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Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

ABSTRACT: Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized.To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies.A database of all oncology clinical trials registered at clinicaltrials.gov between October 1, 2007, and September 30, 2010.Trials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST).A systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly.For each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type.From 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (??=?0.27, P?

SUBMITTER: Oxnard GR

PROVIDER: S-EPMC5574183 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

Oxnard Geoffrey R GR Wilcox Katharine H KH Gonen Mithat M Polotsky Mikhael M Hirsch Bradford R BR Schwartz Lawrence H LH

JAMA oncology 20160601 6

<h4>Importance</h4>Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized.<h4>Objective</h4>To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies.<h4>Data source</h4>A database of all oncology clinical trials re ...[more]

PMID: 26914340

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Project description:Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495.

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Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

Publications

Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

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