A first in human, dose escalation trial of MSC2363318A – a dual p70S6K/Akt inhibitor, for patients with advanced malignancies

Abstract

Background: The PI3K/Akt/PTEN pathway regulates cellular functions including growth, proliferation and metabolism. Aberrant pathway signaling (PTEN loss of function, PIK3CA mutation, Akt amplification, etc.) occurs in >50% of all tumors, and pathway inhibition is used for the treatment of solid tumors and hematopoietic malignancies. Whereas mTOR inhibition activates a negative feedback loop, leading to Akt activation, dual p70S6K/Akt inhibition may improve pathway inhibition whilst blocking negative consequences of Akt activation via the feedback loop. MSC2363318A is a brain penetrant, kinase-selective, ATP competitive inhibitor of p70S6K, Akt1, and Akt3. MSC2363318A exhibits potent anti-proliferative activity in vitro, particularly in tumor cells with PI3K pathway genomic alterations, and antitumor activity in vivo, in xenograft models of breast, pancreatic and ovarian cancers, and glioblastoma. Trial design and current results: This is a standard 3 + 3 dose escalation study of single-agent MSC2363318A given orally daily in 21-day cycles. Eligible patients must have confirmed diagnosis of advanced malignancy with high prevalence of PI3K/Akt/ PTEN pathway genomic or molecular alterations. The primary objective is to determine maximum tolerated dose, identify dose limiting toxicities (DLTs) and establish a recommended phase 2 dose. Secondary objectives include characterization of pharmacodynamic and pharmacokinetic (PK) properties, and evaluation of predictive biomarkers for safety and efficacy. Observed antitumor activity in the dose escalation part will guide the selection of tumor specific cohorts for the expansion phase. Fifteen patients were treated at 5 dose levels ranging from 15-110 mg/day. To date, 1 DLT (G3 lipase increase) has been observed in 1 of 6 patients treated at the 60mg dose. Nine patients have discontinued treatment due to disease progression (n = 7), death (n = 1), or toxicity (n = 1). Best clinical response to date is stable disease (SD) lasting 6-36+ wks (n = 6). Longest SDs are 36+ wks (adenocystic carcinoma of the salivary gland) and 27 wks (recurrent small cell lung cancer). Updated safety, efficacy and biomarker data, individual examples of on target effects in tumor biopsies from the escalation phase, and preliminary PK data will be presented.