A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors

A Multi-indication, Single-treatment Arm, Open-label Phase 2 Study of Regorafenib and Nivolumab in Combination in Patients With Recurrent or Metastatic Solid Tumors

Researchers are looking for a better way to treat people with solid tumors. Before a treatment can be approved for people to take, researchers do clinical trials to better understand its safety and how it works.

In this trial, the researchers want to learn about regorafenib taken together with nivolumab in a small number of participants with different types of tumors. These include tumors in the head and neck, the esophagus, the pancreas, the brain, and the biliary tract. The biliary tract includes gall bladder and bile ducts.

The trial will include about 200 participants who are at least 18 years old. All of the participants will take 90 mg of regorafenib as a tablet by mouth. The dose of regorafenib can be adjusted up to 120 mg or down to 60 mg by the doctor based on how well a participant tolerates treatment. All of the participants will receive 480 milligrams (mg) of nivolumab through a needle put into a vein (IV infusion).

The participants will take treatments in 4-week periods called cycles. They will take regorafenib once a day for 3 weeks, then stop for 1 week. In each cycle, the participants will receive nivolumab one time. These 4-week cycles will be repeated throughout the trial. The participants can take nivolumab and regorafenib until their cancer gets worse, until they have medical problems, or until they leave the trial. The longest nivolumab can be given is up to 2 years.

During the trial, the doctors will take pictures of the participants' tumors using CT or MRI and will take blood and urine samples. The doctors will also do physical examinations and check the participants' heart health using an electrocardiogram (ECG). They will ask questions about how the participants are feeling and if they have any medical problems.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Regorafenib, (Stivarga, BAY73-4506); Drug: Nivolumab (Opdivo)

• Study Type: Interventional
• Enrollment (Actual): 175
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1070
    • Hôpital Erasme/Erasmus Ziekenhuis
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Liege, Belgium, 4000
    • CHU de Liege
• France
  • Bordeaux Cedex, France, 33076
    • Institut Bergonie - Unicancer Nouvelle Aquitaine
  • Lyon, France, 69008
    • UNICANCER - Centre Leon Berard (CLB)
  • Paris, France, 75651
    • Aphp-Hopital La Pitie Salpetriere
  • Saint-Herblain, France, 44800
    • Institut de Cancerologie Ouest - Saint-Herblain
  • Toulouse Cedex 9, France, 31059
    • Institut Claudius Regaud - IUCT Oncopole
  • Villejuif Cedex, France, 94805
    • Gustave Roussy - Departement Oncologie-Radiotherapie
• Italy
  • Milan, Italy, 20162
    • ASST Grande Ospedale Metropolitano Niguarda - Oncologia Falck
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40139
      • AUSL di Bologna_Istituto delle Scienze Neurologiche - UO Oncologia del Sistema Nervoso
  • Lombardia
    • Milano, Lombardia, Italy, 20133
      • IRCCS Foundation Istituto Neurologico Carlo Besta
    • Rozzano, Lombardia, Italy, 20089
      • Humanitas Mirasole S.p.A. - Oncologia Medica ed Ematologia
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Istituto Oncologico Veneto_Padova - UOC Oncologia 1
• Japan
  • Aichi
    • Nagoya, Aichi, Japan, 464-8681
      • Aichi Cancer Center Hospital
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0017
      • Kobe University Hospital
  • Saitama
    • Kitaadachi-gun, Saitama, Japan, 362-0806
      • Saitama Cancer Center
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
    • Koto-ku, Tokyo, Japan, 135-8550
      • The Cancer Institute Hospital of JFCR
• Korea, Republic of
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 03722
      • Severance Hospital, Yonsei University Health System
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 3080
      • Seoul National University Hospital
• Taiwan
  • Taichung, Taiwan, 404327
    • China Medical University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Tainan
    • Taikang, Tainan, Taiwan, 71004
      • Chi Mei Medical Center
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust | The Royal Marden Hospital - The Royal Marsden Clinical Trials Unit (CTU)
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden NHS Trust (Surrey)
  • West Midlands
    • Coventry, West Midlands, United Kingdom, CV2 2DX
      • University Hospitals Coventry and Warwickshire NHS Trust
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope - Duarte Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers / Aurora, CO
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Cancer Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Charles A. Sammons Cancer Center at Dallas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed selected recurrent or metastatic solid tumor types that have progressed after treatment with standard therapies and for which there are no curative intent surgery or chemoradiation.
• Cohort 1: subjects with HNSCC (Head and neck squamous-cell carcinoma) who have not received prior PD-1/PD-L1 inhibitor therapy.
• Cohort 2: subjects with HNSCC who have progressed on or after prior systemic therapy, at least one of which included a PD-1/PD-L1 inhibitor alone or in combination with chemotherapy.
• Cohort 3: subjects with ESCC (Esophageal Squamous Cell Carcinoma) who progressed on or after platinum and/or fluoropyrimidine based regimen.
• Cohort 4: subjects with PDAC (Pancreatic ductal adenocarcinoma) who have progressed on or after gemcitabine or fluoropyrimidine based regimens.
• Cohort 5: subjects with BTC (Biliary tract carcinoma) (intrahepatic or extrahepatic cholangiocarcinoma or gall bladder cancer) who have progressed on gemcitabine or fluoropyrimidine or platinum therapy or a combination of these agents.
• Cohort 6: subjects with Grade IV GBM (Glioblastoma multiforme) or Grade III AA (Anaplastic astrocytoma) (World Health Organization [WHO] criteria) with unequivocal first progression after surgery followed by radiotherapy and temozolomide.
• Documented HPV (Human papilloma virus) / p16 status for oropharyngeal cancer.
• Capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
• Adult participants of legal maturity (18 years or older).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1.

• Adequate hematologic and organ function as assessed by the following laboratory tests performed within 7 d before start of study treatment including:

  • Total bilirubin ≤1.5 x the upper limit of normal (ULN). Total bilirubin (≤3 x ULN) is allowed if Gilbert's syndrome is documented
  • Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤3 x ULN (≤5 x ULN for participants with liver involvement of their cancer)
• Measurable disease by baseline CT or MRI per RECIST 1.1 or RANO.
• Participants must consent to provide recent biopsy/tumor tissue of a primary tumor lesion or from metastases (e.g. liver, lung) for HNSCC (IO treated) for Stage 1 and 2 and in HNSCC (IO naïve) cohort for Stage 2.
• Anticipated life expectancy greater than 3 months.
• Be able to swallow and absorb oral tablets.

Exclusion Criteria:

• Presence of symptomatic central nervous system (CNS) metastases, leptomeningeal metastases or spinal cord compression. Previously-treated lesions should be stable for at least 6 weeks prior to study entry.
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment.
• Prior therapy with PD-1/PD-L1 or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form of immunotherapy to treat cancer (except cohort 2).
• Cohort 2: More than one prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any other form of immunotherapy to treat cancer.

• ESCC:

  • patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., the aorta or respiratory tract).
  • patients who have previously received taxane agents for recurrent/metastatic cancer.

• GBM/AA

  • Primary tumors localized to the brainstem or spinal cord.
  • Presence of diffuse leptomeningeal disease or extracranial disease.
  • Participants requiring > 4 mg of dexamethasone or biologic equivalent per day to control symptoms related to brain tumor and cerebral edema within 21 days of starting study treatment.
• Participants who have known dMMR/MSI-H cancers or NTRK (tropomyosin receptor kinase) fusions.
• Prior therapy with regorafenib.
• Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment.
• Participants who have permanent discontinuation of PD-1/PD-L1 therapy due to toxicity.
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study treatment. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen as per investigator's judgement.

• History of cardiac disorders as defined by:

  • Congestive heart failure ≥ New York Heart Association (NYHA) class 2:
  • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug.
  • Uncontrolled cardiac arrhythmias.
• Poorly controlled hypertension, defined as a blood pressure consistently above 140/90 mmHg despite optimal medical management.
• Participants with an active, known or suspected autoimmune disease.
• History of (non-infectious) pneumonitis that required steroids, current pneumonitis or interstitial lung disease.
• Active infection > NCI-CTCAE Grade 2.
• Positive test (from historical data or tested during screening) for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating presence of virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive (except for participants on anti-viral therapy for HBV with a viral load < 100 IU/mL), or Hepatitis C antibody (anti-HCV) positive (except if HCV-ribonucleic acid [RNA] negative).
• Pregnancy or breast feeding.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial or interfere with the participation for the full duration of the trial.
• Participants with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regorafenib+Nivolumab; Parallel-cohort in adult participants with selected recurrent or metastatic tumors (HNSCC, ESCC, PDAC, BTC, and GBM/AA) who have been previously treated with one or more systemic therapy for the selected tumor indication.	Drug: Regorafenib, (Stivarga, BAY73-4506); Intake orally, starting with 3x 30 mg tablets every day (once daily.) for 21 days of every 28-day cycle (21 days on, 7 days off). If the starting dose is well tolerated dose can be escalated to 120 mg (4x30 mg tablets).; Drug: Nivolumab (Opdivo); 480 mg administered on Day 1 of each treatment cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Tumor response was evaluated as ORR per RECIST 1.1 by local assessments for all tumor types, except for GBM/AA, where ORR per RANO by local assessment was used. ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR). Participants for whom best overall tumor response was not CR or PR, as well as participants without any post-baseline tumor assessment were considered non-responders. Descriptive statistics were done, no inferential statistical analyses were performed.	From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	Defined as the time (in days) from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented). DOR will be defined for responders only, i.e. participants with a CR or PR.	From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
Disease Control Rate (DCR)	CR = Complete response; PR = Partial response; SD = Stable disease	From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
Progression Free Survival (PFS)	PFS was defined as the time (in days) from the start of study intervention to the date of first objectively documented progressive disease (PD) or death from any cause (if no progression was documented).	From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
6 Months PFS	6 Months PFS rate	Up to last participant follow 6 months (approximately 22 months)
Overall Survival (OS)	OS was defined as the time (in days) from the start of study intervention to the date of death due to any cause.	From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
1 Year OS		From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 month]
Number of Participants With Adverse Events	AEs were considered to be treatment-emergent (TEAEs) if they started or worsened after the start of first study drug administration until 30 days after regorafenib treatment discontinuation or 100 days after the last dose of nivolumab, whatever occurred later.	Up to the last participant has been followed for approximately 10 months, summed up to approximately 26 months

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Bristol Myers Squibb Co. and Ono Pharmaceutical Co., Ltd

Publications and helpful links

Helpful Links

• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards.
• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2021
• Primary Completion (Actual): March 9, 2023
• Study Completion (Actual): March 29, 2024

Study Registration Dates

• First Submitted: January 8, 2021
• First Submitted That Met QC Criteria: January 8, 2021
• First Posted (Actual): January 11, 2021

Study Record Updates

• Last Update Posted (Actual): April 18, 2025
• Last Update Submitted That Met QC Criteria: March 27, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: nivolumab; PD-1 inhibitor; regorafenib; Head and Neck Squamous Cell Carcinoma (HNSCC); Pancreatic Ductal Adenocarcinoma (PDAC); Glioblastoma Multiforme (GBM); Anaplastic Astrocytoma (AA); Biliary Tract Carcinoma (BTC); multi-kinase inhibitor; Esophageal Squamous Cell Carcinoma (ESCC)
• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Nivolumab
• Other Study ID Numbers: 21136; 2020-003359-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014. Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No