Regorafenib in Patients With Metastatic Solid Tumors Who Have Progressed After Standard Therapy

NCT02307500 | Completed Phase 2

• 1 other identifier: ONC-2014-001
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single arm, single-stage, phase II trial to evaluate the activity of Regorafenib in patients with metastatic solid tumors (pancreatic cancer, ovarian cancer, melanoma, sarcoma, thymoma (type B2 - B3) and thymic carcinoma, who have progressed after standard therapy.

Conditions

Pancreas Cancer; Ovarian Cancer; Melanoma; Sarcoma; Thymoma Type B3; Thymoma Type B2; Thymic Carcinoma

Outcome Measures

Primary Outcomes (1)

• activity of regorafenib screening, in terms of 2-months progression free survival rate

  to evaluate activity of regorafenib, in terms of 2-months progression free survival rate

  2 months

Secondary Outcomes (3)

• prognosis in terms of progression-free survival

  36 months

• overall survival (OS)

  36 months

• safety profile of regorafenib according to NCI-CTC v.3

  3 months

Study Arms (1)

Regorafenib

EXPERIMENTAL

Regorafenib 160 mg (40 mg tablets), po, every day for 3 weeks of every 4 week cycle

Drug: Regorafenib

Interventions

Regorafenib DRUG

oral therapy

Also known as: Stivarga

Regorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• Patients older then 18 years.
• Locally advanced, recurrent or metastatic histologically confirmed malignancy refractory to available standard treatment, included Pancreatic cancer, Ovarian cancer, Melanoma, Sarcoma
• At least one measurable lesion according to Response Evaluation Criteria In solid tumor
• Eastern Cooperative Oncology Group Performance Status: 0-1
• Life expectancy of at least 12 weeks
• Adequate bone marrow, liver and renal function as assessed by the following laboratory : Hemoglobin \> 9.0 g/dl Absolute neutrophil count \> 1,500/mm3 Platelet count \> 100,000/μl White blood cells \>3.0 x 109/L Total bilirubin \<1.5 times the upper limit of normal Alanine amino transferase and aspartate amino transferase \<2.5 x upper limit of normal (\<5 x upper limit of normal for patients with liver involvement) Serum creatinine \<1.5 x upper limit of normal Alkaline phosphatase \<2.5 x Upper Limit of Normal Prothrombin time / Partial prothrombin time \<1.5 x Upper Limit of Normal Lipase ≤ 1.5 x the Upper Limit of Normal
• Able to swallow and retain oral medication.
• Estimated creatinine clearance \> 30ml/min as calculated using the Cockcroft-Gault equation
• Resolution of any toxic effects of prior therapy to NCI Common Terminology Criteria for Adverse Event, Version 4.0, grade ≤ 1 .
• Women of childbearing potential and men must agree to use adequate contraception

You may not qualify if:

• Prior treatment with regorafenib.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study drug
• Congestive heart failure \>New York Heart Association class 2
• Unstable angina), new-onset angina.Myocardial infarction less than 6 months before start of study drug
• Myocardial infarction less than 6 months before start of study drug.
• Cardiac arrhythmias requiring anti-arrhythmic therapy
• Uncontrolled hypertension.
• Pleural effusion or ascites that causes respiratory compromise
• Ongoing infection \> Grade 2
• Known history of human immunodeficiency virus infection.
• Active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy.
• Subjects with seizure disorder requiring medication.
• History of organ allograft. Subjects with evidence or history of any bleeding diathesis, irrespective of severity.
• Any hemorrhage or bleeding event \> Common Toxicity Criteria for Adverse Effects Grade 3
• Arterial or venous thrombotic or embolic events within the 6 months before start of study medication

Sponsors & Collaborators

• Istituto Clinico Humanitas: lead

Study Sites (1)

Istituto Clinico Humanitas

Rozzano, Milan, 20089, Italy

Location

Related Publications (29)

• Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, Thierauch KH, Zopf D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011 Jul 1;129(1):245-55. doi: 10.1002/ijc.25864. Epub 2011 Apr 22.

  PMID: 21170960 BACKGROUND

• Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000 Sep 14;407(6801):249-57. doi: 10.1038/35025220.

  PMID: 11001068 BACKGROUND

• Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9 Suppl 1:2-10. doi: 10.1634/theoncologist.9-suppl_1-2.

  PMID: 15178810 BACKGROUND

• Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature. 1995 Jul 6;376(6535):66-70. doi: 10.1038/376066a0.

  PMID: 7596436 BACKGROUND

• Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995 Jul 6;376(6535):62-6. doi: 10.1038/376062a0.

  PMID: 7596435 BACKGROUND

• Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R. Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007 Mar 1;13(5):1367-73. doi: 10.1158/1078-0432.CCR-06-2328.

  PMID: 17332278 BACKGROUND

• Amit L, Ben-Aharon I, Vidal L, Leibovici L, Stemmer S. The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors--a meta-analysis and systematic review. PLoS One. 2013;8(1):e51780. doi: 10.1371/journal.pone.0051780. Epub 2013 Jan 22.

  PMID: 23349675 BACKGROUND

• Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J. Vascular-specific growth factors and blood vessel formation. Nature. 2000 Sep 14;407(6801):242-8. doi: 10.1038/35025215.

  PMID: 11001067 BACKGROUND

• Acevedo VD, Ittmann M, Spencer DM. Paths of FGFR-driven tumorigenesis. Cell Cycle. 2009 Feb 15;8(4):580-8. doi: 10.4161/cc.8.4.7657. Epub 2009 Feb 18.

  PMID: 19182515 BACKGROUND

• Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003 May;111(9):1287-95. doi: 10.1172/JCI17929.

  PMID: 12727920 BACKGROUND

• Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009 Mar;10(3):165-77. doi: 10.1038/nrm2639.

  PMID: 19234476 BACKGROUND

• Huang J, Bae JO, Tsai JP, Kadenhe-Chiweshe A, Papa J, Lee A, Zeng S, Kornfeld ZN, Ullner P, Zaghloul N, Ioffe E, Nandor S, Burova E, Holash J, Thurston G, Rudge J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade. Int J Oncol. 2009 Jan;34(1):79-87.

  PMID: 19082480 BACKGROUND

• Bach F, Uddin FJ, Burke D. Angiopoietins in malignancy. Eur J Surg Oncol. 2007 Feb;33(1):7-15. doi: 10.1016/j.ejso.2006.07.015. Epub 2006 Sep 7.

  PMID: 16962282 BACKGROUND

• Saito M, Watanabe J, Fujisawa T, Kamata Y, Nishimura Y, Arai T, Miyamoto T, Obokata A, Kuramoto H. Angiopoietin-1, 2 and Tie2 expressions in endometrial adenocarcinoma--the Ang2 dominant balance up-regulates tumor angiogenesis in the presence of VEGF. Eur J Gynaecol Oncol. 2006;27(2):129-34.

  PMID: 16620053 BACKGROUND

• Szarvas T, Jager T, Totsch M, vom Dorp F, Kempkensteffen C, Kovalszky I, Romics I, Ergun S, Rubben H. Angiogenic switch of angiopietins-Tie2 system and its prognostic value in bladder cancer. Clin Cancer Res. 2008 Dec 15;14(24):8253-62. doi: 10.1158/1078-0432.CCR-08-0677.

  PMID: 19088043 BACKGROUND

• Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010 Feb;10(2):116-29. doi: 10.1038/nrc2780.

  PMID: 20094046 BACKGROUND

• Fletcher JA, Rubin BP. KIT mutations in GIST. Curr Opin Genet Dev. 2007 Feb;17(1):3-7. doi: 10.1016/j.gde.2006.12.010. Epub 2007 Jan 8.

  PMID: 17208434 BACKGROUND

• Lanzi C, Cassinelli G, Nicolini V, Zunino F. Targeting RET for thyroid cancer therapy. Biochem Pharmacol. 2009 Feb 1;77(3):297-309. doi: 10.1016/j.bcp.2008.10.033. Epub 2008 Nov 6.

  PMID: 19028457 BACKGROUND

• Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82-9. doi: 10.1016/0959-437x(94)90095-7.

  PMID: 8193545 BACKGROUND

• Herrera R, Sebolt-Leopold JS. Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention. Trends Mol Med. 2002;8(4 Suppl):S27-31. doi: 10.1016/s1471-4914(02)02307-9.

  PMID: 11927284 BACKGROUND

• Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002 Oct;2(10):795-803. doi: 10.1038/nrc909.

  PMID: 12360282 BACKGROUND

• Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell. 2002 Jun;1(5):413-5. doi: 10.1016/s1535-6108(02)00080-6.

  PMID: 12124170 BACKGROUND

• Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 2002 Mar 15;20(6):1692-703. doi: 10.1200/JCO.2002.20.6.1692.

  PMID: 11896121 BACKGROUND

• Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol. 2008 May;21 Suppl 2(Suppl 2):S37-43. doi: 10.1038/modpathol.2008.10.

  PMID: 18437172 BACKGROUND

• Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002 Aug 15;347(7):481-7. doi: 10.1056/NEJMoa020150.

  PMID: 12181402 BACKGROUND

• Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, Unger C, Kratzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. doi: 10.1158/1078-0432.CCR-11-1900. Epub 2012 Mar 15.

  PMID: 22421192 BACKGROUND

• Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

  PMID: 23177514 BACKGROUND

• Marrari A, Bertuzzi A, Bozzarelli S, Gennaro N, Giordano L, Quagliuolo V, De Sanctis R, Sala S, Balzarini L, Santoro A. Activity of regorafenib in advanced pretreated soft tissue sarcoma: Results of a single-center phase II study. Medicine (Baltimore). 2020 Jun 26;99(26):e20719. doi: 10.1097/MD.0000000000020719.

  PMID: 32590747 DERIVED

• Bozzarelli S, Rimassa L, Giordano L, Sala S, Tronconi MC, Pressiani T, Smiroldo V, Prete MG, Spaggiari P, Personeni N, Santoro A. Regorafenib in patients with refractory metastatic pancreatic cancer: a Phase II study (RESOUND). Future Oncol. 2019 Dec;15(35):4009-4017. doi: 10.2217/fon-2019-0480. Epub 2019 Nov 20.

  PMID: 31746632 DERIVED

MeSH Terms

Conditions

Pancreatic Neoplasms; Ovarian Neoplasms; Melanoma; Sarcoma; Thymoma

Interventions

regorafenib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Gonadal Disorders; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms, Complex and Mixed; Thymus Neoplasms; Thoracic Neoplasms; Lymphatic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Armando Santoro, MD

  Istituto Clinico Humanitas

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2014
• First Posted: December 4, 2014
• Study Start: December 1, 2014
• Primary Completion: December 1, 2017
• Study Completion: August 1, 2020
• Last Updated: September 10, 2022

Record last verified: 2022-09

Locations

IT (1)