Abstract
A randomized phase II study of MLN0128 (M) versus pazopanib (P) in patients (pt) with advanced sarcoma (Alliance A091304)
Journal of clinical oncology, Vol.38(15_suppl), pp.11562-11562
05/20/2020
DOI: 10.1200/JCO.2020.38.15_suppl.11562
Abstract
11562
Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .
Details
- Title: Subtitle
- A randomized phase II study of MLN0128 (M) versus pazopanib (P) in patients (pt) with advanced sarcoma (Alliance A091304)
- Creators
- Matthew Ingham - Columbia University Irving Medical CenterMichelle R. Mahoney - Mayo ClinicFabrizio Remotti - Columbia University Irving Medical CenterArdaman Shergill - University of Illinois at ChicagoMark Andrew Dickson - Memorial Sloan Kettering Cancer CenterRichard F. Riedel - Duke Medical CenterSteven Attia - Mayo Clinic in FloridaAnthony D. Elias - University of Colorado Cancer CenterDavid A. Liebner - The Ohio State UniversityMark Agulnik - Northwestern UniversityKatherine Anne Thornton - Sidney Kimmel Comprehensive Cancer CenterVarun Monga - University of IowaBrian Andrew Van Tine - Washington University in St. LouisGary K. Schwartz - Columbia UniversityWilliam D. Tap - Memorial Sloan Kettering Cancer Center
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.38(15_suppl), pp.11562-11562
- DOI
- 10.1200/JCO.2020.38.15_suppl.11562
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Grant note
- DOI: 10.13039/100000002, name: U.S. National Institutes of Health
- Language
- English
- Date published
- 05/20/2020
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984363459602771
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