Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype occurring in 15-30% of older children and adolescents/young adults (AYAs) with B-ALL. Ph-like ALL is associated with high relapse rates and poor survival despite intensive multi-agent cytotoxic chemotherapy. Development of successful treatment strategies to decrease relapse and improve cure rates in patients with Ph-like ALL remains a major therapeutic gap. Rearrangements of cytokine receptor-like factor 2 (CRLF2-R) with frequent concomitant JAK2 point mutations occur in 50% of Ph-like ALL cases and induce constitutive JAK/STAT and other kinase signaling. An additional 15-20% of Ph-like ALL harbors other JAK pathway alterations, such as JAK2 or EPOR rearrangements, that similarly activate JAK/STAT signaling. Ruxolitinib is a potent, selective JAK1/JAK2 inhibitor with demonstrated activity in preclinical Ph-like ALL models and clinical safety as monotherapy in children with relapsed/refractory cancers. We report the initial safety of ruxolitinib in combination with post-induction chemotherapy in children and AYAs with newly-diagnosed high-risk (HR) Ph-like ALL with CRLF2-R or other JAK pathway alterations treated on the non-randomized, 2-part phase 2 study INCB18424-269 (AALL1521; NCT02723994). Methods: Patients aged 1-21 years at time of diagnosis with HR B-ALL and eligible Ph-like genetic lesions who had completed 4-drug induction chemotherapy as per the Children's Oncology Group (COG) AALL1131 study (NCT02883049) were eligible to participate. Patients were stratified into 4 cohorts by genetic alterations and end-induction flow cytometric minimal residual disease (MRD) status: cohort A = CRLF2-R JAK-mutant, MRD+; B = CRLF2-R JAK-wild-type, MRD+; C = other JAK pathway alterations, MRD+, D = any CRLF2-R or JAK pathway alteration, MRD-. Patients commenced treatment on the INCB18424-269/AALL1521 study at consolidation with ruxolitinib orally twice daily in combination with augmented Berlin-Frankfurt-Münster (aBFM) post-induction chemotherapy as per AALL1131. Five discontinuous dose levels (10-50 mg/m2/dose 14-days-on/14-days-off per cycle [DL-2 to DL2]) and one continuous DL1b (40 mg/m2/dose × 28 days per cycle) of ruxolitinib with aBFM chemotherapy were explored via a standard rolling 6 design. Dose-limiting toxicities (DLTs) were assessed through Day 29 of delayed intensification (DI) and defined as hematologic and non-hematologic toxicity with higher grade or more prolonged duration than observed in children with treated with identical chemotherapy (without ruxolitinib) on other COG HR B-ALL trials. Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted using serial blood samples obtained from patients during consolidation therapy. Results: Forty patients (pts) were enrolled in Part 1 (cohort A, n=10; B, n=9; C, n=5; D, n=16). Four patients discontinued study treatment before the Day 29 DI timepoint, 3 of whom were replaced. Patients had a median age of 14 years, and 67.5% were male. Treatment-emergent adverse events occurred in all patients and included anemia (75%), platelet count decrease and/or thrombocytopenia (65%), febrile neutropenia (72.5%), and AST or ALT increase (57.5%). Thirty-three patients had Grade 3/4 events deemed possibly related to ruxolitinib without identified DLTs. Eleven patients in Part 1 (27.5%) discontinued study therapy for various reasons: CNS relapse (2 pts), end-consolidation MRD+ (4 pts), multi-system organ dysfunction (MSOD; 2 pts), elective MRD- stem cell transplantation (1 pt), psychosocial/compliance issues (2 pts). One patient died of septic shock and MSOD not attributed to ruxolitinib. Preliminary analysis of plasma drug levels at 4 hours post-dose was consistent with the known PK profile of ruxolitinib. PD studies demonstrated dose-dependent inhibition of target phosphoproteins and, importantly, sustained inhibition of phosphorylated STAT5 with continuous ruxolitinib dosing at DL1b. Discussion: These findings demonstrate safety and tolerability of ruxolitinib in combination with intensive multi-agent chemotherapy in children and AYAs with newly-diagnosed HR CRLF2-R/JAK pathway-mutant Ph-like ALL and support continued investigation of treatment efficacy in Part 2 of this trial. Disclosures Tasian: Aleta Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding. Assad:Incyte Corporation: Employment, Equity Ownership. Hunter:Incyte Corporation: Employment. Du:Incyte Corporation: Employment.

A response-adaptive randomization (RAR) design refers to the method in which the probability of treatment assignment changes according to how well the treatments are performing in the trial. Holding the promise of treating more patients with the better treatments, RARs have been successfully implemented in clinical trials. We compared equal randomization (ER) with three RARs: Bayesian adaptive randomization, sequential maximum likelihood, and sequential posterior mean. We fixed the total number of patients, considering as patient horizon, but varied the number of patients in the trial. Among the designs, we compared the proportion of patients assigned to the superior arm, overall response rate, statistical power, and total patients enrolled in the trial if adding an efficacy early stopping rule. Without early stopping, ER is preferred when the number of patients beyond the trial is much larger than the number of patients in the trial. RAR is favored for large treatment difference or when the number of patients beyond the trial is small. With early stopping, the difference between these two types of designs was reduced. By carefully choosing the design parameters, both RAR and ER methods can achieve the desirable statistical properties. Within three RAR methods, we recommend SPM considering the larger proportion in the better arm and higher overall response rate than BAR and similar power and trial size with ER. The ultimate choice of RAR or ER methods depends on the investigator’s preference, the trade-off between group ethics and individual ethics, and logistic considerations in the trial conduct, etc.

We examine three variations of the regularization methods for response-adaptive randomization (RAR) and compare their operating characteristics. A power transformation (PT) is applied to refine the randomization probability. The clip method is used to bound the randomization probability within specified limits. A burn-in period of equal randomization (ER) can be added before adaptive randomization (AR). For each method, more patients are assigned to the superior arm and overall response rate increase as the scheme approximates simple AR, while statistical power increases as it approximates ER. We evaluate the performance of the three methods by varying the tuning parameter to control the extent of AR to achieve the same statistical power. When there is no early stopping rule, PT method generally performed the best in yielding higher proportion to the superior arm and higher overall response rate, but with larger variability. The burn-in method showed smallest variability compared with the clip method and the PT method. With the efficacy early stopping rule, all three methods performed more similarly. The PT and clip methods are better than the burn-in method in achieving higher proportion randomized to the superior arm and higher overall response rate but burn-in method required fewer patients in the trial. By carefully choosing the method and the tuning parameter, RAR methods can be tailored to strike a balance between achieving the desired statistical power and enhancing the overall response rate.

Background Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic marker involved in downregulating gene expression associated with tumor suppression and cell differentiation. Both altered EZH2 expression and EZH1's compensatory activity have been implicated in the development and progression of non-Hodgkin lymphomas (NHLs), including PTCL and ATL. R/R PTCL and ATL are associated with inferior outcomes, and many patients (pts) are not eligible for potentially curative transplants. Valemetostat tosylate (DS-3201b; also known as valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. A first-in-human phase 1 study was conducted for pts with R/R NHL in Japan and the US. Valemetostat demonstrated clinical antitumor activity in pts with NHL, including R/R PTCL and R/R ATL. Treatment with valemetostat 150 or 200 mg/day led to overall response rates (ORRs) of 54.5% (95% CI, 38.8%-69.9%) and 57.1% (95% CI, 28.9%-82.3%) in pts with R/R PTCL (n=44) or R/R ATL (n=14), respectively (EHA 2021. Abstract S218). Durability of response was demonstrated by a median duration of response (DOR) of 56.0 weeks (range, 44.43- -) in PTCL pts. Based on these encouraging efficacy results, a global phase 2 study was designed. Methods VALENTINE-PTCL01 (NCT04703192) is a global, multicenter, open-label, single-arm, noncomparative, 2-cohort, phase 2 study designed to evaluate the efficacy and safety of valemetostat monotherapy in adult pts with R/R PTCL or R/R ATL. Pts with R/R PTCL or R/R ATL are independently enrolled in cohort 1 or 2, respectively (Figure). Eligibility for both cohorts is determined based on a diagnosis made by a local pathologist/investigator and is centrally confirmed. Pts eligible for cohort 1 must have 1 of the following R/R PTCL subtypes: (1) angioimmunoblastic T-cell lymphoma, (2) follicular T-cell lymphoma, (3) nodal PTCL with T-follicular helper (TFH) phenotype, (4) PTCL not otherwise specified, (5) ALK-positive anaplastic large cell lymphoma (ALCL), (6) ALK-negative ALCL, (7) enteropathy-associated T-cell lymphoma, (8) monomorphic epitheliotropic intestinal T-cell lymphoma, (9) hepatosplenic T-cell lymphoma, (10) primary cutaneous γ-δ T-cell lymphoma, or (11) primary, cutaneous, CD8+, aggressive, epidermotropic, cytotoxic T-cell lymphoma. Pts must have ≥1 measurable lesion as assessed by computed tomography (CT). Pts eligible for cohort 2 must have acute, lymphomatous, or unfavorable, chronic-type R/R ATL with evaluable abnormal lymphocytes in the peripheral blood and skin lesions. Pts in both cohorts must have received ≥1 prior line of systemic therapy and have adequate organ function prior to the first dose of valemetostat. Pts with ALCL must have received prior brentuximab vedotin treatment. Pts who progressed after autologous or allogeneic hematopoietic cell transplant are eligible. Biomarker positivity (eg, EZH2 mutation) is not required for inclusion. Pts with active central nervous system involvement are excluded. Valemetostat 200 mg/day is administered orally once daily until disease progression or unacceptable toxicity occurs. The primary endpoint is ORR with valemetostat monotherapy as assessed by blinded independent central review. Pts in cohort 1 will be assessed by CT response criteria according to the 2014 Lugano criteria (J Clin Oncol. 2014;32:3059-68). Pts in cohort 2 will be assessed by the modified 2009 ATL criteria stemming from an international consensus meeting (J Clin Oncol. 2009;27:453-59). Secondary endpoints include DOR, complete response (CR) rate, duration of CR, partial response rate, progression-free survival, overall survival, pharmacokinetics, and safety and tolerability of valemetostat. Safety endpoints include treatment-emergent adverse events (TEAEs); TEAEs of special interest; serious TEAEs; fatal events; TEAEs leading to treatment discontinuation, interruption, or reduction; laboratory assessments; vital signs; and electrocardiogram analyses. VALENTINE-PTCL01 is currently recruiting at multiple sites in North America, Europe, Asia, and Oceania. Figure. VALENTINE-PTCL01 Study Design Figure 1 Figure 1. Disclosures Foss: Daiichi Sankyo: Honoraria; Kura: Honoraria; Acrotech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Kyowa: Honoraria; Mallinckrodt: Honoraria. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Izutsu: Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; Chugai: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Ishitsuka: Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Kato: Daiichi Sankyo: Current Employment; Bristol Myers Squibb: Current equity holder in publicly-traded company. Jin: Daiichi Sankyo: Current Employment, Current equity holder in publicly-traded company. Du: Daiichi Sankyo: Current Employment; Incyte: Other: Spouse's current employer; Nektar Therapeutics: Ended employment in the past 24 months. Inoue: Daiichi Sankyo: Current Employment.