Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

Abstract

BACKGROUND:

This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.

METHODS:

Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients).

RESULTS:

Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers.

CONCLUSIONS:

Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.

CLINICAL TRIAL REGISTRATION:

ClinicalTrials.gov, NCT01058707.

• Authors: Martin H Voss, Michael S Gordon, Monica Mita, Brian Rini, Vicky Makker, Teresa Macarulla, David C Smith, Andrés Cervantes, Igor Puzanov, Roberto Pili, Ding Wang, Shadia Jalal, Shubham Pant, Manish R Patel, Rachel L Neuwirth, Aaron Enke, Yaping Shou, Farhad Sedarati, Douglas V Faller, Howard A Burris 3rd
• Journal: British journal of cancer (Br J Cancer) Vol. 123 Issue 11 Pg. 1590-1598 (11 2020) ISSN: 1532-1827 [Electronic] England
• PMID: 32913286 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• MTOR protein, human
• TOR Serine-Threonine Kinases
• sapanisertib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Carcinoma, Renal Cell (drug therapy)
• Endometrial Neoplasms (drug therapy)
• Female
• Humans
• Kidney Neoplasms (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrazoles (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Urinary Bladder Neoplasms (drug therapy)