Phase I study of sapanisertib (CB-228/TAK-228/MLN0128) in combination with ziv-aflibercept in patients with advanced solid tumors

Abstract

Background: Sapanisertib is a potent ATP-competitive, dual inhibitor of mTORC1/2. Ziv-aflibercept is a recombinant fusion protein comprising human VEGF receptor extracellular domains fused to human immunoglobulin G1. HIF-1α inhibition in combination with anti-angiogenic therapy is a promising anti-tumor strategy. This Phase 1 dose-escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv-aflibercept in advanced solid tumors.

Methods: Fifty-five patients with heavily pre-treated advanced metastatic solid tumors resistant or refractory to standard treatment received treatment on a range of dose levels.

Results: Fifty-five patients were enrolled and treated across a range of dose levels. Forty were female (73%), median age was 62 (range: 21-79), and ECOG PS was 0 (9, 16%) or 1 (46, 84%). Most common tumor types included ovarian (8), colorectal (8), sarcoma (8), breast (3), cervical (4), and endometrial (4). Median number of prior lines of therapy was 4 (range 2-11). Sapanisertib 4 mg orally 3 days on and 4 days off plus 3 mg/kg ziv-aflibercept IV every 2 weeks on a 28-day cycle was defined as the maximum tolerated dose. Most frequent treatment-related grade ≥2 adverse events included hypertension, fatigue, anorexia, hypertriglyceridemia, diarrhea, nausea, mucositis, and serum lipase increase. There were no grade 5 events. In patients with evaluable disease (n = 50), 37 patients (74%) achieved stable disease (SD) as best response, two patients (4%) achieved a confirmed partial response (PR); disease control rate (DCR) (CR + SD + PR) was 78%.

Conclusion: The combination of sapanisertib and ziv-aflibercept was generally tolerable and demonstrated anti-tumor activity in heavily pre-treated patients with advanced malignancies.

Trial registration: ClinicalTrials.gov NCT02159989resesese.

Keywords: VEGF; advanced/refractory cancer; mTOR; mTORC1/2; sapanisertib; targeted therapy.

FIGURE 1

Waterfall plot showing best overall response of evaluable patients on trial. Among 55 patients in the data set, 50 patients were response evaluable, of whom 5 had non‐measurable disease by RECIST v1.1 criteria. Two patients (4%) achieved confirmed partial response (PR), 37 had stable disease (SD) (74%) (including four patients with unconfirmed partial responses); 11 patients (22%) had progression of disease (PD) as best response. Five patients were NE for response. The five patients with non‐measurable, but evaluable disease and are denoted by *; two of these patients had clinical PD, and three of these patients achieved stable disease.

FIGURE 2

Waterfall plot showing best overall response of evaluable patients in the dose expansion cohort. Ten patients were treated in the dose expansion cohort; among nine evaluable patients, one patient achieved confirmed partial response, five patients had stable disease as best response and three patients had progression of disease (one with clinical progression of disease), arbitrarily assigned 20% increase from baseline measurements). *Patient with Li Fraumeni syndrome.