ETCTN/NCI 10330: A phase 2 study of belinostat with SGI-110 (guadecitabine) or ASTX727 (decitabine/cedazuridine) for the treatment of unresectable and metastatic conventional chondrosarcoma.

Authors

null

Kristine Peregrino Lacuna

Columbia University Irving Medical Center, New York, NY

Kristine Peregrino Lacuna , Shing M Lee , Liner Ge , Mihaela Druta , Anthony Paul Conley , Mary Louise Keohan , Mark Agulnik , Melissa Amber Burgess , Anna Weinberg Chalmers , Gina Z. D'Amato , Benjamin Powers , Mahesh Seetharam , Brittany L Siontis , Mia C. Weiss , Sminu (Sam) Bose , Tahir Sheikh , Richard Piekarz , Gary K. Schwartz , Matthew Ingham

Organizations

Columbia University Irving Medical Center, New York, NY, Columbia University - Mailman School of Public Health, New York, NY, Department of Sarcoma, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, University of Texas MD Anderson Cancer Center, Houston, TX, Memorial Sloan Kettering Cancer Center, New York, NY, City of Hope Comprehensive Cancer Center, Duarte, CA, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA, Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, University of Kansas Medical Center, Kansas City, KS, Mayo Clinic Arizona, Scottsdale, AZ, Mayo Clinic, Rochester, MN, Washington University School of Medicine, St. Louis, MO, Cancer Therapy Evaluation Program - National Cancer Institute, Bethesda, MD

Research Funding

U.S. National Institutes of Health
U.S. National Institutes of Health

Background: Conventional chondrosarcoma (cCS) is the 2nd most common primary bone tumor and is resistant to chemotherapy and radiation. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type (wt) cCS harbor epigenetic dysregulation. In preclinical models of IDHm and wt cCS, combination treatment with HDAC and DNMT inhibitors (i) suppressed growth in vitro and in vivo by reversing the hypermethylated state and inducing tumor suppressors, interferon response genes and apoptosis (Sheikh T, Schwartz G. Mol Cancer Ther 2021;20). Methods: NCI 10330 is a single-arm, multicenter, phase 2 study evaluating the HDACi belinostat (B) with the DNMTi SGI-110 (S) or ASTX727 (A). A replaced S due to drug availability (pts were replaced). Pts had advanced cCS, ECOG PS ≤ 2 and could be treatment naïve. Progression was required for grade 1 cCS. Pts received B 1000mg/m2 IV + S 45mg/m2 SC both days 1-5 or B (same dosing) + A (cedazuridine 100mg/decitabine 35mg) PO both days 1-5, in 28-day cycles. 1° endpoint was objective response. A Simon 2-stage design was used. If ≥ 2/13 responses occurred in stage 1, the study would proceed to full accrual. Design had 85% power with α = 0.05 to test ORR 8% vs 28%. 2° endpoints included safety, PFS and OS. A safety lead-in was performed. Paired biopsies were collected. Results: Stage 1 is complete. 19 pts were treated: 6 on B+S and 13 on B+A. Median age was 50 and 67 years, respectively. All pts had prior surgery. 17% (B+S) and 38% (B+A) had prior radiation. 33% (B+S) and 55% (B+A) were IDHm. 67% (B+S) and 75% (B+A) were histologic grade ≥ 2. There were no objective responses. Best response (at 8 weeks) was stable disease (SD) in 4/6 pts (67%) on B+S and 6/10 pts (60%) on B+A. mPFS was 4.2 mos (95% CI 1.97-NR) for B+S and 3.8 mos (95% CI 2.17-NR) for B+A. mOS has not been reached. For B+A, mPFS for IDHm vs wt pts was 4.7 and 3.1 mos, respectively (p=0.21). One pt with IDHm grade 2 cCS who progressed on FT-2102 (IDH1i) remains on B+A > 1 year. There were no DLTs during either safety lead-in. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 17% (B+S) and 69% (B+A). For B+A, the most common grade 3/4 TRAE was neutropenia (54%) and the most common all-grade TRAEs were nausea (69%), leukopenia (61%), neutropenia (54%), anemia (46%) and fatigue (46%). Paired tumor biopsies are being evaluated with whole exome sequencing, RNAseq, methylation array and multiplex IHC with results forthcoming. Conclusions: Combination HDACi + DNMTi was well-tolerated in advanced cCS. There were no objective responses; however, a subset of pts experienced prolonged SD with a trend towards improved mPFS in IDHm pts. Correlative work is ongoing with a focus on differential effects on IDHm tumors and whether modulation of the immune microenvironment might support combinations with immunotherapy. Support: UM1CA186689. Clinical trial information: NCT04340843.

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Abstract Details

Meeting

2023 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Sarcoma

Track

Sarcoma

Sub Track

Bone Tumors

Clinical Trial Registration Number

NCT04340843

Citation

J Clin Oncol 41, 2023 (suppl 16; abstr 11531)

DOI

10.1200/JCO.2023.41.16_suppl.11531

Abstract #

11531

Poster Bd #

465

Abstract Disclosures