Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (DEP CTX) in patients with advanced solid cancers in a phase 1/2 trial (P1/2).

Abstract

3004 Background: DEP CTX is a highly optimized dendrimer nanoparticle formulation of cabazitaxel that achieves sustained cytotoxic drug delivery to tumors via enhanced permeability & retention effects. Unlike standard cabazitaxel (s-CTX), DEP CTX is highly water soluble, does not contain toxic excipients associated with anaphylaxis & does not require steroid/antihistamine premedication. We report the final P2 efficacy and safety results in patients (pts) with advanced/metastatic solid tumors. Methods: Pts were treated with DEP CTX at 20 mg/m2 cabazitaxel, IV 3-weekly. Efficacy was assessed by RECIST v1.1, Prostate Cancer Working Group 3 (PCWG3) guidelines or serum tumor markers; evaluable pts had relevant criteria at baseline and a follow-up assessment per protocol window. Safety was assessed by CTCAE v4.03. (EudraCT 2017-003424-76). Results: In P2, 75 pts were enrolled, prioritizing metastatic castration-resistant prostate cancer (mCRPC, s-CTX’s only approved indication), esophagogastric (EG) & ovarian (OV) cancers. For all pts, median progression free survival (mPFS) and overall survival (mOS) were 3.8 and 9.0 mths, respectively. Objective response rate (ORR) was 20% in 45 evaluable pts. All 25mCRPC pts were heavily pre-treated with a median of 4 prior lines of anticancer treatment. mPFS was 4.4 mths (radiographic or prostate specific antigen [PSA]); mOS was 14.7 mths. The disease control rate (DCR) was 70.6%; ORR was 16.7%. PSA reduced in 90% pts (by > 50% in 52.4%); 87% with bone metastases had no progression or improved. Of 15 EG pts, 9 were adenocarcinoma (ADENO) (3 gastric, 2 esophageal & 4 EG junction) & 6 were esophageal squamous cell carcinoma (SCC). For all EG pts, mPFS was 4.0 mths, mOS was 8.6 mths. mPFS was 4.0/1.9 mths for ADENO/SCC, respectively. Overall, DCR was 80%; ORR 30%. DCR was 100%/50% and the ORR was 33%/25% for ADENO/SCC, respectively. Of 22 OV pts, 96% were platinum resistant (Pt-R), with a median of 4 prior lines of anticancer treatment, including 59% with ≥ 3 platinum lines. mPFS/mOS were 3.1 mths & not reached, respectively. DCR was 66.7%; ORR 17.6%. Treatment related adverse events (TRAEs) were mostly mild/moderate (grade (G) 1/2; 64%/25%). Only 21% of pts had G 3/4 non-hematological TRAEs, while G3/4 lab detected neutropenia was seen in only 23% of pts despite no routine G-CSF. TRAEs observed in ≥10% of pts included fatigue, neutropenia, anemia, thrombocytopenia, diarrhea, nausea, vomiting, peripheral neuropathy and decreased appetite. Conclusions: DEP CTX exhibited clinically meaningful, durable antitumor activity in multiple advanced solid cancers, including mCRPC, Pt-R OV and EG cancers without the need for steroid premedication. The antitumor activity & safety results compare favorably to s-CTX, or standard of care chemotherapy in non-prostate cancers, and highlight the promising potential of dendrimer-enhanced delivery of cabazitaxel. Clinical trial information: 2017-003424-76 .