Phase 1b/2 study of olaratumab plus gemcitabine and docetaxel for the treatment of advanced soft tissue sarcoma (STS) (ANNOUNCE 2): Phase 1b results

Background: Olaratumab (O) is an antibody against plateletderived growth factor receptor alpha. In a randomized phase 2 study, O in combination with doxorubicin (dox) demonstrated a significant improvement of overall survival (OS) over dox alone in patients (pts) with advanced STS. Here we report the safety, tolerability and recommended phase 2 dose (RPTD) of O plus gemcitabine (G) and docetaxel (D) (O + G/D). Methods: This doseescalation study enrolled pts with advanced/metastatic STS, ≤2 prior lines of systemic therapy, no prior G, D or O, and ECOG PS 0-1. Pts received O on Days 1 and 8 at 15 mg/kg (cohort 1) or 20 mg/kg (cohort 2) with G (900 mg/m2 Days 1 and 8) and D (75 mg/m2 Day 8) on a 21-day cycle. The primary objective was to determine the RPTD of O + G/D, with a dose-limiting toxicity (DLT) occurring in Cycle 1 at a rate below 33%. Secondary objectives included safety and pharmacokinetics (PK). Results: 54 pts (cohort 1/2 = 21/33) received at least one dose of treatment. No DLT occurred in cohort 1. In cohort 2, 5 pts (15.2%) experienced 6 DLTs (ALT increase, bacteremia, neutropenia [2 pts], and thrombocytopenia [2pts]). Treatment-related adverse events (TRAEs) reported for cohorts 1 and 2 included all grades (90.5% and 93.9%), Gr 3 (14.3% and 42.4%), Gr 4 (0 and 18.2%), and serious AEs (9.5% and 15.2%), respectively. Common TRAEs (all grades, Gr ≥3) occurring in ≥ 25% of pts were fatigue (66.7%, 11.1%), anemia (61.1%, 18.5%), thrombocytopenia (35.2%, 18.5%), nausea (29.6%, 0%) and diarrhea (27.8%, 3.7%). 1 pt discontinued due to a studyrelated AE of fatigue (cohort 1). Following 2 deaths unrelated to study treatment, cohort 2 was expanded to 33 pts. The PK profile of O + G/D was similar to that of O in combination with other chemotherapies. Conclusions: Both dose levels were tolerated with a higher incidence for known toxicities of G/D in cohort 2. Based on safety and exposure-response analyses across O studies, the RPTD for O + G/D is 20 mg/kg at Days 1 and 8 in Cycle 1, followed by 15 mg/kg at Days 1 and 8 thereafter. The randomized, doubleblinded phase 2 part of the study is enrolling and will compare OS of pts with STS receiving G/D + O vs G/D + placebo (ANNOUNCE 2).