 2003) of FLT3-ITD in varying concentrations of ponatinib. In a preliminary analysis, we have identified resistance-causing substitutions at D835, as well as other residues in the FLT3 activation loop including D839 and N841. Interestingly, one of these substitutions, D835N, confers resistance to ponatinib but not to AC220. A molecular analysis of the ponatinib/FLT3 complex based on the crystal structure of ABL/ponatinib was performed and revealed that isoleucine substitution at the FLT3 “gatekeeper” residue (F691I), as with the T315I mutation in Abl, does not creates substantial steric clash with ponatinib. In contrast, the leucine substitution, (F691L), is more bulky than isoleucine and may cause more steric hindrance. In addition, as leucine is more rigid than isoleucine, more energy would be required for the F691L mutation to adopt a conformation compatible with ponatinib binding. As ponatinib binds to the “DFG-out” inactive conformation of FLT3, activation loop mutations such as D835V/Y and Y842C/H likely destabilize the activation loop conformation of FLT3 required for ponatinib binding. Conclusions: Our studies demonstrate that gatekeeper and, in particular, activation loop substitutions in FLT3-ITD, confer a high degree of cross-resistance to the clinically-active FLT3 TKIs described to date. Ponatinib retains in vitro activity against the gatekeeper mutation FLT3-ITD/F691I, which confers a high degree of in vitro resistance to AC220, but leucine substitution at this residue notably confers a higher degree of resistance to ponatinib. Activation loop mutations confer substantial degrees of in vitro cross-resistance to ponatinib and are predicted to confer clinical resistance. Select substitutions at D835 appear to confer selective resistance to ponatinib. Categorization of the spectrum of resistance-conferring mutations may facilitate a more personalized approach toward patients with FLT3-ITD+ AML treated with clinically-active TKI therapy. Disclosures: Off Label Use: Investigational agent ponatinib will be discussed. Zhu:Ariad Pharmaceuticals: Employment. Shah:Ariad: Consultancy, Research Funding; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

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Combination of Sorafenib and 5-Azacytidine Has Significant Activity in Patients with Relapsed/Refractory or Untreated Acute Myeloid Leukemia and FLT3-ITD mutation

Blood ◽

10.1182/blood.v120.21.1519.1519 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1519-1519

Author(s):

Farhad Ravandi ◽

Mona Lisa Alattar ◽

Mark J. Levis ◽

Guillermo Garcia-Manero ◽

Mary A Richie ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitors ◽

Response Assessment ◽

Cytotoxic Chemotherapy ◽

Off Label Use ◽

Off Label ◽

Acute Myeloid ◽

Refractory Aml

Abstract Abstract 1519 Background: The outcome of patients (pts) with acute myeloid leukemia (AML) and FLT3-ITD mutation is poor, particularly in the relapse setting. Sorafenib is a potent inhibitor of FLT3 kinase with reported clinical activity as a single agent (Metzelder S, Blood, 2009), and in combination with chemotherapy (Ravandi F, JCO, 2010). A potential mechanism of resistance to FLT3 kinase inhibitors is high levels of FLT3 ligand (FL) as seen after myelosuppressive chemotherapy. We hypothesized that combining sorafenib with a less myelosuppressive agent, such as 5-azacytidine (AZA), may lead to higher and more durable responses than cytotoxic chemotherapy. Furthermore, both drugs have demonstrated a potential for inducing differentiation in AML cells, thereby providing further rationale for the combination. Methods: Pts were eligible if they had relapsed or refractory AML, were 18 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. Older pts without prior therapy were also eligible, if they were deemed unsuitable to receive chemotherapy. Presence of FLT3-ITD was not a requirement but these pts were targeted for enrollment. Treatment regimen included AZA 75 mg/m2 daily for 7 days together with sorafenib 400 mg twice daily for 28 days; cycles were repeated in approximately 4 to 5-week intervals. Overall responses were assessed after the completion of at least one cycle of therapy and at the time of the best peripheral blood and bone marrow response. Plasma samples were collected on approximately Day 1 and Day 10 of each cycle. To assess the degree of FLT3 inhibition, the plasma inhibitory activity (PIA) assay was performed using the Molm-14 cell line (Levis M, Blood, 2006). Plasma FL concentrations were measured using an ELISA kit (R&D Systems). Results: 43 pts with AML with a median age of 64 years (range, 24–87) were enrolled. They included 19 (44%) pts with diploid cytogenetics, 11 (26%) with chromosome 5/7 or complex cytogenetic abnormalities, and 13 (30%) with miscellaneous abnormalities. Prior to the initiation of treatment, FLT3-ITD was detected in 40/43 (93%) pts with a median allelic ratio of 0.28 (range, 0 – 0.93). They had received a median of 2 prior treatments (range, 0–7). 16 (37%) pts had received ≥3 prior regimens and 9 had failed therapy with FLT3 kinase inhibitors (5 with AC220, 1 with PKC412, and 6 with sorafenib, either as monotherapy or with chemotherapy or plerixafor); 3 had failed 2 prior FLT3 inhibitors. 6 pts were inevaluable as they discontinued therapy before response assessment at one month and 3 are too early for response assessment. The overall CR/CRi/PR rate among the 34 evaluable pts is 44%, including 10 (29%) with CRi and 4 (12%) with CR and 1 (3%) with PR (in this pt, bone marrow blast declined from 51% to 6% with normalization of blood counts). Overall, pts have received a median of 3 (range, 1–9) treatment cycles with the median number of cycles to response among the responders being 2 (range, 1 – 4) and the median time to achieving response, 2.1 months (range, 0.9 – 4.6 months). The median duration of CR/CRi Is 2.3 months (range, 1 – 12.2+ months). Six pts have proceeded to allogeneic stem cell transplant. The most common study drug-related adverse events were rash and fatigue with no deaths attributable to study medications. One pt developed grade 3 cardiomyopathy suspected to be related to the study regimen. Of the 34 pts included in the clinical analysis, there were 22 pts from whom plasma samples spanning at least one cycle of therapy were available. Among them, 64% achieved FLT3 inhibition to a targeted level of less than 15% of baseline during their first cycle of therapy. Median survival in pts who achieved this degree of inhibition was 238 days, while median survival in pts who did not reach this level was 154 days (p=0.13). Mean FL levels at cycle 1, day 1 and cycle 1, day 10 were 9 pg/mL and 17 pg/mL, respectively. Mean FL levels at cycle 2, day 0 and cycle 2, day 10 were 27 pg/mL and 54 pg/mL, respectively. Conclusions: Combination of AZA and Sorafenib is effective for the treatment of older pts and pts with relapsed and refractory AML and FLT3-ITD mutation. While not statistically significant, there was a trend toward improved survival in pts with adequate FLT3 inhibition during cycle 1. FL levels did not rise to the levels seen in pts receiving cytotoxic chemotherapy. Disclosures: Ravandi: Bayer/Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: Off-label use of sorafenib and 5-azacytidine in patients with acute myeloid leukemia. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy. Garcia-Manero:Celgene: Research Funding. Andreeff:Hoffmann-La Roche: Research Funding; Karyopharm Therapeutics: Unrestricted gift, Unrestricted gift Other. Cortes:Celgene: Research Funding.

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Preclinical and Clinical Resistance Mechanisms To The Investigational Selective FLT3 Inhibitor PLX3397 In FLT3-ITD+ Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.3938.3938 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3938-3938 ◽

Cited By ~ 5

Author(s):

Catherine C Smith ◽

Kimberly Lin ◽

Elisabeth Lasater ◽

Whitney Stewart ◽

Lauren E Damon ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Kinase Domain ◽

Activation Loop ◽

In Vitro Mutagenesis ◽

Mutagenesis Screen ◽

Flt3 Inhibitor ◽

Clinical Resistance ◽

Acute Myeloid

Abstract Background Activating mutations [primarily internal tandem duplication (ITD) events] in FLT3 are detected in 30% of acute myeloid leukemia (AML). The clinically active FLT3 tyrosine kinase inhibitor (TKI) AC220 (quizartinib) has achieved complete remissions in relapsed/refractory FLT3-ITD+ AML patients in a phase II study (Cortes, et al and Levis et al, ASH 2012, abstracts 48 and 673) but is vulnerable to resistance-conferring mutations in the FLT3 kinase domain (KD). The F691L “gatekeeper” substitution was the most commonly detected mutation in an in vitro mutagenesis screen for AC220 resistance (Smith et al, Nature 2012). This mutation, and substitutions at the activation loop residue D835, have been associated with acquired clinical resistance to AC220 (Smith et al, Nature 2012; Alber et al, Leukemia 2013). Mutations at gatekeeper residues such as F691 have repeatedly surfaced as mediators of clinical resistance to TKIs. Identifying TKIs that retain activity against these substitutions has consistently proven challenging. PLX3397 is a potent and selective inhibitor of FMS, KIT and FLT3-ITD with a half-life of 20 hours in humans, resulting in µM steady-state plasma concentrations at the recommended phase II dose for AML patients. PLX3397 retains activity against the AC220-resistant FLT3-ITD/F691L mutant, but not against several D835 mutants (Smith et al., ASH 2011, abstract 764). In this study, we conducted a mutagenesis screen of FLT3-ITD and FLT3-ITD/F691L to identify single and compound mutations that confer resistance to PLX3397 and may cause acquired resistance in patients. Results PLX3397 inhibited the proliferation of BaF3/ FLT3-ITD cells at a concentration well below that achieved in patients (IC50 0.14 µM) and retained activity against cells expressing the FLT3-ITD/F691L mutant (IC50 0.350 µM). Other AC220-resistant mutants (D835V/Y/F and Y842C/H) conferred substantial cross-resistance to PLX3397 (∼50 to 400-fold shift in IC50 of FLT3-ITD; ranging from 7.2 to >10 µM). An in vitro mutagenesis screen of FLT3-ITD identified several mutations conferring resistance to PLX3397, including novel substitutions in 3 residues which conferred ≥10X resistance relative to FLT3-ITD: D835E/G/N, D839A/G and R845G (IC50s 1.4 to 4.1 µM). Given the in vitro activity of PLX3397 against the AC220-resistant F691L mutant, it is anticipated that PLX3397 will be administered to patients who acquire resistance to AC220 or sorafenib due to this mutation; a mutagenesis screen of FLT3-ITD/F691L was therefore conducted. We identified multiple KD mutations in FLT3-ITD/F691L conferring ≥10X resistance to PLX3397 (compared to FLT3-ITD) including several mutations in the FLT3 activation loop: D835H/G/E/N, D839A/G/N, N841K, Y842S, R845G (IC50s 1.6 to >10 µM), and 2 mutations in residues located in the tyrosine kinase domain 1 (TK1) domain: N676S, a residue previously implicated in clinical resistance to the FLT3 inhibitor PKC412 (IC50 2.8 µM), and M664I, a residue not previously linked to FLT3 inhibitor resistance (IC50 2.0 µM). While all identified mutants conferred some degree of resistance to PLX3397 in the absence of an F691L mutation, most conferred a higher degree of resistance in the setting of F691L, suggesting a cooperation between the gatekeeper residue and residues in the activation loop and TK1 domain that impacts PLX3397 binding. Finally, we conducted a preliminary analysis of samples from AML patients who relapsed after an initial response to PLX3397. Using Pacific Biosciences Single Molecule Real-Time Sequencing, we identified evolution of polyclonal FLT3 KD mutations at the D835 residue at the time of relapse in 2 patients, including, in one patient, novel PLX3397-resistant D835E/H mutations identified in our mutagenesis screen. Analysis of additional patient samples for single and compound resistant mutations is ongoing and will be presented. Conclusions PLX3397 harbors promise for the treatment of FLT3-ITD+ AML, particularly for patients who have developed resistance to FLT3 TKIs due to the gatekeeper F691L mutation. However, a mutagenesis screen reveals PLX3397 is vulnerable to mutations in the FLT3 activation loop and TK1 domain. Patients acquire secondary FLT3 KD mutations at the time of resistance to PLX3397, confirming the mechanism of action of this clinically active FLT3 inhibitor. A multi-site phase I/II study of PLX3397 in FLT3-ITD+ AML is ongoing. Disclosures: Smith: Plexxikon Inc: Research Funding. Off Label Use: Unapproved drugs for AML: AC220 and PLX3397. Le:Plexxikon Inc: Employment. Zhang:Plexxikon Inc: Employment. West:Plexxikon Inc: Employment. Shah:Ariad Pharmaceuticals: Consultancy, Research Funding; Plexxikon Inc: Research Funding; Ambit Biosciences: Research Funding.

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Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽

10.1182/blood-2018-99-117566 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4059-4059

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

Gabriela S. Hobbs ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Dose Escalation ◽

Proteasome Inhibitor ◽

Myeloid Leukemia ◽

Research Funding ◽

Remission Rate ◽

Secondary Aml ◽

Grade 3 ◽

Acute Myeloid

Abstract Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged >60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed. 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. 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; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12 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 and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival. Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 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 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%. Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. Table. Table. Disclosures Amrein: Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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A Phase I Study of Lenalidomide and Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.2318.2318 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2318-2318

Author(s):

Elizabeth A. Griffiths ◽

William Brady ◽

Wei Tan ◽

Carlos E Vigil ◽

James E. Thompson ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase I Study ◽

Response Rate ◽

Single Agent ◽

Grade 3 ◽

Acute Myeloid ◽

Intermediate Dose

Abstract Background: Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Although cytarabine arabinoside (AraC) is the most active drug, constituting the backbone of a majority of r/r regimens, the benchmark response to therapy remains a dismal 17 to 20% (Burnett, Wetzler et al. JCO, 2011.). The immunomodulatory drug lenalidomide (Len), is approved by the Food and Drug Administration for multiple myeloma and myelodysplasia and has demonstrated activity as a single agent in AML at doses as high as 50 mg for 21 days (d) of a 28 d cycle (Blum et al, JCO, 2010.). Based upon this activity profile we developed a phase I study to evaluate the safety and tolerability of Len in combination with AraC in patients with r/r AML. Methods: Eligible patients were older than 18 years(y), had r/r AML with an Eastern Cooperative Oncology Group performance status better than 2 and adequate renal and hepatic function. Patients were excluded for active CNS disease, uncontrolled infections, congestive heart failure, adrenal insufficiency, anti-cancer therapy within 14 d of enrollment, or prior exposure to Len. All enrolled patients had to practice appropriate contraception. Patients received AraC 1.5 g/m2/d over 3 hours on d 1-5 of a 28 day cycle, with a plan for standard 3+3 Len dose escalation. Initial patients received Len 25 mg on d 6-10 (n= 3), subsequent patients received doses between 25 and 10 mg (dose de-escalation) on d 6-26 with 2 d of rest prior to the next cycle. Following induction, patients who had residual AML (>5%) could receive a second identical course of therapy, provided they demonstrated an improvement in blast percentage relative to baseline. Patients who achieved CR received maintenance with Len 10 mg/d continuously. A 12 patient expanded cohort was enrolled at the maximum tolerated dose (MTD) to assess efficacy. Responses were assessed by International Working Group Criteria for AML (Cheson B et al. JCO, 2003.). Patient Characteristics: Fifty-one patients were consented and 45 were treated on study, 32 of these were evaluable for response, all patients were evaluated for toxicity. Approximately half the patients were female (20/45). The median age was 66 y (range 33-82) and median WBC 2.42x109/L (range 0.18-63.15). Four patients (8%) had an antecedent hematological disorder. By European LeukemiaNet criteria 2 patients (4%) had favorable risk disease, 8 (18%) were Int-1, 12(27%) were Int-2 and 11 (24%) were adverse risk; 12(27%) patients were not evaluable by ELN due to lack of karyotype or molecular data from diagnosis. Twelve patients had primary refractory AML. Results: The MTD for Len given on d 6-26 in combination with AraC at 1.5 g/m2/d x 5 d was 10 mg. Dose de-escalation from the starting dose of 25 mg on this schedule was required due to excess toxicity. The most commonly observed non-hematologic drug related adverse events seen on the study (all < grade 2 unless indicated) were nausea, increased liver function tests (>grade 3), rash (grade >3), hypokalemia (> grade 3) and fatigue. At the 25 mg dose level the dose limiting toxicity was rash, while patients enrolled at the 15 mg dose level experienced dose limiting elevation in LFTs, fatigue and bleeding. Five patients achieved a CR (16%), 5 demonstrated CRi (16%) and there were 3 hematological improvements (HI) for an overall response rate (CR+Cri+HI) of 41% (13/32). The median overall survival (OS) (95% confidence interval) for patients treated on study was 5.8 (2.5, 10.6) months and disease free survival was 3.4 (2.3, 6.2) months. Conclusions: Although prior interesting data support the activity of single agent high dose Len in r/r AML, our single institute phase I study of intermediate dose AraC followed by Len was associated with marked skin and other toxicities at the Len 25 mg dose level, precluding dose escalation to the historically more active 50 mg dose. The CR rate in this study was not dissimilar to previously reported responses with single agent or combination AraC based regimens. Issues of dose and schedule for this combination may have had a significant impact on the potential benefit for these two drugs in combination. Nevertheless, the overall low CR rate from this study does not suggest any superiority for this combination in comparison with the historical single agent response rate for intermediate dose AraC in r/r AML. Disclosures Griffiths: Celgene, Incyte and Alexion: Honoraria; Astex Pharmaceuticals: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Other. Wetzler:MedPace: Consultancy; Bristol Myers Squibb: Research Funding; Jazz Pharmaceuticals: Consultancy; Sigma Tau: Consultancy; Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Plexus: Consultancy; Celgene: Research Funding.

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