Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma

Abstract

Purpose: SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort.

Patients and methods: This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS.

Results: Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation.

Conclusion: The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

Trial registration: ClinicalTrials.gov NCT02048371.

Conflict of interest statement

Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Lara E. Davis

Consulting or Advisory Role: Immune Design, Loxo, Epizyme

Christopher W. Ryan

Consulting or Advisory Role: Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer

Research Funding: Argos Therapeutics (Inst), Bristol-Myers Squibb (Inst), CytRx (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Exelixis (Inst), Genentech (Inst), GlaxoSmithKline/Novartis (Inst), Janssen (Inst), Karyopharm Therapeutics (Inst), MabVax (Inst), Merck (Inst), Morphotek (Inst), Threshold Pharmaceuticals (Inst), TRACON Pharma (Inst), Pfizer (Inst)

Kristen N. Ganjoo

Consulting or Advisory Role: Daiichi Sankyo, Novartis, Immune Design, Janssen, Eli Lilly

Elizabeth T. Loggers

Research Funding: Daiichi Sankyo (Inst), Epizyme (Inst), Bayer HealthCare Pharmaceuticals (Inst)

Sant Chawla

Honoraria: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research Through Collaboration, Janssen

Consulting or Advisory Role: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research Through Collaboration, Janssen,

Speakers’ Bureau: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research Through Collaboration, Janssen

Research Funding: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research Through Collaboration, Janssen

Mark Agulnik

Consulting or Advisory Role: Novartis, Eli Lilly, Immune Design, Bayer HealthCare Pharmaceuticals

Speakers’ Bureau: Janssen, Eisai, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals

Damon Reed

Consulting or Advisory Role: Loxo, Shire, Epizyme

Vicky Keedy

Consulting or Advisory Role: Karyopharm Therapeutics

Research Funding: Medpacto (Inst), Plexxikon (Inst), Roche (Inst), Daiichi Sankyo (Inst), Eli Lilly (Inst), BioMed Valley Discoveries (Inst), Immune Design (Inst), GlaxoSmithKline (Inst), TRACON Pharma (Inst), Advenchen Laboratories (Inst)

Daniel Rushing

Honoraria: Bayer HealthCare Pharmaceuticals, Eisai, Eli Lilly

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals, Eisai, Eli Lilly

Denise K. Reinke

Research Funding: Sarcoma Alliance for Research Through Collaboration (Inst)

Richard F. Riedel

Employment: Biotech Prosthetic Orthotics of North Carolina (I), Limbguard (I)

Leadership: Biotech Prosthetic Orthotics of North Carolina (I), Limbguard (I)

Stock and Other Ownership Interests: Biotech Prosthetic Orthotics of North Carolina (I), Limbguard (I)

Consulting or Advisory Role: GlaxoSmithKline, Novartis, Merck, Eli Lilly, Eisai, Daiichi Sankyo, Loxo, Ignyta, Bayer HealthCare Pharmaceuticals, NanoCarrier

Research Funding: Novartis (Inst), Eisai (Inst), TRACON Pharma (Inst), Threshold Pharmaceuticals (Inst), Bayer HealthCare Pharmaceuticals (Inst), Agios (Inst), Karyopharm Therapeutics (Inst), Immune Design (Inst), Merck (Inst), AADi (Inst), Plexxikon (Inst), Arog (Inst), Eli Lilly (Inst), Daiichi Sankyo (Inst), Astex Pharmaceuticals (Inst), Ignyta (Inst), Roche/Genentech (Inst), NanoCarrier (Inst)

Patents, Royalties, Other Intellectual Property: PandoNet/Limbguard (I)

Travel, Accommodations, Expenses: Janssen, EMD Serono, Daiichi Sankyo, Ignyta, NanoCarrier

Steven Attia

Research Funding: AB Science (Inst), TRACON Pharma (Inst), CytRx (Inst), Bayer HealthCare Pharmaceuticals (Inst), Novartis (Inst), Daiichi Sankyo (Inst), Eli Lilly (Inst), Immune Design (Inst), Karyopharm Therapeutics (Inst), Epizyme (Inst), Blueprint Medicines (Inst), Genmab (Inst), CBA Pharma (Inst), Desmoid Tumor Research Foundation, Merck (Inst), Philogen (Inst), Gradalis (Inst), Deciphera (Inst), Takeda Pharmaceuticals (Inst), Incyte (Inst), Springworks (Inst), Adaptimmune (Inst), Advenchen Laboratories (Inst), Bavarian Nordic (Inst), BTG (Inst)

Travel, Accommodations, Expenses: Immune Design

Leo Mascarenhas

Honoraria: Bayer HealthCare Pharmaceuticals

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals, Eli Lilly (Inst)

Speakers’ Bureau: Bayer HealthCare Pharmaceuticals

Research Funding: AstraZeneca/MedImmune (Inst)

Travel, Accommodations, Expenses: Bayer HealthCare Pharmaceuticals, AstraZeneca/MedImmune, Eli Lilly

Robert G. Maki

Honoraria: Eli Lilly, Springer, Wiley

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals, Eli Lilly/ImClone, Sarcoma Alliance for Research Through Collaboration, AADi, Karyopharm Therapeutics, Arcus Ventures, American Board of Internal Medicine, Deciphera, Foundation Medicine, Janssen Scientific Affairs, TRACON Pharma

Research Funding: TRACON Pharma (Inst), Eli Lilly (Inst), Regeneron (Inst), Immunocore (Inst), Daiichi Sankyo (Inst), Presage Biosciences (Inst), Xencor (Inst), Pfizer (Inst), FORMA Therapeutics (Inst), Deciphera (Inst), AbbVie (Inst)

Patents, Royalties, Other Intellectual Property: UpToDate: I write and edit chapters for their online text book; Springer and Wiley: books for contributions I have made to the published texts

Travel, Accommodations, Expenses: TRACON Pharma, Bayer HealthCare Pharmaceuticals

No other potential conflicts of interest were reported.

Figures

FIG 1.

SARC024 study schema. Imaging occurred every 8 weeks for the first 32 weeks and then every 12 weeks.

FIG 2.

CONSORT diagram. (*) Physician decision (n = 1), second cancer (n = 1), noncompliance (n = 1), and alternate therapy (n = 2). (†) Physician decision (n = 1) and financial reason (n = 1).

FIG 3.

Kaplan-Meier estimates for (A) progression free survival (PFS), (B) overall survival (OS), and (C) OS after crossover from placebo to regorafenib. HR, hazard ratio.