PMH-001: A first-in-human phase I study of the novel microtubule disruptor CCI-001 in patients with advanced cancer.

e15167 Background: CCI-001 is a thiocolchicine derivative, ßIII tubulin-selective microtubule disruptor being studied in the first in human PMH-001 Phase I trial as monotherapy (dose-escalation, -expansion) and in combination with carboplatin and gemcitabine. Methods: PMH-001 Part 1 was an open-label, single agent dose-escalation study. Objectives were to determine the recommended Phase II dose (RPIID) of IV CCI-001 (primary) and to assess CCI-001 safety, PK profile, and clinical response rate (secondary). Metastatic solid tumour patients were dosed on days (D) D1, 8 and 15 of each 28-day cycle (C) until progression or unacceptable toxicity. PK sampling was on C1D1 and 15, and pre-dose C2D1 to evaluate Cmax, Tmax, AUC and T 1/2 . Dose-escalation was a 3+3 design. Toxicity was evaluated with CTCAE v5.0 criteria, and efficacy by CT imaging (baseline, every 8 weeks) using RECIST 1.1. Results: Part 1 had 6 dose levels: 1.2 mg/m 2 (5 pts), 2.4 mg/m 2 (3 pts), 4.8 mg/m 2 (6 pts), 6.0 mg/m 2 (6 pts), 7.5 mg/m 2 (6 pts), and 6.75 mg/m 2 (6 pts). Of 32 pts (14 male, 18 female) treated, 25 were evaluable for safety, 20 for PK and 23 for response. Of 305 TRAEs, 10 (3.3%) were ≥ Gr 3, with those occurring in ≥ 5% of pts being neutropenia (4 pts). There were 3 DLTs: Gr 3, Gr 4 neutropenia at 4.8, 6 mg/m 2 (related) and 1 death at 7.5 mg/m 2 (cardiac, unrelated). Twelve pts (38%) had a dose interruption, 4 pts (13%) had dose reduction, and 1 pt (3.1%) was discontinued (unrelated TEAE). Two pts (6.2%) withdrew (personal decision; toxicity). The MTD of 7.5 mg/m 2 was due to fatigue (non-DLT, intolerable Gr 2), and RPIID was assigned at 6.75mg/m 2 . Of response-evaluable pts, the overall response rate (ORR) was 1 of 23 or 4.3% (partial response, squamous cell carcinoma of the lung, 7.5 mg/m 2 , who previously failed paclitaxel). Twelve pts (52.2%) showed stable disease (SD) as Best Overall Response (BOR). Median number of weeks on trial (n = 23) was 8.0 (range 8 to 40 weeks), with 6 pts on therapy for ≥ 6 cycles (months). Median progression-free survival (PFS) was 8.0 weeks (n = 18 after censoring). One patient (6.75 mg/m 2 , lung cancer) went off trial at C10 D15 ( > 2 dose reductions), but was still on treatment at C12D1 at 4.8 mg/m 2 . CCI-001 AUCinf and Cmax increased in a dose-dependent manner, with no accumulation between C1D1 and C1D15. No CCI-001 was detected pre-dose C2D1. At 6.75 mg/m 2 , CCI-001 mean C1D1 AUCinf, Cmax and T 1/2 were, respectively, 2080 h*ng/mL, 643 ng/mL and 8.6 h (n = 2). Cl obs and VD obs were, respectively, 6.2 L/h and 77 L. Conclusions: The RPIID of single agent CCI-001 is 6.75 mg/m 2 . CCI-001 was well tolerated at all dose levels tested, with AEs typical for a drug of this class. Peripheral neuropathy was rare (3 Gr 1 AEs, 2 related). The early safety and response data suggest a role for CCI-001 in combination with other anticancer drugs. Clinical trial information: NCT04823897 .