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1954 Updated Analyses of a Phase 1b/2 Study of Onvansertib, a PLK1 Inhibitor, in Combination with Decitabine in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
AML, Biological, Diseases, Therapies, enzyme inhibitors, Myeloid Malignancies, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Amer M. Zeidan, MBBS, MHS1, Tara Lin, MD2, Pamela S. Becker, MD, PhD3, Gary J. Schiller, MD4, Prapti Patel, MD5, Alexander I. Spira, PhD, MD, FACP6*, Michaela L. Tsai, MD7*, Errin Samuëlsz8*, Sandra L Silberman, MD, PhD9, Maya Ridinger8*, Mark Erlander, PhD8* and Eunice S. Wang, MD10

1Yale University and Yale Cancer Center, New Haven, CT
2University of Kansas Medical Center, Westwood, KS
3University of Washington Inst. for Stem Cell and Regenerative Med., Seattle, WA
4David Geffen School of Medicine at University of California, Los Angeles, CA
5University of Texas Southwestern Medical Center, Dallas, TX
6Virginia Cancer Specialists, Fairfax, VA
7Minnesota Oncology, Minneapolis, MN
8Cardiff Oncology, San Diego, CA
9SLS Oncology LLC, Durham, NC
10Roswell Park Comprehensive Cancer Center, BUFFALO, NY

Background: The polo-like kinase 1 (PLK1) is a serine/threonine kinase master regulator of the cell cycle, overexpressed in acute myeloid leukemia (AML) blasts. Onvansertib is an oral, highly selective next-generation PLK1 inhibitor that demonstrated anti-tumor activity in AML preclinical models, including venetoclax-resistant models. Here we report updated results of an ongoing Phase 1b/2 (Ph1b/2) study of onvansertib in combination with decitabine in patients with relapsed or refractory (R/R) AML (NCT03303339).

Methods: R/R AML patients were treated for 5 days with onvansertib (orally) and decitabine (20 mg/m2 IV qd x 5d) within a 21 to 28-day cycle. The Ph1b was a dose-escalation of onvansertib, assessing first-cycle dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and preliminary efficacy of the combination. The ongoing Ph2 is exploring the safety, PK and efficacy at the MTD. For correlative studies, blood samples were collected before and 3hr post-treatment to evaluate engagement of a PLK1 target in circulating blasts. Target engagement was defined as a ≥50% decrease in the phosphorylation of the translationally controlled tumor protein (pTCTP) in patients with at least 10% circulating blasts. Mutational profiling was performed at baseline using targeted next-generation sequencing to identify driver mutations. Plasma-derived circulating tumor DNA (ctDNA) was serially monitored by digital droplet PCR to assess changes in mutant allele frequency (MAF) and correlation with clinical response.

Results: As of 22July2020, 23 patients were treated with onvansertib (12 - 90 mg/m2) and decitabine in the Ph1b and 25 patients with onvansertib 60 mg/m2 + decitabine in the Ph2. In the Ph1b, treatment was well tolerated through the first 5 dose-levels (12-60 mg/m2). Two of the 6 patients treated at 90 mg/m2 experienced a DLT (grade 4 rash and grade 3 mucositis) and the MTD was established at 60 mg/m2. To-date, most frequent grade 3-5 adverse events were hematologic (neutropenia, thrombocytopenia, leukopenia), febrile neutropenia and at higher doses rash and stomatitis were noted. Five deaths occurred on the trial but none were attributed to treatment. At data cutoff, 36 (75%) patients had at least 1 bone marrow biopsy (19 in Ph1b, 17 in Ph2), and 8 (22%) patients achieved a complete remission with or without hematologic count recovery (CR/CRi, 5 in the Ph1b and 3 in the Ph2), with median time to achieve CR/CRi of 66 days. Two Two patients proceeded to transplant following CR and 4 patients remain on treatment with duration of response of 9, 10, 17 and 20 months, respectively. Five responders had received 1 prior line of treatment (anthracycline-based induction) and 2 were treatment naïve for AML but had received azacitidine for myelodysplastic syndrome. By performing baseline genomic profiling, we observed that that 8 (80%) of the 10 patients with mutations in the splicing factors SRSF2 or SF3B1 had an objective response (4 CR, 1 CRi, 1 morphological leukemia free-state and 2 partial responses). Serial monitoring of ctDNA showed that patients achieving CR/CRi had a greater decrease in MAF during the first cycle than non-responders, regardless of the time at which clinical response was documented. Additionally, target engagement in circulating blasts was observed in a subset of patients, and was associated with a greater decrease in bone marrow blasts reflecting a better clinical response.

Conclusion: The combination of onvansertib and decitabine is well tolerated and continues to demonstrate encouraging anti-leukemic activity, particularly in patients with spliceosome mutations, evidence of target engagement and decreased mutant ctDNA levels following treatment. Updated safety, efficacy, and biomarker analyses will be presented.

Disclosures: Zeidan: Abbvie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Astex: Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Novartis: Consultancy, Honoraria, Research Funding. Lin: Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Abbvie: Research Funding; Aptevo: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Seattle Genetics: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding; Genetech-Roche: Research Funding. Becker: Cardiff Oncology: Research Funding; SecuraBio: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; JW Pharmaceutical: Research Funding; Pfizer: Research Funding; Accordant Health Services/Caremark: Membership on an entity's Board of Directors or advisory committees; Invivoscribe: Research Funding. Schiller: Astellas Pharma: Honoraria, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Celgene: Research Funding, Speakers Bureau; Ono Pharma: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Celator: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Constellation: Research Funding; Mateon: Research Funding; Kaiser Permanente: Consultancy; Tolero: Research Funding; Trovagene: Research Funding; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Stemline: Speakers Bureau; Actinium: Research Funding; Abbvie: Research Funding; Ariad: Research Funding; FujiFilm: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Kite Pharma: Research Funding; Karyopharm: Research Funding; Jazz Pharmaceuticals: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Gamida: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding. Patel: DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Spira: Cardiff Oncology: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Merck: Consultancy; BMS: Consultancy; Incyte: Consultancy; Janssen: Consultancy; ADCT: Research Funding. Samuëlsz: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company. Silberman: Cardiff Oncology: Consultancy, Current equity holder in publicly-traded company. Ridinger: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company. Erlander: Cardiff Oncology: Current Employment, Current equity holder in publicly-traded company. Wang: Macrogenics: Consultancy; PTC Therapeutics: Consultancy; Astellas: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy.

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