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

Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04704154
• Other study ID #: 21136
• Secondary ID: 2020-003359-13
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: February 3, 2021
• Est. completion date: March 27, 2024

Study information

• Verified date: February 2024
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 175
• Est. completion date: March 27, 2024
• Est. primary completion date: March 9, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

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).
• Nivolumab (Opdivo)
480 mg administered on Day 1 of each treatment cycle.

Locations

Country	Name	City	State
Belgium	Hôpital Erasme/Erasmus Ziekenhuis	Brussels
Belgium	UZ Antwerpen	Edegem
Belgium	CHU de Liège	Liege
France	Institut Bergonié - Unicancer Nouvelle Aquitaine	Bordeaux
France	Centre Léon Bérard	Lyon
France	Hôpital de la Pitié-Salpétrière	Paris
France	Institut de Cancérologie de l'Ouest - Saint Herblain	Saint-Herblain
France	Institut Claudius Regaud - iUCT Oncopole	Toulouse Cedex 9
France	Institut Gustave Roussy - Département de Médecine Oncologique	Villejuif Cedex
Italy	AUSL di Bologna	Bologna	Emilia-Romagna
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milano	Lombardia
Italy	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano	Lombardia
Italy	Istituto Clinico Humanitas - Humanitas Mirasole S.p.A.	Milano	Lombardia
Italy	Istituto Oncologico Veneto IRCCS (IOV)	Padova	Veneto
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	Saitama Cancer Center	Kita-Adachigun	Saitama
Japan	Kobe University Hospital	Kobe	Hyogo
Japan	The Cancer Institute Hospital of JFCR	Koto-ku	Tokyo
Japan	Aichi Cancer Center Hospital	Nagoya	Aichi
Korea, Republic of	Seoul National University Hospital	Seoul	Seoul Teugbyeolsi
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chi-Mei Medical Center, Liouyine	Tainan
Taiwan	Taipei Veterans General Hospital	Taipei
United Kingdom	University Hospitals Coventry and Warwickshire NHS Trust	Coventry	West Midlands
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Royal Marsden Hospital (London)	London
United Kingdom	Royal Marsden NHS Trust (Surrey)	Sutton	Surrey
United States	Rocky Mountain Cancer Centers / Aurora, CO	Aurora	Colorado
United States	Baylor Charles A. Sammons Cancer Center at Dallas	Dallas	Texas
United States	City of Hope National Medical Center	Duarte	California
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Sarah Cannon Cancer Center	Nashville	Tennessee
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Bristol Myers Squibb Co. and Ono Pharmaceutical Co., Ltd

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Japan,  Korea, Republic of,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 dosing up to the end of the study (LPLV), summing up to approximately 4 years
Secondary	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 dosing up to the end of the study (LPLV), summing up to approximately 4 years
Secondary	Disease control rate (DCR)	CR = Complete response; PR = Partial response; SD = Stable disease	From first dosing up to the end of the study (LPLV), summing up to approximately 4 years
Secondary	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 dosing up to the end of the study (LPLV), summing up to approximately 4 years
Secondary	6 months PFS		6 months
Secondary	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 dosing up to the end of the study (LPLV), summing up to approximately 4 years
Secondary	1 year OS		1 year
Secondary	From first dosing up to the end of the study (LPLV), summing up to approximately 4 years	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

External Links

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