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88 BONE MARROW BLAST (BMBL) RESPONSE CORRELATES WITH OVERALL SURVIVAL IN RIGOSERTIB-TREATED PATIENTS WITH HIGHER-RISK MDS AFTER FAILURE OF HYPOMETHYLATING AGENTS (HMAS): A NEW RESPONSE CRITERION?
S44
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Poster Presentations 87 A PHASE II STUDY OF THE EFFICACY AND SAFETY OF AN INTENSIFIED SCHEDULE OF AZACITIDINE IN HIGHER RISK MDS PATIENTS: A STUDY BY THE GFM L. Ades1, A. Guerci-Bresler2, P. Cony Makhoul3, L. Legros4, J. Delaunay5, C. Recher6, M. Sebert7, J. Lejeune8, S. Chevret8, P. Fenaux7 1 Hématologie Sénior, Hopital Saint-Louis, Paris, France; 2 Hématologie, CHU Nancy, Nancy, France; 3Hématologie, CHU Annecy, Annecy, France; 4Hématologie, CHU Nice, Nice, France; 5 Hématologie, CHU Nantes, Nantes, France; 6Hématologie, CHU Toulouse, Toulouse, France; 7Hopital Saint-Louis, Hématologie Sénior, Paris, France; 8Hopital Saint-Louis, DBIM, Paris, France Background: Survival improvement with AZA in higher risk MDS remains modest and the CR+PR rate is only about 30%, with typical 7 day schedules every 28 days. Reversal of gene hypomethylation is seen at the end of each cycle, and increasing the number of treatment days could improve AZA results. We tested the effect on response and OS of an intensified AZA regimen. Methods: Untreated patients aged 18-75 years with ECOG 0–2 and Higher risk MDS, CMML with WBC <13,000/mm3 and marrow blasts >10%, or AML with 20-30% marrow blasts were eligible. Patients received AZA 75mg/m2/dx5 days every 14 days for 4 cycles (AZA-14). Those achieving CR/PR/HI then received 4 cycles of AZA during 5 days every 21 days (AZA-21), followed by classical 7 day cycles every 28 days, ie 20% increase in the number of days of AZA during the first 8 treatment weeks. Patients not obtaining CR, PR or HI after the initial 4 cycles of AZA-14, received 4 additional cycles of AZA-14. Patients not obtaining CR, PR or SD+HI after 8 cycles of AZA-14 were discontinued. Median [IQR] are reported. Results: 27 patients (M/F:20/7, age 66 [58; 70]) were enrolled between 2011 and 2013, including 20 MDS, 5 AML and 2 CMML. Karyotype (IPSS) was favorable in 12, int in 6 , unfav in 9 patients. IPSS was int-1 in 3, int-2 in 15 and high in 9 patients. The median n° of cycles was 12 and 23 patients received >= 6 cycles. Cycle 2 was delayed beyond d15 in only 1 patient, but cycles 3 and 4, were delayed at a median of d35 and d51 from AZA onset. 2 patients terminated the study before cycle 4. 13 patients had died and 38 grade 3-4 SAEs were reported in 13 patients. Overall, 1 patient achieved CR, 6 PR, 7 marrow CR, 5 SD+HI, 3 SD without HI and 1 progressed (ORR 70% (19/27), 95% CI [48.9; 86.2]). With a median follow up of 15 months, 1 year OS was 71% [55-92]. Conclusion: In those relatively ‘fit” Higher risk MDS, an intensified AZA schedule seemed feasible without obvious increase in toxicity compared to the classical 7 day schedule. Cycles were delayed in a limited proportion of patients and no extra toxicities were observed. Both the ORR of 70% and the 71% OS at 1 year are encouraging.
88 BONE MARROW BLAST (BMBL) RESPONSE CORRELATES WITH OVERALL SURVIVAL IN RIGOSERTIB-TREATED PATIENTS WITH HIGHER-RISK MDS AFTER FAILURE OF HYPOMETHYLATING AGENTS (HMAS): A NEW RESPONSE CRITERION? L.R. Silverman1, P. Fenaux2, A. Al-Kali3, M.R. Baer4, M. Sekeres5, G. Roboz6, G. Gaidano7, B. Scott8, P. Greenberg9, U. Platzbecker10, D.P. Steensma11, S. Kambhampati12, K.A. Kreuzer13, L. Godley14, R. Collins15, E. Atallah16, S.C. Navada1, N. Azarnia17, G. Garcia-Manero18 1 Division of Hematology/Onocology, Icahn School of Medicine at Mount Sinai, New York, USA; 2Service d’Hématologie Séniors,
Hospital St Louis, Paris, France; 3Department of Hematology, Mayo Clinic, Rochester, USA; 4Greenebaum Cancer Center, University of Maryland, Baltimore, USA; 5Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, USA; 6Leukemia Service, Weill Cornell Medical College, New York, USA; 7Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 8Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA; 9Department of Medicine (Hematology), Stanford Medical School, Stanford, USA; 10 Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany; 11Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 12Department of Internal Medicine, University of Kansas Medical Center, Westwood, USA; 13Department of Internal Medicine, Universitätsklinikum Köln, Köln, Germany; 14Department of Medicine, University of Chicago Medical Center, Chicago, USA; 15 Department of Internal Medicine, University of Texas, Dallas, USA; 16 Division of Hematology and Oncology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, USA; 17Department of Biometrics, Onconova Therapeutics Inc, Newtown, USA; 18Department of Leukemia, MD Anderson Cancer Center, Houston, USA Background: Complete or partial bone marrow (BM) response or stabilization after 4-8 weeks of treatment with rigosertib was evaluated as a potential surrogate for predicting survival in HR-MDS patients after HMA failure (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized, IRB-approved, Phase III trial.
Fig. 1. Overall survival by 4-week and 12-week bone marrow blast response among Rigosertib-treated patients.
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Table 1. Number (%) of Rigosertib Patients with 4- and 12-week Bone Marrow Blast Response: ITT Population and Patients with Primary HMA Failure 4-week
12-week
Primary Primary ITT HMA Failure ITT HMA Failure N = 199 N = 127 N = 199 N = 127 Patients with BMBL assessment 156 (78) BM complete response 22 BM partial response 8 Stable disease 77 Progressive disease
103 (81)* 14 8 51
86 (43) 11 9 32
57 (45)* 7 7 25
30
34
18
49
S45
Conclusions: Consistent with previous observations in Phase II studies, BMBL response at 4 or 12 weeks was correlated with OS in this population. These data suggest that BMBL response at 4 or 12 weeks may serve as a biomarker as an intermediate clinical endpoint (ICE) in rigosertib trials. Further studies are underway to determine whether BMBL response can be considered a broader response biomarker for other agents that can serve as an ICE.
*BM assessment was optional for BSC patients.
89 A PHASE I STUDY OF THE COMBINATION OF AZACITIDINE AND ORAL RIGOSERTIB IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) OR ACUTE MYELOID LEUKEMIA (AML) S.C. Navada1, G. Garcia-Manero2, K. Hearn2, R. Odchimar-Reissig1, E. Demakos1, Y. Alvarado2, N. Daver2, C. DiNardo2, M. Konopleva2, G. Borthakur2, N. Azarnia3, L.R. Silverman1 1 Division of Hematology/Onconolgy, Icahn School of Medicine at Mount Sinai, New York, USA; 2Department of Leukemia, MD Anderson Cancer Center, Houston, USA; 3Biometrics, Onconova Therapeutics Inc, Newtown, USA
Fig. 2. Overall survival by 4-week and 12-week bone marrow blast response among Rigosertib-treated patients with primary HMA failure.
Methods: After signing informed consent, patients with HRMDS progressing on, failing to respond to, or relapsing after HMA treatment were randomized 2:1 to rigosertib or best supportive care (BSC). BMBL response at each timepoint was assessed as complete response (mCR), partial response (mPR), stable disease (SD), progressive disease (PD), or not evaluable. Results: Since no difference in overall survival (OS) was noted between patients who had objective BM response and those with SD, a landmark analysis was conducted that separated patients at 4 and 12 weeks into response categories of BM response+SD vs. PD (Table 1 and Figure 1). The landmark analysis of patients with primary HMA failure demonstrated that, at both timepoints, rigosertib-treated patients with mCR+mPR+SD had significantly greater OS than those with PD (Figure 2).
Background: Rigosertib is a PI3/polo-like kinase inhibitor that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent in clinical trials in both higher-risk and lower-risk MDS patients. Azacitidine (AZA) is first-line therapy for patients with higher-risk MDS. In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells (Skidan et al, AACR Proceedings, 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. Methods: Patients with MDS and non-proliferative AML who were previously untreated or had failed or progressed on a hypomethylating agent (HMA), were included in this phase I combination study. Oral rigosertib was administered twice daily on days 1-21 of a 28-day cycle. Patients were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg BID, [2] 280 mg BID, [3] 560 mg qAM and 280 mg qPM. AZA was administered at the standard dose of 75 mg/m2/day SC or IV on days 8-14 in each of the cohorts. Results: Eighteen patients have been treated; MDS: intermediate-1 (3), intermediate-2 (6) high risk (3), CMML (1), and AML (5); median age 70.5 years; 61% male. Patients have received 1-14 cycles of treatment. Cytogenetic profiles by MDS IPSS were good (8), poor (8), and intermediate (2). Eleven of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. 56% of patients received prior treatment with an HMA: AZA (6), decitabine (4). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Drug-related dysuria/cystitis was not reported in this population. Responses according to IWG 2006 criteria were observed in the bone marrow and peripheral blood: CRi (complete response with incomplete blood recovery) (4), mCR (marrow CR) (5), stable disease (2). Four of 6 (67%) patients with MDS, who had failed prior HMA, responded to the combination: CRi (2), mCR (2), SD (1), PD (1). Conclusions: The combination of oral rigosertib at 560 mg/280 mg BID and standard-dose AZA appears to be safe and well-tolerated in patients with MDS and non-proliferative AML. The AE profile is not significantly different from AZA alone. Responses in patients failing an HMA suggest synergy for the combination, which will be explored further in the ongoing phase II study.
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Poster Presentations 87 A PHASE II STUDY OF THE EFFICACY AND SAFETY OF AN INTENSIFIED SCHEDULE OF AZACITIDINE IN HIGHER RISK MDS PATIENTS: A STUDY BY THE GFM L. Ades1, A. Guerci-Bresler2, P. Cony Makhoul3, L. Legros4, J. Delaunay5, C. Recher6, M. Sebert7, J. Lejeune8, S. Chevret8, P. Fenaux7 1 Hématologie Sénior, Hopital Saint-Louis, Paris, France; 2 Hématologie, CHU Nancy, Nancy, France; 3Hématologie, CHU Annecy, Annecy, France; 4Hématologie, CHU Nice, Nice, France; 5 Hématologie, CHU Nantes, Nantes, France; 6Hématologie, CHU Toulouse, Toulouse, France; 7Hopital Saint-Louis, Hématologie Sénior, Paris, France; 8Hopital Saint-Louis, DBIM, Paris, France Background: Survival improvement with AZA in higher risk MDS remains modest and the CR+PR rate is only about 30%, with typical 7 day schedules every 28 days. Reversal of gene hypomethylation is seen at the end of each cycle, and increasing the number of treatment days could improve AZA results. We tested the effect on response and OS of an intensified AZA regimen. Methods: Untreated patients aged 18-75 years with ECOG 0–2 and Higher risk MDS, CMML with WBC <13,000/mm3 and marrow blasts >10%, or AML with 20-30% marrow blasts were eligible. Patients received AZA 75mg/m2/dx5 days every 14 days for 4 cycles (AZA-14). Those achieving CR/PR/HI then received 4 cycles of AZA during 5 days every 21 days (AZA-21), followed by classical 7 day cycles every 28 days, ie 20% increase in the number of days of AZA during the first 8 treatment weeks. Patients not obtaining CR, PR or HI after the initial 4 cycles of AZA-14, received 4 additional cycles of AZA-14. Patients not obtaining CR, PR or SD+HI after 8 cycles of AZA-14 were discontinued. Median [IQR] are reported. Results: 27 patients (M/F:20/7, age 66 [58; 70]) were enrolled between 2011 and 2013, including 20 MDS, 5 AML and 2 CMML. Karyotype (IPSS) was favorable in 12, int in 6 , unfav in 9 patients. IPSS was int-1 in 3, int-2 in 15 and high in 9 patients. The median n° of cycles was 12 and 23 patients received >= 6 cycles. Cycle 2 was delayed beyond d15 in only 1 patient, but cycles 3 and 4, were delayed at a median of d35 and d51 from AZA onset. 2 patients terminated the study before cycle 4. 13 patients had died and 38 grade 3-4 SAEs were reported in 13 patients. Overall, 1 patient achieved CR, 6 PR, 7 marrow CR, 5 SD+HI, 3 SD without HI and 1 progressed (ORR 70% (19/27), 95% CI [48.9; 86.2]). With a median follow up of 15 months, 1 year OS was 71% [55-92]. Conclusion: In those relatively ‘fit” Higher risk MDS, an intensified AZA schedule seemed feasible without obvious increase in toxicity compared to the classical 7 day schedule. Cycles were delayed in a limited proportion of patients and no extra toxicities were observed. Both the ORR of 70% and the 71% OS at 1 year are encouraging.
88 BONE MARROW BLAST (BMBL) RESPONSE CORRELATES WITH OVERALL SURVIVAL IN RIGOSERTIB-TREATED PATIENTS WITH HIGHER-RISK MDS AFTER FAILURE OF HYPOMETHYLATING AGENTS (HMAS): A NEW RESPONSE CRITERION? L.R. Silverman1, P. Fenaux2, A. Al-Kali3, M.R. Baer4, M. Sekeres5, G. Roboz6, G. Gaidano7, B. Scott8, P. Greenberg9, U. Platzbecker10, D.P. Steensma11, S. Kambhampati12, K.A. Kreuzer13, L. Godley14, R. Collins15, E. Atallah16, S.C. Navada1, N. Azarnia17, G. Garcia-Manero18 1 Division of Hematology/Onocology, Icahn School of Medicine at Mount Sinai, New York, USA; 2Service d’Hématologie Séniors,
Hospital St Louis, Paris, France; 3Department of Hematology, Mayo Clinic, Rochester, USA; 4Greenebaum Cancer Center, University of Maryland, Baltimore, USA; 5Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, Cleveland, USA; 6Leukemia Service, Weill Cornell Medical College, New York, USA; 7Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 8Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA; 9Department of Medicine (Hematology), Stanford Medical School, Stanford, USA; 10 Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany; 11Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 12Department of Internal Medicine, University of Kansas Medical Center, Westwood, USA; 13Department of Internal Medicine, Universitätsklinikum Köln, Köln, Germany; 14Department of Medicine, University of Chicago Medical Center, Chicago, USA; 15 Department of Internal Medicine, University of Texas, Dallas, USA; 16 Division of Hematology and Oncology, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, USA; 17Department of Biometrics, Onconova Therapeutics Inc, Newtown, USA; 18Department of Leukemia, MD Anderson Cancer Center, Houston, USA Background: Complete or partial bone marrow (BM) response or stabilization after 4-8 weeks of treatment with rigosertib was evaluated as a potential surrogate for predicting survival in HR-MDS patients after HMA failure (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized, IRB-approved, Phase III trial.
Fig. 1. Overall survival by 4-week and 12-week bone marrow blast response among Rigosertib-treated patients.
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Table 1. Number (%) of Rigosertib Patients with 4- and 12-week Bone Marrow Blast Response: ITT Population and Patients with Primary HMA Failure 4-week
12-week
Primary Primary ITT HMA Failure ITT HMA Failure N = 199 N = 127 N = 199 N = 127 Patients with BMBL assessment 156 (78) BM complete response 22 BM partial response 8 Stable disease 77 Progressive disease
103 (81)* 14 8 51
86 (43) 11 9 32
57 (45)* 7 7 25
30
34
18
49
S45
Conclusions: Consistent with previous observations in Phase II studies, BMBL response at 4 or 12 weeks was correlated with OS in this population. These data suggest that BMBL response at 4 or 12 weeks may serve as a biomarker as an intermediate clinical endpoint (ICE) in rigosertib trials. Further studies are underway to determine whether BMBL response can be considered a broader response biomarker for other agents that can serve as an ICE.
*BM assessment was optional for BSC patients.
89 A PHASE I STUDY OF THE COMBINATION OF AZACITIDINE AND ORAL RIGOSERTIB IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) OR ACUTE MYELOID LEUKEMIA (AML) S.C. Navada1, G. Garcia-Manero2, K. Hearn2, R. Odchimar-Reissig1, E. Demakos1, Y. Alvarado2, N. Daver2, C. DiNardo2, M. Konopleva2, G. Borthakur2, N. Azarnia3, L.R. Silverman1 1 Division of Hematology/Onconolgy, Icahn School of Medicine at Mount Sinai, New York, USA; 2Department of Leukemia, MD Anderson Cancer Center, Houston, USA; 3Biometrics, Onconova Therapeutics Inc, Newtown, USA
Fig. 2. Overall survival by 4-week and 12-week bone marrow blast response among Rigosertib-treated patients with primary HMA failure.
Methods: After signing informed consent, patients with HRMDS progressing on, failing to respond to, or relapsing after HMA treatment were randomized 2:1 to rigosertib or best supportive care (BSC). BMBL response at each timepoint was assessed as complete response (mCR), partial response (mPR), stable disease (SD), progressive disease (PD), or not evaluable. Results: Since no difference in overall survival (OS) was noted between patients who had objective BM response and those with SD, a landmark analysis was conducted that separated patients at 4 and 12 weeks into response categories of BM response+SD vs. PD (Table 1 and Figure 1). The landmark analysis of patients with primary HMA failure demonstrated that, at both timepoints, rigosertib-treated patients with mCR+mPR+SD had significantly greater OS than those with PD (Figure 2).
Background: Rigosertib is a PI3/polo-like kinase inhibitor that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent in clinical trials in both higher-risk and lower-risk MDS patients. Azacitidine (AZA) is first-line therapy for patients with higher-risk MDS. In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells (Skidan et al, AACR Proceedings, 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. Methods: Patients with MDS and non-proliferative AML who were previously untreated or had failed or progressed on a hypomethylating agent (HMA), were included in this phase I combination study. Oral rigosertib was administered twice daily on days 1-21 of a 28-day cycle. Patients were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg BID, [2] 280 mg BID, [3] 560 mg qAM and 280 mg qPM. AZA was administered at the standard dose of 75 mg/m2/day SC or IV on days 8-14 in each of the cohorts. Results: Eighteen patients have been treated; MDS: intermediate-1 (3), intermediate-2 (6) high risk (3), CMML (1), and AML (5); median age 70.5 years; 61% male. Patients have received 1-14 cycles of treatment. Cytogenetic profiles by MDS IPSS were good (8), poor (8), and intermediate (2). Eleven of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. 56% of patients received prior treatment with an HMA: AZA (6), decitabine (4). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Drug-related dysuria/cystitis was not reported in this population. Responses according to IWG 2006 criteria were observed in the bone marrow and peripheral blood: CRi (complete response with incomplete blood recovery) (4), mCR (marrow CR) (5), stable disease (2). Four of 6 (67%) patients with MDS, who had failed prior HMA, responded to the combination: CRi (2), mCR (2), SD (1), PD (1). Conclusions: The combination of oral rigosertib at 560 mg/280 mg BID and standard-dose AZA appears to be safe and well-tolerated in patients with MDS and non-proliferative AML. The AE profile is not significantly different from AZA alone. Responses in patients failing an HMA suggest synergy for the combination, which will be explored further in the ongoing phase II study.