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)

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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A Phase II Study of Panobinostat with Lenalidomide and Weekly Dexamethasone in Myeloma

Blood ◽

10.1182/blood.v126.23.4226.4226 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4226-4226 ◽

Cited By ~ 14

Author(s):

Ajai Chari ◽

Hearn Jay Cho ◽

Siyang Leng ◽

Amishi Dhadwal ◽

Gillian Morgan ◽

...

Keyword(s):

Dendritic Cells ◽

High Risk ◽

Mhc Class Ii ◽

Research Funding ◽

High Dose ◽

Cell Mediated Immunity ◽

Phase 2 ◽

Cytokine Analysis ◽

Phase 2 Study ◽

Grade 3

Abstract Background: Treatment options for multiple myeloma (MM) refractory (ref) to immunomodulatory drugs (IMID) and proteasome inhibitors (PI) are urgently needed. Epigenetic agents e.g. the pan histone deacetylase inhibitor (HDACi) panobinostat (pan) to modulate the acetylation of histones and oncogenic proteins are promising. Preclinically in MM, pan is syngeristic when combined with dexamethasone (dex), lenalidomide (len), and bortezomib (btz) (Ocio EM et al. Haematologica 2010). The phase 3 PANORMA 1 study of 768 patients randomized to receive IV btz and dex with either pan or placebo revealed a 3.9 month increase in PFS and increased CR rates with pan but at the cost of an increase in grade 3/4 diarrhea from 8% to 25% (San Miguel, Lancet 2014). The safety/preliminary efficacy of pan-len-dex was assessed in a phase 1b study (Mateos et al, ASCO 2010) but was complicated by high dose dex toxicities. The maximum tolerated doses were used for this phase 2 study, however, we attenuated the schedule so that pan is given thrice weekly every other week (instead of weekly) and dex is given only weekly (table 1). Methods: Inclusion criteria were patients with rel or rel/ref MM (including IMID/PI ref), measurable disease, adequate organ function and hematologic parameters. Patients previously treated with a HDACi or currently receiving QTC prolonging medications were excluded. The primary objective in this open label, single arm phase 2 study was to evaluate the best overall response rate (ORR). Secondary objectives were to evaluate safety, duration of response (DOR), and overall and progression-free survival (PFS). Each drug was administered at the doses and schedule shown in Table 1. Results: 26 evaluable patients with progressive disease (PD) at screening have been enrolled with a median age of 64 (44% > 65 yo) and a median of 2 lines of therapy over 4 years since diagnosis. High-risk molecular findings were present in 14 patients (54%), including 4 with del p53 and 10 with gain of 1q21 by FISH (4 with concurrent t(4;14)). 22 (85%) were len- ref, & 35, 54, 23% were ref to each: pomalidomide (pom), btz, & carfilzomib. Responses include 2 complete responses (CR), 4 very good partial responses (VGPR), 4 PRs, 9 minimal responses (MR), and 3 stable diseases (SD), for an ORR of 38%, CBR (>MR) of 73%, and a median DOR of 6 mos. The median PFS was 6.5 mos. In the 22 len-ref pts, there were 4 VGPRs, 2 PRs, 8 MRs & 3 SDs, with a median PFS of 5.5 mos. Responses were even seen in 10 pom-ref pts including 1 VPGR, 1 PR, and 4 MRs. Grade 3/4 toxicities (regardless of drug attribution) were primarily hematologic, with neutropenia (40%), thrombocytopenia (23%) and anemia (4%) respectively. Grade 3/4 nonhematologic AEs included infections in 5 (1 while neutropenic), 3 diarrhea (transient), 4 fatigue & 1 pulmonary embolus and 1 pt each with: neck pain, QTc prolongation & weight loss. Patients requiring dose reductions of len/pan respectively were 4/4 for ANC, 5/1 for plts, 1/1 for febrile neutropenia & 5 len for fatigue, & 1 pan for asymptomatic T wave inversions. No doses were held or reduced for GI toxicities. Preliminary results from RNA-seq of bone marrow (BM) aspirates comparing > PR responders (R) vs < PR non responders (NR) identify 261 differentially expressed transcripts (p<0.05). Network analysis revealed "Antigen Presentation/Cell mediated immunity" as a top network function with TLR3 and MHC Class II complex as focus molecules. Immunophenotyping of the tumor microenvironment showed increased CD1c+ myeloid dendritic cells in Rs and conversely, increased CD123+ plasmacytoid dendritic cells in NRs (p<0.05). BM cytokine analysis revealed higher IL-6 and alpha-interferon levels at baseline in Rs. Interestingly, protein levels of Cereblon, Ikaros and Aiolos were not significantly different in the 2 groups. Conclusions: In rel/ref MM, the completely oral pan len dex demonstrates encouraging ORR, DOR, and PFS, even in len-ref patients with high-risk molecular findings, indicating the essential role of pan in attaining responses. In notable contrast to PANORMA 1, this regimen is well tolerated with no significant GI toxicities and primarily expected hematologic toxicities. Updated results of planned 27 pts, including correlatives, will be presented at the annual meeting. Table 1. Study Drug Doses Study Pan 20 mg po Len 25 mg po Dex 40 mg po Mateos et al Day 1,3,5,8,10,12,15,17,19 Day 1-21 Day 1-4, 9-12,17-20 Current study Day 1,3,5,15,17,19 Day 1-21 Day 1, 8, 15 Disclosures Chari: Onyx: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Catamero:Millennium / Takeda: Other: Lecturer; Onyx: Other: Lecturer; Celgene: Honoraria, Other: Lecturer. Verina:Celgene: Other: Lecturer. Jagannath:Celgene: Honoraria; Janssen: Honoraria; Merck: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

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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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Final Results of a Phase 1/2 Study of SYK Inhibitor Entospletinib in Combination with Obinutuzumab in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood-2021-146348 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2643-2643

Author(s):

Alexey V. Danilov ◽

Vi Lam ◽

Bria Thurlow ◽

Stephen E. Spurgeon ◽

Byung Park ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Phase 2 ◽

Grant Funding ◽

Bcr Signaling ◽

Syk Inhibitor ◽

Grade 3 ◽

Research Grant

Abstract Therapeutic resistance and intolerance of Bruton tyrosine kinase (BTK) inhibitors is an emerging need in CLL. SYK is integral to the activation of BTK and the B-cell receptor (BCR) signaling cascade and is overexpressed in CLL. We have shown that BAFF-mediated SYK activation triggered BCR signaling and rendered protection of CLL cells from spontaneous apoptosis in vitro. Single agent small molecule SYK inhibitor entospletinib was efficacious in treatment of patients with R/R CLL. Here we report final results of a single arm, open label, investigator-initiated phase 1/2 clinical trial which evaluated safety and efficacy of entospletinib in combination with obinutuzumab, a glycoengineered monoclonal anti-CD20 antibody, in patients with R/R CLL (NCT03010358). Patients enrolled in the Phase 1 dose-escalation portion of the trial included adults with CLL or non-Hodgkin lymphoma (Phase 1 part only) after ≥1 prior therapy. Patients were enrolled at 2 dose levels to receive entospletinib 200 or 400 mg twice-daily orally according to 3+3 design. The primary endpoint for the phase 1 portion of the study was to determine the RP2D of the combination. All patients received single agent entospletinib as part of a 7-day run-in. Thereafter, patients received entospletinib on days 1-28 of each 28-day cycle continuously, and obinutuzumab intravenously in standard doses for 6 cycles. Once the RP2D was determined, a phase 2 study enrolled patients with R/R CLL only, where complete response (CR) was the primary endpoint. A total of 24 patients (22 CLL, 2 follicular lymphoma) were enrolled. Twelve patients were enrolled in the phase 1 part of the study. The phase 2 part of the study included 17 patients with CLL. Of 6 patients who received entospletinib 200 mg on the Phase 1 part of the study, one patient experienced a DLT (grade 3 asymptomatic AST/ALT abnormalities) attributed to entospletinib. No DLTs were observed among the six patients who received entospletinib 400 mg. Thus, entospletinib 400 mg twice-daily was determined to be the RP2D in combination with obinutuzumab. Efficacy of entospletinib+obinutuzumab was analyzed in the 21 patients with CLL, of which 17 received entospletinib at RP2D (400 mg twice daily). Patients with CLL had a median age of 66 years. Thirteen patients (62%) had TP53 aberration (n=9), complex karyotype (n=6), or NOTCH1 or SF3B1 mutation. The median number of prior therapies was two (range, 1-6). Seven patients had received prior ibrutinib (4 patients discontinued due to intolerance and 2 due to progression). Median follow-up was 31 months. Among the 21 efficacy-evaluable participants with CLL, the ORR was 67% (95%CI, 43-85%). Three patients (14%, 95%CI 3-36%) achieved a CR, and 11 patients (53%) had a partial response (PR). patients with confirmed CR had undetectable MRD in the bone marrow. Median event-free survival was 27.5 months (95%CI: 16 months-NR), treatment duration - 31 months (95%CI: 27-40; Figure). Thirteen patients with high-risk CLL had an ORR of 54% (5 PRs and 2 CRs). Among the eight patients who had previously received kinase inhibitors, ORR was 62.5% (all PRs). Treatment-related adverse events were reported in 96% of patients (Table). Grade 3 or higher AEs occurred in 65%. Neutropenia (43.5%; including 4 patients [17%] who had transient grade 4 neutropenia attributed to obinutuzumab) was the most common grade ≥3 hematologic toxicity. The median onset of neutropenia was 7 days after the first obinutuzumab infusion, median duration was 28 days. Growth factor support was not required and grade ≥3 infection occurred in only 1 patient. Only one patient on study discontinued therapy due to adverse events (recurrent AST/ALT abnormalities which resolved upon cessation of entospletinib). Pharmacodynamic analysis demonstrated that treatment with entospletinib led to rapid downmodulation of pSTAT3 and the anti-apoptotic protein MCL1 in CLL cells. Furthermore, six months of combination therapy was accompanied by a reduction in IFNγ secretion in CD4 + T-cells and a reversal of exhausted phenotype, as evidenced by downregulation of PD-1. Thus, the combination of entospletinib and obinutuzumab shows an acceptable safety profile. Efficacy of this combination (EFS 27.5 months in predominantly high-risk population ) compares favorably with chlorambucil/obinutuzumab in R/R CLL (13 months), thus warranting continued exploration of the regimen. Figure 1 Figure 1. Disclosures Danilov: Genentech: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding. Spurgeon: Bristol Myers Squibb: Other: Institution: Research Grant/Funding; BeiGene: Other: Institution: Research Grant/Funding; AstraZeneca: Other: Institution: Research Grant/Funding; Acerta Pharma: Other: Institution: Research Grant/Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Other: Institution: Research Grant/Funding; Genentech: Consultancy, Other: Institution: Research Grant/Funding; Karyopharm: Consultancy; Velos Bio: Consultancy, Other: Institution: Research Grant/Funding; Gilead Sciences: Other: Institution: Research Grant/Funding; Ionis: Other: Institution: Research Grant/Funding; Merck & Co., Inc.: Other: Institution: Research Grant/Funding; Fred Hutchinson Cancer Research Center: Other: Data Safety Monitoring Board. Kittai: Abbvie: Consultancy; Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy.

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Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Blood ◽

10.1182/blood.v120.21.2737.2737 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2737-2737 ◽

Cited By ~ 1

Author(s):

Naokuni Uike ◽

Michinora Ogura ◽

Yoshitaka Imaizumi ◽

Norio Asou ◽

Atae Utsunomiya ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets <10,000/uL or bleeding requiring platelet transfusion); ALT/AST elevation of Grade 4 or that of Grade 3 lasting 7 or more days; and/or clinically unacceptable Grade 3 or higher other non-hematological adverse events (AEs). Treatment was continued until the development of unacceptable toxicity or progressive disease (PD). Response was assessed by internationally accepted standard criteria for ATL and PTCL. Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets <10,000/uL) and 4 patients received lenalidomide for 37, 56, 138, and 387 days, respectively, until PD in 3 patients and unrelated death in one. The sixth patient is still receiving lenalidomide for 28+ days without a DLT. In Cohort 3, 2 patients had DLTs (thrombocytopenia, platelets <10,000/uL in one patient and Grade 3 prolongation of QTc interval in one patient on concomitant fluconazole with preexisting cardiac disease and grade 1 QTc prolongation at baseline), 1 patient received lenalidomide for 71 days before withdrawal of consent, and 1 patient is still receiving lenalidomide for 323+ days without a DLT. Based on these results, 25 mg daily per 28-day cycle was regarded as the MTD. Other Grade 3/4 non-DLT AEs occurring in 2 or more patients included neutropenia (n=8), lymphocytopenia (n=7), thrombocytopenia (n=3), skin rash (n=3), hyperbilirubinemia (n=2), and increased ALT/AST (n=2). Among the 9 ATL patients, 3 achieved partial responses (PR) with hematological complete response in 2 patients, including the disappearance of skin lesions in 1 patient. These responses occurred between 54 and 57 days, and lasted for 92, 279+ and 505 days. Among the 4 PTCL patients, 1 achieved a PR at day 106 with >75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

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First Clinical Results Of a Randomized Phase 2 Study Of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA), In Adult Patients With Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v122.21.497.497 ◽

2013 ◽

Vol 122 (21) ◽

pp. 497-497 ◽

Cited By ~ 19

Author(s):

Hagop M. Kantarjian ◽

Elias Jabbour ◽

Karen Yee ◽

Patricia Kropf ◽

Casey O'Connell ◽

...

Keyword(s):

Dna Methylation ◽

Research Funding ◽

Remission Rate ◽

Phase 2 ◽

Elderly Aml ◽

Phase 2 Study ◽

Treatment Naïve ◽

Grade 3 ◽

Randomized Phase 2 ◽

Refractory Aml

Abstract Background SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding.

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Phase 1 Trial of Sorafenib and Everolimus In Patients with Lymphoma or Multiple Myeloma.

Blood ◽

10.1182/blood.v116.21.2802.2802 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2802-2802 ◽

Cited By ~ 2

Author(s):

Shaji Kumar ◽

Luis F Porrata ◽

Stephen M. Ansell ◽

Joseph P Colgan ◽

Betsy LaPlant ◽

...

Keyword(s):

Disease Progression ◽

Dose Level ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Phase 2 ◽

Level 3 ◽

Level 1 ◽

Grade 3 ◽

Level 2

Abstract Abstract 2802 Background: Redundancy of pro-survival signaling pathways promotes survival and drug resistance in lymphoid and plasma cell malignancies. In particular, the PI3K-Akt and the MEK-ERK pathways have been shown to play an important role in the proliferation and survival of these malignant cells induced by various cytokines in the tumor microenvironment. Sorafenib, a Raf kinase and VEGF receptor inhibitor, and everolimus, an mTOR inhibitor, have synergistic cytotoxicity in myeloma and lymphoma cells due to inhibition of multiple signaling pathways. Methods: We designed a Phase 1/2 clinical trial to identify the maximum tolerated doses of the two drugs used in combination and the efficacy of the combination. Patients (Pts) with relapsed myeloma or lymphoma were eligible for enrollment. Pts were required to have an absolute neutrophil count ≥1500 × 10(6)/L, a platelet count ≥75,000, and a serum creatinine 21.5 mg/dL. The study utilized the classic 3+3 design. Extensive pharmacokinetic studies were performed to better delineate potential drug interactions. Results: Twenty-six pts were accrued from August 2007 to February 2009. Four pts discontinued sorafenib during cycle 1 for various reasons (2 patient refusal, 1 unrelated medical condition and 1 physician discretion) and were excluded from MTD determination. An additional pt did not have measurable disease and was ineligible, leaving 19 pts with lymphoma (including 6 with Hodgkin lymphoma) and 2 with myeloma for phase I analysis. The pts had a median age of 56 years (range, 22, 69) and were heavily pretreated with a median of 4 prior therapies (range, 1–10). Eighteen (86%) had received a prior stem cell transplant. Four dose limiting toxicities were seen across all dose levels (Table). These included grade 3 vomiting (level 1), grade 4 thrombocytopenia (level 2 and 3, one each) and grade 2 hand and foot rash leading to treatment delay (level 3). Overall, 13 pts experienced a grade 3 or 4 hematologic toxicity. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 19%, 43%, and 38% of pts, respectively. Four pts have experienced a grade 3 non-hematologic toxicity; no grade 4 non-hematologic toxicities were seen. Grade 3 non-hematologic toxicities included hypokalemia, weight loss, vomiting, hand-foot skin reaction, fatigue, and elevated alkaline phosphatase. Dose level 1 (sorafenib 200 mg and everolimus 5 mg daily) was best tolerated and was selected for phase 2 evaluation. The ORR was 33% (7/21;95% CI: 15–57%, Table) with 3 pts at dose level 0 (2 PR, 1 CR), one at level 2 (1 PR) and three at level 3 (2 PR, 1 CR) responding. The responders included 5 pts with Hodgkin's disease and one each with an NK cell and T-cell lymphoma. Pts have received a median of 6 cycles (range: 1–19) of treatment. 16 pts have discontinued treatment due to disease progression (13 pts), non-resolution of cytopenias (1 pt), physician discretion (1 pt), and death on study due to lymphoma (1 pt). Disease progression has been seen in 16 pts; 9 pts have died. Median follow-up for pts still alive is 18.7 months (range: 11.5–29.4). 6 pts died from disease progression, one each due to sepsis unlikely related to treatment, cholecystitis, and unknown causes. Sorafenib is metabolized by the cytochrome P450 CYP3A enzyme and RAD-001 mainly by the CYP3A4 system in the liver, hence there is a potential for interactions. The detailed PK analyses performed as part of this trial showed a decrease in the RAD001 levels following initiation of sorafenib on day 8 of cycle 1 (Figure). Conclusion: The combination of sorafenib and everolimus is safe at a recommended phase 2 dose of sorafenib 200 mg and everolimus 5 mg daily. There is no significant drug interaction seen. Activity has been observed, especially in the setting of Hodgkins Disease. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Witzig:Novartis and Celgene: Patents & Royalties, Research Funding, Served on advisory boards with Novartis and Celgene – both uncompensated with compensation to Mayo Clinic.

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

Blood ◽

10.1182/blood.v128.22.1064.1064 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1064-1064

Author(s):

Anna B. Halpern ◽

Sarah A. Buckley ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Response Rate ◽

Phase 1 ◽

Hematologic Toxicity ◽

Hypomethylating Agents ◽

Refractory Acute Myeloid Leukemia ◽

Pre Treatment ◽

Grade 3 ◽

Refractory Aml

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

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Phase-1 Study of PF-114 Mesylate in CML Failing Prior Tyrosine Kinase-Inhibitor Therapy

Blood ◽

10.1182/blood-2018-99-116803 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 790-790 ◽

Cited By ~ 5

Author(s):

Anna G Turkina ◽

Olga Vinogradova ◽

Elza Lomaia ◽

Evgeniya Shatokhina ◽

Oleg Shukhov ◽

...

Keyword(s):

Tyrosine Kinase Inhibitor ◽

Research Funding ◽

Kinase Inhibitor ◽

Phase 1 ◽

Skin Toxicity ◽

Skin Lesions ◽

Phase 2 ◽

Phase 1 Study ◽

Phase 2 Study ◽

Grade 3

Abstract Background: PF-114 mesylate is a 4th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCRABL1 isoforms including those with a BCRABL1T315I. We present data from a phase-1 study in subjects with chronic or accelerated phase chronic myeloid leukaemia (CML) failing ≥2 TKIs or who have BCRABL1T315I (NCT02885766). Methods: 3+3 dose-escalation design to determine maximum tolerated dose (MTD) followed by expanded cohorts for doses ≤MTD. The primary objective was to determine the MTD and identify dose-limiting toxicities (DLTs) during cycle 1 (28 days). Secondary objectives included safety and anti-CML activity based on hematological, cytogenetic, and molecular criteria. Adverse events (AEs) were assessed and graded using NCI-CTCAE v4.03. Results: 51 subjects were enrolled as of June 26, 2018. Daily doses were 50 mg (n=3), 100 mg (n=3), 200 mg (n=9), 300 mg (n=11), 400 mg (n=12), 500 mg (n=3), 600 mg (n=6), 750 mg (n=4) given on a continuous QD schedule. Median age was 50 years (range, 29-82 years). Median interval from diagnosis to study-entry was 10 years (range, 0-23 years). Subjects had baseline ECOG performance scores <2. 13 subjects were reported to have BCRABL1T315I. Subjects were heavily pre-treated: 25 had received ≥3 prior TKIs; 5 subjects with BCRABL1T315I received 1 prior TKI. 600 mg was identified as the MTD with 1 of 6 subjects experiencing a DLT at this dose (Gr 3 psoriasis-like skin lesion). Similar grade-3 skin lesions were also identified at the dose of 750 mg in 2 subjects and at 400 mg in 1 subject. Therapy is ongoing in 23 subjects at doses 200, 300 and 400 mg with median duration of exposure of 5 (range, 1-21), 3 (range, 1-12) and 4 (range, 1-19) cycles. Other subjects discontinued because of progression (n=16), AEs (n=6) or other reasons (n=6). The most common of non-hematologic toxicity was skin toxicity, which was common at doses of ≥400 mg. Grade-3 skin toxicity occurred in 3 subjects on daily dose 750 mg, 4 subjects on dose 600 mg, 1 patient on dose 500 mg and 3 subjects on dose 400 mg. Skin lesions resolved rapidly upon drug discontinuation and topical therapy. No other drug related non-hematologic grade-3 toxicities except a single case of grade-3 hepatitis on dose 400 mg were observed. No deterioration of ankle-brachial index or vascular occlusive events were observed. A complete hematologic response was achieved in 8 of 19 evaluable subjects including 3 of 8 with BCRABL1T315I. Major cytogenetic response was achieved in 6 of 21 evaluable subjects including 3 of 7 with BCRABL1T315I. Major molecular response was achieved in 2 of 18 subjects completing ≥13 cycles. Most cytogenetic and molecular responses were achieved at doses 200 and 300 mg which were well-tolerated and will be considered for the phase-2 study. Conclusion: MTD of PF-114 is 600 mg with skin toxicity as the DLT. The best safety/efficacy ratio was seen at doses of 200 and 300 mg which are being studied in expanded cohorts and soon in a phase-2 study. Disclosures Turkina: Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations. Shukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Novartis: Other: provided consultations and performed lectures. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ottmann:Novartis: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Fusion Pharma: Consultancy, Research Funding. Mikhailov:Fusion Pharma: Employment. Novikov:Fusion Pharma: Employment. Shulgina:Fusion Pharma: Employment. Chilov:Fusion Pharma: Employment.

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a Phase 2 Study of Alemtuzumab-Ofatumumab (A+O) Combination in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.4686.4686 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4686-4686 ◽

Cited By ~ 3

Author(s):

Shuo Ma ◽

Steven T. Rosen ◽

Olga Frankfurt ◽

Jane N. Winter ◽

Jennifer Kreutzer ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Hematologic Toxicity ◽

Phase 2 ◽

Early Stopping ◽

First Line ◽

Oncology Research ◽

Phase 2 Study ◽

Frontline Treatment ◽

Grade 3

Abstract Background Current standard immunochemotherapy is highly effective as frontline treatment of CLL but has several limitations including poor tolerability in older patients with comorbidities, potential long-term marrow toxicity, and limited efficacy in high risk CLL. Therapy with monoclonal antibodies alone may offer an alternative, non-stem cell toxic treatment option. Our prior study of alemtuzumab-rituximab in previously untreated CLL showed promising results with good tolerability although lymph node responses were suboptimal (Frankfurt et al., Leuk Lymphoma 2014). Ofatumumab showed improved complement-mediated cytotoxicity over rituximab for CLL in vitro and significant clinical activity in refractory CLL. In this study we aim to test safety and effectiveness of alemtuzumab-ofatumumab (A+O) combination as a frontline treatment for CLL. Methods This phase 2 study of A+O first-line treatment for CLL is conducted at Northwestern University in Chicago and Karolinska University Hospital in Stockholm with an accrual goal of 60 patients. Eligibility requires symptomatic, previously untreated CLL, and PS ≤ 2. There was no exclusion for baseline cytopenia or upper age limit. Alemtuzumab (Alem) is given subcutaneously tiw for up to 18 weeks (dose escalation 3mg-10mg-30mg for week 1 and 30mg per dose for subsequent weeks). Starting week 3, ofatumumab (Ofa) is added intravenously q2 weeks up to 8 doses at 300mg for dose 1 and 2000mg for doses 2-8. All patients received anti-herpes, anti-fungal and anti-PCP prophylaxis. Cytomegalovirus (CMV) was monitored by PCR every other week. Bone-marrow biopsy and CT scans are required for response assessment (IWCLL 2008 criteria). Minimal residual disease (MRD) was assessed in bone-marrow using 6-color flow. Hematologic toxicity was assessed using IWCLL 2008 criteria and non-hematologic toxicity graded by CTCAE 4.0. Results To date the study has enrolled 41 patients among whom 31 patients have completed treatment and are reported here in this interim analysis. Median age was 63 (45-77) years; 58% had Rai stage III/IV; 48% had unmutated IgHV, and 7/31 were 17p- and/or had TP53 mutation. During initial safety run-in period to assess dose-limiting toxicity (DLT), one patient after 18 weeks of therapy developed prolonged cytopenia and died of sepsis, and another patient after 14 weeks of therapy developed grade 4 neutropenia which resolved after 16 days. Both patients achieved MRD-negative complete bone-marrow response with hypocellularity. It was speculated that the cause may be continued treatment with Alem beyond the point of MRD-negative CR in bone-marrow. Early stopping rules were implemented using BM biopsy after 9 and 12 weeks of treatment. Alem is stopped if CR in the bone-marrow is achieved, or if cellularity <10%. Ofa is stopped if CR in lymph-nodes on CT after achieving bone-marrow CR. Since this protocol modification after the initial 9 patients, no further DLT was observed and the safety committee approved continued enrollment. The most frequent treatment-emergent AE included neutropenia, anemia, thrombocytopenia, Alem-related local injection-site reaction, Ofa-related infusion-symptoms, pyrexia, and fatigue. Grade 3-4 hematologic AEs included neutropenia (39%), thrombocytopenia (26%). The most frequent Grade 3-4 non-hematologic AE was febrile neutropenia (23%). CMV-reactivation occurred in 16 cases successfully treated with oral valganciclovir or IV ganciclovir. All patients achieved blood lymphocyte response within 4 weeks. Of 31 patients evaluable for response, 11 met early stopping criteria after achieving MRD-negative bone marrow CR (8/11 overall CR) with a median of 10 weeks of Alem and 5 doses of Ofa. The remaining patients (except one with PD) completed all 18 weeks of Alem and 8 doses of Ofa treatment. Overall response rate (ORR) was 97% with 42% CR and 55% PR. MRD by bone marrow flow-cytometry was negative in 12/13 CR patients and 4/17 PR patients. All but one patient remain alive at follow-up and three required subsequent treatment due to progressive disease. Conclusions The combination of alemtuzumab-ofatumumab as first-line CLL treatment produced high response rates, including MRD-negative CR, and had acceptable safety. Early stop after achieving CR prevented late-onset cytopenia. Disclosures Ma: GlaxoSmithKline: Research Funding; National Comprehensive Cancer Network (NCCN) Oncology Research Program: Research Funding. Off Label Use: Alemtuzumab and ofatumumab used in combination. Österborg:GlaxoSmithKline: Research Funding. Lundin:GlaxoSmithKline: Research Funding.

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