Alvarado, Yesid

Abstract The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

Abstract Background: Mcl-1 is an anti-apoptotic protein in the Bcl-2 family that contributes to the pathophysiology of certain B-cell malignancies and AML. Dependence on Mcl-1 is associated with poor prognosis, and increased Mcl-1 levels is a common mechanism of resistance to venetoclax. Voruciclib (VORU), a potent oral CDK9 inhibitor (Ki <10 nM), was shown to decrease Mcl-1 protein expression in preclinical models, supporting its evaluation as a single agent and in combination with venetoclax in AML and B-cell malignancies. In two dose escalation phase 1 studies of VORU in patients (pts) with solid tumors, the maximum tolerated dose (MTD) was established at 350 mg when administered daily continuously and 600 mg when administered on days 1 to 14 in a 21-day cycle. Based on concentrations needed for antitumoral activity in preclinical models, pharmacokinetic (PK) results predict a dose of ~200 mg could be sufficient for target inhibition. The present phase 1 study is the first to evaluate the MTD, recommended Phase 2 dose (RP2D), dose-limiting toxicities (DLT), safety, PK, and preliminary efficacy of VORU in pts with relapsed/refractory hematologic malignancies (NCT03547115). Methods: Pts with relapsed B-cell lymphoma, chronic lymphocytic leukemia (CLL), or AML were eligible if age ≥18 years, ECOG performance status ≤1, disease progression after failure of standard therapies, adequate hepatic and renal function, and no prior CDK9 therapy. Dose escalation started at 50 mg, followed a 3+3 design, and DLTs were assessed in Cycle 1. Initially VORU was administered once daily continuously in a 28-day cycle (Group I). After 2 DLTs were observed at 100 mg, administration was changed to once daily on days 1 to 14 in a 28-day cycle (Group II), patients with prior allogeneic transplant were excluded, and dose escalation (100, 150, 200 mg) proceeded in separate cohorts for AML and B-cell malignancies. Disease response was assessed by the Lugano, iwCLL, and 2017 ELN criteria. Results: To date 28 pts have been enrolled: 14 AML, 7 diffuse large B-cell lymphoma (DLBCL), 3 follicular lymphoma (FL), 2 CLL and 2 mantle cell lymphoma. Group I enrolled 16 pts, 8 each at 50 mg and 100 mg. Group II enrolled 12 pts, 10 with AML administered VORU at 100, 150 or 200 mg and 2 pts with B-cell malignancies administered VORU at 100 mg. Dose escalation in AML is completed. Median age was 71 years (range 40-90) and 54% of pts were male. Pts were generally heavily pretreated, with a median of 3 prior therapies (range 1-8). Median number of VORU cycles administered was 2 (range 1-4). Drug-related serious adverse events (SAEs) were reported in Group I only and consisted of 2 DLT of Gr 3 pneumonitis at 100 mg, both in AML pts treated with allogeneic transplant followed by GVHD in the preceding 12 months, one of whom also had a concurrent Gr 3 differentiation syndrome (DS), and 1 SAE not meeting DLT criteria, a Gr 3 hypoxemic respiratory failure in Cycle 4 in a pt with DLBCL at 50 mg. One AML pt developed ischemic bowel thought to be due to disease progression. Symptoms consistent with DS were observed in 4 AML pts. In Group II, no DLTs have been observed to date and there were no Gr 3-5 drug-related adverse events reported. There is no evidence of significant drug-related neutropenia in pts with B-cell malignancies. To date, in Groups I and II combined, 1 AML pt achieved a morphologic leukemia-free state, 2 AML pts achieved stable disease (SD), and 3 pts with B-cell malignancies had a best response of SD, including 1 FL pt who achieved a 42% reduction in SPD, and 1 CLL pt with relapsed disease after chemoimmunotherapy, venetoclax, and ibrutinib who had stable blood counts. Conclusions: VORU at doses up to 200 mg administered on 14 consecutive days in a 28-day cycle was well tolerated with no DLTs observed. Consistent with the phase 1 studies in solid tumors, no significant myelosuppression was seen in pts with B-cell malignancies. The safety profile does not indicate overlapping toxicities with venetoclax. Disease stabilization was observed in heavily pretreated pts and differentiation syndrome was observed in AML indicating biologic activity. Enrollment at 200 mg will continue in an expansion cohort in AML. A forthcoming protocol amendment will evaluate VORU in combination with venetoclax in pts with relapsed AML to exploit the dual inhibition of Bcl-2 and Mcl-1. Disclosures Konopleva: Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. Brander: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Genentech: Consultancy, Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; TG Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding; LOXO: Research Funding; AstraZeneca: Research Funding; MEI Pharma: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Verastem: Consultancy; Novartis: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy. Patel: TG Therapeutics: Consultancy, Speakers Bureau; Curis, Inc: Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Juno Pharmaceuticals: Consultancy; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; MEI Pharma: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy; Abbvie: Consultancy; Aptevo Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; Velos Bio: Research Funding; Millenium/Takeda: Research Funding. Diefenbach: Celgene: Research Funding; Trillium: Research Funding; IMab: Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Gilead: Current equity holder in publicly-traded company; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; IGM Biosciences: Research Funding; MEI: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding. Al Malki: Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Abedin: Pfizer: Research Funding; Amgen: Honoraria; Helsinn: Research Funding; Astellas Pharma Inc.: Research Funding; Agios: Honoraria; Actinium: Research Funding; AltruBio: Research Funding. Ghalie: MEI Pharma: Current Employment, Current equity holder in publicly-traded company. Davids: Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. OffLabel Disclosure: Vorucicilb is an investigational CDK inhibitor being evaluated in patients with hematologic malignancies, specifically relapsed AML and B-cell malignancies. The abstract submitted to ASH 2021 reports the results of the completed dose escalation portion of a phase 1 study.

Abstract Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: 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; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.

AbstractTrabectedin is an FDA‐approved DNA minor groove binder that has activity against translocation‐associated sarcomas. Lurbinectedin is a next‐generation minor groove binder with preclinical activity against myeloid leukemia cells. A dose‐finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Forty‐two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1‐hour intravenous infusion in a 3 + 3 study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose‐limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary toxicity (n = 2), and renal failure (n = 2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and 2 patients a morphologic leukemia‐free state. Most (n = 30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease‐related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21‐23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single‐agent lurbinectedin was transiently leukemia suppressive for some patients.