A Phase I/II Study of Regorafenib Plus Avelumab in Solid Tumors (REGOMUNE)

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    Institut Bergonié
Updated on 4 March 2022
malignant disease
ct scan
platelet count
monoclonal antibodies
systemic therapy
serum pregnancy test
measurable disease
lung cancer
neutrophil count
liver metastasis
pet scan
cancer chemotherapy
vascular endothelial growth factor
differentiated thyroid cancer
cervical carcinoma
lung carcinoma
proto-oncogene tyrosine-protein kinase ros


Assessment of the efficacy and safety of Regorafenib and Avelumab in patients with advanced or metastatic solid tumors (ten cohorts), once the Recommanded Phase II Dose (RP2D) has been determined (phase I trial).

Assessement of the efficacy and safety of a low-dose of regorafenib (80mg/day) with avelumab in patients with advanced or metastatic colorectal tumors.


This is a multicenter, prospective open-labeled phase Ib trial based on a dose escalation study design (3+3 traditional design) assessing three dose levels of Regorafenib given in combination with Avelumab (no dose escalation for Avelumab) in patients with advanced digestive solid tumors followed by independent phase II trials to evaluate the association of Regorafenib at the RP2D with Avelumab in 10 cohorts of advanced or metastatic tumors :

  • Cohort A: Colorectal cancer not MSI-H or MMR-deficient
  • Cohort B: GIST
  • Cohort C: Oesophageal or gastric carcinoma
  • Cohort D: Biliary tract cancer, hepatocellular carcinoma
  • Cohort E: Soft-tissue sarcoma (STS)
  • Cohort F: Radioiodine-refractory differentiated thyroid cancer (RR-DTC)
  • Cohort G: Neuroendocrine gastroenteropancreatic tumors (GEP-NETs)
  • Cohort H: Non-small cell lung cancer (NSCLC)
  • Cohort I: Solid tumors (including soft-tissue sarcoma) with immune signature (TLS+).

In addition, to evaluate in a phase II trial, the association of a low-dose of regorafenib (80mg/day) with avelumab :

  • Cohort A': colorectal not MSI-H or MMR-deficient (low dose)

Condition Colorectal Cancer Not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma, Biliary Tract Cancer, Hepatocellular Carcinoma, Soft-tissue Sarcoma, Thyroid Cancer, Gastro-enteropancreatic Neuroendocrine Tumor, Non-small Cell Lung Cancer, Solid Tumor, Adult
Treatment Phase 1 : Regorafenib, Phase 1 : Avelumab, Phase 2 : Regorafenib, Phase 2 : Avelumab, Phase 2: low-dose Regorafenib
Clinical Study IdentifierNCT03475953
SponsorInstitut Bergonié
Last Modified on4 March 2022


Yes No Not Sure

Inclusion Criteria

Dose escalation part: histologically confirmed non MSI-H or deficient-MMR colorectal cancer, or GIST, or esophageal or gastric carcinoma or hepatobiliary cancers
Phase II trials : histologically confirmed
non MSI-H or deficient-MMR colorectal cancer (cohort A)
or GIST (cohort B). As recommended diagnosis by INCa, patients with GIST must have histologically confirmed by central review, except if it has been already confirmed by the RRePS Network
or esophageal or gastric carcinoma (cohort C)
or hepatobiliary cancers (cohort D)
or soft-tissue sarcoma (STS) (cohort E). As recommended diagnosis by INCa, patients with STS must have histologically confirmed by central review, except if it has been already confirmed by the RRePS Network
or radioiodine-refractory differentiated thyroid cancer [RR-DTC] (cohort F)
or neuroendocrine gastroenteropancreatic tumors grade 2 and 3
Advanced non resectable / metastatic disease
or Non-small cell lung cancer (cohort H)
Patients for which either there is no further established therapy that is known to provide clinical benefit, OR (for patients to be treated with 160 mg regorafenib) regorafenib monotherapy is an approved or established therapeutic option
or Solid tumors including soft-tissue sarcoma with immune signature (cohort I), i.e. presence of tertiary lymphoid structures on tumor sample as determined by central review
Age ≥ 18 years
Life expectancy > 3 months
ECOG, Performance status ≤ 1
Measurable disease according to RECIST
Adequate hematological, renal, metabolic and hepatic functions
Except for cohorts F and H, ≥ 1 previous line (s) of systemic therapy
Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l, lymphocytes ≥ 1000/mm3
Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement for AP exclusively and ≤ 5 x ULN in case of liver metastasis for AST and ALT)
Total bilirubin ≤ 1.5 x ULN
Albumin ≥ 25g/l
Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula)
Creatine phosphokinase (CPK) ≤ 2.5 x ULN
INR < 1.5 x ULN
Cohort specific criteria: Patients with hepatocellular carcinoma must have a correct hepatocellular function, id est Child-Pugh A
aPTT ≤ 1.5 X ULN
Lipase ≤ 1.5 X ULN
At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy
No prior or concurrent malignant disease diagnosed or treated in the last 2 years
Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication
except for adequately treated in situ carcinoma of the cervix, basal or
Both women and men must agree to use an highly effective method of contraception throughout the treatment period and for eight weeks after discontinuation of treatment. Acceptable methods for contraception are described in protocol section 7.4.1
squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma
Voluntary signed and dated written informed consents prior to any specific study procedure
Patients with a social security in compliance with the French law
Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0))
Documented disease progression (as per RECIST v1.1) before study entry. For patients of cohort E (STS) and cohort I (Solid-tumors - TLS+): this progression will be confirmed by central review on the basis of two CT scan or MRI obtained not less than 6 months in the period of 12 months prior to inclusion. For patients of cohort F (RR-DTC): this progression will be confirmed by central review on the basis of two CT scan or MRI obtained at less than 12 months prior to inclusion
For patients in cohort H: subjects with histologically or cytologically confirmed diagnosis of non-squamous NSCLC. Documents disease progression based on radiographic imaging, during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/IV or metastatic disease. Two components of treatments must have been received in the same line or as separate lines of therapy: a maximum of 1 line of platinum-containing chemotherapy regimen, and a maximum of 1 line of PD(L)1 mAb containing regimen. No EGFR, ALK, ROS1 positive tumor mutations. Subjects with known BRAF molecular alterations must have had disease progression after receiving the locally available SoC treatment for the molecular alteration

Exclusion Criteria

Previous treatment with Avelumab or Regorafenib
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways), except for cohort H
Participation to a study involving a medical or therapeutic intervention in the last 30 days
Evidence of progressive or symptomatic or newly diagnosed central nervous system (CNS) or leptomeningeal metastases
Previous enrolment in the present study
Men or women of childbearing potential who are not using an effective method of contraception as previously described
Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons
Known hypersensitivity to any involved study drug or of its formulation components
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan or interstitial lung disease with ongoing signs and symptoms at inclusion. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS)
Has known hepatitis B or hepatitis C, active and/or treated by antiviral therapy
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
Major surgical procedure or significant traumatic injury within 28 days before start of study medication
other form of immunosuppressive therapy within 7 days prior to the first dose
Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis
of trial treatment
Patients with evidence or history of any bleeding diathesis, irrespective of severity
Non-healing wound, non-healing ulcer, or non-healing bone fracture requiring orthopedic treatment
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication)
Ongoing infection > Grade 2 as per NCI CTCAE v5.0
Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
Myocardial infarction less than 6 months bedfore start of study drug
Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
Uncontrolled cardiac arrhythmias
Pregnant or breast-feeding patients
Individuals deprived of liberty or placed under legal guardianship
Prior organ transplantation, including allogeneic stem-cell transplantation
Congestive heart failure ≥ New York Heart Association (NHYA) class 2
Known alcohol or drug abuse
Vaccination within 4 weeks of the first dose of Avelumab and while on trial is prohibited except for administration of inactivated vaccines
Patients with any condition that impairs their ability to swallow and retain tablets
Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
Patient with oral anticoagulation therapy
Suspected or known intraabdominal fistula
For cohort H: received more than 2 prior lines of therapy for NSCLC, including subjects with BRAF molecular alteration and subjects with knwon EGFR/ALK/ROS1 molecular alterations are excluded
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