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)

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

Blood ◽

10.1182/blood.v126.23.1339.1339 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1339-1339

Author(s):

Asma Anwar ◽

Anna B. Halpern ◽

Megan Othus ◽

Bart L. Scott ◽

Paul C. Hendrie ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Phase 1 ◽

Early Death ◽

Hematologic Toxicity ◽

Phase 2 ◽

Persistent Disease ◽

Phase 2 Study ◽

Grade 3 ◽

Refractory Aml

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

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Phase 3 Study of Pomalidomide with Cyclophosphamide and Dexamethasone Versus Pomalidomide and Dexamethasone in Asian Patients with Relapsed/Refractory Myeloma (RRMM) - Interim Analysis of a Trial By the Asian Myeloma Network (AMN)

Blood ◽

10.1182/blood-2020-139019 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Wee-Joo Chng ◽

Xinhua Li ◽

Cindy Lin ◽

Jin Seok Kim ◽

Hiroshi Handa ◽

...

Keyword(s):

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Prior Exposure ◽

Phase 2 ◽

Asian Patients ◽

Phase 2 Study ◽

Grade 3 ◽

Experienced Grade

Background Pomalidomide is an immunomodulatory drug that has been approved for the treatment of relapse refractory myeloma. A previous small randomized phase 2 study in the United States showed that combination of Pomalidomide, cyclophosphamide and dexamethasone induce a greater response rate than pomalidomide and dexamethasone1. In our prior study, AMN0012, we should that in patients with sub-optimal response to pomalidomide and dexamethasone, the addition of cyclophosphamide can increase response resulting in improvement of progression free survival. In the current study, we seek to randomize Asian patients with RRMM between PCD and PD to confirm the benefit of PCD. Method We conducted a prospective randomized trial of pomalidomide (4mg daily for 21 days followed by 7 days rest) plus dexamethasone 40mg once weekly for 4 weeks with or without cyclophosphamide (400mg once a week) in patients with relapse and refractory myeloma that has to be refractory to lenalidomide and has prior exposure to proteasome inhibitors. Each cycle is 4 weeks. Patients from Singapore, Japan and Korea (NCT03143049) were included in this Asian Myeloma Network trial. The trial was started in Sep 2017 and is still ongoing. To date, 53 patients have been recruited so far. This interim report presents data available up till the data cut-off date of 24 June 2020. Results Forty-six patients have available base line information and safety data and is included in this interim analysis. 50% of patients are male and median age of the cohort is 68 years old. 39% and 28% of patients are International Stage System (ISS) stage 2 and 3 respectively. 20% of patients have abnormal creatinine clearance. Median prior line of treatment is 3. All patients are refractory to lenalidomide and 96% have prior exposure to bortezomib. In addition, 12 patients (26%) and 5 (11%) have been treated with Carfilzomib and Ixazomib respectively. 15 (33%) patients had prior high dose melphalan and autologous stem cell transplant. 20 (44%) patients required dose reduction of pomalidomide, cyclophosphamide or dexamethasone. 89% of patients experience adverse events (AEs) of any grade. Of the 297 episodes of AEs, 43% are grade 3 or higher, with 50% of these episodes related to the study drugs. 57% of patients experienced serious AEs (SAEs) of any grade. Of the 74 episodes of SAE, 89% are grade 3 or higher, with 49% of these episodes related to the study drugs. Almost all of these events are related to cytopenias and infections. 20 (44%) of the patients develop grade 3 neutropenic fever and 9 (20%) patients have grade 3 or higher pneumonia. Only 1 patient experienced grade 3 peripheral neuropathy, 1 patient develop grade 3 pulmonary embolism, 1 patient developed grade 3 venous thromboembolism, and 1 patient experienced grade 3 renal impairment. At a median follow-up of 10.9 months, 9 of the 46 patients have died, and 21 have progressed. Three patients withdrew due to toxicity. While the overall response of the study population is not part of this interim analysis, we assessed the response of patients from the National University Cancer Institute, Singapore which has the highest number of patients recruited to get an idea of the therapeutic efficacy. Of the 14 patients recruited at NCIS, 1 patient achieved CR, 3 VGPR, 7 PR, producing a response rate of 79%. Conclusion In this interim analysis of a prospective randomized study of pomalidomide and dexamethasone with or without cyclophosphamide in Asian patients, we demonstrated the feasibility and efficacy of this combination. Longer follow-up and final analysis of the study will be needed to ascertain the therapeutic advantage of PCD over PD in relapse and refractory myeloma that is refractory to lenalidomide. References 1. Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. 2. Soekojo CY, Kim K, Huang SY, Chim CS, Takezako N, Asaoku H, Kimura H, Kosugi H, Sakamoto J, Gopalakrishnan SK, Nagarajan C, Wei Y, Moorakonda R, Lee SL, Lee JJ, Yoon SS, Kim JS, Min CK, Lee JH, Durie B,Chng WJ. 3. Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network. Blood Cancer J. 2019 Oct 8;9(10):83. Disclosures Chng: Novartis: Honoraria; Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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Phase I Study of a Liposomal Carrier (CPX-351) Containing a Synergistic, Fixed Molar Ratio of Cytarabine (Ara-C) and Daunorubicin (DNR) in Advanced Leukemias

Blood ◽

10.1182/blood.v112.11.2984.2984 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2984-2984 ◽

Cited By ~ 2

Author(s):

Eric J. Feldman ◽

Jeffrey Lancet ◽

Jonathan E. Kolitz ◽

Ellen Ritchie ◽

Alan F. List ◽

...

Keyword(s):

Bone Marrow ◽

Phase I ◽

Dose Escalation ◽

Phase I Study ◽

Molar Ratio ◽

Phase 2 ◽

Phase 2 Study ◽

Grade 3 ◽

Refractory Aml

Abstract Background: CPX-351 is a liposomal formulation of Ara-C and DNR which fixes the synergistic 5:1 molar ratio found to enhance efficacy in both in vitro and in vivo preclinical leukemia models. CPX-351 overcomes the pharmacokinetic (PK) differences of each drug, enabling the maintenance of the 5:1 molar ratio for extended periods of time after IV administration and the delivery of this ratio to bone marrow. Preclinical data from in vitro models show that CPX-351 is actively internalized by leukemic cells within vacuoles and subsequently releases DNR intracellularly. A Phase I study was performed with CPX-351 in patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Objectives: to determine safety, tolerability, and pharmacokinetics of a 90 min IV infusion of CPX-351 given on days 1, 3, 5 to patients with advanced leukemia and MDS, and to seek preliminary evidence of antitumor activity. Methods: Patients with relapsed/refractory AML/ALL and MDS were eligible. A second induction course was permitted if the day 14 bone marrow showed evidence of antileukemic effect and persistent leukemia. Dosing started at 3 units/m2 (1 u = 1 mg Ara-C and 0.44 mg DNR) using single patient cohorts and dose doublings. Three patient cohorts and 33% dose increments began after evidence of antileukemic activity and continued until limiting toxicities (DLTs) completed dose escalation. PK samples were collected after each dose. Results: Forty-seven subjects received 69 courses of CPX-351: Male/Female = 31/16, median age = 62 years (range 23–81); 44 patients had AML and 3 patients had ALL; median number of prior regimens = 2 (1–7). Thirty-seven patients entered the escalation phase of the study and ten subjects, most in first relapse, were treated after completion of dose escalation to confirm safety. At 24 u/m2 antileukemic effects were observed leading to increased cohort size to 3 and decreased escalation rate to 33%. The MTD and recommended Phase 2 dose was 101 u (101 mg Ara-C + 44 mg DNR)/m2 after observing 3 DLTs (decreased LVEF, hypertensive crisis, prolonged aplasia) at 134 u/m2. Adverse events data are available for 36 of 37 patients from the escalation phase of the study. Nonhematologic grade 3–5 toxicities occurring in more than one patient included: infections (58%), dyspnea (11%), fever (11%), hypophosphatemia (8%), hypokalemia (6%), renal failure (6%), skin rash (6%), headache (6%) hyperglycemia (6%) hypoxia (6%) and respiratory failure (6%). Mucositis of any grade was observed in 42% of patients with 3% having grade 3 mucositis. Diarrhea of grade 1 and 2 severity occurred in 39% of patients. Interim analysis of PK data demonstrates maintenance of the 5:1 molar ratio and detectable encapsulated drug persisting up to 24 hours. The average half-lives were 35 hr for total Ara-C and 23 hr for DNR, significantly longer than reported for the conventional drugs. Overall, 11 patients achieved CR/CRp. Among the 19 patients treated at the MTD, 5 of the 13 patients evaluable for response achieved CR. Six patients were treated above the MTD (134 u/m2) and 2 achieved CR. Median time to CR was 43 days. Conclusions: The recommended phase 2 dose is 101 u/m2. CPX-351 was well tolerated, with no unexpected toxicities noted up to the MTD. GI toxicities and mucositis were transient and nearly always of mild to moderate severity. Reduced LV function was observed in two patients both with substantial prior anthracycline exposure. CRs were observed in heavily pre-treated patients with relapsed/refractory AML. Future plans include a randomized Phase 2 study comparing CPX-351 versus Cytarabine + Daunorubicin (“7 + 3”) in older (>60 yo) subjects with previously untreated AML, and a phase 2 study in patients with AML in 1st relapse.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 1 Study of Concomitant High Dose Lenalidomide and 5-Azacytidine Induction in the Treatment of Acute Myeloid Leukemia,

Blood ◽

10.1182/blood.v118.21.3616.3616 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3616-3616

Author(s):

Giridharan Ramsingh ◽

Peter Westervelt ◽

Amanda Cashen ◽

Geoffrey L. Uy ◽

Keith Stockerl-Goldstein ◽

...

Keyword(s):

Complete Remission ◽

Progressive Disease ◽

Phase 1 ◽

Hematological Toxicity ◽

High Dose ◽

Phase 2 ◽

Elderly Aml ◽

Grade 3 ◽

Induction Cycle ◽

Refractory Aml

Abstract Abstract 3616 Novel therapies for elderly and relapsed AML are needed. We recently published an institutional phase 2 trial using high dose (50mg/day × 28 days) single agent lenalidomide (HDL) followed by maintenance of 10 mg daily for 12 months in responders in elderly untreated AML patients (≥ 60 years) showing a complete remission (CR)/complete remission with incomplete blood count recovery (CRi) of 30% (Fehniger et al, Blood, 2011). Azacitidine (AZA) given IV or SC has also shown significant response in patients with MDS and AML. Recently Pollyea et al (JCO 29: 2011 (suppl; abstr #6505) reported on a phase 1 trial combining AZA and escalating doses of lenalidomide repeated sequentially in 6 week cycles in patients with untreated AML. Here, we report on a phase 1 single institutional study to evaluate the toxicities and feasibility of combining HDL and AZA concurrently as induction followed by a less intensive lenalidomide and AZA maintenance schedule in untreated elderly AML (≥60 years) or relapsed/refractory AML ≥18 years. Treatment schedule: 2 cycles of induction (each 28 days) of lenalidomide 50 mg PO days 1–28 and AZA at 3 dose cohorts 25 mg/m2 (cohort 1), 50 mg/m2 (cohort 2) and 75 mg/m2 (cohort 3) given IV days 1–5. Thereafter patients were given maintenance cycles (every 28 days) with lenalidomide 10 mg PO days 1–28 and AZA 75 mg/m2 days 1–5 for a total of 12 cycles. The median age was 74 (range 63–81); 7 males, 8 females; 6 with newly diagnosed elderly AML and 9 with relapsed or refractory AML. The median WBC count was 2600 (range 300–13100). The median bone marrow blast percentage was 22% (range 2–90%),with normal cytogenetics in 7 (63.6%), monosomy 7 in 3 (20%), trisomy 8 in 1 (6.7%), and other in 4 (26.6%). 8 patients were enrolled in cohort 1, 4 patients in cohort 2 and 3 patients in cohort 3. 2 patients in cohort 1 and 1 patient in cohort 2 who received less than 1 induction cycle (2 withdrew consent and 1 had progressive disease) were replaced. 11 (73.3%) of patients completed 1 induction cycle and 7 (46.7%) of patients completed 2 induction cycles and 5 (30%) patients went on to maintenance therapy. Patients remained on therapy for a median of 2 months (range 0.5–13 months). Dose limiting toxicities (DLT) observed included grade 3 rash in cohort 1 leading to expansion of the cohort to include 3 additional patients. To date grade 3/4 non-DLT hematological toxicity was seen in 6/11 (54.1%) patients. The most common 3/4 non-DLT non-hematological toxicity was neutropenic fever seen in 5/11 (45.4%). The most common grade 1/2 toxicity was fatigue in 7/11 (63.6%). 40% (6/15) of patients died, all due to progressive disease. Of the 11 evaluable patients 7 (63.6%) responded to treatment with CR/CRi in 3 (27.3%) and partial remission (PR) in 4 (36.4%) with the median duration of response of 3 months (range 0.5–11 months). In summary combination of lenalidomide with AZA appears to be a feasible regimen with acceptable toxicities. A phase 2 multicenter extension of this study with untreated elderly AML at the maximum tolerated dose of AZA and HDL will be initiated soon. Disclosures: Off Label Use: Here we discuss the use of lenalidomide and azacytidine in relapsed refractory or elderly AML. Stockerl-Goldstein:Celgene: Speakers Bureau. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau.

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A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

Blood ◽

10.1182/blood.v122.21.4086.4086 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4086-4086

Author(s):

Chul Won Jung ◽

Lee-Yung Shih ◽

Zhijian Xiao ◽

Jie Jin ◽

Hsin-An Hou ◽

...

Keyword(s):

Primary Endpoint ◽

Research Funding ◽

Phase 2 ◽

Spleen Volume ◽

Open Label ◽

Phase 3 ◽

Phase 2 Study ◽

Open Label Phase ◽

Large Phase ◽

Grade 3

Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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An Open-Label Phase 2 Study Of Ofatumumab In Combination With a Novel AKT Inhibitor (Afuresertib) In Previously Treated Patients With Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4175.4175 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4175-4175

Author(s):

Christine I. Chen ◽

Susi Snitzler ◽

Trina Wang ◽

Harminder Paul ◽

Lisa W Le ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Treatment Phase ◽

Phase 2 ◽

Akt Inhibitor ◽

Advisory Committees ◽

Phase 2 Study ◽

Previously Treated ◽

Grade 3

Abstract Introduction Ofatumumab is a novel anti-CD20 monoclonal antibody which led to impressive single-agent responses of 47-58% in a phase 2 study of CLL patients (pts) with refractory disease (Wierda et al 2010). Unfortunately, response durations were short (median 5.6-7.1 mos). In order to improve upon these results, we combined ofatumumab with a novel pan-AKT kinase inhibitor, afuresertib (GSK2110183). The AKT pathway plays a centralized role in tumor differentiation, migration, proliferation and survival and is frequently aberrantly activated in CLL (Longo et al 2007). Single agent afuresertib is very well-tolerated with minimal myelotoxicity in relapsed/refractory hematologic malignancies (Spencer et al ASH 2011). We present an interim analysis of the initial 19 of 31 planned pts in an ongoing trial of ofatumumab and afuresertib in relapsed/refractory CLL. Methods Previously treated CLL pts who have received at least one prior fludarabine-containing regimen with disease progression are eligible. During the initial 6 month Treatment Phase, ofatumumab 2000mg IV is administered weekly for 8 doses, then once every 4 week cycle for 4 doses (dose/schedule identical to the pivotal phase 2 trial) with afuresertib 125mg orally daily. An initial 10 day Lead-in Phase with afuresertib alone allows for evaluation of pharmacodynamic (PD) changes in phosphoproteins and pharmacokinetic (PK) studies. Pts are assessed for safety and response on day 1 of each cycle. Pts achieving SD, PR or CR by the end of the Treatment Phase proceed to the Maintenance Phase with single-agent afuresertib for a maximum of 12 mos (12 cycles). Results Demographics: To date, 19 pts have been enrolled. Median age is 65 yrs (range 43-76), baseline median Hb 108g/L (range 80-145), absolute lymphocytes 29.7 x109/L (range 1.0-464.9), β2M 4.42mg/L (range 1.42-3.21), bulky nodes ≥5cm in 5 pts (32%), organomegaly in 8 pts (42%), del17p/del11q on FISH in 9 pts (47%), and ZAP70+ in 13 pts (68%). Eight pts (42%) were fludarabine-refractory; only 2 pts had received prior alemtuzumab. The median number of prior therapies was 2 (range 1-6). Toxicity: Hematologic: 4 pts (21%) developed Gr 3-4 neutropenia during at least 1 cycle; 1 pt (5%) had a febrile neutropenia event. Only 2 pts (10.5%) have developed Gr 3-4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Most common related grade 3-4 toxicities were GI: dyspepsia (53%), diarrhea (37%), nausea (21%), temporally related to oral afuresertib and easily managed symptomatically. Infusion reactions to ofatumumab were frequent (12 pts; 63%) with grade 3 reactions in 3 pts. Five pts (26%) developed non-infectious pneumonitis, with 3 pts requiring hospitalization. Two pts with preexisting atrial arrhythmias sustained exacerbation with weekly ofatumumab infusions. Most infections were mild, with only 1 grade 3 cellulitis. Efficacy: Of the 19 response-evaluable pts receiving a median of 6 cycles (range 1-9), 8 pts (42%) have achieved a PR, 11 SD (58%), and no CR. Response onset was rapid at a median 0.9 mos (range 0.8-2.8). At a median follow-up of 6.8 mos (range 0.3-12.9 mos), 5 pts (26%) have progressed and one patient has died after cycle 1 on therapy due to progressive CLL. PD Studies: CD19+ cells are assayed for phosphorylated AKT and its downstream targets RAS40 and GSK3 in addition to phospho-proteins of alternative pathways including ERK and pS6 by multiplexed phospho-flow cytometry. Peripheral blood samples are collected at screening and on cycle 1 day 10, after dosing with afuresertib. Of the 7 patients evaluated thus far, 5 demonstrated constitutive AKT phosphorylation at baseline. Partial inhibition of AKT signaling evidenced by increased phosphorylation of AKT and inhibition of GSK3 and/or RAS40 phosphorylation in response to BCR stimulation was observed post-treatment, indicating target engagement by afuresertib. PK Studies: Afuresertib exposure (Cmax and AUC) was similar when afuresertib was administered alone or in combination with ofatumumab. Conclusion Preliminary results from this phase 2 study suggests that a combination of ofatumumab plus a novel oral AKT inhibitor, afuresertib, has activity in previously treated CLL and is generally well-tolerated with minimal myelotoxicity. Response data are encouraging but whether durable responses can be achieved requires more mature follow-up. Disclosures: Chen: Johnson & Johnson: Consultancy, Research Funding; Lundbeck: Consultancy; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria. Off Label Use: Off-label use of ofatumumab and afuresertib for the treatment of relapsed/refractory CLL. Smith:GSK: Employment, Equity Ownership. Johnston:Roche: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)

Blood ◽

10.1182/blood.v124.21.3099.3099 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3099-3099 ◽

Cited By ~ 3

Author(s):

Beth Christian ◽

Lai Wei ◽

Jennifer Sexton ◽

Samantha M. Jaglowski ◽

Steven M. Devine ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Dose Level ◽

Research Funding ◽

Erythema Nodosum ◽

Altered Mental Status ◽

Phase 2 ◽

Phase 2 Study ◽

Grade 3 ◽

Dose Reductions

Abstract Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007). Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents. Disclosures Christian: Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin's lymphoma.

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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 randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.217 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 217-217 ◽

Cited By ~ 20

Author(s):

Eileen Mary O'Reilly ◽

Do-Youn Oh ◽

Neesha Dhani ◽

Daniel John Renouf ◽

Myung Ah Lee ◽

...

Keyword(s):

Objective Response ◽

Ductal Adenocarcinoma ◽

Immune Checkpoints ◽

Controlled Study ◽

Phase 2 ◽

Intrinsic Resistance ◽

Multiple Cancer ◽

Phase 2 Study ◽

Grade 3 ◽

Randomized Phase 2

217 Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) > 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.

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