A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer

• Published in: British journal of cancer 2023-01, Vol.128 (1), p.30-41
• Main Authors: Curigliano, Giuseppe, Shapiro, Geoffrey I., Kristeleit, Rebecca S., Abdul Razak, Albiruni R., Leong, Stephen, Alsina, Maria, Giordano, Antonio, Gelmon, Karen A., Stringer-Reasor, Erica, Vaishampayan, Ulka N., Middleton, Mark, Olszanski, Anthony J., Rugo, Hope S., Kern, Kenneth A., Pathan, Nuzhat, Perea, Rachelle, Pierce, Kristen J., Mutka, Sarah C., Wainberg, Zev A.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 692/4028/67/1059/153; 692/4028/67/1347; Antineoplastic Agents - adverse effects; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cisplatin; Cisplatin - adverse effects; Drug Resistance; Epidemiology; Humans; Malignancy; Molecular Medicine; Morpholines - therapeutic use; Mucositis; Oncology; Patients; Phosphoinositide-3 Kinase Inhibitors; Solid tumors; TOR protein; Triazines; Triple Negative Breast Neoplasms - drug therapy; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-022-02025-9

Background This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours. Methods Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m 2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion. Results Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis ( n  = 3). Based upon reprioritisation of the sponsor’s portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients ( N  = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2–73.8%]) and four of 12 in second/third-line (33.3% [9.9–65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response. Conclusions Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC. Clinical trial ClinicalTrial.gov: NCT01920061.