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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04704154
Recruitment Status : Active, not recruiting
First Posted : January 11, 2021
Last Update Posted : September 21, 2022
Bristol Myers Squibb Co. and Ono Pharmaceutical Co., Ltd
Information provided by (Responsible Party):

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: Regorafenib, (Stivarga, BAY73-4506) Drug: Nivolumab (Opdivo) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 175 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 3, 2021
Estimated Primary Completion Date : March 9, 2023
Estimated Study Completion Date : August 16, 2024

Resource links provided by the National Library of Medicine

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.

Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to the last participant having been followed for approximately 10 months, summing up to approximately 2.5 years ]
    • Per Response evaluation criteria in solid tumors 1.1 (RECIST 1.1) by local assessment for all solid tumors except GBM/AA (Glioblastoma multiforme/Anaplastic astrocytoma)
    • Per Response assessment in neuro-oncology (RANO) by local assessment for GBM/AA

Secondary Outcome Measures :
  1. Duration of response (DOR) [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]
  2. Disease control rate (DCR) [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]
  3. Progression free survival (PFS) [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]
  4. 6 months PFS [ Time Frame: 6 months ]
  5. Overall survival (OS) [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]
  6. 1 year OS [ Time Frame: 1 year ]
  7. Severity of AEs (adverse events) per CTCAE v 5.0 [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]
    CTCAE: Common terminology criteria for adverse events

  8. Number of participants with adverse events [ Time Frame: From first dosing up to the end of the study (LPLV), summing up to approximately 4 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04704154

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Sponsors and Collaborators
Bristol Myers Squibb Co. and Ono Pharmaceutical Co., Ltd
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT04704154    
Other Study ID Numbers: 21136
2020-003359-13 ( EudraCT Number )
First Posted: January 11, 2021    Key Record Dates
Last Update Posted: September 21, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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.clinicalstudydatarequest.com 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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Pancreatic Ductal Adenocarcinoma (PDAC)
Head and Neck Squamous Cell Carcinoma (HNSCC)
Esophageal Squamous Cell Carcinoma (ESSC)
Glioblastoma Multiforme (GBM)
Anaplastic Astrocytoma (AA)
Biliary Tract Carcinoma (BTC)
PD-1 inhibitor
multi-kinase inhibitor
Additional relevant MeSH terms:
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Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action