Abstract: Myelofibrosis (MF)‐associated constitutional symptoms can severely impact health‐related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24‐week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods Longitudinal symptom change was evaluated using mixed‐effect model repeated measure (MMRM) methodology with individual item‐level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item‐level odds ratios using multiple predictive imputations for missing data. Results Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of 〈 1.5 points between groups for each post‐baseline visit in SIMPLIFY‐1. In SIMPLIFY‐2, the improvement in TSS observed in momelotinib‐treated patients was consistent with that observed in SIMPLIFY‐1, whereas progressive TSS deterioration was observed with control. Item‐level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib‐treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY‐1 and SIMPLIFY‐2, respectively. Odds ratios for between‐group comparison ranged from 0.75 to 1.21 in SIMPLIFY‐1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY‐2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor‐naïve and JAK inhibitor‐exposed settings.

Abstract: Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43] ; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62] ; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p  = 0.0001; SIMPLIFY-2 HR = 0.226, p  = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p   〈  0.0001) and multivariate (HR = 0.311; p   〈  0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib’s pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

Abstract: Momelotinib (MMB), a JAK1, JAK2 and ACVR1 inhibitor, has demonstrated clinically comparable splenic and symptomatic benefits to ruxolitinib (RUX), the standard-of-care JAK1/JAK2 inhibitor for myelofibrosis (MF), a condition marked by splenomegaly, constitutional symptoms and progressive anemia and thrombocytopenia. MMB also uniquely restores iron homeostasis and red blood cell production, reduces or eliminates the need for transfusions and improves or maintains platelet (PLT) counts. Consistent with MMB's differentiated biological profile, low myelosuppressive potential and favorable hematological tolerability, prolonged, near-maximal MMB dose intensity can be maintained regardless of underlying PLT values. In contrast, RUX's hematological toxicity profile necessitates attenuated starting doses for thrombocytopenic (TCP) patients with PLTs & lt;200 × 109/L and substantive, progressive dose reduction to mitigate against RUX-induced thrombocytopenia. Here we report post-hoc comparative efficacy analyses for RUX and MMB for spleen, symptom and transfusion independence (TI) response in patients with a baseline PLTs & lt;150 × 109/L versus the ITT populations from the two previously-completed global Phase 3 SIMPLIFY studies. A retrospective analysis of spleen, symptom and TI response rates at week 24 was conducted in the TCP and ITT groups from SIMPLIFY-1 (S1), a double-blind Phase 3 study in intermediate/high risk MF patients randomized 1:1 to MMB or RUX over a 24-week treatment period, and SIMPLIFY-2 (S2), a Phase 3 study comparing MMB to best available therapy (BAT) in previously RUX-exposed MF patients. A baseline PLTs ≥50 × 109/L was required in S1, while there was no lower PLT limit for S2. Most subjects randomized to BAT (88%) received RUX during the 24-week randomized period. In S1, 9.5% and 24% of 432 subjects randomized had a PLT count of & lt;100 and & lt;150 × 109/L, respectively, at baseline. At week 24, MMB demonstrated a consistent splenic response rate (SRR) of 23% in patients with baseline PLTs & lt;150 × 109/L and 27% in the ITT. A markedly reduced SRR was observed for the TCP group on RUX (4%) in comparison to the ITT (29%). Total symptom score (TSS) response rate was 28% in both the TCP and ITT in the MMB arm. In the RUX arm, the TSS response rate was lower in the TCP group (32%) than in the ITT (42%). MMB treatment elicited a TI response rate of 62% and 67% in the TCP and ITT groups, respectively, while for RUX the equivalent response rates were 43% and 49%. Of the 40 MMB subjects that discontinued therapy prior to week 24, 1 (2.5%) and 7 (17.5%) had a baseline PLTs & lt;100 and & lt;150 × 109/L, respectively. Of the 16 RUX subjects who discontinued therapy prior to week 24, 5 (31.4%) and 11 (69%) had baseline PLTs & lt;100 and & lt;150 × 109/L, respectively. In S2, 44% of 156 subjects randomized had a PLT count of & lt;100 and another 22% had PLTs 100-150 × 109/L at baseline. The TSS response with MMB was 24% for the TCP and 26% in the ITT. Notably, this TSS response rate was retained even in patients with PLTs & lt;100 × 109/L. Similarly, splenic and TI outcomes with MMB in the TCP were within 1-2% of the ITT response rates for these endpoints. Response rates in the control arm of S2 were low for both TCP and ITT (SRR 7 vs 6%, TSS 3 vs 6% and TI 22 vs 21%). These retrospective analyses of data from the two Phase 3 SIMPLIFY studies demonstrate that MMB efficacy is maintained in TCP patients and is comparable to that observed in the broader JAKi-naïve and previously JAKi-treated ITT populations in S1 and S2. These data contrast with RUX data from S1 where the SRR was markedly decreased and the TSS moderately decreased in TCP patients, consistent with reduced RUX dose intensity and higher rates of early discontinuation in this subset. Consequently, for patients in S1 with low PLTs, MMB and RUX demonstrated similar symptomatic benefit, while MMB had a more favorable profile for splenic volume reduction and TI. Response rates for the three parameters in the MMB arm of S2 were comparable between the TCP and ITT groups. Response rates in the control arm were low and not substantially different between the TCP and ITT groups, with most patients receiving very low dose intensity of RUX. Together, the findings of comparable spleen, symptom and TI response in the TCP and ITT groups treated with MMB suggest that the compound could become the optimal JAK inhibitor therapy for intermediate/high risk MF patients with underlying disease-related or prior RUX-induced thrombocytopenia. Disclosures Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Mayer:Principia Biopharma: Research Funding; AbbVie: Research Funding. Illés:Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nagy:MorphoSys AG: Patents & Royalties. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; YuhanPharma: Research Funding. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Verstovsek:Promedior: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding. Klencke:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Donahue:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Incyte: Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding.

Abstract: Not available.

Abstract: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors.

Abstract: Carfilzomib is a next-generation proteasome inhibitor with single-agent activity in patients with relapsed and refractory multiple myeloma (R/R MM). In PX-171-003-A1, a single-arm phase 2 study of carfilzomib monotherapy in heavily pretreated patients, the overall response rate was 23.7%, 37% of patients achieved ≥ minimal response and median overall survival (OS) was 15.6 months. Based on this study, carfilzomib was recently approved by the US Food and Drug Administration for the treatment of R/R MM. Herein we describe the trial design and rationale for a phase 3 randomized study, FOCUS (Car F ilz O mib for Advan C ed Refractory M U ltiple Myeloma European S tudy), being conducted to compare OS after treatment with single-agent carfilzomib to best supportive care (BSC) regimen in R/R MM. Methods Patients must have received ≥3 prior regimens, must be responsive to at least 1 line of therapy, and be refractory to their most recent therapy. Eligible patients are randomized 1:1 to receive either carfilzomib (28-day cycles at 20 mg/m 2 IV on Days 1–2 of Cycle 1, escalating to 27 mg/m 2 IV on Days 8, 9, 15, and 16 and continuing at 27 mg/m 2 through Cycle 9 and Days 1, 2, 15, and 16 ≥ Cycle 10) or an active BSC regimen (corticosteroid treatment of prednisolone 30 mg, dexamethasone 6 mg, or equivalent every other day with optional cyclophosphamide 50 mg PO once daily). Patients will continue treatment until disease progression, unacceptable toxicity, or treatment discontinuation and will then enter long-term follow-up for survival. The primary endpoint is OS and secondary endpoints include progression-free survival, overall response rate, and safety. Disease assessments will be determined according to the International Myeloma Working Group Uniform Response Criteria with minimal response per European Blood and Marrow Transplantation Group criteria. Conclusions This phase 3 trial will provide more rigorous data for carfilzomib, as this is the first carfilzomib study with OS as the primary endpoint and will not be confounded by crossover and will provide more robust secondary response and safety results that will add to the data set from prior phase 2 studies. FOCUS will facilitate regulatory approvals around the world and expand treatment options for patients with R/R MM. Trial registration EudraCT No. 2009-016840-38; NCT01302392.