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Protocol NumberBAY 73-4506 / 21136
Completed

2020-10-16 - 2024-04-30

Phase II

Recruiting3

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

  • Trial Applicant

    BAYER TAIWAN COMPANY LTD.

  • Sponsor

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Yi-Ping Hung Division of Hematology & Oncology
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 林正耀 Division of Hematology & Oncology
Chi Mei Hospital, Liouying

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Li-Yuan Bai Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Recurrent or metastatic solid tumor

Objectives

To explore the potential to enhance anti-tumor response through combining of an ICI with an anti-VEGF MKI, this open-label, multi-center Phase 2 study of regorafenib and nivolumab aims to evaluate the safety and efficacy of the combination in multiple cohorts of participants with selected advanced solid tumors.

Test Drug

BAY 73-4506 (Regorafenib)Nivolumab

Active Ingredient

BAY 73-4506 (Regorafenib)
Nivolumab

Dosage Form

tablet
vial

Dosage

100mg/10mL

Endpoints

To evaluate efficacy of the regorafenib and nivolumab combination by cohort
●ORR per RECIST 1.1a by local assessment for all solid tumors except GBM/AA
●ORR per RANOa by local assessment for GBM/AA

Inclution Criteria

Participants are eligible to be included in the study only if all the following criteria apply (unless where specified for specific tumor indication). Reintroduction of the same chemotherapy in sequential order and locoregional treatments such as hepatic arterial infusion therapy is not considered as a new line of treatment:
Cohort 1 (HNSCC, IO naïve)
101 Cohort 1: Histologically confirmed recurrent or metastatic HNSCC (from any of the following primary sites only: oral cavity, oropharynx, hypopharynx and larynx) that is not amenable to curative intent surgery or chemoradiation.
102 Cohort 1: Progressed on or after 1, 2 or 3 lines of prior systemic therapy for recurrent or metastatic disease containing platinum chemotherapy or fluoropyrimidine or cetuximab, or a combination of these agents.
103 Cohort 1: Documented HPV p16 status for oropharyngeal cancer (historical results are acceptable if available).
104 Cohort 1: For Stage 2 participants only: Provision of recent tumor tissue defined astumor tissue obtained within 180 d of enrollment and after the last dose of most recent anti-cancer therapy or tissue from a new biopsy.
Cohort 2 (HNSCC, IO treated)
201 Cohort 2: Histologically confirmed recurrent or metastatic HNSCC (from any of the following primary sites only: oral cavity, oropharynx, hypopharynx and larynx) that is not amenable to curative intent surgery or chemoradiation.
202 Cohort 2: Progressed on or after 1, 2 or 3 lines of prior systemic therapy for recurrent or metastatic disease containing PD-1/PD-L1 inhibitor alone or in combination withchemotherapy. One of these prior lines should contain a PD-1/PD-L1 inhibitor.
Progression on a prior PD-1/PD-L1 inhibitor regimen should meet the following criteria:
Has received at least 2 doses of an anti-PD-1/PD-L1 mAb.
Has demonstrated disease progression after anti-PD-1/PD-L1 therapy as defined by RECIST. Confirmation of radiographic progression on prior anti-PD-1/PD-L1 therapy is required with a scan confirming progression at least 4 weeks after the
initial progression date. Screening scans can be used as the confirmation of progression.
203 Cohort 2: Documented HPV p16 status for oropharyngeal cancer (historical results are acceptable if available).
204 Cohort 2: Provision of recent tumor tissue defined as tumor tissue obtained within 180d of enrollment and after the last dose of most recent anti-cancer therapy or tissue from a new biopsy.
Cohort 3 (ESCC)
301 Cohort 3: Histologically or cytologically confirmed recurrent or metastatic ESCC that is not amenable to curative intent surgery or chemoradiation.
302 Cohort 3: Progression on or after 1 line of systemic therapy for recurrent or metastatic disease with platinum and/or fluoropyrimidine based regimen.
Cohort 4 (PDAC)
401 Cohort 4: Histologically or cytologically confirmed recurrent or metastatic PDAC that is not amenable to curative intent surgery.
402 Cohort 4: Progression on or after 1 or 2 lines of systemic therapy for recurrent or metastatic disease with gemcitabine or fluoropyrimidine based regimens.
Cohort 5 (BTC)
501 Cohort 5: Histologically or cytologically confirmed recurrent or metastatic BTC, namely cholangiocarcinoma (intrahepatic or extrahepatic) or gall bladder cancer, that is not amenable to curative intent surgery, transplantation, or ablative therapies.
502 Cohort 5: Progression on or after 1 or 2 lines of systemic therapy for recurrent or metastatic disease containing gemcitabine or fluoropyrimidine or platinum therapy or a combination of these agents.
Cohort 6 (GBM/AA)
601 Cohort 6: Histologically or cytologically confirmed Grade IV GBM or Grade III AA (World Health Organization [WHO] criteria) established following either a surgical resection or biopsy. This includes participants with prior diagnosis of lower grade
astrocytoma from a biopsy that has been upgraded to a histologically verified glioblastoma or anaplastic astrocytoma after a subsequent definitive surgery. AA isonly allowed in Stage 2.
602 Cohort 6: Unequivocal first progression after surgery followed by radiotherapy and temozolomide. Evidence of recurrent disease (RD) should be demonstrated by disease progression on biopsy or on MRI based on RANO criteria (using the postchemoradiation or post-radiation scan as baseline).
For all cohorts
1. Capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. A signed informed consent must be obtained prior to conducting any study-specific procedures.
2. Male and female adult participants 18 years of age or age of legal maturity or older on day of signing the ICF.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1.
4. Adequate hematologic and organ function as assessed by the following laboratory tests performed within 7 d before start of study treatment: 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) Platelet count ≥100,000 /mm3, Hemoglobin (Hb) ≥9 g/dL, white blood cell count(WBC) ≥2000/μL absolute neutrophil count (ANC) ≥1500/mm3. Red blood cell(pRBC) transfusion is allowed if Hb meets the criteria for at least 14 days after transfusion. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥40 mL/min (measured or calculated using the Cockcroft-Gault formula) Prothrombin time-international normalized ratio (PT-INR) <2.3 and activated partial thromboplastin time (aPTT)<1.5 x ULN.
5. Measurable disease by baseline CT or MRI per RECIST 1.1 criteria for all cohorts except GBM/AA. For GBM/AA, participants should have measurable disease as defined by RANO criteria at baseline by MRI. Previously irradiated lesions should not be counted as target lesions unless there have been demonstrated progression in the lesion since radiotherapy before study enrollment and no other lesions are available for selection as target lesions.
6. Participants must consent to provide biopsy/tumor tissue of a primary tumor lesion or from metastases (e.g. liver, lung) and as defined below:
Provision of archival tumor tissue sample is mandatory if available.
Recent tumor tissue samples, defined as tumor tissue obtained within 180 d of enrollment and after the last dose of most recent anti-cancer therapy or tissue from a new biopsy, are mandatory in HNSCC (IO treated) cohort for Stage 1 and 2 and
in HNSCC (IO naïve) cohort for Stage 2.
Recent tumor tissue samples as defined above are mandatory if medically feasible (as judged by the Investigator) for all participants in ESCC, PDAC, BTC, and for participants in Stage 1 in HNSCC (IO naïve) cohort. For GBM/AA cohorts, recent
tumor tissue samples are optional.
7. Anticipated life expectancy greater than 3 months
8. Be able to swallow and absorb oral tablets
9. Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception (see Section 10.4) for the duration of study intervention and 7 months (or 210 days) after last dose of regorafenib and 5 months after the last dose of nivolumab.
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (see Section 10.4) for the duration of study intervention and 4 months (or 120 days) after last dose of regorafenib and 7 months after the last dose of nivolumab. In addition, male participants must be willing to refrain from sperm donation during this time.
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:
Cohort 1 (HNSCC IO naïve)
101 Cohort 1: Histologically confirmed non-squamous, nasopharyngeal, or salivary histology of head and neck cancer, or squamous cell carcinoma that originated from the skin, or of unknown primary origin.
102 Cohort 1: More than 3 prior lines of systemic anticancer therapy for recurrent/metastatic cancer
103 Cohort 1: Presence of symptomatic central nervous system (CNS) metastases, leptomeningeal metastases or spinal cord compression. Previously treated lesionsshould be stable for at least 6 weeks prior to study entry.
104 Cohort 1: 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. Inhaled or topical steroids, and
adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
105 Cohort 1: 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.
Cohort 2 (HNSCC IO treated)
201 Cohort 2: Histologically confirmed non-squamous, nasopharyngeal, or salivary histology of head and neck cancer, or squamous cell carcinoma that originated from the skin, or of unknown primary origin.
202 Cohort 2: More than 3 prior lines of systemic anticancer therapy for recurrent/metastatic cancer
203 Cohort 2: Presence of symptomatic CNS metastases, leptomeningeal metastases or spinal cord compression. Previously treated lesions should be stable for at least 6 weeks prior to study entry.
204 Cohort 2: 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. Inhaled or topical steroids, and
adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
205 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.
Cohort 3 (ESCC)
301 Cohort 3: More than 1 prior line of systemic anticancer therapy for recurrent/metastatic cancer
302 Cohort 3: Patients with apparent tumor invasion on organs located adjacent to the esophageal disease (e.g., the aorta or respiratory tract).
303 Cohort 3: Patients who have previously received taxane agents for recurrent/metastatic cancer.
304 Cohort 3: Presence of symptomatic CNS metastases, leptomeningeal metastases or spinal cord compression. Previously treated lesions should be stable for at least 6 weeks prior to study entry.
305 Cohort 3: 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. Inhaled or topical steroids, and
adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
306 Cohort 3: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of immunotherapy to treat cancer.
Cohort 4 (PDAC)
401 Cohort 4: More than 2 prior lines of systemic anticancer therapy for recurrent/metastatic cancer
402 Cohort 4: Presence of symptomatic CNS metastases, leptomeningeal metastases or spinal cord compression. Previously treated lesions should be stable for at least 6 weeks prior to study entry.
403 Cohort 4: 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. Inhaled or topical steroids, and
adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
404 Cohort 4: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of immunotherapy to treat cancer.
Cohort 5 (BTC)
501 Cohort 5: More than 2 prior lines of systemic anticancer therapy for recurrent/metastatic cancer.
502 Cohort 5: Presence of symptomatic CNS metastases, leptomeningeal metastases or spinal cord compression. Previously treated lesions should be stable for at least 6weeks prior to study entry.
503 Cohort 5: 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. Inhaled or topical steroids, and
adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
504 Cohort 5: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of immunotherapy to treat cancer.
Cohort 6 GBM/AA
601 Cohort 6: Primary tumors localized to the brainstem or spinal cord.
602 Cohort 6: Locally directed therapies administered by injection convection-enhanced delivery within 6 months of start of study treatment.
603 Cohort 6: Presence of diffuse leptomeningeal disease or extracranial disease
604 Cohort 6: 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. Also excluded are participants who have a condition (other than symptoms related to brain tumor and cerebral edema) requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or
topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
605 Cohort 6: Major ongoing safety issues following surgery (e.g. infection requiring intravenous [IV]) antibiotics)
606 Cohort 6: CNS hemorrhage of Grade >1 on baseline MRI scan, unless subsequently documented to have resolved
607 Cohort 6: Prior therapy with PD-1/PD-L1 or CTLA-4 inhibitors, or any form of immunotherapy to treat cancer.
All cohorts
1. Participants who have known dMMR/MSI-H cancers or NTRK mutations
2. Prior therapy with regorafenib
3. Uncontrolled hypercalcemia (e.g. causing signs and symptoms putting the participant at risk as judged by the investigator)
4. Uncontrolled pleural effusions (e.g. causing signs and symptoms putting the participant at risk as judged by the investigator)
5. Participants receiving any other investigational treatment at the time of informed consent
6. Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment
7. Previous radiotherapy is acceptable under the following conditions:
Therapy completed more than 4 weeks before the baseline (at screening) scan.
Palliative radiotherapy for bone metastases or soft tissue lesions is allowed and should be completed > 7 days prior to baseline scan.
Participants must have recovered from all therapy-related toxicities to Grade < 1.
If the site of previous radiotherapy is the only site of disease, it should show evidence of disease progression.
8. Participants having unresolved clinically significant toxicity of greater than or equal to National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE, v5.0)
Grade 2 attributed to any prior therapies (excluding anemia, lymphopenia, alopecia, skin pigmentation, platinum-induced neurotoxicity, and endocrine disorders due to prior IO treatment that are well controlled).
9. Participants who have permanent discontinuation of PD-1/PD-L1 therapy due to toxicity.
10. 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
11. 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 (e.g. not well controlled on medications or causing signs and symptoms putting the participant at risk as judged by the investigator).
12. Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg despite optimal medical management.
13. Persistent proteinuria of NCI-CTCAE Grade 3 or higher. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is <3.5 g/24 hr.
14. Major surgical procedure or significant traumatic injury within 28 days before start of study treatment. Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Central line placement and minor invasive biopsy are not considered major surgery.
15. Non-healing wound, non-healing ulcer, or non-healing bone fracture.
16. Participants with evidence or history of any bleeding diathesis, irrespective of severity.
17. Any hemorrhage or bleeding event ≥ NCI-CTCAE Grade 3 within 28 days prior to the start of study treatment.
18. Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g.,Crohn’s disease, malabsorption, or ≥ NCI-CTCAE Grade 2 diarrhea of any etiology.
19. Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus (T1DM), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
20. History of (non-infectious) pneumonitis that required steroids, current pneumonitis or interstitial lung disease.
21. Participants with previous malignancies (except superficial esophageal cancer, nonmelanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was
achieved at least 3 years prior to informed consent signature and no additional therapy is required or anticipated to be required during the study period.
22. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (for doses >10 mg daily prednisone quivalent) or any other form of immunosuppressive therapy.
23. Active infection > NCI-CTCAE Grade 2
24. Positive test (from historical data or tested during screening) for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
25. 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).
26. Pregnancy or breast feeding.
27. Psychological, familial, or sociological condition potentially hampering compliance with the study protocol
28. Previous treatment with live vaccine within 30 days of planned start of study treatment (seasonal flu vaccines that do not contain a live virus are permitted).
29. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
30. 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.
31. Participants with a current or past history of interstitial lung disease or pulmonary fibrosis diagnosed based on imaging or clinical findings.

The Estimated Number of Participants

  • Taiwan

    14 participants

  • Global

    175 participants

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