Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma

Abstract Background: Cutaneous T-cell Lymphomas (CTCL) include several variants of extra-nodal non-Hodgkin's lymphomas characterized by their skin lesions and T-cell surface markers. The most common, mycosis fungoides (MF), often has an indolent course but can transform and rapidly disseminate. While skin-directed therapies are effective for early-stage MF, patients with refractory, transformed or late-stage disease require systemic therapy. Methods: Adult patients with CTCL including MF, transformed MF (T-MF), Sézary syndrome (SS), primary cutaneous anaplastic large cell lymphoma (ALCL), ≥ 1 prior systemic therapy, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were eligible and signed consent. FOL was administered weekly via intravenous push for 3 of 4 weeks; BEX was self-administered orally with food. The standard 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD), with cohort expansion for dose-limiting toxicities (DLTs). The MTD was the highest dose with < 33% DLT incidence in any cohort. DLTs included the following in Cycle 1: ≥ Grade 3 neutropenia (or G-CSF administered), thrombocytopenia, treatment-related non-hematologic toxicity, hyperlipidemia, or hypothyroidism, and treatment-related adverse events (AEs) causing BEX dose omission for ≥10/28 days or FOL dose omission/reduction. Results: In Cohort 1 (15 mg/m2 FOL + 150 mg/m2 BEX), 0/3 patients had DLTs. In Cohort 2a (15 mg/m2 FOL + 300 mg/m2 BEX), 2/3 patients had DLTs: Grade 3 neutropenia and Grade 2 hypotension (n = 1) and Grade 4 neutropenia and thrombocytopenia (n = 1). Therefore, the combination MTD was identified as 15 mg/m2 + 150 mg/m2. An additional 28 patients were enrolled at the MTD for a total of 34 patients (53% male, 47% female) in the study; all have discontinued treatment. The median age was 66 (range 39-85) years, and the median number of prior therapies was 4 (range 2-14). Histology included MF (53%), T-MF (32%), SS (12%), and ALCL (3%). ECOG PS was 0 (68%), 1 (18%), or 2 (15%). Patients received a median of 6 (range 1-33) cycles of therapy. All patients reported ≥ 1 AE. The most common (>20%) FOL-related AEs were mucositis or mucosal inflammation (68%), fatigue (41%), neutropenia and nausea (32% each), and anemia (24%). The most common (>20%) BEX-related AEs were hypertriglyceridemia (56%), fatigue (44%), neutropenia (32%), nausea (26%), and uncorrected hypothyroidism (24%). Grade 3 and 4 AEs were reported for 79% and 9% of patients, respectively: neutropenia (29% and 6%), hypertriglyceridemia (29% and 0%), and stomatitis (21% and 0%) and one Grade 5 AE of respiratory failure. Serious adverse events (SAEs) were reported for 35% of all patients; SAEs in > 1 patient were neutropenia and hypotension (6% each). Dose omissions and reductions for AEs were required for 74% and 21% of patients, respectively. AEs led to discontinuation for 32% of all patients, most commonly stomatitis (9%) and anemia, fatigue, and neutropenia (6% each). The overall Objective Response Rate was 61% (20/33 evaluable patients); 18/30 [60%] in Cohort 1 and 2/3 [67%] in Cohort 2. Four [12%] patients had a complete response, 16 [48%] partial response, 11 [33%] stable disease, and 2 [6%] progressive disease. Duration of Response ranged from 0-29+ months; median Response Duration was not reached, as 14 patients (3 CRs, 11 PRs) remained in response. Median PFS at the MTD was 12.8 (range 0.5-29.9+) months. Table 1. Response by CTCL Subtype Objective Response Rates CTCL Subtype Overall CR PR All Evaluable, n=33 20 (61%) 4 16 ALCL, n = 1 1 (100%) 1 0 MF, n = 19 12 (63%) 2 10 T-MF, n = 10 5 (50%) 1 4 SS, n = 3 2 (67%) 0 2 Conclusions: The combination of FOL + BEX was well tolerated and efficacious in patients with various CTCL subtypes, as measured by response rates (61% including patients with durable CRs) in this dose-finding study. Disclosures Duvic: Celgene: Membership on an entity's Board of Directors or advisory committees; Therakos: Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Consultancy; Allos (spectrum): Research Funding; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Oncoceutics: Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int'l: Consultancy. Bhat:Spectrum Pharmaceuticals, Inc: Employment.

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Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-152947 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4426-4426

Author(s):

Mahesh Swaminathan ◽

Amanda Przespolewski ◽

Elizabeth A. Griffiths ◽

James E. Thompson ◽

Amro Elshoury ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Dose Finding ◽

High Dose ◽

Advisory Committees ◽

High Dose Cytarabine ◽

Finding Study ◽

Dose Finding Study ◽

Grade 3

Abstract Background: Thrombocytopenia is prevalent at presentation and following induction chemotherapy (chemo) regimens in patients (pts) with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML). Eltrombopag (EPAG), oral, nonpeptide thrombopoietin (TPO)-receptor agonist, is currently approved for treatment of chronic immune thrombocytopenia, hepatitis-associated thrombocytopenia, and aplastic anemia. It has also been evaluated as a strategy to mitigate chemo-induced thrombocytopenia in pts with solid tumors, myelodysplastic syndrome, and following allotransplant. Prior studies have demonstrated that EPAG can directly inhibit the proliferation of human AML cells in vitro. Although EPAG has been studied following induction and consolidation chemo in the frontline AML setting, to date, the tolerability and efficacy of EPAG in pts receiving salvage chemo for R/R AML is not known. Objectives: This study's objectives were to (a) estimate the maximum tolerated dose (MTD) and tolerability of EPAG, (b) examine platelet (plt) response (defined as plt count ≥ 100 x 10 9/L), and (c) anti-leukemic activity of EPAG in pts receiving high dose cytarabine (HiDAC) and mitoxantrone (Mito) for R/R AML. Methods: In this phase I open-label study, adult pts (³ 18 yrs) with R/R AML with adequate organ functions and grade 4 thrombocytopenia following HiDAC (given every 12 hrs (3 g/m 2 for age < 50; 1.5 g/m 2 for age ≥50) for 12 doses) and Mito (dosed at 12 mg/m 2 x 3 doses every other day) were eligible. All pts must have had marrow hypoplasia demonstrated on Day 14 ± 3 days from the initiation of HiDAC. EPAG was started daily on Day 14 ± 3 days with dose determined using a standard '3+3' dose-escalation design. EPAG was discontinued if an adequate plt response was achieved or following 9 weeks of therapy. The dose-limiting toxicity (DLT) window was defined as the first 15 days of EPAG dosing. Results: Nine pts with R/R AML were enrolled (Table 1). Median age was 64 yrs (range, 33-80), and 5 pts were men. All pts had intermediate (6/9, 67%), adverse (2/9, 22%), or unknown (1/9, 11%) cytogenetic risk disease. One (1/9) pt had NPM1+FLT3-ITD+ disease. Five pts (56%) had relapsed disease (2pts had prior allotransplant). All pts received HiDAC+Mito chemo and started on EPAG on Day 14 ± 3 days. Three received EPAG 150 mg, and 6 pts received 200 mg daily. The median duration on EPAG was 26 days (range, 11-82). One pt experienced a DLT of grade 3 myocardial ischemia while receiving EPAG 200 mg/day and was taken off study. No other DLTs were reported, and no MTD was determined. The most frequent grade ³3 adverse events (AEs, Table 2): were bacteremia (56%), neutropenic fever (44%), and hyperbilirubinemia (33%). Similarly, common grade 1-2 AEs consisted of hyperbilirubinemia, tachycardia, and confusion (33% each, respectively). At a median follow-up of 30.3 months (mo), all 9 pts had discontinued EPAG. Six pts (67%) achieved plt response (3 each in 150 mg and 200 mg/day dose level). The median time to achieve plt response and the duration of plt response was 27 days (range, 14-41) and 40.5 mo (range, 2-49.6), respectively. Three other pts discontinued EPAG therapy: 1 each due to cardiac ischemia, donor lymphocyte infusion, and patient choice, respectively (Table 3). Of note, 7/9 pts (78%) had clinical response: CR in 5 (56%), CRc (CR+CRp) in 6 (67%), MLFS in 1 (11%, Table 4). Two (2/7 responders) went on to subsequent allotransplant, and 6 died; 2-progressive disease, one each from pneumonia, failure to thrive, encephalopathy, and unknown cause, respectively. Among the 6 pts who achieved plt recovery on EPAG, 5 achieved CR and 1-MLFS following HiDAC+Mito. Conclusion: This phase 1 dose-finding study demonstrated that EPAG 150-200 mg daily following HiDAC+Mito chemo for R/R AML was well tolerated with one DLT of cardiac ischemia (200 mg dose). Two-thirds (67%) of pts achieved plt recovery on EPAG after a median of 27 days (range, 14-41). In these small number of pts (n=9), addition of EPAG therapy did not seem to adversely affect clinical outcomes (CRc 67%) and may have contributed to long-term platelet recovery. Further studies are required to determine the optimal schedule and potential benefit of EPAG added to chemo regimens for R/R AML. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

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Safety and Efficacy of Subcutaneous (SC) Blinatumomab for the Treatment of Adults with Relapsed or Refractory B Cell Precursor Acute Lymphoblastic Leukemia (R/R B-ALL)

Blood ◽

10.1182/blood-2021-150018 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2303-2303

Author(s):

Pilar Martínez Sánchez ◽

Paul Gordon ◽

Stefan Schwartz ◽

Giuseppe Rossi ◽

Francoise Huguet ◽

...

Keyword(s):

Steady State ◽

Board Of Directors ◽

Research Funding ◽

Dose Finding ◽

Publicly Traded ◽

Advisory Committees ◽

Pharmacodynamic Profile ◽

Finding Study ◽

Phase 1B ◽

Dose Finding Study

Abstract Background Blinatumomab is a BiTE ® (bispecific T cell engager) molecule that engages patients' T cells to the CD19 antigen on lymphoid tumor cells. Blinatumomab administered as a 28-day continuous intravenous infusion (cIV) is approved in multiple regions for the treatment of R/R B-ALL in adults and children. Subcutaneous delivery may improve the convenience and satisfaction of patients with R/R B-ALL who are candidates for blinatumomab therapy. Here we report the results from the first cohort of adults with R/R B-ALL receiving SC blinatumomab. Methods In this ongoing multicenter, single arm, open-label, phase 1b dose-finding study (NCT04521231), patients received multiple cycles of SC blinatumomab. Each cycle included a treatment period and a treatment-free interval. In cohort 1, cycle 1, patients received a lower first dose of SC blinatumomab for several days followed by a higher dose multiple times weekly; in subsequent cycles, patients received the higher dose several times weekly during the treatment period. Bone marrow (BM) evaluation was performed on day 27 of each cycle. Results Six patients from cohort 1 were included in this June 22, 2021 data cutoff. Median age was 64 (range 38-83) years. The number of prior therapies ranged from 2-4. Two patients had disease refractory to primary therapy or salvage therapy, 2 patients relapsed after chemotherapy, and 2 patients relapsed after prior allogeneic hematopoietic stem cell transplant. Median BM blast count at study start was 85% (range 28%-95%). Only 1 patient had <50% BM blasts (BM blasts=28%). At enrollment, all patients had an ECOG score of 0-1. The median number of SC blinatumomab cycles initiated was 1 (range 1-3). Preliminary pharmacokinetic results support the SC dosing intervals used in this study and potentially longer intervals. Exposures for SC doses were similar to the efficacious exposures of the approved cIV regimen: mean average concentrations at steady state of 215 and 853 pg/mL for the lower and higher SC dosing regimens of cohort 1, respectively, vs mean steady state concentrations of 228 and 616 pg/mL for 9 and 28 µg/day cIV dosing, respectively. The pharmacodynamic profile following SC blinatumomab of peripheral immune cell redistribution (circulating CD3+ and CD8+ CD69+ T cells), transient cytokine elevation (IL-6, IL-10, IFN-γ) and CD19+ B cell counts declining below the detection limit was consistent with the historical pharmacodynamic profile following cIV blinatumomab. No grade ≥3 cytokine release syndrome events were reported (Table). One patient developed herpes encephalitis and experienced a grade 5 neurological event unrelated to blinatumomab; no other neurological events were reported. Two patients discontinued treatment because of adverse events (injection site reaction in patient with no response, hyperleukocytosis due to disease progression). Three patients had complete hematological response (CR) with no measurable residual disease (MRD) (<10 -4) within 2 cycles and 1 patient had a morphological partial response (95% BM blasts at start of cycle 1 to 22% blasts on day 15). This patient discontinued on day 15 of cycle 1 after progression of extramedullary disease. At the time of the data cutoff, 2 patients remained on study. These patients had CR with no MRD. Conclusions In this phase 1b dose-finding study, SC blinatumomab has demonstrated encouraging anti-leukemia activity in heavily pretreated patients with R/R B-ALL. Pharmacokinetic and pharmacodynamic results support the use of SC dosing in this population. The safety profile was manageable and consistent with that reported for cIV blinatumomab. Figure 1 Figure 1. Disclosures Gordon: Amgen: Current Employment, Current equity holder in publicly-traded company. Schwartz: Morphosys: Research Funding; Pfizer: Honoraria, Speakers Bureau; Gilead: Other: Travel grants, Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants. Rossi: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Alexion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Hernández-Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wong: Amgen: Current equity holder in publicly-traded company; Amgen: Current Employment. Markovic: Amgen: Current Employment, Current equity holder in publicly-traded company. Katlinskaya: Amgen: Current Employment, Current equity holder in publicly-traded company. Panwar: Amgen: Current Employment, Current equity holder in publicly-traded company. Zugmaier: Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed; receives royalties of family members of international applications published as WO2010/052014; WO2010/052013; WO2011/051307; WO2012/055961; WO 2012/062596; WO2014/122251; and WO2015/181683; Amgen: Current Employment; Amgen: Current equity holder in publicly-traded company.

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An Open-Label, Phase 2, Dose-Finding Study of Sotatercept (ACE-011) in Patients with Low or Intermediate-1 (Int-1)-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion

Blood ◽

10.1182/blood.v124.21.3251.3251 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3251-3251 ◽

Cited By ~ 15

Author(s):

Rami S Komrokji ◽

Guillermo Garcia-Manero ◽

Lionel Ades ◽

Abderrahmane Laadem ◽

Bond Vo ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Dose Finding ◽

Open Label ◽

Advisory Committees ◽

Treatment Start ◽

Finding Study ◽

Dose Finding Study ◽

Dose Levels

Abstract Introduction: Anemia, a hallmark of MDS, is challenging to treat, particularly after failure of erythropoiesis-stimulating agents (ESAs). Sotatercept (ACE-011) is a novel and first-in-class activin type IIA receptor fusion protein that acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation (Carrancio et al. Br J Haematol 2014;165:870-82). Treatment with sotatercept stimulated erythropoiesis and significantly increased hemoglobin (Hb) levels in healthy volunteers (Sherman et al. J Clin Pharmacol 2013;53:1121-30), supporting its clinical development for the treatment of anemia in patients (pts) with lower-risk MDS. Methods: The primary objective of this phase 2, open-label, dose-finding study is to determine a safe, tolerable, and effective dose of sotatercept resulting in erythroid hematological improvement (HI-E; modified IWG 2006 criteria) in pts with anemia and IPSS-defined Low or Int-1-risk MDS or non-proliferative CMML (white blood cells < 13,000/µL). Secondary objectives include rate of RBC-transfusion independence (RBC-TI) ≥ 8 weeks. Eligible pts had anemia (≥ 2 RBC units transfusion requirement in the 12 weeks prior to enrollment for Hb ≤ 9.0 g/dL) with no response, loss of response, or low chance of response to ESAs (serum erythropoietin [EPO] > 500 mIU/mL). Pts received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every 3 weeks. ClinicalTrials.gov identifier: NCT01736683. Results: As of May 22, 2014, a total of 54 MDS pts were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Median age was 71 years (range 56–86) and median time from diagnosis was 4 years (range 0–31); most pts were male (70%). Pts received a median of 6 RBC units (range 0–18) in the 8 weeks prior to treatment start. Forty-five pts (83%) received ≥ 4 RBC units in the 8 weeks prior to treatment start (high transfusion burden; HTB), and 9 pts (17%) received < 4 units in the 8 weeks prior to treatment start (low transfusion burden; LTB). Nineteen pts (35%) had IPSS Low and 34 pts (63%) had IPSS Int-1-risk MDS; IPSS risk data were missing for 1 pt. Fifty-one pts (94%) had prior treatment with ESAs, 30 (56%) with hypomethylating agents, 26 (48%) with lenalidomide, and 26 (48%) with other MDS treatments; 15 pts (28%) had serum EPO > 500 mIU/mL. Of the 53 pts evaluable for efficacy, HI-E was observed in 21 pts (40%) overall: 0, 4 (67%), 8 (40%), and 9 pts (45%) in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Nineteen of 44 HTB pts responded with a ≥ 4 RBC units/8 weeks transfusion burden reduction; duration of transfusion response appeared to be dose-dependent. Five HTB pts achieved RBC-TI ≥ 8 weeks, with RBC-TI duration ranging from 59–345+ days. Eight of 9 LTB pts showed Hb increases, not influenced by transfusion, ranging from 1.3–3.8 g/dL. Of these, 2 pts had a Hb increase ≥ 1.5 g/dL sustained for ≥ 8 weeks. Pts with Hb > 11.0 g/dL were subject to dose delay per protocol, which may have impacted Hb increase sustainability. RBC-TI ≥ 8 weeks was achieved in 6 LTB pts. Increases in platelet and neutrophil levels were seen in pts with baseline thrombocytopenia and pts with baseline neutropenia, respectively. Sotatercept was generally well tolerated. Twenty pts (37%) reported ≥ 1 suspected treatment-related adverse event (AE); fatigue (11%), headache (9.3%), decreased appetite (7.4%), and nausea (7.4%) were the most common. Of 35 pts (65%) who discontinued treatment, 28 discontinued due to lack of therapeutic effect and 4 due to AEs. Of those AEs leading to discontinuation, 3 were suspected to be treatment-related: 1 pt with grade 2 hemolytic anemia, 1 pt with grade 3 hypertension, and 1 pt with grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg dose groups, respectively. Other reasons for discontinuation were withdrawal of consent (n = 2; 4%) and pt decision (n = 1; 2%). Conclusions: Sotatercept was well tolerated in lower-risk MDS pts at the dose levels tested, with promising evidence of clinical activity in this largely HTB cohort of ESA-refractory, anemic, lower-risk MDS pts. Further exploration of higher sotatercept dose levels and longer-term treatment is planned. PF and AFL contributed equally to this abstract as senior co-authors. Disclosures Komrokji: Celgene Corporation: Consultancy, Research Funding. Off Label Use: Sotatercept (ACE-011) is an investigational agent that is being assessed for efficacy and safety in myelodysplastic syndromes.. Garcia-Manero:Celgene Corporation: Research Funding. Ades:Novartis: Research Funding; Celgene Corporation: Research Funding. Laadem:Celgene Corporation: Employment, Equity Ownership. Vo:Celgene Corporation: Employment. Prebet:Celgene Corporation: Honoraria. Boyd:US Oncology: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corporation: Membership on an entity's Board of Directors or advisory committees. Beyne-Rauzy:Novartis: Research Funding; Celgene: Research Funding. Zou:Celgene: Employment. Attie:Acceleron Pharma: Employment. Sherman:Acceleron Pharma: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding. List:Celgene: Consultancy.

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Iadademstat in Combination with Azacitidine Generates Robust and Long Lasting Responses in AML Patients (ALICE Trial)

Blood ◽

10.1182/blood-2021-152183 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3376-3376

Author(s):

Olga Salamero ◽

Tim C.P Somervaille ◽

Antonieta Molero ◽

Evelyn Acuña-Cruz ◽

Jose Pérez-Simón ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Objective Response ◽

Therapeutic Options ◽

Dose Finding ◽

Open Label ◽

Advisory Committees ◽

Platelet Recovery

Abstract Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy. Elderly patients were historically treated with chemotherapy, with ORRs below 30%. Despite treatment improvements with the recent approval of the combination venetoclax plus azacitidine, with 64% of ORR and overall survival of 14.7 months, 25% of patients continue to be refractory and 50% are estimated to relapse. The management of AML, especially in elderly or unfit patients, remains a major challenge. Lysine-specific histone demethylase 1 (LSD1) contributes to the malignant transformation event in AML. Iadademstat (iada) selectively inhibits LSD1 and has shown efficacy in preclinical models, including promoting differentiation in AML. Iada has been administered so far to +100 oncology patients in different clinical trials, showing good safety. With a favorable ADME profile and high bioactivity allowing low dosing regimens, a low DDI risk is anticipated, making iada suitable for different drug combinations and offering additional therapeutic options for patients. This is a 36-month update of the ongoing Phase II ALICE clinical trial of iadademstat plus azacitidine in front-line AML patients. Methods: ALICE (EudraCT 2018-000482-36) is an open-label, single arm, Phase IIa clinical trial to assess the safety, tolerability, dose finding and efficacy of iadademstat in combination with azacitidine for the treatment of adult AML patients. ALICE includes AML patients, who have not received prior treatment other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or have refused this treatment option. Secondary end points of the study address the anti-leukemic activity of the combination (overall response rate, time to response and duration of response) along with PK/PD measures. Results: Current unaudited data corresponds to 34 patients enrolled, including 22 evaluable patients (with at least 1 bone marrow disease evaluation). Evaluable patients achieved an 73% objective response rate (ORR): 5 complete remissions (CR), 6 CR with incomplete hematological recovery (CRi) and 5 Partial Remissions (PR). The current median Time to Response is 30 days, with some durable responses, extending for more than one year in five patients, with the longest CR up to date above 930 days (still ongoing, with CR and MRD negative). Moreover, 5 patients became transfusion independent and MRD negative. The number of adverse events (AEs) reported is in line with the usual evolution of the disease and with other AML trials. Only 2 AEs (in 2 patients) were deemed as serious reactions, probably related to treatment: one differentiation syndrome (G3) and one intracranial hemorrhage (G5). The most frequent reported adverse reaction was thrombocytopenia, observed in almost half of patients (47%), although 63% of patients had presented with grade ≥3 thrombocytopenia at baseline, making difficult to unequivocally attribute observed cytopenias to treatment. Of note, patients that showed response experienced platelet recovery within the first 3 cycles of treatment. Other than the hematological events, the iada-azacitidine combination appears to be safe and well tolerated. We have not observed other significant non-hematological toxicities or other organ-related toxicities. We expect to achieve full patient recruitment of the ALICE study (36 subjects) in October 2021 and will report updated safety and efficacy results based on an October data cut-off. Conclusions: Data to date indicate that iadademstat has a good safety profile and produces robust, fast and in some cases durable responses. Iadademstat appears to be an active candidate for combination with azacitidine and other agents. Drug-related toxicity appears to be predictable, manageable, and restricted to hematologic events. Considering the novel mechanism of action of iadademstat, a pro-differentiating agent, combination strategies with iadademstat might increase therapeutic options for AML patients in first line treatment, as well as for refractory, intolerant, or relapsed patients. Disclosures Salamero: Pfizer: Consultancy; BMS/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Somervaille: Novartis: Consultancy, Honoraria. Molero: AbbVie: Honoraria; Jansen: Honoraria; BMS-Celgene: Other: Travel, accommodation expenses. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gutierrez: Oryzon Genomics: Current Employment. Buesa: Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

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Preliminary Study of Ruxolitinib and Venetoclax for Treatment of Patients with T-Cell Prolymphocytic Leukemia Refractory to, or Ineligible for Alemtuzumab

Blood ◽

10.1182/blood-2021-149228 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1201-1201

Author(s):

Charles Herbaux ◽

Stéphanie Poulain ◽

Damien Roos-Weil ◽

Jacques-Olivier Bay ◽

Yann Guillermin ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Advisory Committees ◽

Prolymphocytic Leukemia ◽

Oncology Research ◽

Grade 3 ◽

Stat Pathway

Abstract Background: Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are 2 drug candidates recently identified as promising candidate for the treatment of T-Cell prolymphocytic leukemia (T-PLL). We recently reported that JAK/STAT pathway inhibition with RUX enhances BCL-2 dependence, thereby sensitizing T-PLL cells to VEN (Herbaux et al., Blood, 2021). We also showed that JAK/STAT pathway mutational status could impact RUX activity. Here, we report results on the 15 first patients who were treated with RUX and VEN oral combination for T-PLL. All patients were refractory to, or ineligible for alemtuzumab, the principal therapeutic option to date. Methods: In this multicenter retrospective study from the French Innovative Leukemia Organization, 15 patients with T-PLL (according to consensus criteria) were included. All patients were informed about the off-label use of this combination and provided informed consent. Patients received a maximum dose of RUX 15 mg twice daily, and VEN 800 mg daily. VEN was started with daily ramp-up from 20 mg to 800 mg over 6 days, with TLS prophylaxis (rasburicase and IV hydration). Responses were assessed by consensus criteria. Next generation sequencing (NGS) was performed using a custom-designed panel of 33 genes, including among others: ATM, TP53, IL2R, JAK1, JAK3, and STAT5B. CytoScan HD microarray (Affymetrix) were used to study copy number variation and or uniparental disomy. In vivo dynamic BH3 profiling (DBP) was performed on samples obtained from two patients on treatment. Results: All 15 patients were refractory or relapsing after chemotherapy (mostly bendamustine and pentostatin), except one. They were either refractory to (n=10) or ineligible (n=5) for alemtuzumab (ineligibility was decided by the treating physician based on age and comorbidities). The median age was 70 years (48-88). Within a week of starting RUX, a transient increase of the absolute lymphocyte count was observed in 66.6% of the patients. Based on the molecular status of the JAK/STAT pathway, we established 2 groups of patients. One with samples where no mutations were found (WT, n=3), and one with at least one mutation in the JAK/STAT pathway (MUT, n=12). The overall response rate (ORR) was 73.3%, with only partial responses. Five patients nearly fulfilled CR criteria except that they had persistent lymphocytosis (over 4 x 10 9/L), all of them were in the MUT group. ORR was 83.3% in the MUT group, and only one patient of the WT group obtained a PR. With a median follow-up of 73 days (22 to 368), the median progression free survival was significantly shorter in the WT group in comparison to the MUT group (1.8 months versus 5.6 months, p=0.04, Figure). Of note, four patients were treated with VEN monotherapy before the start of the combination with RUX. With that treatment, 3 of these patients achieved stable disease followed by progression within 2 to 3 months, while 1 was primary refractory to VEN monotherapy. The most frequent reported adverse events (AEs) of the RUX plus VEN combination were cytopenias, with 46.6% grade 3 or 4 thrombocytopenia and 40% grade 3 or 4 neutropenia. DBP showed that overall priming and BCL2 dependence increased in vivo (n=2) during the treatment with RUX and VEN. Finally, SNP arrays identified clonal evolution in the 3 patients evaluated sequentially (before treatment versus at progression). In one case, emergence of EZH2 and JAK1 mutation was also observed at progression using NGS. Conclusions: These preliminary results suggest promising activity of RUX plus VEN in T-PLL, and justify the development of a prospective clinical trial of this combination. Our data seem to show that this combination may be especially active for patients with JAK/STAT pathway activating mutations and that disease progression is associated with clonal evolution. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Lemonnier: Gilead: Other: travel grant; Institut Roche: Research Funding. Laribi: Jansen: Research Funding; AstraZeneca: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; BeiGene: Other: Personal Fees. Moreaux: Diag2Tec: Consultancy. Morschhauser: Janssen: Honoraria; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Davids: Ascentage Pharma: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Eli Lilly and Company: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Research to Practice: Consultancy; BeiGene: Consultancy; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. OffLabel Disclosure: Ruxolitinib and venetoclax are used offlabel for patients refractory to current therapeutic options, based on preclinical data.

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Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma

Blood ◽

10.1182/blood-2019-126148 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1612-1612 ◽

Cited By ~ 1

Author(s):

Hamza Hashmi ◽

Alicia Darwin ◽

Christina A Bachmeier ◽

Julio Chavez ◽

Bijal Shah ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.

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EORTC 21012: Phase II Multicentre Study of Caelyx™ Monotherapy In Patients with Advanced Mycosis Fungoides Stage IIb, Iva and IVb with or without Previous Chemotherapy.

Blood ◽

10.1182/blood.v116.21.2823.2823 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2823-2823

Author(s):

Reinhard Dummer ◽

Sean Whittaker ◽

Baktiar Hasan ◽

Juergen C Becker ◽

Michael Weichenthal ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Mycosis Fungoides ◽

Patient Population ◽

Research Funding ◽

Infectious Complications ◽

Advisory Committees ◽

Recombinant Interferon ◽

Dermatologic Toxicity ◽

Grade 3

Abstract Abstract 2823 Background: Cutaneous lymphomas consist of a heterogeneous group of diseases that are characterized by a clonal accumulation of lymphocytes in the skin. The estimated incidence is 1–2/100.000 per year. The more advanced stages have a poor prognosis and treatments are usually palliative, such as combination of PUVA with retinoids or recombinant interferon alpha. CHOP or COPBLAM are widely used in analogy to other peripheral T-cell lymphomas, but have severe, sometimes lethal infectious complications and short response duration. Some studies indicated response rates after CHOP chemotherapy regimen are between 40% and 70% in cutaneous T-cell lymphoma (CTCL). However, these studies include patients in various disease stages, that might not necessarily need aggressive treatment and without precise information concerning the CTCL subtype. Therefore, there is an urgent need for multicenter trials designed to test a clearly defined patient population. Pegylated liposomal doxorubicin (PLD, Caelyx™) is an antineoplastic antibiotic with pharmacologic actions similar to those of daunorubicin. PLD provides a longer circulation time and a higher drug concentration in tumors than in normal tissue that could lead to reduced side effects in particular life-threatening cardiotoxicity and neutropenia with infectious complications. Material and methods: Eligible patients had histologically confirmed Mycosis Fungoides stage IIb, IVa, or IVb, WHO performance status (PS) 0–2, no systemic treatment with steroids and refractory or recurrent disease after at least 2 or more previous therapies. Caelyx 20 mg/m2 was administered on days 1 and 15 in a 28-day cycle for a maximum of 6 cycles. The primary endpoint was response rate (RR), defined as patients achieved either complete clinical response (CCR) or partial response (PR). Using the Fleming design with α= 0.1 and β= 0.05 and aiming at a RR = 45% and powered to rule out a RR < 25%, 48 patients who are eligible and started treatment are required. To declare success, a 1-sided 90% confidence interval (CI) for RR should exclude 25% (the rate used in the null hypothesis). Results: Between November 22, 2003 and July 3, 2009, 9 centers registered 49 patients. All of them were eligible and started treatment. The majority of patients were male (67%), had PS 0, 1 (43%, 53%) and were between 56–65 and 66–75 year old (33% and 31%). The median (range) number of chemotherapy cycles received was 5(1-6) and the majority of patients had relative dose intensity of 90–110% and 70–90% (53% and 35%). Eighty eight percents of patients received prophylactic antiemetics; 84% had PS 0–1 during treatment. There was no Grade 3–4 hematological toxicity; only grade 2 neutropenia (4%), leukopenia (4%) and anemia (4%) were observed during treatment. Grade 3/4 non-hematologic/non biochemical toxicities were cardiac (2%), allergy (2%), constitutional symptom (4%), hand foot reaction (2%), other dermatologic toxicity (6%), other gastro intestinal toxicity (4%) and other infection (4%). One patient (2%) had grade 4 cardiac ischemia. Of 49 patients who were eligible and started treatment, 20 (40.8%) were responders: 3 (6.1%) CCR and 17 (34.7%). The 1-sided 90% CI for the RR is: (31.2%, 100%). Conclusion: The primary RR endpoint of the study was reached (ie, 1-sided 90% CI excludes 25%). We conclude that Caelyx™ should be considered for further investigation. Caelyx™ has an acceptable safety profile with only a few toxicities and no sepsis observed in this patient population of advanced age. Its efficacy appears promising. Disclosures: Dummer: Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dhome: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Transgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Schering Plough: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Becker:SheringPlough International: Consultancy. Weichenthal:Schering-Plough : Honoraria, Research Funding.

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

Blood ◽

10.1182/blood.v120.21.2737.2737 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2737-2737 ◽

Cited By ~ 1

Author(s):

Naokuni Uike ◽

Michinora Ogura ◽

Yoshitaka Imaizumi ◽

Norio Asou ◽

Atae Utsunomiya ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Study ◽

Grade 3

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

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A Phase Ib/IIa Trial of the Combination of Romidepsin, Lenalidomide and Carfilzomib in Patients with Relapsed/Refractory Lymphoma Shows Complete Responses in Relapsed and Refractory T-Cell Lymphomas

Blood ◽

10.1182/blood.v128.22.2991.2991 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2991-2991 ◽

Cited By ~ 13

Author(s):

Neha Mehta-Shah ◽

Alison J Moskowitz ◽

Matthew Lunning ◽

Peggy Lynch ◽

Mark Scheuerman ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

T Cell Lymphoma ◽

Hematologic Toxicity ◽

Advisory Committees ◽

Grade 3

Abstract Background:Epigenetic manipulation and immunomodulation are therapeutic strategies in hematologic malignancies. In our previous study, the combination of romidepsin and lenalidomide demonstrated a 58% overall response rate, complete response rate of 11% and median event free survival was 16 weeks in patients (pts) with relapsed or refractory T-cell lymphoma. Given the potential synergy of proteasome inhibitors with histone deacetylase inhibitors and lenalidomide, we conducted a phase Ib/IIa study to evaluate the safety and toxicity of romidepsin and lenalidomide in combination with carfilzomib in pts with relapsed or refractory lymphoma. Here we report the safety, toxicity, and maximum tolerated dose (MTD) from the completed phase I portion of the study as well as the efficacy data from the completed T-cell lymphoma phase IIa cohort. Methods: The phase I portion evaluated toxicity and defined MTD. The clinicalactivity of the combination of romidepsin, lenalidomide, and carfilzomib was assessed in the phase I and lineage specific phase IIa cohorts. Romidepsin and carfilzomib were given IV on days 1, 8 and lenalidomide was given orally on days 1-14 of a 21-day cycle. A standard 3+3 dose escalation schema was followed: The starting dose was romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2. Dose-limiting toxicity (DLT) was defined in cycle 1 as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity, grade ≥ 3 thrombocytopenia with bleeding, grade 3 hematologic toxicity resulting in a significant delay of treatment or inability to receive day 1 of cycle 2 due to continued drug related toxicity. Tumor response was based on disease-specific criteria.Pts could be treated until progression, intolerance, or response adequate to allow allogeneic transplantation. Results:20 pts were enrolled with 19 evaluable for toxicity (1 patient with T-cell lymphoma progressed prior to receipt of any study drug). 17 pts were treated for T-cell lymphoma (11 in the phase 1 portion and 6 in the phase IIa cohort): peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)-9, angioimmunoblastic T-cell lymphoma (AITL)-4 (one with concurrent diffuse large B-cell lymphoma-DLBCL), mycosis fungoides (MF)-2, transformed MF-1, extra-nodal NK/T-cell lymphoma (ENKTCL)-1. 3 pts in the phase 1 portion were treated for B-cell lymphoma: DLBCL-3. The T-cell lymphoma cohort is complete and efficacy data is reported here. Dose level 2 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 45mg/m2) exceeded the MTD with 2/6 DLTs: 1 pt with grade 3 thrombocytopenia resulting in treatment delay and 1 pt with grade 4 thrombocytopenia. There were no DLTs among 6 pts treated in dose level 1 (romidepsin 8 mg/m2,lenalidomide 15 mg, carfilzomib 36mg/m2) and dose level 1 was deemed the MTD. Grade 3-4 toxicities in >10% pts included neutropenia and thrombocytopenia. SAEs included: infection-3, progression of disease resulting in hospitalization-3, fever-2, febrile neutropenia-1, DVT-1, edema-1, dyspnea-1, atrial flutter-1, generalized weakness-1, and vomiting with diarrhea-1. Of the 16 pts with T-cell lymphoma evaluable for response, the overall response rate was 50% (8/16, 95% CI: 25 to 75%). The complete responses rate was 31% (5/16, 95% CI: 11 to 59%) and the partial response rate was 19% (3/16, 95% CI: 4 to 46%). Complete responses were seen in AITL (4/5) and PTCL-NOS (1/8) with 3 pts in CR proceeding to allogeneic stem cell transplantation. Partial responses were seen in PTCL-NOS-1, AITL-1, and transformed MF-1. In T-cell lymphoma, the median event free survival for all pts was 9.7 weeks (95% CI: 6.0 to NR) and for responders was not reached (95% CI: 15.0 to NR). The median time to response was 5.8 weeks. The median duration of response was 9.6 weeks (95% CI: 8.0 to NR). 3 pts underwent allogeneic transplantation following this therapy and another 2 pts with CR remain in continuous remission. Median duration of follow up was 20.4 weeks (range 3.4-40.9 weeks). Conclusions: The MTD dose for phase 2 study was identified as romidepsin 8mg/m2, lenalidomide 15mg and carfilzomib 36mg/m2. No unexpected toxicities have emerged. The preliminary overall and complete response rates of this regimen are promising in T-cell lymphoma, particularly in AITL, and warrants further study. An expansion cohort in B-cell lymphoma cohort is ongoing. Disclosures Moskowitz: Seattle Genetics: Consultancy, Research Funding; BMS: Consultancy. Lunning:Gilead: Consultancy; Bristol-Myer-Squibb: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Spectrum: Consultancy; Celgene: Consultancy. Kumar:Celgene: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria, Other: Scientific Advisory Board. Zelenetz:Gilead Sciences: Research Funding. Hamlin:Novartis: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Seattle Genetics: Research Funding; Molecular Templates: Research Funding. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding. Palomba:Pharmacyclics: Consultancy. Dogan:Seattle Genetics: Consultancy; Consulting Cancer Panel: Membership on an entity's Board of Directors or advisory committees; Cancer Genetics: Membership on an entity's Board of Directors or advisory committees; Peerview Institute: Consultancy. Horwitz:Bristol-Myers Squibb: Consultancy; Infinity: Consultancy, Research Funding; Celgene: Consultancy; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Huya: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding.

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The Pralatrexate - Romidepsin Doublet: A Well Tolerated and Highly Effective Combination for Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1824.1824 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1824-1824 ◽

Cited By ~ 3

Author(s):

Jennifer E Amengual ◽

Renee Lichtenstein ◽

Celeste Rojas ◽

Ahmed Sawas ◽

Changchun Deng ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Median Number ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Genetics Research ◽

The Mean ◽

Grade 3

Abstract Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas in which only ~25% of patients experience long-term survival with CHOP chemotherapy. Recently several drugs have been approved for this entity including pralatrexate (P), romidepsin (R), and belinostat which have response rates ranging from 26%-29% as single agents. Based on our demonstration of synergy of P+R in preclinical models of TCL, we initiated a study on the safety and efficacy of P+R in a phase I-II study for relapsed or refractory lymphomas (NCT01947140) and sought to evaluate biological mechanisms of synergy. A 3+3 dose-escalation study started at P 10mg/m2 and R 12mg/m2 with escalation to P 25 mg/m2 and R 14 mg/m2. Patients were treated on 1 of 3 dosing schedules (weekly x 3 Q28D; weekly x 2 Q21D and QOW Q28D). The primary objective was to determine MTD and DLT; the secondary objective included describing ORR (CR+PR). Patients were required to have relapsed lymphoma of any subtype, ECOG PS ≤2, and adequate organ and marrow function. There was no upper limit to the number of prior therapies or transplantation. Twenty-six patients were enrolled and were evaluable for toxicity. Median age was 52 yrs (23-73) and 58% were male. The median number of prior therapies was 3 (range 1-16). Histologies included HL (N=3), B-cell (N=10 of which FL=4) and T-cell (N=13). The median number of cycles completed was 4 (range 1-12). There were 3 DLTs in cohort 4 (P 20mg/m2 & R 12mg/m2given weekly x 2 Q21D) consisting of 2 Grade 3 oral mucositis and 1 Grade 4 sepsis. The QOW Q28D schedule had no mucositis at all dose levels. Patients dosed at the MTD (P 25 mg/m2 & R 12mg/m2 QOW) did not experience any toxicities. The grade 3/4 toxicities reported in >5% of patients were: neutropenia (31%), thrombocytopenia (31%), anemia (23%), oral mucositis (15%), hyponatremia (8%), pneumonia (8%) and sepsis (8%). Twenty-two patients were evaluable for response, 1 patient is currently on therapy. The ORR in the total, non-PTCL and PTCL populations was 59%; 33% (no CR) and 77% respectively. Of the PTCL patients 4/13 (31%) achieved a CR, 6/13 (46%) achieved a PR, and 1 patient had stable disease. The mean duration of response (DOR) for all patients on the study (N=13) was 6.1 months (1.1 - 26.5), for the non-PTCL population (N=3) was 4.8 m (1.1-11) and for the PTCL population (N=10) was 6.55 months (range 1.6 - 26.5 +ongoing). The mean progression free survival (PFS) for all patients on study (N=26) was 4.8 m (.3 - 30.2), for the non-PTCL population (N=13) was 2.8 m (0.3-14.5), and for the PTCL population was 6.13 months (range 1.5 - 30.2 +ongoing). Pharmacokinetic studies were performed for P and R and data for the first 15 patients is presently available for reporting. PK analyses were performed using WinNonLin® to determine Cmax and AUC. Preliminary Cmax results for P 10 mg/m2 and P 15 mg/m2 are 1810+/-1063 ng/mL and 2748+/-995 ng/mL, respectively. Preliminary Cmax results for R 12 mg/m2 and R 14 mg/m2 are 420+/-198 ng/mL and 552+/- 346 ng/mL, respectively. After infusion with P 10 mg/m2 or 15 mg/m2 PK analysis indicate AUC0-24.08h of 3616+/-1543 h*ng/mL and 4104+/-2124 h*ng/mL, respectively. AUC0-28h after treatment with R 12 mg/m2or 14 mg/m2 was 1503+/-1286 h*ng/ml and 2535+/-2560 h*ng/mL. These values are consistent with that observed for both of these drugs in previous studies. Results from the phase I study conclude that the combination of P + R given on the QOW schedule is safe and very well tolerated. These data support the lineage specific activity of the P+R combination, which is currently being expanded to a multicenter Phase II for PTCL. Figure Figure. Disclosures Amengual: Bristol-Myers Squibb: Research Funding; Acetylon Pharmaceuticals, Inc: Research Funding. Sawas:Seattle Genetics: Honoraria; Gilead Sciences: Speakers Bureau. O'Connor:Spectrum: Research Funding; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Spectrum: Research Funding; TG Therapeutics: Research Funding; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding.

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