Phase I Study of Sapanisertib (CB-228/Tak-228/MLN0128) in Combination With Ziv-Aflibercept in Patients With Advanced Solid Tumors

Authors

Niamh Coleman
Bettzy Stephen
Siqing Fu
Daniel Karp
Vivek Subbiah
Jordi Rodon Ahnert
Sarina A Piha-Paul
John Wright
Senait N Fessahaye
Fengying Ouyang
Bulent Yilmaz
Funda Meric-Bernstam
Aung Naing

Publication Date

2-1-2024

Journal

Cancer Medicine

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.

Keywords

Humans, Female, Middle Aged, Male, Treatment Outcome, Neoplasms, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Antineoplastic Combined Chemotherapy Protocols, Adenine, Benzoxazoles, advanced/refractory cancer, mTOR, mTORC1/2, sapanisertib, targeted therapy, VEGF

Comments

Supplementary Materials

Data Availability Statement

PMID: 38400671