1526MO - GEMMK: A phase I study of gemcitabine (gem) and pembrolizumab (pem) in patients (pts) with leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma UPS)

Background

Patients with advanced LMS and UPS have poor outcomes. Single agent immunotherapy (IO) results have been disappointing, whereas IO-cytotoxic combinations may improve outcomes. Gem-induced apoptosis may generate a more favourable immune microenvironment, providing rationale for the evaluation of gem in combination with a checkpoint inhibitor. The aim of this phase I trial (NCT03123276) was to determine the safety and maximum tolerated dose (MTD) of gem + pem.

Methods

Gem + pem were administered Day 1, gem Day 8 (6-8 cycles), followed by single agent pem 200mg Day 1 (to a max of 2 years) IV Q3weeks (wks) for pts with advanced LMS or UPS using a 3+3 design with 3 gem doses (800, 1000, 1200 mg/m²). Pre- and on treatment biopsies were mandated. The primary endpoint was safety (CTCAE v4.0) and secondary endpoints: radiological response (RECIST v1.1) at 9 wks and median progression-free survival (mPFS).

Results

Thirteen pts (2 UPS, 11 LMS) were enrolled. The median age was 51 yrs (range 40-67), 77% female, median of 1 (range 1-4) previous treatments. There was one dose-limiting toxicities (DLTs) observed at gem 1000, but not confirmed in the expanded cohort. The MTD of gem was not reached, recommended gem dose was 1200mg/m². Detailed safety data will be presented. There were 16 SAE's, fever (n=10/16) was the most frequent. Common adverse events were neutropenia (n=11/13 pts; G3 n=2/13, G4 n=4/13), rash (n=10/13), fatigue (n=9/13), hypothyroidism (n=7/13), diarrhoea (n=7/13), nausea (n=6/13), fever (n=5/13). At 9 wks, 92% of pts (95%CI 57-99) were progression free. mPFS was 5.1m (95% CI 2-9); 11/13 pts had progressed at a median follow up of 5.1m. Best response at 9wks for LMS pts was SD (n=8/11) and PD (n=3/11); UPS PR (n=2/2). Most patients (n=10/13) discontinued due to PD, 2 remain on study (1 each on 1000 and 1200mg/m²) and 1 patient withdrew consent. Translational work is ongoing.

Conclusions

Gem-pem is safe and efficacy continues to be evaluated in the expansion cohort. A MTD dose expansion cohort is fully enrolled and follow-up is ongoing.

Clinical trial identification

NCT03123276.

Editorial acknowledgement

Legal entity responsible for the study

The Royal Marsden NHS Foundation Trust.

Funding

Merck, Sharp & Dohme Corp.

Disclosure

N. Fotiadis: Other, Personal, Other, Consultation Fee: Johnson and Johnson; Other, Personal, Other, Consultation Fees: Boston Scientific; Other, Personal, Funding: Replimune. R.L. Jones: Other, Personal, Research Grant: MSD; Other, Personal, Research Grant: GSK; Other, Personal, Other, Consultation Fees: Adaptimmune, Athenex, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, UptoDate. All other authors have declared no conflicts of interest.