A First in Class, Open-Label, First-in-Human, Phase I Trial of Daily Oral Pclx-001

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. In vitro, cell lines of hematologic cancer origin were exquisitely sensitive to PCLX-001. PCLX-001 regressed subcutaneous tumors in murine xenograft models derived from lymphoma cell lines, 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.

Methods and Results:

We are accruing to a multicenter, open-label, phase I dose-escalation study of daily oral PCLX-001 comprised of two parts (dose escalation and dose expansion). Eligible patients 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. Dose escalation has proceeded through 20 mg, 40 mg, 70 mg and 100 mg with each cohort achieving dose proportional pharmacokinetics without dose limiting toxicity. Three patients have been treated at each dose level of 20 mg, 40 mg, and 70 mg and five patients were treated in the 100 mg cohort. To date no dose limiting toxicities, neutropenia, or other safety signals have been observed. Noncompartmental pharmacokinetic analyses demonstrate an apparent terminal half-life of 8.5+/- 3h, rapid achievement of steady state and no PCLX-001 accumulation or induction of metabolism. PCLX-001 trough plasma concentrations at the higher dose cohorts exceed the EC₉₀ required to inhibit cultured hematologic cells. Dose expansion in twenty patients with relapsed/refractory B-cell lymphoma will follow identification of the PCLX-001 maximally tolerated dose.

Conclusions:

Our results support the ongoing development of PCLX-001 as an oral, daily anticancer therapy. Updated study results will be presented, summarizing the safety and efficacy outcomes in PCLX-001 treated patients.

Sangha:Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck: 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; 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; Sanofi: 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; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche/Genentech: 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; Eli-Lilly: 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. Sehn:AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Debiopharm, Genmab, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Novartis, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Consultancy; Teva, Roche/Genentech: Consultancy, Honoraria, Research Funding; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Honoraria; Chugai: Consultancy, Honoraria. Kuruvilla:Abbvie: Consultancy, Honoraria; Astra Zeneca: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Other: DSMB; Merck: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Antengene: Consultancy; Medison Ventures: Consultancy; Seattle Genetics: Consultancy, Honoraria; Inctye: Honoraria; Pfizer: Honoraria; Lymphoma Canada: Membership on an entity's Board of Directors or advisory committees. Weickert:Pacylex Pharmaceuticals, Inc.: Current Employment. Berthiaume:Pacylex Pharmaceuticals, Inc.: Current equity holder in private company. Mackey:Pacylex Pharmaceuticals, Inc.: Current equity holder in private company.