Efficacy and Safety of TRC105 Plus Pazopanib vs Pazopanib Alone for Treatment of Patients With Advanced Angiosarcoma: A Randomized Clinical Trial

Abstract

Importance: Angiosarcoma is a rare sarcoma subtype with a poor outcome. Carotuximab plus pazopanib produced a median progression-free survival (PFS) of 7.8 months in pazopanib-naive patients with chemotherapy-refractory angiosarcoma in a phase 1/2 trial.

Objective: To determine whether carotuximab plus pazopanib improves PFS compared with pazopanib alone in patients with advanced angiosarcoma.

Design, setting, and participants: The TAPPAS Trial: An Adaptive Enrichment Phase 3 Trial of TRC105 and Pazopanib vs Pazopanib Alone in Patients With Advanced Angiosarcoma was a multinational, multicenter, open-label, parallel-group, phase 3 randomized clinical trial of 123 patients 18 years or older with advanced angiosarcoma that was conducted between February 16, 2017, and April 12, 2019, at 31 sites in the US and the European Union. Patients were randomized 1:1 to receive pazopanib alone or carotuximab plus pazopanib. The trial incorporated an adaptive enrichment design. Inclusion criteria were no more than 2 prior lines of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. The efficacy analysis used the intent-to-treat population; the safety analysis included all patients who received a dose of either study drug.

Exposures: Oral pazopanib, 800 mg/d, or intravenous carotuximab, 10 mg/kg, administered weekly, plus oral pazopanib, 800 mg/d, with dose modification allowed per patient tolerance or until disease progression.

Main outcomes and measures: The primary end point was PFS, assessed by blinded independent radiographic and cutaneous photographic review per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, version 1.1. Secondary end points included the objective response rate and overall survival. An interim analysis to determine the final sample size was conducted after enrollment of 123 patients. PFS in the group receiving pazopanib alone was compared with PFS in the group receiving carotuximab plus pazopanib using the log rank test.

Results: Of 114 patients with evaluable data (53 in the pazopanib arm and 61 in the carotuximab plus pazopanib arm), 69 (61%) were female and the median age was 68 years (range, 24-82 years); 57 (50%) had cutaneous disease and 32 (28%) had had no prior treatment. The primary end point (PFS) was not reached (hazard ratio [HR], 0.98; 95% CI, 0.52-1.84; P = .95), with a median of 4.3 months (95% CI, 2.9 months to not reached) for pazopanib and 4.2 months (95% CI, 2.8-8.3 months) for the combination arm. The most common all-grade adverse events in the single-agent pazopanib arm vs the combination arm were fatigue (29 patients [55%] vs 37 [61%]), headache (12 patients [23%] vs 39 [64%]), diarrhea (27 patients [51%] vs 35 [57%]), nausea (26 patients [49%] vs 29 [48%]), vomiting (12 patients [23%] vs 23 [38%]), anemia (5 patients [9%] vs 27 [44%]), epistaxis (2 patients [4%] vs 34 [56%]), and hypertension (29 patients [55%] vs 22 [36%]).

Conclusions and relevance: In this phase 3 randomized clinical trial, carotuximab plus pazopanib did not improve PFS compared with pazopanib alone in patients with advanced angiosarcoma.

Trial registration: ClinicalTrials.gov Identifier: NCT02979899.

Conflict of interest statement

Conflict of Interest Disclosures: Prof Jones reported receiving grants from TRACON Pharmaceuticals to conduct the trial and personal fees from Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii Sankyo, Deciphera, Immune Design, Lilly, Merck, PharmaMar, SpringWorks, TRACON Pharmaceuticals, and UpToDate outside the submitted work; in addition, Prof Jones had a patent pending for Biomarker. Dr Brohl reported receiving personal fees from Bayer, EMD Serono, and Deciphera outside the submitted work. Dr Chawla reported receiving grants or contracts from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharmaceuticals, Karyopharm Therapeutics, Sarcoma Alliance for Research Through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, and NKMAX; personal fees from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharmaceuticals, Karyopharm Therapeutics, SARC, Janssen, Advenchen Laboratories, Bayer, NKMAX, and Inhibrx; payment or honoraria from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharmaceuticals, Karyopharm Therapeutics, SARC, Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMAX, and Tyme; and stock or stock options from AADi, Cellestia Biotech, and Immix BioPharma outside the submitted work. Dr Italiano reported receiving personal fees from Bayer, Merck, Roche, and SpringWorks; grants from Merck Sharp & Dohm, Merck, Roche, AstraZeneca, and Bristol Myers Squibb; and nonfinancial support from Birdie Pharmaceuticals and Epizyme outside the submitted work. Dr Attia reported receiving grants from TRACON Pharmaceuticals Research funding to institution only to pay for conduct of study to conduct the trial and grants from AB Science, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint, Genmab, CBA Pharma, the Desmoid Tumor Research Foundation, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, SpringWorks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG Research, PTC Therapeutics, GlaxoSmithKline, and Forma Therapeutics outside the submitted work. Dr Burgess reported receiving grants from Merck outside the submitted work. Dr Cranmer reported receiving grants from TRACON Pharmaceuticals to conduct the trial as well as grants from Eli Lilly, AADi, Blueprint Medicines, Iterion, Gradalis, Philogen, Advenchen Laboratories, and CBA Pharma and personal fees from Blueprint Medicines, Daiichi Sankyo, and Regeneron outside the submitted work. Dr Cheang reported receiving royalties for the Breast Cancer Bioclassifier patent. Ms Robertson reported being an employee of TRACON Pharmaceuticals during the conduct of the study. Ms Adams reported receiving personal fees from and being an employee of TRACON Pharmaceuticals during the conduct of the study and receiving personal fees from TRACON Pharmaceuticals outside the submitted work. Dr Theuer reported being an employee of TRACON Pharmaceuticals during the conduct of the study. Dr Maki reported receiving grants and personal fees from TRACON Pharmaceuticals during the conduct of the study and receiving grants from Bayer, SpringWorks, Genentech, and Presage; personal fees from Deciphera, AADi, Karyopharm, Physicians’ Education Resource, SpringWorks, the American Board of Internal Medicine, the American Association for Cancer Research, and the American Society of Clinical Oncology; and royalties from UpToDate, Springer, and Wiley outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Reasons for not beginning treatment or withdrawal from the trial were not captured in the case report form, but most cases were owing to patient decision. The primary end point (progression-free survival) was analyzed in the intent-to-treat population, which represented all randomized patients as of the data cutoff for the interim analysis. aA total of 53 patients were included in the safety analysis. bA total of 61 patients were included in the safety analysis.

Figure 2.. Kaplan-Meier Plot of Progression-Free Survival by Blinded Independent Radiographic Review

Dotted blue lines represent median progression-free survival. HR indicates hazard ratio.

Figure 3.. Kaplan-Meier Plot of Overall Survival

Dotted blue lines represent median overall survival. HR indicates hazard ratio.