scholarly journals 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 ◽  
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.

scholarly journals Phase 1 Trial of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndromes (MDS)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1339-1339
Author(s):  
Asma Anwar ◽  
Anna B. Halpern ◽  
Megan Othus ◽  
Bart L. Scott ◽  
Paul C. Hendrie ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Early Death ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Persistent Disease ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: Although some adults with AML or high-risk MDS will experience long-term disease-free survival after initiation of curative-intent therapy, most patient will require therapy re-induction therapy either for primary induction failure of disease recurrence after an initial complete remission (CR) was achieved. The outcomes with standard regimens for relapsed/refractory AML are generally poor, with CR rates often not exceeding 15-20%. Data from a large single arm phase 2 study in poor-risk relapsed/refractory AML suggested tolerability and encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (G-CLAM). Given recent data suggesting benefit of escalated doses of anthracyclines in AML, the goal of our phase 1 study was to determine the maximum tolerated dose (MTD) of mitoxantrone within G-CLAM in adults with relapsed/refractory AML or high-risk MDS and estimate the efficacy of this regimen. Patients and Methods: Adults ≥18 years of age with relapsed or refractory AML (APL excluded) or high-risk MDS (>10% blasts) were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a risk of early death with standard induction chemotherapy of ≤3%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal). Excluded were patients with concomitant illness with expected survival <1 year and those with active, uncontrolled infection. Cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day on days 1-3, as compared to 10 mg/m2/day used in standard-dose G-CLAM). Other drug doses were G-CSF 300 or 480 μg/day (for weight <76 kg vs. ≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). A second identical course of G-CLAM was given in the case of persistent disease. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia or infection or constitutional symptoms, if recovery to grade ≤2 within 14 days. Results: 26 patients (14M, 12F), median age 57 (range: 37-77) years, median TRM score 1.73 (range: 0.29-3.92) with relapsed/refractory AML (n=23), or high-risk MDS (n=3) and cytogenetically favorable (n=2), intermediate (n=13), and adverse (n=11) disease characteristics were enrolled. One DLT occurred at dose level 1 (nausea) and 2 at dose level 4 (encephalitis and cardiogenic shock), establishing G-CLAM with mitoxantrone at 16 mg/m2/day as the MTD in our study. 2 patients (8% [95% exact confidence interval: 1-25%]) died within 28 days of treatment initiation from sepsis and cardiogenic shock, respectively. Overall, 13/26 patients (50% [30-70%]) achieved a CR (n=8) (31% [14-52%]), CRp (n=1) (4% [0-20%]), or CRi (n=4) (15% [4-35%]) with 1-2 cycles of re-induction therapy; one patient each achieved a leukemia-free state and partial remission (in a patient presenting with myeloid sarcomas); nine patients (35% [17-56%]) had persistent disease. We were unable to assess response in 2 patients due to early death (n=1) and refusal for marrow re-assessment (n=1). 7/13 responders (54%) had no evidence of residual disease by flow cytometry at best response. Among responders, median times to an absolute neutrophil count ≥500/µL and a platelet count of 50,000/µL were 33 (range: 17-51) and 31 (range: 18-54) days, respectively. Besides infections and neutropenic fever, nausea, hypoxia (fluid overload/infection-related), and maculopapular rash were the most common grade ≥3 adverse events. Conclusion G-CLAM with mitoxantrone up to 16 mg/m2/day is feasible, well tolerated, and effective in relapsed/ refractory AML/high-risk MDS. A phase 2 study based on these findings has been initiated. Disclosures Scott: Celgene Corporation: Consultancy, Speakers Bureau. Becker:Igenica: Research Funding. Walter:Pfizer, Inc.: Consultancy; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy.

scholarly journals Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1453-1453 ◽  
Author(s):  
Justin Watts ◽  
Maria R. Baer ◽  
Jay Yang ◽  
Shira Dinner ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Human Tissue ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Grade 3

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

scholarly journals Lenalidomide Plus R-CHOP (R2CHOP) in Patients with Follicular Lymphoma: Data from a Phase 1/2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5322-5322
Author(s):  
Ayed O. Ayed ◽  
Levi Pederson ◽  
William R. Macon ◽  
Betsy R. Laplant ◽  
Craig B. Reeder ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Ecog Performance Status ◽  
Grade 3

Abstract Background Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL) with heterogeneous outcomes and remains largely incurable. Immunochemotherapy (IC) continues to be the standard therapy backbone in the frontline and relapsed settings, though novel agents are increasingly used and investigated. Lenalidomide is an immunomodulatory molecule with known single-agent activity in relapsed lymphoma. It is also active in the frontline setting and has been reported to be effective and tolerated in upfront combination regimens in FL (Fowler et al, Lancet Oncol. 2014, 15(12):1311-8). Here we report our experience with frontline use of R2CHOP (lenalidomide in combination with R-CHOP) in patients with FL. Methods A phase 1/2 study of R2CHOP was conducted in NHL patients with primarily diffuse large B-cell lymphoma (DLBCL). While the phase 2 study was focused on DLBCL patients, treatment-naive patients with stage II-IV, histologically-confirmed FL (grades 1, 2, and 3a) meeting criteria for therapy were eligible for the phase 1 part of the study. Additionally, FL patients were identified in the phase 2 portion of the study after central pathology review. These patients were allowed to complete therapy and were followed accordingly. Treatment consisted of 6 cycles of R2CHOP with lenalidomide given on days 1-10 and R-CHOP given in 21-day cycles. All patients received pegfilgrastim and aspirin (if not on anticoagulation) along with other supportive measures per provider discretion. Primary objectives were safety assessment and efficacy. Results Ten patients with FL (3 had grade 1, 3 had grade 2, and 4 had grade 3a) were enrolled in the R2CHOP phase 1/2 study at Mayo Clinic. One patient was in the phase 1 arm at dose level 2 (lenalidomide 20 mg/d) and 9 patients were in the phase 2 arm (lenalidomide 25 mg/d). The mean age was 60.8 years (range: 41-82). Eight out of ten patients were male; 5/10 had ECOG performance status of 0; 5/10 had an IPI score of intermediate or higher. All patients completed 6 cycles of planned treatment. One patient required lenalidomide dose adjustment due to toxicity. There were no lenalidomide dose interruptions. The overall response rate (ORR) was 100% and the complete response (CR) rate defined by PET imaging was 90%. Eight out of ten remain progression-free and 9/10 are alive at a median follow-up of 4.6 years (range: 2.1-5.3). Estimated progression-free survival (PFS) at 5 years was 79% (95% CI: 56-100%). The main toxicity was reversible myelosuppression with 80% treatment-related hematologic grade 3 or higher adverse events (AEs) (leukopenia 80%, neutropenia 80%, thrombocytopenia 40%, anemia 20%, transaminitis 20%). Rate of nonhematologic grade 3 or higher AEs was 20% (fatigue 10%, pneumonia 10%). Conclusions Frontline therapy with R2CHOP in patients with untreated FL appears to be effective and associated with acceptable toxicity. The observed PET-based CR rate and PFS were promising in this cohort. Whether R2CHOP is superior to lenalidomide/rituximab alone or standard bendamustine/rituximab will require randomized studies. Figure Estimated PFS in FL patients treated with upfront R2CHOP. Figure. Estimated PFS in FL patients treated with upfront R2CHOP. Disclosures Reeder: Celgene: Research Funding; Novartis: Research Funding; BMS: Research Funding; Millennium: Research Funding. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; karyopharm: Honoraria; medscape: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Celgene: Research Funding.

The Novel KSP Inhibitor ARRY-520 Demonstrates Single-Agent Activity in Refractory Myeloma: Results From a Phase 2 Trial in Patients with Relapsed/Refractory Multiple Myeloma (MM)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2935-2935
Author(s):  
Sagar Lonial ◽  
Adam Cohen ◽  
Jeffrey Zonder ◽  
William I Benzinger ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Safety Profile ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Novel Agent

Abstract Abstract 2935 Background: ARRY-520 is a potent, selective inhibitor of kinesin spindle protein (KSP, eg5) which is required for cell cycle progression through mitosis. Treatment with ARRY-520 arrests cells in mitosis with subsequent onset of apoptosis due to degradation of survival signals during mitotic arrest. While immunomodulators [IMiDs] and proteasome inhibitors have improved outcomes in MM, patients with MM that is refractory to both bortezomib (BTZ) and thalidomide (THAL) or lenalidomide (LEN) have a poor prognosis with median survival of 9 months. Since ARRY-520 is a novel agent with a unique mechanism of action (MOA) relative to current standard-of-care (SOC) agents, it might be expected to show activity in patients refractory to other drugs. Preclinically, ARRY-520 showed activity in BTZ-refractory models, suggesting prior treatments may not predict patient response to ARRY-520. Methods: This Phase 2 study was designed to evaluate the efficacy, safety and biological effects of 1.5 mg/m2/day ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had relapsed or refractory MM with ≥ 2 prior lines of therapy (including both BTZ and an IMiD), unless refusing or ineligible for this therapy. Results: Thirty-two patients have been treated, with a median age of 65 years (range 51–82) and a median of 5 prior regimens (n = 31; range 2–20). Twenty-eight patients received prior BTZ, 28 patients prior LEN, 17 patients prior THAL and 25 patients had an autologous stem cell transplant. One patient has been lost to follow-up. ARRY-520 demonstrated an acceptable safety profile, confirming the safety profile observed in the Phase 1 study. The most commonly reported (≥ 10% of patients) treatment-related adverse events (AEs) included hematologic events such as anemia (11 patients [34%], 4 Grade 3/4 [12%]), neutropenia (11 patients [34%], 9 Grade 3/4 [28%]) and thrombocytopenia (20 patients [63%], 11 Grade 3/4 [34%]), as well as fatigue (4 patients [16%], 2 Grade 1/2 and 2 Grade 3) and mucositis (4 patients [13%], all Grade 1/2). No treatment-related events of alopecia or neuropathy were reported. One patient discontinued study due to a treatment-related AE of blisters. ARRY-520 has shown preliminary activity as a single agent in this heavily pretreated population. To date, of 32 evaluable patients, 3 confirmed partial responses (PR) and 2 confirmed minimal responses (MR) have been observed, per International Myeloma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EMBT) criteria. PRs had a median of 5 prior therapies (range 2–8). As observed in the Phase 1 study, the time to response with ARRY-520 was prolonged. Notably, clinical responses have been observed in this study in patients refractory to both LEN and BTZ. To date, in this ongoing study 33% (5/15) of patients with disease refractory to both LEN and BTZ achieved clinical benefit (PR + MR + SD > 4 months). While this trial has been fully recruited, as of July 2011, 8 patients remain on study. Conclusions: ARRY-520 is a novel agent with a differentiated MOA relative to other myeloma drugs. ARRY-520 shows promising evidence of single-agent clinical activity and an acceptable safety profile in heavily pretreated patients with MM. Notably, ARRY-520 has demonstrated activity in patients refractory to both LEN and BTZ, a population with limited treatment options. An expansion cohort is planned in order to evaluate the safety and efficacy of ARRY-520 in combination with dexamethasone in patients who are refractory to their last myeloma treatment and refractory to prior LEN, BTZ and dexamethasone. Disclosures: Lonial: Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Merck: Consultancy. Off Label Use: ARRY-520. Cohen:Celgene: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Zonder:Millenium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Benzinger:Array BioPharma: Research Funding. Kaufman:Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Alexanian:Array BioPharma: Research Funding. Thomas:Array BioPharma: Research Funding; Centecor: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Millenium: Research Funding. Weber:Array BioPharma: Research Funding. Walker:Array BioPharma: Employment, Equity Ownership. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Shah:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy; Onyx: Consultancy, Research Funding.

The AKT Inhibitor MK2206 In Combination With Rituximab and Bendamustine Is Tolerable and Active In Relapsed Or Refractory Chronic Lymphocytic Leukemia: Results From a Phase 1 Study (NCCTG N1087 Alliance)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2882-2882
Author(s):  
Wei Ding ◽  
Tait D Shanafelt ◽  
Clive S. Zent ◽  
Jose F. Leis ◽  
Betsy R. LaPlant ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Leukemic Cells ◽  
Phase 2 ◽  
Akt Inhibitor ◽  
Safety And Efficacy ◽  
Trial Testing ◽  
Grade 3

Abstract Backgrounds B cell receptor (BCR) signals and microenvironment protection have been recognized to have key influences on CLL survival and activation. Akt activation is down-stream of the BCR signaling cascade and is critical in the mediation of the bi-directional interactions between CLL B-cells and bone marrow stroma. MK2206 is an allosteric Akt inhibitor previously tested for safety in solid tumor patients. Our preclinical data has demonstrated the synergy of MK2206 with bendamustine (B) to induce CLL apoptosis in vitro. MK2206 also abolished the signal activation and cytokine production induced by BCR ligation in CLL leukemic cells (Ding, ASH 2012). Therefore, we conducted a phase 1 trial testing the safety and efficacy of MK2206 in combination with bendamustine and rituximab (BR) for patients with relapsed/refractory CLL. Methods A phase 1 dose-escalation study was designed to define the maximum tolerated dose (MTD) as well as the safety and efficacy of 3 dose levels (90 mg or 135 mg or 200 mg weekly) of the oral Akt inhibitor MK2206 in combination with bendamustine (70 mg/m2 daily for 2 days in each cycle) and rituximab (cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2) therapy in relapse/refractory CLL patients. To test the targeting efficacy of MK2206 on Akt and downstream signals, we designed a one-week “run-in” of single agent MK2206 before the initiation of BR during cycle 1. MK2206 was then given along with BR on day 1 of cycles 2-6. Tumor response was evaluated 2 months after the 6th/last cycle of therapy based on IWCLL 2008 criteria. Correlative laboratory studies included assessment of Akt signaling and the plasma cytokine levels (multiplex beads assay (Invitrogen)) at baseline and after one week of first dose of single agent MK2206. Results Nine patients (median age 68) were enrolled in the phase I portion of this trial. All 9 patients had unmutated immunoglobulin heavy chain variable region genes (IGHV) and 4 had del(11q). Six had received prior chemoimmunotherapy (CIT: FCR or PCR or PCO) and 5 had high risk disease defined as early progression within 26 months of the last CIT. Three had received alemtuzumab containing regimen. We have observed potent lymphocyte mobilization in all evaluated patients (n=7) after one-dose of MK2206 during week 1 (mean increase ALC: 35%) as well as reductions of plasma CCL3, CCL4 and CCL2 in the majority of the patients. A single dose-limiting toxicity (DLT) (febrile neutropenia and hemolytic anemia) was observed at dose level 1 (90 mg weekly) among 6 patients treated at this dose. Two patients with dose-limiting toxicities at dose level 2 (135 mg weekly) were observed where one patient had a rash and one patient had dehydration and febrile neutropenia among three patients treated at this dose. Accordingly, the 90 mg once weekly dose was determined to be the MTD for phase 2 trial testing. The most frequent grade 3 or 4 adverse events observed to date were neutropenia (44%) including febrile neutropenia (22%), rash (22%), diarrhea (22%), nausea and vomiting (11%), dehydration (11%), hemolytic anemia (11%) and thrombocytopenia (11%). The frequency of cytopenias was similar to the published German experience with BR (50% grade 3 or 4 hematological toxicities compared to 44% in N1087) in relapsed CLL patients (Fischer, JCO 2011). The median number of cycles received was 6 (range 1-6). Using an intent to treat analysis, two patients achieved complete response (CR, n= 2, 22%), one patient achieved nodular partial response (nPR, n=1, 11%) and five patients achieved a partial response (PR, n=5, 56%). The overall response rate (ORR) is 89%. Conclusion The Akt inhibitor MK2206 in combination with BR is well tolerated in patients with relapsed/refractory CLL. Single dose of MK2206 inhibits Akt phosphorylation, mobilizes leukemic cells and decreases plasma cytokines involved in BCR signals. The preliminary efficacy of this combination demonstrated promising results with a 89% ORR and 22% CR albeit in the small phase 1 cohort. These results compare favorably to BR alone (9% CR and 59% ORR) in relapsed/refractory CLL patients. Phase 2 testing of this combination is now underway. Acknowledgment This work was supported by the funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA025224 and CA33601). Disclosures: Off Label Use: MK2206, used in a phase 1 trial of relapsed CLL disease. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

scholarly journals A Phase 1/2 Study of Umbralisib Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 360-360 ◽  
Author(s):  
Paul M. Barr ◽  
Brian T. Hill ◽  
Shuo Ma ◽  
Andrea M Baran ◽  
Andrew Bui ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Monitoring ◽  
Phase 2 ◽  
Advisory Committees ◽  
Grade 3

Background:Despite the effectiveness of novel agents in treating CLL, single agent use requires prolonged administration which can lead to drug resistance, toxicity and considerable cost over time. Combinations may provide deeper prolonged remissions using defined treatment durations. Umbralisib (Umbra) is a novel, highly-specific PI3Kδ inhibitor and ublituximab (Ubli) is a chimeric monoclonal antibody targeting a unique epitope on CD20 and glycoengineered to enhance antibody dependent cellular toxicity. Combining these agents with the BCL2 inhibitor venetoclax (Ven) may prevent drug resistance (Choudhary, Cell Death Dis 2015), avoid tumor lysis syndrome (TLS) and achieve undetectable minimal residual disease (MRD). This phase 1/2 trial evaluates the safety and efficacy of Umbra + Ubli + Ven for 12 cycles followed by MRD evaluation in relapsed or refractory CLL patients (pts). Methods:Pts received three 28-day cycles of Umbra daily along with Ubli, administered weekly during cycle 1, then once during cycles 2 and 3, followed by Umbra + Ven for 9 additional cycles. During the phase 1 study, dose levels including Umbra 600mg and 800mg were tested with Ubli 900mg and Ven, increased in standard fashion to 400 mg during cycle 4. The primary endpoint for phase 1 was safety; the primary endpoint for phase 2 was complete remission (CR) rate by iwCLL criteria. MRD negativity (&lt;10-4by 8-color flow cytometry) was a key secondary endpoint with bone marrow and peripheral blood MRD negative pts stopping therapy after 12 cycles and other pts continuing on single agent Umbra. Results: 21 pts have been treated to date: 9 in phase 1 and 12 in phase 2. Baseline demographics were as follows: male/female (12/9), median age 65 yrs (range 49-83), median prior therapies 2 (1-5). 9 pts had prior ibrutinib of which 4 were BTK inhibitor refractory. BTK resistance mutations were found in 2 pts. High risk genetic features included unmutated IGHV genes (11 pts), del17p or del11q (7 pts), TP53 mut (1 pt), NOTCH1 mut (4 pts) and SF3B1 mut (1 pt). Baseline TLS risk was high, medium and low risk in 2, 12 and 7 pts respectively. During dose escalation, 3 pts were treated using Umbra 600mg and subsequently 6 pts using Umbra 800mg. No DLTs occurred, and the MTD was not reached. As such, the phase 2 dose used was Ubli 900 mg + Umbra 800 mg with venetoclax, undergoing ramp up to 400 mg. For all pts treated to date, the most common AEs were (all causality and all grade; &gt;20% of pts) infusion reactions (62%), thrombocytopenia (57%), neutropenia (52%), anemia (52%), fatigue (52%), ALT or AST increase (43%), nausea (33%), diarrhea (29%) and headache (24%). Grade 1 creatinine increase, hypocalcemia and hyperkalemia were observed in 12 (57%), 6 (29%) and 5 (24%) of pts respectively. These AEs predominately occurred outside of venetoclax ramp up. Grade 3/4 AE's occurring in ≥ 2 pts included neutropenia (n=4, 19%), infusion reaction (n=2, 10%) and thromboembolism (n=2, 10%). No grade ≥ 3 PI3Kδ-associated toxicities were noted (0 events of pneumonitis, colitis or grade 3/4 transaminitis). No events of TLS were observed. One pt discontinued study treatment due to grade 3 rash. All pts were converted to low TLS risk after 3 cycles of Umbra + Ubli, except for 1 pt who remained medium risk after discontinuing Ubli secondary to a grade 3 infusion reaction, allowing outpatient venetoclax initiation in all pts. In evaluable pts, the overall response rate was 85% (11/13) after cycle 3, 100% (9/9) after cycle 7 and 100% (5/5) after cycle 12. Of the 5 pts who finished 12 cycles of therapy, a median reduction in nodal disease of 87% occurred resulting in 2 CRs and 3 PRs by iwCLL criteria. 4 pts have undetectable MRD (&lt;0.01%) in both the peripheral blood and bone marrow and have stopped therapy. MRD was undetectable in peripheral blood and intermediate (0.01% - 1.0%) in the bone marrow for 1 pt who continues on Umbra. With a median f/u of 4.2 months (range 0.2-14.2), no pts have experienced disease progression. (Figure) Conclusion: We established the phase 2 dose of Umbra + Ubli + Ven and demonstrated good tolerability in pts with relapsed or refractory CLL. Preliminary results suggest that this chemotherapy-free regimen can provide undetectable MRD after only 12 cycles, representing an effective treatment plan for this population. Ongoing enrollment is focused on pts who have relapsed after BTK inhibitors and a multi-center trial is planned to further develop the triplet regimen. Figure Disclosures Barr: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Amgen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ma:Janssen: Consultancy, Speakers Bureau; Beigene: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; Juno: Research Funding; Incyte: Research Funding; Kite: Consultancy; Genentech: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Sportelli:TG Therapeutics: Employment. Miskin:TG therapeutics Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment. Friedberg:Acerta: Other: Data & Safety Monitoring Committee; Bayer: Honoraria, Other: Data & Safety Monitoring Committee. Zent:Astra Zeneca: Research Funding; Mentrik Biotech: Research Funding. OffLabel Disclosure: umbralisib and ublituximab as treatment of CLL

scholarly journals A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4774-4774
Author(s):  
James R. Berenson ◽  
Laura V. Stampleman ◽  
Alberto Bessudo ◽  
Peter J. Rosen ◽  
Leonard M Klein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Phase 1 ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Great Promise ◽  
Phase 2 ◽  
Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2719-2719 ◽  
Author(s):  
Luhua Wang ◽  
Luis Fayad ◽  
Fredrick B. Hagemeister ◽  
Sattva Neelapu ◽  
Felipe Samaniego ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Employment Equity ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 919-919
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2936-2936
Author(s):  
Victor H Jimenez-Zepeda ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Vishal Kukreti
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Phase 1 ◽  
Prior Exposure ◽  
Rank Test ◽  
Continuous Variables ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

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