Clinical trial NCT04704154: A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Solid Tumors
Keywords: Pancreatic Ductal Adenocarcinoma (PDAC)
Head and Neck Squamous Cell Carcinoma (HNSCC)
Esophageal Squamous Cell Carcinoma (ESCC)
Glioblastoma Multiforme (GBM)
Anaplastic Astrocytoma (AA)
Biliary Tract Carcinoma (BTC)
PD-1 inhibitor
nivolumab
regorafenib
multi-kinase inhibitor
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Bristol Myers Squibb Co. and Ono Pharmaceutical Co., Ltd
First posted: 2021-01-11
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
measure: Disease Control Rate (DCR)
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
measure: Progression Free Survival (PFS)
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
measure: 6 Months PFS
timeFrame: Up to last participant follow 6 months (approximately 22 months)
measure: Overall Survival (OS)
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 months
measure: 1 Year OS
timeFrame: From first participant enrolled to cut-off date (ie after the last participant has been followed for approximately 10 months) approximately 26 month]
measure: Number of Participants With Adverse Events
timeFrame: Up to the last participant has been followed for approximately 10 months, summed up to approximately 26 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope - Duarte Cancer Center
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers / Aurora, CO
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Charles A. Sammons Cancer Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Brussels
country: Belgium
facility: Hôpital Erasme/Erasmus Ziekenhuis
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Liege
country: Belgium
facility: CHU de Liège
city: Bordeaux Cedex
country: France
facility: Institut Bergonie - Unicancer Nouvelle Aquitaine
city: Lyon
country: France
facility: UNICANCER - Centre Leon Berard (CLB)
city: Paris
country: France
facility: APHP-Hopital la Pitie Salpetriere
city: Saint-Herblain
country: France
facility: Institut de Cancerologie Ouest - Saint-Herblain
city: Toulouse Cedex 9
country: France
facility: Institut Claudius Regaud - iUCT Oncopole
city: Villejuif Cedex
country: France
facility: Gustave Roussy - Departement Oncologie-Radiotherapie
city: Bologna
country: Italy
facility: AUSL di Bologna_Istituto delle Scienze Neurologiche - UO Oncologia del Sistema Nervoso
state: Emilia-Romagna
city: Milano
country: Italy
facility: IRCCS Foundation Istituto Neurologico Carlo Besta
state: Lombardia
city: Rozzano
country: Italy
facility: Humanitas Mirasole S.p.A. - Oncologia Medica ed Ematologia
state: Lombardia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto_Padova - UOC Oncologia 1
state: Veneto
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda - Oncologia Falck
city: Nagoya
country: Japan
facility: Aichi Cancer Center Hospital
state: Aichi
city: Kobe
country: Japan
facility: Kobe University Hospital
state: Hyogo
city: Kitaadachi-gun
country: Japan
facility: Saitama Cancer Center
state: Saitama
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Koto-ku
country: Japan
facility: The Cancer Institute Hospital of JFCR
state: Tokyo
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Seoul Teugbyeolsi
city: Taikang
country: Taiwan
facility: Chi Mei Medical Center
state: Tainan
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Trust (Surrey)
state: Surrey
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry and Warwickshire NHS Trust
state: West Midlands
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust | The Royal Marden Hospital - The Royal Marsden Clinical Trials Unit (CTU)
Study officials:
References: