An Open-Label, First-in-Human, Phase I Trial of Daily Pclx-001
Bibliographic record
Abstract
Abstract Background: Myristoylation regulates numerous membrane-bound signal transduction pathways important in cancer biology. This modification is catalyzed by N-myristoyltransferases 1 and 2 (NMT1 and NMT2). PCLX-001 is an oral small molecule with high affinity for both NMT proteins (IC50 of 5nM and 8nM, respectively) with high bioavailability and drug-like pharmacokinetic properties. In ex vivo sensitivity screening cell lines of hematologic cancer origin were exquisitely sensitive to PCLX-001, although high sensitivities and cell killing were also seen in some solid tumor lines derived from lung, pancreas, breast, colon, and bladder carcinomas. PCLX-001 demonstrated strong preclinical single-agent antitumor activity and tolerability in vivo in subcutaneous tumor xenograft models derived from lymphoma cell lines, lung cancer cell lines, a breast cancer cell line, as well as in a patient derived xenograft model from a patient with refractory DLBCL. The primary objective of this study is to determine the MTD and/or recommended phase II dose, safety, tolerability, and pharmacokinetics of PCLX-001 as a single agent, in patients with refractory lymphomas and advanced solid tumors. The secondary objective of the study is to evaluate the preliminary single agent anti-tumor activity of PCLX-001 in the patient populations studied. Methods: We are now accruing to a multicenter, open-label, phase I dose-escalation study of oral PCLX-001 comprised of two parts (dose escalation and dose expansion). Eligible patients will have: histologically-confirmed advanced solid tumor or B-cell lymphomas who have failed prior therapy and/or are not eligible for therapies; ages ≥ 18 years; adequate organ function; life expectancy of at least 12 weeks; and measurable disease. Part A (dose-escalation) patients will be accrued in cohorts of 3 to 6 patients to each dose level, starting at 20 mg daily on a 28 day cycle. Dose escalation will follow a modified Fibonacci design such that the magnitude of escalation decreases as the dose level nears the human equivalent dose of the highest non-severely toxic dose in dogs and then escalate at 1.4 times the previous dose. Dose escalation and determination of the maximum tolerated dose will be based on the occurrence of dose limiting toxicities in cycle 1. Part B will have two single agent expansion cohorts (n = 20 each) in advanced solid malignancies and relapsed/refractory B-cell lymphoma, to determine the preliminary clinical activity of PCLX-001 to determine the recommended phase II dose. Results: Updated study results will be presented, summarizing the outcomes in the preliminary dose cohorts. Disclosures Sangha: Pfizer: Honoraria; Boehringer-Ingelheim: 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; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mackey: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company. Sehn: Debiopharm: Consultancy; Genmab: Consultancy; Novartis: Consultancy. Kuruvilla: AbbVie: Honoraria; Amgen: Honoraria; Medison Ventures: Honoraria; Seattle Genetics: Honoraria; Incyte: Honoraria; Antengene: Honoraria; TG Therapeutics: Honoraria; Pfizer: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Merck: Honoraria; BMS: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board. Weickert: Pacylex Pharmaceuticals, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Berthiaume: Pacylex Pharmaceuticals, Inc.: Current holder of individual stocks in a privately-held company.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.006 | 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".