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Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1? in advanced solid tumors.

ABSTRACT: PURPOSE:Hypoxia-inducible factor 1 (HIF-1) ? is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1? expression in preclinical models. We designed a pilot trial to measure HIF-1? inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1?, after treatment with oral topotecan. EXPERIMENTAL DESIGN:Topotecan was administered orally at 1.6 mg/m(2) once daily for 5 days/week for 2 weeks, in 28-day cycles. Objectives were to determine inhibition of expression of HIF-1? and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment. RESULTS:Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m(2)/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1? nuclear staining became undetectable after treatment (7.5%-50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1? in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1? in tumor and reduction in tumor blood flow on DCE-MRI. CONCLUSIONS:This multihistology, target assessment trial of a small molecule inhibitor of HIF-1? showed that topotecan could decrease HIF-1? expression in advanced solid tumors.

SUBMITTER: Kummar S

PROVIDER: S-EPMC3149769 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors.

Kummar Shivaani S Raffeld Mark M Juwara Lamin L Horneffer Yvonne Y Strassberger Agnes A Allen Deborah D Steinberg Seth M SM Rapisarda Annamaria A Spencer Shawn D SD Figg William D WD Chen Xiaohong X Turkbey Ismail Baris IB Choyke Peter P Murgo Anthony J AJ Doroshow James H JH Melillo Giovanni G

Clinical cancer research : an official journal of the American Association for Cancer Research 20110614 15

<h4>Purpose</h4>Hypoxia-inducible factor 1 (HIF-1) α is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1α expression in preclinical models. We designed a pilot trial to measure HIF-1α inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF-1α, after treatment with oral topotecan.<h4>Experimental design</h4>Topotecan was administered orally at 1.6 mg ...[more]

PMID: 21673063

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Project description:Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

Dataset Information

Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1? in advanced solid tumors.

Publications

Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors.

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