Background: Stabilized mutant p53
protein (mutp53) is a novel target in
epithelial ovarian cancer. Due to aberrant conformation, mutp53
proteins depend on folding support by the Hsp90 chaperone. Hsp90 blockade induces degradation of mutp53, resulting in
tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor
ganetespib combined with
paclitaxel provided the rationale for testing the combination in
platinum-resistant
ovarian cancer (PROC) patients in the GANNET53 trial (NCT02012192). Methods: Eligible patients had high-grade PROC with ≤ 4 prior lines of
chemotherapy. Weekly
paclitaxel (80 mg/m2) and increasing doses of
ganetespib (100, 150 mg/m2) were given i.v. on days 1, 8, 15 in a 28 days cycle until
disease progression or unacceptable toxicity. Endpoints were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity (with exceptions) occurring in cycles 1&2. Results: Ten patients (median age 59 years; range 43-70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with
paclitaxel +
ganetespib 100 mg/m2), nor in cohorts 2 and 3 (6 patients treated with
paclitaxel +
ganetespib 150 mg/m2). The most common adverse event (AE) related to
ganetespib was transient grade 1/2
diarrhea (n = 6). Related grade 1/2 AEs in >2 patients included QTc prolongation (n = 4),
nausea (n = 3),
anemia (n = 3),
headache (n = 3),
fatigue (n = 3), and dyspnoea (n = 3). Most frequently related grade 3/4 AEs were
diarrhea (n = 3) and
neutropenia (n = 2). There was 1 death on study due to
hemorrhage from a
duodenal ulcer. Three patients discontinued study treatment due to serious AEs (digestive
hemorrhage n = 1,
cardiac failure n = 1,
abdominal pain and
vomiting n = 1), 6 due to progressive disease, one due to investigator and patient decision. Two patients achieved a partial response (ORR 20%) and 4 patients a stable disease (disease control rate of 60%). Median PFS was 2.9 months (1.6 months in cohort 1 at 100 mg/m2
ganetespib, 5.1 months in cohorts 2+3 at 150 mg/m2
ganetespib). Conclusions: The combination of
ganetespib 150 mg/m2 with
paclitaxel 80 mg/m2 once weekly for 3 out of 4 weeks was generally well-tolerated with no DLTs, and therefore chosen for the randomized phase II trial.