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

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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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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Gemtuzumab Ozogamicin In Combination With Vorinostat and Azacitidine In Older Patients With Relapsed Or Refractory Acute Myeloid Leukemia (AML): Final Results From A Phase 1/2 Study

Blood ◽

10.1182/blood.v122.21.3936.3936 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3936-3936 ◽

Cited By ~ 1

Author(s):

Roland B. Walter ◽

Bruno C. Medeiros ◽

Kelda M. Gardner ◽

Kaysey F. Orlowski ◽

Leonel Gallegos ◽

...

Keyword(s):

Research Funding ◽

Blood Count ◽

Treatment Initiation ◽

Phase 1 ◽

Gemtuzumab Ozogamicin ◽

Hematologic Toxicity ◽

First Relapse ◽

Grade 3 ◽

Refractory Aml ◽

Count Recovery

Abstract Background Epigenetic therapeutics such as the histone deacetylase (HDAC) inhibitor, vorinostat, and the DNA methyltransferase (DNMT) I inhibitor, azacitidine, sensitize AML cells in vitro to the CD33-targeting immunoconjugate, gemtuzumab ozogamicin (GO). This observation, together with the improved clinical activity when HDAC inhibitors are used with DNMT inhibitors, prompted a phase 1/2 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1stsalvage therapy. Methods Patients aged ≥50 years were eligible if they had an ECOG performance status of 0-3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation (HCT) were eligible if relapse occurred 6-12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. If there was persistent leukemia on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission was not achieved by the end of cycle 3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle 6. During phase 1, patients were assigned to therapy according to a “3+3” study design; dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results 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; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). During phase 2, a Simon minimax two-stage design was to monitor whether a response rate of 0.34 was reached, with type I and II errors set at 0.1 and assuming a historical CR rate of 17% in these patients. Results 52 eligible patients, median age 64.8 (range, 50.2-78.9) years, with either primary refractory disease (n=29) or first relapse (n=23; median duration of first CR: 3 months) were enrolled and received a median of 2 (range, 1-4) cycles of therapy. During dose escalation, 1 DLT (death due to sepsis and respiratory failure) occurred at the 4th tested dose level after cycle 1, identifying vorinostat (400 mg/day orally from days 1-9), azacitidine (75 mg/m2/day IV or SC from days 1-7), and GO (3 mg/m2/day IV on days 4 and 8) as the maximum tolerated dose (MTD). A total of 43 patients received therapy at the MTD level. Ten of these achieved CR, while 8 achieved CRi, for a CR/CRi rate of 18/43 (41.9%; exact 95% CI: 27.0-57.9%). Thirteen of the 18 patients that achieved CR/CRi were taken off protocol to receive additional, more intensive consolidative chemotherapy, including HCT (n=12). Of these 18 patients, 5 relapsed after a median of 122 (38-146) days, while 3 died while in remission after a CR duration of 46, 97, and 130 days, and 10 are in ongoing remission after a median of 326 (68- 710) days, respectively. Median overall survival for the 18 patients achieving CR/CRi was significantly longer than for those 21 patients who failed therapy but lived at least 29 days (i.e. did not experience treatment-related mortality) after treatment initiation (224.5 [range 70-798]) vs. 95 [36-900] days, log rank P-value=0.0023). Four patients died within 28 days of treatment initiation. Besides grade 3-4 cytopenias, infectious complications were the most common grade 33 adverse events. Only 1 patient developed possible liver toxicity (abdominal pain/distention and mild ascites) after 4 cycles of therapy, although bilirubin and transaminases were only minimally elevated and doppler studies were unremarkable. Conclusion Our study indicates that GO in combination with vorinostat and azacitidine has encouraging anti-AML activity in older adults with relapsed/refractory AML. Disclosures: Walter: Amgen, Inc: Research Funding; Seattle Genetics, Inc: Consultancy, Research Funding. Off Label Use: Use of vorinostat/azacitidine/gemtuzumab ozogamicin for the treatment of relapsed/refractory 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): A Phase 1 Study

Blood ◽

10.1182/blood.v124.21.3730.3730 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3730-3730

Author(s):

Anna B. Halpern ◽

Elihu H. Estey ◽

Megan Othus ◽

Kaysey F. Orlowski ◽

Morgan A. Powell ◽

...

Keyword(s):

High Risk ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Salvage Therapy ◽

Hematologic Toxicity ◽

Refractory Disease ◽

Off Label Use ◽

Off Label ◽

Grade 3 ◽

Refractory Aml

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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A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v128.22.1068.1068 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1068-1068 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

Bart L. Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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Dose Escalation Study of BET Inhibitor PLX2853 in Patients with Relapsed or Refractory Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2019-127497 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1391-1391 ◽

Cited By ~ 1

Author(s):

Naveen Pemmaraju ◽

Uma Borate ◽

Melhem Solh ◽

Gautam M. Borthakur ◽

Amy E. DeZern ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Plasma Concentrations ◽

Target Engagement ◽

Advisory Committees ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Background: PLX2853 is an orally available, non-benzodiazepine BET (bromodomain and extraterminal domain) inhibitor that exhibits low nanomolar potency and a modest preference for binding to the second bromodomain (BD2) of the BET proteins. By regulating genes (e.g. MYC and BCL2) critical to leukemic cell growth and survival, PLX2853 demonstrated broad anti-leukemic activity both as a single agent and in combination with other therapeutic agents in preclinical models. The pharmacokinetic (PK) profile in solid tumor patients revealed a short half-life (< 3 hour) enabling high peak plasma concentrations and nearly complete elimination from the plasma 9 hour post dose. Since strong and prolonged suppression of BET proteins have often untoward effects in normal tissues, the PLX2853 PK profile is hypothesized to be associated with improved tolerability by allowing transient target engagement followed by time for recovery after daily dosing. Methods: We are conducting an open-label, Phase 1b (Ph1b) study of PLX2853 as a single oral agent administered daily in adult patients with relapsed or refractory acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) using a modified continuous reassessment model (mCRM) with escalation with overdose control (EWOC) to determine the recommended phase 2 dose (RP2D). Up to 36 patients are expected to enroll. The dosing cycle and dose limiting toxicity window (DLT) is 21 days. Primary objectives include safety and PK. Secondary objectives include measures of preliminary efficacy, and exploratory objectives include pharmacodynamics (PD) biomarker assessments in various tissues. Enrollment through Cohort 2 (40 mg QD) is ongoing as of July 2019. Results: Five subjects with relapsed or refractory AML (median age 65 years) have received PLX2853 in escalating doses from 20 to 40 mg QD. Among these first 5 patients treated, the most common treatment emergent adverse events (AEs) regardless of causality in > 1 patient: decreased appetite (n=3), nausea (n=2), diarrhea (n=2), peripheral edema (n=2), cough (n=2), oropharyngeal pain (n=2), blood bilirubin increase (n=2), anemia (n=2), febrile neutropenia (n=2), fatigue (n=2), bacteremia (n=2), headache (n=2), dyspnea (n=2), and hypertension (n=2). Most were grade (G) 1-2. Treatment emergent AEs > G2 in > 1 patient included: anemia (n=2), febrile neutropenia (n=2) and hypertension (n=2). No treatment-related serious AEs or DLTs have been observed. Following a 20 mg daily dose of PLX2853, median time to reach maximal plasma concentrations (Tmax) is 1 hour and the absorption half-life (T1/2) is < 3 hours. Conclusions: In an ongoing Ph1b study, PLX2853 has now completed its first dosing cohort for patients with relapsed or refractory AML or high risk MDS, and no DLT has been observed yet. As dose escalation continues, PK, PD, preliminary safety and efficacy data will be assessed further to determine the clinical significance of target engagement. This clinical trial is registered at clinicaltrials.gov: NCT03787498. Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Borthakur:Polaris: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; NKarta: Consultancy; Incyte: Research Funding; Janssen: Research Funding; GSK: Research Funding; PTC Therapeutics: Consultancy. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Zhang:Plexxikon Inc.: Employment. Powell:Plexxikon Inc.: Employment. Severson:Plexxikon Inc.: Employment. Inokuchi:Plexxikon Inc.: Employment. Matusow:Plexxikon Inc.: Employment. Halladay:Plexxikon Inc.: Employment. Hsu:Daiichi Sankyo, Inc.: Employment. Watkins:Plexxikon Inc.: Employment. Walling:Myovant Sciences: Consultancy; Nurix: Consultancy; Aduro Biotech: Consultancy; Plexxikon: Consultancy; CytomyX: Consultancy; Flag Therapeutics: Consultancy; Aminex: Consultancy; Immunext: Consultancy; SensenBio: Consultancy; Harpoon Therapeutics: Consultancy. Tsiatis:Plexxikon Inc.: Employment. Mims:PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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A Phase I Pilot Study of Bystander Vaccine and Lenalidomide Immune Augmentation In Patients with Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v116.21.2925.2925 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2925-2925

Author(s):

Eric Padron ◽

Rami S. Komrokji ◽

Jeffrey E. Lancet ◽

Alan F. List ◽

Sophie Dessureault ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Cell Line ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Response Rates ◽

World Health ◽

International Prognostic Scoring System ◽

Hypomethylating Agents ◽

Grade 3

Abstract Abstract 2925 Introduction: Antineoplastic vaccine strategies aimed at augmenting immuno-surveillance have been limited by the lack of known tumor antigens and the inability to sustain an immune response. A “bystander” vaccine approach has been tested with a K562-GMCSF transfected cell line in combination with autologous cells in acute myeloid leukemia (AML) and in combination with imatinib in chronic myeloid leukemia (CML). Lenalidomide, a thalidomide analogue approved for the treatment of deletion 5q MDS, has stimulatory effects on CD8+ T cells and augments vaccine response in a colon cancer and melanoma model. We present results of a phase I, dose escalation study using a K562-GMCSF-CD40 Ligand transfected, “bystander” vaccine in combination with lenalidomide in International Prognostic Scoring System (IPSS) intermediate and high risk MDS patients who failed hypomethylating agents. Methods: The study was a standard “3+3”, dose escalation phase I design. Eligibility was restricted to patients with a diagnosis of MDS subtypes RAEB-1, and RAEB-2 by World Health Organization classification (WHO), or RAEB-t by FAB criteria. An ANC greater than 500/μl and platelet count greater than 20,000/μl were required. Prior therapy with lenalidomide, secondary MDS, and a diagnosis of proliferative CMML were excluded. GM-CSF and CD40L constructs were transfected into the K562 cell line. Co-transfected clones were selected and subcutaneously injected in the axillary nodal basin of subjects on days 8 and 22 of a 28-day cycle for a total of four cycles. Lenalidomide was administered at a daily dose of 10mg on days 1 through 21 every 28 days until disease progression or limiting toxicity. Toxicities were monitored weekly and BM biopsy repeated after 2 & 4 cycles and at discontinuation of vaccine therapy. The dose escalation of vaccine was 10 × 106 cells in cohort 1, 30 × 106 in cohort 2, 60 × 106 in cohort 3 and 120 cells × 106 in cohort 4. MTD was defined as the highest dose level at which <1 out of 6 subjects experience a DLT. Responses were measured using the international working group criteria (IWG) 2006 for MDS. Results: Between March 2009 and August 2010, eleven patients were enrolled after signing informed consent. The median age was 74 years, with a male predominance (n=9). According to WHO classification, 4 patients had RAEB-1, 6 had RAEB-2, and 1 had AML (RAEB-t by FAB). The IPSS score at study entry was int-1 (4), int-2 (3), and high risk (4). After four cycles of therapy, no treatment related grade 3 or 4 toxicities were seen in cohorts 1–3 (10-60 × 106 cells). Two participants in cohort 2 (30 × 106) developed grade 3 myelosuppression deemed disease related by the investigator. One participant in cohort 2 died while on this study secondary to a non-treatment related pneumonia. Dose limiting toxicity (DLT) was reached in cohort 4 (120 × 106). One patient developed grade 3 dyspnea and fatigue after one injection of vaccine. This cohort will be expanded to a total of 6 patients. Grade 1 toxicities in all cohorts included rash, myelosuppression, nausea, vomiting, and fatigue. The IWG response rates were complete response (CR) in 2/11 (18%), marrow CR (1/11) (9%), and partial response (PR) in 1/11 (9%). The overall response rate was 4/11 (36%). In all patients who achieved a CR the median duration of response was 367 days (136-490). Conclusions: Although the MTD has not been reached, this cell-based immunotherapy was well tolerated. Response rates and the duration of these responses in patients who failed hypomethylating agents is encouraging and warrants further investigation. Accrual to the study is ongoing and updated data will be presented. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. List:Celgene: Research Funding.

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The BENDALEM CLL 6 AGMT Study – Bendamustine Combined with Alemtuzumab In Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): Results of a Planned Interim Analysis

Blood ◽

10.1182/blood.v116.21.4633.4633 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4633-4633

Author(s):

Alexander Egle ◽

Thomas Melchardt ◽

Lukas Weiss ◽

Michael Steurer ◽

Richard Greil

Keyword(s):

High Risk ◽

Interim Analysis ◽

Response Rate ◽

Single Agent ◽

Infectious Complications ◽

Cross Resistance ◽

Hematologic Toxicity ◽

Complex Karyotype ◽

End Of Treatment ◽

Grade 3

Abstract Abstract 4633 Introduction: Relapse of CLL presents a crucial problem to clinicians and patients. Improvement of the first line therapy incorporating fludarabine and monoclonal antibodies may result in relapse of disease, which might be more difficult to treat. Alemtuzumab showed efficacy in first and second line treatment and combinations of alemtuzumab with chemotherapy yielded promising results in relapsed or refractory CLL patients. We have previously reported the feasibility and efficacy of combining fludarabine and 16 weeks of alemtuzumab in pretreated CLL patients (Flusalem trial, Egle et al. EHA 2009). Bendamustine was effective in CLL as a single agent as well as in combination with rituximab. We hypothesised, that a combination of bendamustine with alemtuzumab may display little cross-resistance, given the prevalent initial treatments in our cohort. Study design: The protocol combines 4 cycles of bendamustine (70 mg/m2 i.v. 2d, q4w) with continuous alemtuzumab (30 mg s.c. 3× weekly for 16 weeks) allowing an out-patient management in pretreated CLL patients. Valganciclovir prophylaxis was mandatory for all patients with positive cytomegalovirus (CMV) serology, Valaciclovir was used for patients with negative serology. We herewith present the first 7 patients recruited into the study as result of a planned interim analysis following a Gehan design. We evaluated response rate, safety profile and toxicities with the regimen in relapsed/refractory patients. MRD analysis will be included in the follow-up phase. Results: Mean age of patients was 70 years (range 54–80). Three out of 7 patients had stage RAI III/IV and mean WBC count was 126 G/L. Median number of previous treatment lines was 2 (range 1–7) and the regimes included FCR, and other rituximab or alemtuzumab combinations. All patients had at least one high risk feature from CD38, FISH or IgVH mutation status. Abberations detected by FISH included 2 patients with del17p, one with del11q and one with tri12. One patient had a highly complex karyotype with >8 chromosomal aberrations in conventional cytogenetics. Regarding toxicities, almost exclusively hematological and infectious complications were observed. Grade 3 and 4 leukopenia was expected in this combination and occurred in all patients, necessitating G-CSF treatment in 6/7 patients. Two patients had grade 3 or 4 thrombocytopenia and 3 patients received transfusions. No tumor lysis syndrome was detected. The median cumulative dose of alemtuzumab was 1453 mg (maximal scheduled dose: 1483 mg), reflecting and the feasibility of the regimen. Bendamustine dose had to be reduced by greater than 25% in 3/7 patients due to hematologic toxicity. CD4 T cell depletion was profound and rapid. After 2 cycles of treatment the median CD4 count was 55/μ l. This was not relevantly different from our previous experience with the combination of fludarabine and alemtuzumab. In the current study, 3 of 7 patients had asymptomatic CMV reactivation, but no symptomatic infection was observed. Five of 7 patients had serious adverse events due to infections, including one fatal outcome due to pneumonia, 2 months after the end of treatment. Response assessment at the end of treatment (4 cycles) showed 3 complete remissions (including 1 unconfirmed CR, without bone marrow sampling), 2 partial remissions and 1 stable disease. One treatment failure with early progressive disease occurred in the patient with the very complex karyotype. This patient had received 7 prior treatment lines and had been refractory to the last two lines (FCR and Ofatumumab). The two patients with del17p achieved PR and SD, respectively. The overall response rate was 71% and slightly lower than that reported in our previous Flusalem trial. Summary/Conclusions: Bendamustine combined with 16 weeks of subcutaneous alemtuzumab was feasible in an out-patient setting in pretreated CLL patients with high risk profile. Haematological and infectious complications comprise the most important toxicities. One grade 5 toxicity was not judged to be a safety signal in this extensively pretreated patient population. In comparison to the Flusalem trial, molecular high risk features were much more common, which may explain the slightly lower rate of responses. According to the Gehan analysis this interim analysis refutes the futility hypothesis and the study currently continues to recruit patients. Disclosures: Egle: Mundipharma: Honoraria, Research Funding, Speakers Bureau. Greil:Mundipharma: Honoraria, Speakers Bureau.

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MDS-420: Sabatolimab Plus Hypomethylating Agents (HMAs) in Patients with High-/Very High-risk Myelodysplastic Syndrome (HR/vHR-MDS) and Newly Diagnosed Acute Myeloid Leukemia (ND-AML): Subgroup Analysis of a Phase 1 Study

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/s2152-2650(21)01811-5 ◽

2021 ◽

Vol 21 ◽

pp. S350

Author(s):

Guillermo Garcia-Manero ◽

Andrew H. Wei ◽

Kimmo Porkka ◽

Steve Knapper ◽

Elie Traer ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Phase 1 ◽

Hypomethylating Agents ◽

Newly Diagnosed ◽

Phase 1 Study ◽

Very High ◽

Acute Myeloid

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A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Blood ◽

10.1182/blood-2021-148808 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4432-4432

Author(s):

Gautam Borthakur ◽

Brian A. Jonas ◽

Emily L Roberts-Thomson ◽

Glenn C. Michelson ◽

Mark R Bray

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Cancer Center ◽

Advisory Committees ◽

Grade 3 ◽

Acute Myeloid ◽

Refractory Aml

Abstract Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in a number of effects including the centrosome amplification often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. A Phase 1 study has been completed evaluating CFI-400945 as a monotherapy in solid tumors, showing a tolerable safety profile and promising signs of activity. Given acute myeloid leukemia (AML) is characterized by genomic instability, CFI-400945 has been evaluated in pre-clinical and clinical studies in AML. In pre-clinical studies, CFI-400945 showed potent activity towards leukemia cell lines and primary human samples in vitro, as well as marked efficacy in two subcutaneous models of leukemia. A prior Phase 1 trial in AML was initiated at the Princess Margaret Cancer Center (PMCC), and of six patients evaluable for response, two (33%) achieved complete remission (CR) at 96 mg and 128 mg, and 3 patients (50%) had stable disease (with one patient having a 78% reduction in marrow blast count) at 64 mg (2 patients) and 96 mg [re: Murphy et al, ASH 2020]. Responses were seen in patients with adverse cytogenetics. The optimal dosing of CFI-400945 and its potential role as a combination agent are not yet clinically defined. Study Design and Methods: The study (TWT-202) has 4 parts, Part 1A (1A): a single agent dose escalation portion, Part 1B (1B): a food effect portion once the MTD of 1A is determined, and combinations with azacitidine (2A), and decitabine (2B). TWT-202 uses an updated version of investigational product which is identical in formulation to the drug used in the PMCC study, but which may result in higher exposures at a given dose. This study will therefore refine the dose through escalation cohorts. For parts 1A and 1B, patients with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Patients with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For parts 2A and 2B, patients should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated patients who decline or are ineligible for intensive therapy may be included. The study will use a standard 3 + 3 design. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose limiting toxicities (DLTs) is <1 out of 6 at highest dose level below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: As of June 21, 2021, 2 patients had been enrolled into the study, one of the patients (50%) received >3 prior therapies (including venetoclax). Neither patient had had stem cell transplant at study entry. Both patients had secondary AML (one with antecedent MDS with excess blasts and the other with CMML). Both patients received 32 mg of CFI-400945 for 21 days followed by a 7-day rest. Both patients completed cycle 1 and neither experienced a DLT. Both patients experienced a single serious treatment emergent adverse event (SAE) of febrile neutropenia each, with neither event considered related to CFI-400945. There were 13 Grade 3 or greater TEAE's, including anemia, thrombocytopenia (3 events each), febrile neutropenia (2 events), agitation, angioinvasive fungal sinusitis, acute kidney injury, hypotension and neutropenia (1 event each). None of the grade 3 or greater TEAE's were considered related to CFI-400945. Neither patient responded to therapy at 32 mg and both came off treatment after one cycle due to progressive disease. PK and PD studies are pending. Conclusion: CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in the Part 1A and Part 1B monotherapy cohorts. Updated safety, efficacy, PK, and PD data for the study will be presented at the time of the meeting. Disclosures Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy. Roberts-Thomson: Treadwell Therapeutics: Current Employment. Michelson: Treadwell Therapeutics: Consultancy. Bray: Treadwell Therapeutics: Current Employment.

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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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