Trial in Progress: Phase 1b Bridging Study of the Pharmacokinetics (PK), Safety, and Efficacy of Orally Administered Olverembatinib (HQP1351) in Patients with Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph⁺ ALL)
Bibliographic record
Abstract
Abstract Background: Management of CML using tyrosine kinase inhibitors (TKIs) is often constrained by treatment failure, which portends a poor prognosis, particularly among patients who fail second-generation TKIs because of resistance. Treatment failure may be due to therapeutic resistance (whether BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, and compound mutations complicate management with all members of the class (including third-generation TKI ponatinib). Olverembatinib (HQP1351) is a novel, potent, orally active BCR-ABL1 TKI with promising activity against CML, including antitumor activity regardless of genotype, and a preliminarily favorable safety profile. Methods: This open-label bridging trial is evaluating the PK, efficacy, and safety of olverembatinib administered orally every other day (QOD) in adults who have chronic-phase, accelerated-phase, or blast-phase CML (CP-CML, AP-CML, or BP-CML) and Ph⁺ ALL, with or without the T315I mutation, and have experienced resistance to or intolerance (including NCI CTCAE v5.0 grade ≥ 2 adverse events) of at least 3 TKIs. Eligible patients have no residual grade ≥ 2 adverse events (other than alopecia or skin pigmentation change) due to prior treatments, a maximum ECOG performance status of 2, and a minimum life expectancy of 3 months. Study participants are being randomly allocated in a 1:1:1 ratio to 3 dose cohorts: 30, 40, or 50 mg of oral olverembatinib QOD over a cycle length of 28 days, with 10 patients per cohort and randomization stratified according to CML phase (CP-CML, AP-CML, or BP-CML) or Ph⁺ ALL and T315I mutational status. Study endpoints comprise the PK profile of olverembatinib at Cycle 1 Day 1 and Day 27; efficacy endpoints of major cytogenetic and hematologic responses; and safety. The recommended phase 2 dose of olverembatinib will be determined based on a comprehensive assessment of PK, safety, and efficacy data in US and Chinese patients. As of July 14, 2021, 14 of 30 patients have been enrolled. Internal study identifier HQP1351-CU-101. Clinicaltrial.gov identifier: NCT04260022. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; NOVA Research: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Mukherjee: Genentech: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Partnership for Health Analytic Research: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; BioPharm: Consultancy; AAMDS in Joint Partnership with Cleveland Clinic Taussig Cancer Institute: Honoraria; Eusa Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Teaching and Speaking; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; McGraw Hill: Honoraria, Other: Editor of Hematology Oncology Board Review (ongoing); Bristol-Myers Squibb Co.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research/Independent Contractor, Research Funding; Jazz Pharmaceuticals: Research Funding. Oehler: OncLive: Honoraria; Pfizer: Research Funding; Takeda: Consultancy; BMS: Consultancy. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Lu: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Fu: Ascentage Pharma Group Inc: Current Employment, Current equity holder in publicly-traded company. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.005 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".