scholarly journals Final Results from a Phase I Trial Combining Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4073-4073
Author(s):  
Amy Wang ◽  
Howard Weiner ◽  
Richard A. Larson ◽  
Olatoyosi Odenike ◽  
Andrew S Artz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Induction Phase ◽  
Advisory Committees ◽  
Count Recovery

Abstract Background: Selinexor, an exportin 1 (CRM1/XPO1) inhibitor, has demonstrated anti-leukemic effects as a single agent and in combination with anthracyclines and DNA damaging agents. HiDAC/Mito is an effective induction regimen for patients with relapsed/refractory (R/R) AML and has a reported overall response rate (ORR) of 55% at our institution. We hypothesized that adding selinexor to HiDAC/Mito would be feasible and have synergistic anti-leukemic effects. Early results of the trial were previously reported (Wang et al., J Hematol Oncol, 2018), and here we present more mature data on survival and relapse. Methods: We performed a phase 1 dose escalation trial with cohort expansion in patients with AML. This study tested increasing doses of selinexor combined with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of the regimen. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase. HiDAC (1.5 to 3 g/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) were only evaluated during dose escalation and was defined as any grade 3 or greater non-hematologic toxicity, except transient (<48 hours) nausea/vomiting or liver function abnormalities, or by persistent bone marrow aplasia lasting >56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: The study enrolled a total of 28 patients from October 2015 to October 2017. Selinexor dose levels were 60mg (n=3) and 80mg (n=25). Median age = 61 (range 37 - 76). De novo AML = 15 (54%); secondary AML = 12 (43%), and therapy-related AML = 1 (3%). Of these, 13 patients had R/R disease (6 primary refractory, 6 in first relapse, 1 in second relapse). Fifteen (54%) patients were previously untreated. Molecular/genetic subgroup profiles by European Leukemia Net 2010 criteria included favorable = 6 (21%), intermediate I = 9 (32%), intermediate II = 5 (18%), and adverse = 8 (29%). No DLTs were observed in dose escalation. Myelosuppression was universal. Median time to count recovery (ANC >1.0 x 109/L, platelet count >100 x 109/L for the 16 responding patients was 46 days. Febrile neutropenia occurred in 21 (75%) patients. Common selinexor-related adverse effects included diarrhea (32%), electrolyte disturbances (32%), bacteremia (32%), anorexia (29%), nausea/vomiting (29%), fatigue (25%), and acute kidney injury (25%). One patient from the expansion cohort died from hemorrhagic stroke prior to completing induction. The ORR was 64% (18/28 pts): complete remission (CR) = 46% (13 pts), CR with incomplete count recovery (CRi) = 14% (4 pts), partial remission (PR) = 4% (1 pt), and treatment failure (TF) = 36% (9 pts). ORR was 87% (9 CR, 3 CRi, 1 PR, 2 TF) for newly diagnosed pts and 38% (4 CR, 1 CRi, 8 TF)) for R/R pts. Of the responders, 6 proceeded to consolidation without allo-SCT, 10 eventually underwent allo-SCT, and 2 relapsed prior to either. The 10 non-responding patients proceeded to another line of therapy, and 3 eventually underwent allo-SCT. Eleven (40%) patients are alive with a median observation period of 13 months (range 8 days to 34 months). The median relapse free survival (RFS) and overall survival (OS) was 11 and 16 months, respectively. The 1-year PFS and OS was 44% and 61%, respectively. Median OS was 9 months for non-responders and 19 months for responders (HR 1.8, 95% CI 0.6 - 5.7, p=0.2); 1-year OS rates were 50% vs 67%, respectively. One CR patient completed consolidation and maintenance without allo-SCT remains in remission 33 months later. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. This regimen yields an ORR of 64% based on currently available data. We had previously reported molecular correlatives demonstrating the effect of selinexor. The recommended phase 2 dose is 80mg of selinexor. Figure. Figure. Disclosures Larson: Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Odenike:Agios: Research Funding; Astex: Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; NS Pharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; ABBVIE: Honoraria, Research Funding; Janssen: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Liu:BMS: Research Funding.

Phase 1 Study of the Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4082-4082 ◽  
Author(s):  
Jatin J. Shah ◽  
Donna M. Weber ◽  
Sheeba K. Thomas ◽  
Raymond Alexanian ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Stem Cell Transplant ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Kinesin Spindle Protein

Abstract Abstract 4082 Background: ARRY-520, a novel kinesin spindle protein (KSP) inhibitor, has been studied as a single agent and in combination with dexamethasone, and demonstrated promising clinical activity in patients with bortezomib- and lenalidomide-refractory multiple myeloma (MM). Carfilzomib, a novel irreversible proteasome inhibitor (PI), has also demonstrated single agent activity in relapsed and refractory MM, and recently received regulatory approval for this indication. Preclinical data support the presence of synergy with the combination of a PI and a KSP inhibitor via the latter's ability to down-regulate Mcl-1, supporting our hypothesis that the combination of carfilzomib and ARRY-520 (Car-ARRY) would be highly active in relapsed and/or refractory myeloma. We therefore aimed to combine these two agents for the first time, and here report the initial findings from the phase I dose-escalation in patients with relapsed and/or refractory MM. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and the safety/tolerability of the Car-ARRY combination. Secondary objectives were to determine efficacy as measured by the overall response rate, time to progression, progression free survival and time to next therapy. Patients had to have myeloma that was relapsed and/or refractory, be ineligible for autologous stem cell transplant, bortezomib refractory/intolerant, and prior lenalidomide exposure. ARRY-520 was administered intravenously over 1 hour on days 1, 2, 15 and 16, while carfilzomib was administered intravenously over 30 minutes on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. All patients received growth factor support with filgrastim. Dose-escalation used a standard 3+3 schema proceeded based on dose-limiting toxicities (DLTs) during cycle 1, with planned escalation of the dose of ARRY-520. Dose level 1 was ARRY-520 0.75 mg/m2, and carfilzomib was dosed at 20 mg/m2 for cycle 1 on days 1 and 2 and all subsequent dose were at 27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: To date, 8 patients have been enrolled in the ongoing dose escalation phase. The median age was 66 (range 47–80), 6/8 were males, and the median number of prior therapies was 4 (range 2–10). 7/8 patients had undergone prior autologous stem cell transplant, and all patients were bortezomib refractory or intolerant. In the first cohort, 3 patients were enrolled and no dole limiting toxicity (DLT) was observed. During the second cohort, ARRY-520 was escalated to 1 mg/m2 with carfilzomib at 20/27 mg/m2, and among the first 3 patients, one patient suffered a DLT in the form of an admission for influenza pneumonia with non-neutropenic fever. Expansion of cohort 2 is currently underway. Among the 6 patients who completed the first cycle of therapy, 5 remain on study. In the first cohort, one patient remains on study with 6 cycles and achieved a near complete remission, 1 patient achieved stable disease, and 1 patient suffered disease progression after first cycle. In the second cohort, all three patients who completed the first cycle have stable disease and remain on trial. In the first 6 toxicity-evaluable patients who have completed one cycle, grade (G) 3 events included one each of pneumonia, diarrhea, and hyperglycemia. There was limited hematologic toxicity with 4/6 patients with G1/2 thrombocytopenia, 3/6 patients with G1/2 anemia, and 1/6 patient with G1/2 neutropenia. Additional G1/2 non-hematologic toxicity included 3/6 patients with diarrhea, 3/6 patients with dyspnea, 3/6 patients with transient elevations in creatinine and 3/6 patients with aspartate aminotransferase elevations. An MTD has not been established and enrollment is ongoing in cohort 2 with carfilzomib at 20/27mg/m2 and ARRY-520 at 1.0 mg/m2. Conclusions: The combination of ARRY-520 and carfilzomib is well tolerated with limited hematologic toxicity and a manageable side effect profile. Notably, in this patient population, with patients who have bortezomib refractory/intolerant myeloma, the combination has demonstrated early signals of activity. Updated safety and efficacy data for all patients will be presented at the meeting. Disclosures: Shah: Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: This presentation will include information about Arry-520 which is not yet approved for use in patients with multiple myeloma. Wang:Pharmacyclic: Research Funding; onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hilder:Array BioPharma: Employment. Orlowski:onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; array biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Combination of Selinexor with High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in Acute Myeloid Leukemia (AML) Is Feasible and Tolerable

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 212-212 ◽  
Author(s):  
Amy Y Wang ◽  
Howie Lawrence Weiner ◽  
Margaret Green ◽  
Richard A. Larson ◽  
Olatoyosi Odenike ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Research Funding ◽  
Remission Induction ◽  
Nuclear Staining ◽  
Advisory Committees ◽  
Biomarker Analysis ◽  
Count Recovery

Abstract Background: Selinexor, an exportin 1 (XPO1) inhibitor, has demonstrated anti-leukemic effect as a single agent. There are also data demonstrating synergistic killing of leukemia cells with the combination of selinexor with anthracyclines and/or DNA damaging agents. The HiDAC/Mito combination is an effective induction regimen for relapsed/refractory (R/R) AML patients with a reported overall response rate (ORR) of 55% at our institution. We hypothesize that adding selinexor to HiDAC/Mito is feasible and has synergistic anti-leukemic effects. Methods: We performed a phase I dose escalation trial with cohort expansion in patients with AML that combined increasing doses of selinexor with age-adjusted HiDAC/Mito (NCT02573363). The primary endpoint was to determine the maximum tolerated dose of selinexor when given in combination with HiDAC/Mito. Selinexor was given orally on days 2, 4, 9, and 11 during the induction phase of the study. HiDAC (1.5 to 3 gm/m2 depending on age, IV over 3 hours) followed immediately by Mito (20 to 30 mg/m2 IV over 1 hour) was administered on day 1 and 5. Initial selinexor dose was 60mg (~35mg/m2) followed by a dose escalation to a target level of 80mg (~50mg/m2). Patients who entered remission proceeded to stem cell transplantation (SCT) or consolidation chemotherapy with HiDAC/selinexor followed by maintenance therapy with weekly selinexor alone for up to one year. Dose limiting toxicity (DLT) was defined as any grade 3 or greater non-hematologic toxicity, except transient (<48 hours) nausea/vomiting or liver function abnormalities, or by persistent bone marrow aplasia lasting >56 days in the absence of disease. Once a dose level was declared tolerable, more patients could be enrolled at that level to provide additional safety, tolerability, and efficacy data. Results: As of July 2016, 12 patients had enrolled. Selinexor dose levels were 60mg (n=3) and 80mg (n=9). Median age = 61 (range 44 - 74). De novo AML = 5 (42%); secondary AML = 3 (25%), R/R AML = 4 (33%). Eight (67%) patients were previously untreated, 1 (8%) was beyond the first relapse, and 3 (25%) had primary refractory disease. Prior therapies included combination cytarabine with anthracycline, HiDAC, decitabine, and clinical trial agents. Molecular/genetic subgroup profiles by European Leukemia Net (ELN) criteria included favorable = 1 (8%), intermediate I = 5 (42%), intermediate II = 1 (8%), and adverse = 5 (42%). Only 10 patients are evaluable for safety and efficacy at the time of analysis. Myelosuppression was the most common side effect and was universal. Median and average times to count recovery for responding patients from day 1 were 38 and 47 days, respectively. Febrile neutropenia was observed in 8 patients (80%), compared to our historical experience of 64% for HiDAC/Mito alone. Other significant adverse events included line-associated thromboses (n=3), cardiac toxicity (n=3), cerebellar toxicity (n=1), arm cellulitis (n=1), and syncope (n=1). No DLTs were observed. 30 and 60-day induction mortality was 10% (1 patient with R/R AML died from progressive disease). Ten patients are evaluable for response: complete remission (CR) = 4 (40%), CR with incomplete count recovery (CRi) = 1 (10%), partial remission (PR) = 1 (10%), and treatment failure (TF) = 4 (40%). Thus, the ORR is 60%. Of those who responded, 2 patients proceeded to consolidation, 1 underwent allo-SCT, and 3 are in preparation for allo-SCT. No response was achieved in patients with R/R AML. Bone marrow samples from screening and day 12 of treatment were used for biomarker analysis in three CR patients. A marked reduction in KI67, MYC, FLT3, KIT, and DNA damage response proteins was observed in the remaining tumor cells in the post-treatment samples. Staining for P53 showed an increase in nuclear staining intensity, which is consistent with the known effect of selinexor on tumor cells. Conclusions: The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses up to 80mg/day or ~50 mg/m2/day twice weekly. It yields an ORR of 60% based on currently available data. The recommended phase II dose is 80mg of selinexor. Additional molecular correlative studies are evaluating patients' marrow and blood samples for markers that predict response and relapse. Disclosures Odenike: Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stock:Sigma-Tau: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Gilead Sciences: Honoraria; Amgen: Honoraria; Royalties for a chapter in Up to Date: Patents & Royalties. Liu:Karyopharm: Research Funding; BMS: Research Funding.

Phase 1 Study Of The Novel Kinesin Spindle Protein Inhibitor ARRY-520 + Carfilzomib (Car) In Patients With Relapsed and/Or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1982-1982 ◽  
Author(s):  
Jatin J. Shah ◽  
Lei Feng ◽  
Sheeba K. Thomas ◽  
Donna M. Weber ◽  
Michael Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Kinesin Spindle Protein

Abstract Background ARRY-520, a kinesin spindle protein (KSP) inhibitor, has demonstrated promising clinical activity, both as a single agent and combined with dexamethasone in patients (pts) with bortezomib- and lenalidomide-refractory MM with a single agent response rate (≥ MR) of 19-33%. The maximum tolerated dose (MTD) of ARRY-520 as a single agent was 1.5 mg/m2 administered on days 1 and 2 every 2 weeks with minimal non-hematologic toxicity. Carfilzomib, an irreversible proteasome inhibitor (PI), also has demonstrated single agent activity in RRMM and received accelerated approval by the Food & Drug Administration (FDA). Preclinical data demonstrate synergy between the combination of a PI and ARRY-520 and the minimal overlapping side effect profile support the hypothesis that the combination of carfilzomib and ARRY-520 could be an attractive regimen. Methods The primary objective was to determine the MTD and the safety/tolerability of carfilzomib and ARRY-520 in RRMM. Secondary objectives were to determine efficacy as measured by the overall response rate (ORR), time to progression, progression free survival and time to next therapy. Pts had to be ineligible for autologous stem cell transplant (ASCT), have disease refractory/intolerant to bortezomib, and have had prior lenalidomide exposure. ARRY-520 was administered intravenously (iv) on days 1, 2, 15 and 16; carfilzomib was administered intravenously on days 1, 2, 8, 9, 15 and 16 of a 28 day cycle. All pts received growth factor support in cycle 1. Dose-escalation used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Four dose levels were studied with ARRY-520 escalated from 0.75 to 1.5 mg/m2 with the approved fixed dose of carfilzomib 20/27 mg/m2. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results 20 pts were enrolled in the completed phase 1 dose escalation portion of the study. The median age was 61 (range 43-80), and pts had received a median of 4 lines of prior therapy (range 2-10). 16/20 pts were lenalidomide refractory/intolerant; 20/20 pts were bortezomib refractory/intolerant; and 18/20 pts had prior ASCT. Two pts in cohort 2 were not DLT evaluable due to non-compliance with study-related therapy in cycle 1 and replaced for assessment of DLT. No DLTs were observed in 3 patients dosed in cohort 1, with ARRY-520 at 0.75 mg/m2. In cohort 2, 1/6 patients encountered a DLT with influenza pneumonia and non-neutropenic fever. In cohort 3, 5 patients were enrolled, ARRY-520 was dose escalated to 1.25 mg/m2, 2 patients were unevaluable for assessment of DLT, and no DLTs were encountered in the remaining 3 patients. The final planned cohort 4 was full dose ARRY-520 at 1.5 mg/m2 and carfilzomib 20/27 mg/m2, where 1/6 patients encountered a DLT of non-neutropenic fever and pneumonia. Therefore, the MTD of ARRY-520 with carfilzomib 20/27 mg/m2 was established at 1.5 mg/m2. Among 19/20 patients evaluable for efficacy, for an ORR (≥ MR) was 58%: including nCR (n=1), uPR/PR (n=6), MR (n=4), uSD/SD (n=4) and PD (n=4). Among 20 pts enrolled to date, 10 patients remain on study, 6 discontinued due to progressive disease, 1 pt was lost to follow-up, 1 patient died with febrile neutropenia in cycle 4 related to treatment, and 2 pts withdrew consent after 1 cycle of therapy. Treatment emergent SAEs included 5 pts with 6 incidences of pneumonia (influenza; n=1), 1 patient each with G3 bacteremia, G2 lethargy, G3 febrile neutropenia(FN) and G5 FN. Conclusions MTD has been established at the maximum planned dose level 4, with carfilzomib 20/27mg/m2 and ARRY-520 at 1.5 mg/m2. ARRY-520 can be safely combined carfilzomib in patients with RRMM and the combination is well tolerated with limited hematologic toxicity with growth factor support. The combination is very active in a heavily pretreated patient population with an ORR (≥MR) of 58%. Enrollment in a dose expansion at dose level 4 is underway. In addition a second dose escalation of ARRY-520 and increasing doses of carfilzomib in a 30 minute infusion is also enrolling. Disclosures: Shah: Array biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Millennium: Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: ARRY-520 in relapsed/refractory myeloma. Thomas:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Hilder:Array BioPharma: Employment. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Venetoclax Combined with Rituximab, Ifosfamide, Carboplatin and Etoposide Chemoimmunotherapy (VICER) for Treatment of Relapsed Diffuse Large B Cell Lymphoma: Results from the Phase 1 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 397-397 ◽  
Author(s):  
Paolo Caimi ◽  
Deepa Jagadeesh ◽  
Kirsten Marie Boughan ◽  
Robert M. Dean ◽  
Brenda Cooper ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Second Line ◽  
Advisory Committees ◽  
Line Therapy ◽  
Grade 3

Abstract Introduction: Diffuse large B cell lymphoma (DLBCL) patients (pts) with relapsed or refractory (r/r) disease after front line chemoimmunotherapy have poor survival. Standard second line therapy for r/r DLBCL consists of platinum-based chemotherapy followed by autologous stem cell transplant (ASCT). Approximately 50% of pts do not respond to second line therapy, highlighting the need for increased efficacy of these regimens. The antiapoptotic protein Bcl-2 is overexpressed in approximately 30% of DLBCL cases. Preclinical and early clinical data suggest that addition of venetoclax (VEN), a potent selective Bcl-2 inhibitor, to chemoimmunotherapy augments response rates and durability in lymphoma. We conducted a phase 1 dose escalation and dose expansion study to evaluate the safety and efficacy of VEN in combination with R-ICE (rituximab, ifosfamide, carboplatin and etoposide) (VICER) r/r DLBCL pts. Here we present the results after completion of VEN dose escalation. Methods: Patients (≥18 years of age) with r/r DLBCL who failed one or two lines of therapy were enrolled. The primary objective was to determine the recommended phase 2 dose (RP2D) of VEN when combined with R-ICE. VEN was given orally on days 1 - 10 of each 21 - day cycle x 3 cycles. Dose escalation was conducted according to a 3+3 design, with 3 dose levels (400, 600 and 800mg). R-ICE was given at standard dose and schedule on days 1 - 3 of each cycle for 3 cycles. No intra-patient dose escalation was allowed. Tumor lysis syndrome (TLS) mitigation included inpatient administration, hydration, allopurinol and frequent laboratory evaluation during cycle 1. All patients received pegfilgrastim; use of prophylactic antibiotics during neutropenia was left at the discretion of the treating physician. Results: As of July 20, 2018, 18 pts with DLBCL (14 male, 4 female) were enrolled (VEN 400mg, n = 3; 600 mg, n = 3; 800 mg, n = 12). Median age of pts was 55.5 years [range 27-78]. All pts received rituximab and anthracycline containing first - line therapy, 4 patients had failed a second line of therapy. One patient experienced dose limiting toxicity (DLT) at 800 mg VEN, with acute renal failure, febrile neutropenia, sepsis and rapid tumor progression and died after cycle 1. No other DLTs were observed. Hematologic toxicity was common, with grade ≥3 anemia in 6 (33%) pts; grade ≥3 neutropenia in 14 (78%) pts and grade ≥3 thrombocytopenia in 10 (55%) pts. Five (28%) pts experienced febrile neutropenia. The most common non-hematologic all-grade treatment emergent adverse events (TEAEs) were fatigue (7 [38%] pts), nausea (6 [33%] pts); diarrhea (6 [33%] pts), anorexia (5 [27%] pts], infection (5 [27%] pts) and sensory neuropathy (5 [27%] pts). Grade ≥3 TEAEs included infection (4 [22%] pts), cholecystitis (2 [11%]) and one case each (5.5%) of peripheral edema, acute renal failure, acute coronary syndrome, atrial fibrillation, hyponatremia and hypokalemia. One case of laboratory TLS occurred, but no clinical TLS was observed. At data cutoff, the intent-to-treat (ITT) population included 13 patients that had at least one cycle of therapy and end of treatment response or had discontinued prior to response assessment; 3 pts did not complete all planned cycles of VICER: one patient died after DLT, one patient proceeded to ASCT in complete remission (CR) after 2 cycles and another withdrew after cycle 1, achieving partial remission (PR) with additional 2 cycles of R-ICE. Nine pts (69%) achieved CR and 2 (15%) achieved PR (overall response rate (ORR): 11/13 [84.6%]) (Tables 2 and 3). Figure 1 depicts tumor response data. Among 11 responding pts, 7 have undergone stem cell collection, with a median CD34 cell count of 3.73x106 cells/kg. Seven pts have completed their ASCT, with hematopoietic engraftment in all cases. Median follow up of patients in CR/PR is 6 months (range 1 - 12), none has experienced progression. Conclusions: In this Phase 1 study, VICER shows encouraging antilymphoma activity in r/r DLBCL, including double hit/double expressor lymphomas, with high rates of complete metabolic response (69% CR by PET), which is higher than historical levels reported with R-ICE alone (CR typically <45%). The RP2D of VEN is 800 mg. Hematologic toxicity - particularly neutropenia - is common, and G-CSF support as well as antibiotic prophylaxis are necessary to prevent infectious complications. Updated safety, progression-free survival and response data will be presented at the meeting. Disclosures Caimi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2154-2154
Author(s):  
Noa Biran ◽  
Shijia Zhang ◽  
Scott D. Rowley ◽  
David H. Vesole ◽  
Michele L. Donato ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Conditioning Regimen ◽  
High Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Grade 3 ◽  
High Dose Melphalan

Abstract Background: A regimen of escalating doses of thalidomide, in combination with bortezomib and high dose melphalan (Mel/Vel/Thal) was evaluated as a conditioning regimen for autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM) in a phase I/II study. Methods: Patients received Mel/Vel/Thal as a second of tandem ASCT if they achieved <CR to their first ASCT (tandem), or as conditioning for a salvage ASCT (salvage). Exclusion criteria were dose-intense therapy within 56 days, uncontrolled infections, severe organ dysfunction, Karnofsky score <70%, or painful grade 2 or greater peripheral neuropathy. Conditioning consisted of Vel 1.6 mg/m2 intravenously on days -4 and -1 with Mel 200 mg/m2 on day -2. Thal was given on days -5 through -1 and was administered in a planned step-wise dose escalation of 600, 800 and 1000 mg (in cohorts of 3 pts). Dexamethasone (Dex) 10-20 mg was given prior to Vel and Mel. All pts received G-CSF every other day starting day +3 until engraftment. Serious adverse events (SAEs) were graded according to CTCAE version 3. Results: Twenty-nine pts were enrolled: 9 in the phase 1 dose-escalation phase and an additional 20 pts in phase 2. In the phase I portion, all pts experienced somnolence, with grade 3 occurring in 1 pt at the 800 mg/day dose. Subsequently, Dex 40 mg was given with first dose of Thal at the 1000 mg level with decreased severity of somnolence. No dose limiting toxicities defined as ≥ grade 4 non-hematological SAEs occurred in the phase I portion, allowing full dose escalation with 9 pts enrolled. The maximum tolerated dose for Thal was not reached and the 1000 mg dose was chosen for the phase 2 dose expansion. No regimen related mortality occurred in either phase I or phase II portion of the study. All SAEs except lethargy and dizziness occurred after ASCT and were not attributed to Thal. The most common grade 1 and 2 non-hematologic toxicities included nausea (65.5%), mucositis (51.7%), diarrhea (48.3%), somnolence (48.3%), lethargy (27.6%), and vomiting (17.2%). The most common grade 3 non-hematologic adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and somnolence (13.8%), which increased risk of falls. SAEs included somnolence (13.8%), tumor lysis syndrome (3.4%), and engraftment syndrome (3.4%). All transplant-related SAEs resolved by day +28 after ASCT. All pts achieved prompt hematological recovery with the median time to ANC >500/uL 10 days (range, 8-14 days), and platelet >20,000 12 days (range 9-26 days). All pts received at least one ASCT prior to enrolling on the study. Seventeen pts (59%) had interim salvage chemotherapy between their upfront and Mel/Vel/Thal ASCT (i.e. received a salvage ASCT), with median time from first to salvage ASCT 29 months. The remaining 12 (41%) went directly from an upfront ASCT Mel-based ASCT to the Mel/Vel/Thal ASCT (tandem ASCT) within 6 months of the first ASCT. Twenty-seven (93%) were Durie-Salmon stage III, and 13 (44%) had >2 prior lines of therapy. Of those who had Mel/Vel/Thal as a salvage ASCT, 70% had ≥3 prior lines of therapy. The overall response rate (ORR) was 69% with 38% complete remission. ORR for Mel/Vel/Thal compared to upfront Mel ASCT was 69% versus 62% with 11 patients achieving CR with Mel/Vel/Thal compared to 5 patients with Mel alone (Figure 1). Ten of 27 evaluable patients (37%) had an upgrade in response in the Mel/Vel/Thal salvage ASCT compared to their upfront ASCT: 2 pts (7%) went from PD to PR, 1 (4%) from SD to CR, 1 (4%) from PR to VGPR; 3 (11%) from PR to CR and 2 (7%) from VGPR to CR. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. Of those who underwent tandem Mel followed by Mel/Vel/Thal ASCT the median PFS was 14.9 months with a median OS not yet reached at time of analysis. For the 17 patients who received a salvage Mel/Vel/Thal ASCT, median PFS from their upfront ASCT was 11.9 months, compared to 9.1 months with the salvage Mel/Vel/Thal ASCT. Conclusions: High-dose Thal up to 1000 mg daily for 5 days can be safely combined with Vel and dose-intense Mel as an ASCT conditioning regimen with acceptable toxicities. Confirmation of potential synergistic effects of this combination regimen will require an appropriately designed phase III study. Figure 1 Figure 1. Disclosures Biran: BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
Author(s):  
Noopur Raje ◽  
Paul Richardson ◽  
Parameswaran N Hari ◽  
Anuj Mahindra ◽  
Sarah Kaster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Oral Steroid ◽  
High Dose ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

scholarly journals Phase II Study of Midostaurin + Chemotherapy in Pediatric Patients with Untreated, Newly Diagnosed, FLT3-Mutated Acute Myeloid Leukemia (AML)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3835-3835
Author(s):  
Dirk Reinhardt ◽  
Christian Michel Zwaan ◽  
Albert Hoenekopp ◽  
Julie Niolat ◽  
Sophie Ifrah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Pediatric Patients ◽  
Single Agent ◽  
High Dose ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Advisory Boards ◽  
High Dose Cytarabine

Background: In pediatric patients with AML, the presence of FLT3-internal tandem duplication (ITD) mutation is indicative of high-risk disease and confers a worse prognosis and a greater chance of relapse. Midostaurin is a multikinase inhibitor with potent activity against both mutated and non-mutated FLT3. In adult patients with FLT3-mutated AML, midostaurin in combination with chemotherapy has demonstrated good safety/tolerability and significantly improved overall survival (OS) and event-free survival (EFS) compared with placebo + chemotherapy. We present here the design of an ongoing phase II study (NCT03591510) evaluating midostaurin combined with standard chemotherapy and as a single-agent post-consolidation therapy in newly diagnosed pediatric patients with FLT3-mutated AML, other than acute promyelocytic leukemia. Study Design and Methods: This open-label, single-arm study is composed of 2 parts. For Part 1, the primary objective is to determine the recommended phase II dose (RP2D) of midostaurin in combination with chemotherapy, as determined by the occurrence of dose-limiting toxicities. For Part 2, in which patients will receive the RP2D of midostaurin, the primary objective is to evaluate the efficacy of midostaurin + chemotherapy as measured by the EFS rate at 24 mo (for regulatory purposes outside the US) or to assess the safety/tolerability of midostaurin + chemotherapy (for regulatory purposes within the US). Secondary objectives include safety/tolerability (outside US) and EFS at 24 mo (within US), other efficacy parameters (including OS, complete remission [CR], CR with incomplete blood count recovery [CRi], cumulative incidence of relapse, and minimal residual disease-negative status), and characterization of the pharmacokinetics of midostaurin. Eligible patients are aged 3 mo to < 18 yr with expected survival of > 12 wk, have a Lansky or Karnofsky performance status of ≥ 60, and have previously untreated de novo AML with FLT3 mutation: ITD and/or mutation in the tyrosine kinase domain, with mutant/wild-type signal ratio cutoff of ≥ 0.05. Exclusion criteria include any concurrent malignancy, Philadelphia chromosome or BCR-ABL1-positive AML, AML associated with Down syndrome, secondary AML, symptomatic leukemic central nervous system involvement, bone marrow failure syndrome, or prior treatment with a FLT3 inhibitor. Patients are to receive 5 treatment blocks: 2 of standard induction (Blocks 1-2) and 3 of consolidation (Blocks 3-5) chemotherapy, each with sequential twice-daily (BID) oral midostaurin. In Part 1 of the study, midostaurin will be given at a starting dose of 30 mg/m2 BID; dose escalation and determination of RP2D will be facilitated by a Bayesian hierarchical logistic regression model guided by escalation with overdose control principle. In Part 2, midostaurin will be administered at the RP2D. Induction therapy will be the local standard chemotherapy regimen with midostaurin starting after 24 hr from identification of FLT3 abnormalities and continuing for 14 d for Block 1, and FLADx (fludarabine + high-dose cytarabine on D1-5, daunorubicin on D2, 4, 6) with sequential midostaurin on D8-21 for Block 2. Patients demonstrating CR or modified CRi will proceed to consolidation with the following chemotherapy regimens, each with sequential midostaurin on D8-21: HAM (high-dose cytarabine on D1-3, mitoxantrone on D3, 4) for Block 3, HA3E (high-dose cytarabine on D1-3, etoposide on D1-5) for Block 4, and HiDAC (high-dose cytarabine on D1-3) for Block 5. Patients must be in continued remission (CR or modified CRi) to receive each block of consolidation therapy. Patients who complete Block 5 and remain in remission will proceed to 12 × 28-d cycles of post-consolidation therapy with single-agent midostaurin. Patients may undergo allogeneic hematopoietic stem cell transplantation at any time at the investigator's discretion. Overall, the aim is to recruit a minimum of 52 patients, including at least 49 at the RP2D dose. This study is currently enrolling patients at 13 centers in 7 countries (as of July 26, 2019), and a total of 37 centers in 14 countries are planned. Disclosures Reinhardt: Novartis: Other: Participation in Advisory Boards; Jazz: Other: Participation in Advisory Boards, Research Funding; CSL Behring: Research Funding; Roche: Research Funding. Zwaan:BMS: Research Funding; Servier: Consultancy; Sanofi: Consultancy; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Roche: Consultancy; Incyte: Consultancy. Hoenekopp:Novartis Pharma AG Basel: Employment, Equity Ownership. Niolat:Novartis Pharma: Employment. Ifrah:Novartis: Employment. Noel-Baron:Novartis: Employment, Equity Ownership. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Midostaurin is a kinase inhibitor approved in combination with chemotherapy for the treatment of FLT3-mutated AML in adults; the study reported here is in pediatric patients with FLT3-mutated AML.

scholarly journals A Single Arm, Phase II Study of Eltrombopag to Enhance Platelet Count Recovery in Older Patients with Acute Myeloid Leukemia (AML) Undergoing Remission Induction Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2595-2595
Author(s):  
Sudipto Mukherjee ◽  
Hong Li ◽  
Brian P. Hobbs ◽  
Aaron T. Gerds ◽  
Anjali S. Advani ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Maculopapular Rash ◽  
Remission Induction ◽  
Second Malignancy ◽  
Advisory Committees ◽  
Start Date ◽  
Marrow Fibrosis ◽  
Count Recovery

Background: For patients (pts) with AML undergoing induction chemotherapy (IC), incomplete platelet (plt) recovery can lead to an increased risk of bleeding, prolonged dependence on plt transfusions, plt alloimmunization, as well as delay in post-remission therapy. Eltrombopag is a thrombopoietin receptor agonist that stimulates megakaryopoiesis and has anti-leukemic effects. Herein, we present the final results of a phase 2 trial evaluating the efficacy of eltrombopag in accelerating plt count recovery in older AML pts receiving IC (NCT02071901). Methods: All newly diagnosed FLT3-negative AML pts > 60 years (yrs) with ECOG scores of 0-2, no active second malignancy, and no evidence of marrow fibrosis at the time of AML diagnosis were included. Acute promyelocytic (AML-M3), megakaryocytic (AML-M7), and AML arising from myeloproliferative neoplasms were excluded. Pts with any arterial or venous thrombotic event (excluding line thrombosis) within the past 12 months were excluded. IC consisted of an anthracycline (daunorubicin at 45 mg/m2 x 3 days) and infusional cytarabine (100 mg/m2 x 7 days). Eltrombopag was administered starting day 15 (range, day 15-18) of IC in pts who had marrow blasts <5% on day 14 (range, day 14-17). The primary endpoint was the proportion of pts achieving plt count > 50000/µL by day 24 of IC. In a historical cohort of 220 older AML pts (excluding APL and AML-M7) treated with IC between 2004 and 2011 at Cleveland Clinic, 60% achieved a plt count > 50,000/µL by day 24. Eltrombopag was administered at a dose of 200 mg with a one-time maximal dose escalation to 300 mg daily if plts remained < 50,000/µL after 2 weeks on treatment. Eltrombopag was discontinued once plts exceeded 100,000/µL. Informed consent was obtained prior to start of IC, and eligibility was determined on day 14. Results: Between 9-2014 and 9-2018, 93 pts were consented, of whom 31 met the eligibility criteria. Sixty seven percent of pts were ineligible as they had >5% blasts on day 14 marrow and the remaining met one or more of the following exclusion criteria: acute clinical worsening; use of supraphysiologic dose of steroids (n=1); marrow fibrosis (n=1); active second malignancy (n=1); elevated transaminases (n=5), and elevated serum creatinine (n=1). Median age was 67 years (range, 60-78), 38% were female, and 81% had a good ECOG status (ECOG 0 or 1). Most pts (84%) had de novo AML, 16% had secondary AML. By CALGB/Alliance criteria, 82% had intermediate cytogenetics, 9% had adverse karyotype and in 9% cytogenetic analysis was unsuccessful. The median eltrombopag treatment duration was 10 days (range, 8-11 d), and no dose escalations were required. Trends in the levels of plt count over time are shown in Figure 1. Median times from the start date of eltrombopag to plt >50,000/µL, and >100,000/µL were 7 d (range, 6-8) and 10 d (range, 8-11), respectively (Figure 2). By day 24 of IC, 30 of 31pts (97%) had plt >50,000/µL. The median peak plt count reached on eltrombopag was 606,000/µL (range, 280- 1,935,000/µL). The median time to reach peak plt count from start date of eltrombopag was 14 d (range, 13-36). Pts received a median of 4 units of plt transfusions (range, 3-11) in the first 14 days of induction (1 unit every 3.6 days), while during the eltrombopag treatment period, the median requirement decreased to 2 units (range, 0-6) or 1 unit every 4.8 d (P=.04). Ninety percent of pts achieved complete remission at a median time of 30 d [95% confidence interval (CI), 25-34d] from IC. No death occurred during treatment. The most common any grade toxicities (incidence > 15%) were maculopapular rash (28%), nausea (24%), increased alkaline phosphatase (24%), anorexia (20%), headache (20%), increased aspartate aminotransferase (16%), hypocalcemia (16%), and hypokalemia (16%). Grade 3/4 toxicities were reported at 4% (n=1) for febrile neutropenia, fever, pain, decreased white blood cell count, hypocalcemia, hypokalemia, generalized muscle weakness, maculopapular rash, and thromboembolic event. Median overall survival time from IC was 11.2 months (95% CI, 1.9, 14.8 m). Conclusion: In this study, eltrombopag appeared to hasten plt recovery and reduce plt transfusions without increasing rates of refractory disease in older FLT3-negative AML pts undergoing IC, without any limiting toxicities. Additional analyses are currently underway to evaluate durability of platelet responses, responses in other cell lineages and survival. Disclosures Mukherjee: Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Gerds:Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Sierra Oncology: Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding. Advani:Abbvie: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 1 Dose Escalation Study of Milademetan in Combination with 5-Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3932-3932
Author(s):  
Courtney D. DiNardo ◽  
Rebecca Olin ◽  
Jo Ishizawa ◽  
Hiroyuki Sumi ◽  
Jingdong Xie ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Ecog Ps ◽  
Mdm2 Inhibitor

Background: The tumor suppressor p53, encoded by the TP53 gene, is negatively regulated by murine double minute 2 (MDM2), an E3 ubiquitin ligase. Deregulation of MDM2 results in the degradation of p53, leading to cessation of the protein's multiple tumor-suppressive functions, including the induction of apoptosis and reactivation of aberrantly silenced genes. Although TP53 is not frequently mutated in AML, p53 pathway dysfunction is prevalent, with MDM2 overexpression being frequently observed. Disrupting MDM2's negative regulatory effect to reactivate functional p53 is a promising strategy for the treatment of AML. Milademetan (DS-3032b) is a small-molecule MDM2 inhibitor that disrupts the p53-MDM2 interaction and has demonstrated single-agent activity in preclinical and clinical studies of AML. Survival rates are poor for patients with relapsed/refractory (R/R) AML or high-risk MDS which underpins the rationale for combination treatments to build on the efficacy of available agents. AZA, a hypomethylating agent, is part of the standard of care for AML and MDS. Reactivation of p53-inducible genes with milademetan combined with hypomethylation and direct cytotoxicity with AZA has shown activity in preclinical models of AML. Study Design and Methods: This open-label, 2-part, multicenter, phase 1 dose-escalation and -expansion study (NCT02319369) evaluates milademetan in combination with AZA in patients with R/R AML or high-risk MDS. Key inclusion criteria comprise a diagnosis of R/R AML or high-risk MDS; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2; and adequate renal, hepatic, and clotting functions. Additional inclusion criteria for newly diagnosed patients is ineligibility for intensive induction chemotherapy due to advanced age (≥ 75 years), congestive heart failure, or ECOG PS of 3 that is not related to leukemia. Key exclusion criteria include acute promyelocytic leukemia, central nervous system leukemia, unresolved toxicity from previous anticancer therapy, mean QTcF interval >450 ms for males or >470 ms for females, or prior treatment with an MDM2 inhibitor. During part 1 (dose escalation), patients with R/R AML or high-risk MDS receive single-agent milademetan (part 1; completed) or milademetan in combination with AZA at different dose schedules (part 1A; ongoing). Milademetan is administered as a single agent on days 1-21 of each 28-day cycle (21/28 schedule) at a starting dose of 60 mg and escalating to 90, 120, 160, and 210 mg. Less frequent dosing schedules will also be evaluated, starting with the maximum tolerated dose (MTD) determined from the 21/28 schedule. In part 1A, AZA will be administered at 75 mg/m2 subcutaneously or intravenously on days 1-7 of each 28-day cycle, with milademetan treatment on days 5-14 or 8-14. The primary objectives of part 1 are to assess safety and tolerability, determine the MTD of single-agent milademetan and in combination with AZA, and identify the recommended dose for expansion (RDE) for milademetan plus AZA. During part 2 (dose expansion), 3 cohorts of patients with either (1) R/R AML, (2) newly diagnosed AML, or (3) high-risk MDS will receive milademetan in combination with AZA at the RDE. The primary objectives of part 2 are to confirm safety and tolerability, evaluate response to combination treatment, and identify a recommended phase 2 dose. Pharmacokinetics and pharmacodynamics of milademetan as a single agent and in combination with AZA will be evaluated in both parts. Approximately 80 patients are planned to be enrolled in part 1, and up to 40 patients are planned to be enrolled for each cohort in part 2. This study is currently recruiting in the United States. Disclosures DiNardo: agios: Consultancy, Honoraria; medimmune: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria. Olin:Spectrum: Research Funding; Revolution Medicine: Consultancy; Mirati Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Research Funding; Ignyta: Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Astrazeneca: Research Funding; Daiichi Sankyo: Research Funding; Clovis: Research Funding. Ishizawa:Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Sumi:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Kato:Daiichi Sankyo, Inc.: Employment; Celgene: Employment, Equity Ownership. Kumar:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy.

Response Adapted Lenalidomide Based Therapy For Newly Diagnosed (ND) Standard Risk Older Adults With Multiple Myeloma (MM): An International Collaboration

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3201-3201
Author(s):  
Rachid Baz ◽  
Hui-Yi Lin ◽  
Sung-Soo Yoon ◽  
Kihyun Kim ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Single Agent ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
The Us ◽  
Standard Risk

Abstract Introduction Older MM patients continue to have poor outcomes. Lenalidomide (L) and low dose dexamethasone (D) was found to result in better overall survival than L and high dose D in ND MM (Rajkumar et al. Lancet Oncol 2010). In an attempt to decrease toxicity from therapy in this vulnerable patient population, we have initiated two phase II clinical trials evaluating a response adapted therapy using single agent L with sequential addition of corticosteroids. The trials had similar design and were conducted in one site in the United States (US) and multiple sites in South Korea (SK). Methods Eligible patients had symptomatic standard risk MM (b2microglobulin (b2m)≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to undergo high-dose melphalan. Patients received L on D1-21 every 28 days for 2 cycles based on renal function. If patients had a minimal response (MR) or better (25% reduction in serum M spike) after 2 cycles, they continued on single agent L until progressive disease. If patients had stable disease (SD) after 2 cycles, prednisone 100 mg PO D1-5 (P) was added to their L. In the event of progressive disease on single agent L or on LP, therapy was changed to L (at the tolerated dose) with dexamethasone 40 mg PO weekly (D). Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG and the primary end point was the 1 year progression free survival (PFS)of LD. Results Between 2/2010 and 6/2013, 61 patients were enrolled (34 in SK and 27 in the US). The median age was 73 (range 48-85) and 58% were males. Compared to US, patients in SK had a younger age, lower weight and body surface area and a higher proportion of ISS 2. There were no differences in baseline performance status, hematologic parameters, creatinine clearance or baseline b2m. The overall response rate (≥PR) to single agent L was 48% (59% & 38% for US and SK) and the clinical benefit rate (≥MR) 64% (74% & 56% for the US and SK respectively). After a median follow up of 13.2 months, P was added for 16 patients (26%) and 7 (44%) had ≥PR. D was added for 14 patients (23%) and 10 patients (71%) had ≥PR. The 1 year dexamethasone free survival was 75% (84% & 67% in the US and SK respectively). To date, 3 patients progressed after the addition of D and the 1 year LD PFS was 90% (95% CI 78-96%). There were no statistical differences in grade 3/4 hematologic adverse events (table). Lenalidomide dose reduction was more frequent in the US (59% vs. 26%) however discontinuation from therapy for causes other than progressive disease or death was more frequent in SK (41% vs. 18%). Conclusion In This elderly patient population, response adapted (sequential) therapy results in outcomes comparable to LD in younger patients with MM with 78% of patients not requiring the addition of D. Social and ethnic causes of differential tolerance to therapy should be studied further. Disclosures: Baz: Celgene: Research Funding; Millenium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Off Label Use: lenalidomide in newly diagnosed myeloma. Alsina:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Shain:Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Kwak:celgene: Research Funding.

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