Colorectal Cancer Not MSI-H or MMR-deficientPhase 1/2REGOMUNENCT03475953

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

A Phase 1/2 study testing Phase 1 : Regorafenib, Phase 1 : Avelumab and Phase 2 : Regorafenib in people with Colorectal Cancer Not MSI-H or MMR-deficient and GIST, run by Institut Bergonié at 7 sites in France.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record

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Trial summary

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). Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Colorectal Cancer Not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma
What is being tested?: Phase 1 : Regorafenib, Phase 1 : Avelumab and Phase 2 : Regorafenib
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 747 participants
Where: 7 sitesFrance
Study dates: 4 May 2018to 31 Dec 2025
Phase: Phase 1/2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Histology:
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),

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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
or Non-small cell lung cancer (cohort H)
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.
or urothelial cancer (cohort J)
or HPV-associated cancer (cohort K) with molecular confirmation p16 positive status,
triple negative breast cancer (cohort L)
or TMB-high solid tumors (cohort M) with status TMB-high already known
or MSI-high solid tumors (cohort N) with status MSI-high already known
or Non clear-cell renal carcinoma (cohort O)
or Malignant pleural mesothelioma (cohort P).
Advanced non resectable / metastatic disease,
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,
Age ≥ 18 years,
ECOG, Performance status ≤ 1,
Measurable disease according to RECIST,
Life expectancy > 3 months,
Except for cohorts F and H, ≥ 1 previous line (s) of systemic therapy,
Adequate hematological, renal, metabolic and hepatic functions:
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 and/or liver metastasis 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
aPTT ≤ 1.5 X ULN
Lipase ≤ 1.5 X ULN.
Cohort specific criteria: Patients with hepatocellular carcinoma must have a correct hepatocellular function, id est Child-Pugh A.
No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
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)),
Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication,
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,
Voluntary signed and dated written informed consents prior to any specific study procedure,
Patients with a social security in compliance with the French law.
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
For patients with urothelial cancer (cohort J):
A maximum of 1 line of PD(L)1 mAb containing regimen, and
Patients must have received at least 4 months of PD(L1) mAb treatment.
For HPV-associated cancer (cohort K), TMB-high solid tumors (cohort M) MSI-high solid tumors (cohort N), Non clear-cell renal carcinoma (cohort O):
o No previous line of PD(L)1 mAb containing regimen
For malignant pleural mesothelioma (Cohort P):
A maximum of 1 line of PD(L)1 mAb containing regimen, and
Patients must have received at least 4 months of PD(L1)/ CTLA-4 mAb treatment in the case they received this treatment
For triple-negative breast cancer patients (Cohort L)
A maximum of 1 line of PD(L)1 mAb containing regimen, and
Patients must have received at least 4 months of PD(L1) mAb treatment
For TMB-High cancer patients (Cohort M):
TMB-High is defined as TMB score > 16 mutations /megabase on tissue or blood sample

Who cannot join

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 (NSCLC), Cohort I (Solid tumors (including Soft Tissue Sarcoma) with immune signature (TLS+)) and cohort P (malignant pleural mesothelioma),
Evidence of progressive or symptomatic or newly diagnosed central nervous system (CNS) or leptomeningeal metastases,
Men or women of childbearing potential who are not using an effective method of contraception as previously described;
Participation to a study involving a medical or therapeutic intervention in the last 30 days,
Previous enrolment in the present study,

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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
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
Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
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,
Has known hepatitis B or hepatitis C, active and/or treated by antiviral therapy
Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS),
Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis,
Major surgical procedure or significant traumatic injury within 28 days before start of study medication,
Non-healing wound, non-healing ulcer, or non-healing bone fracture requiring orthopedic treatment,
Patients with evidence or history of any bleeding diathesis, irrespective of severity,
Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
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,
Congestive heart failure ≥ New York Heart Association (NHYA) class 2,
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,
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,
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

Trial locations and contacts

7 sites in 1 country.

Sophie COUSIN, MD contact

+33 5.56.33.33.33

s.cousin@bordeaux.unicancer.fr

Simone MATHOULIN-PELISSIER, MD, PhD contact

s.mathoulin@bordeaux.unicancer.fr

City, postcode or hospital

Sites recruiting now only

7 sites in 1 country

France7 sites, 7 recruiting

Institut Bergonié
Bordeaux, 33076
Sophie COUSIN, MD
Sophie COUSIN, MD
Recruiting
Centre Hospitalier Régional Universitaire - CHU Morvan
Brest, 29200
Jean-Philippe METGES, MD, PhD
Recruiting
Centre Léon Bérard
Lyon, 69008
Philippe CASSIER, MD
Recruiting
Institut de Cancérologie de Montpellier
Montpellier, 34298
Antoine ADENIS, MD, PhD
Recruiting
Institut Curie
Paris, 75248
Segolene HESCOT, segolene.hescot@curie.fr
Recruiting
IUCT Oncopôle - Institut Claudius Regaud
Toulouse, 31059
Carlos GOMEZ-ROCA, MD
Recruiting
Institut Gustave Roussy
Villejuif, 94800
Christophe MASSARD, MD, PhD
Recruiting

Other trials in France

About this study

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

Read the detailed description

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 17cohorts 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)
Cohort J: urothelial cancer
cohort K: HPV-associated cancer with molecular confirmation p16 positive status
cohort L: triple netagtive brest cancer
cohort M: TMH-high solid tumors with status TMB-high already known
cohort N: MSI-high solid tumors with status MSI-high already known
cohort O: non clear-cell renal carcinoma
cohort P: malignant pleural mesothelioma

Conditions: Colorectal Cancer Not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma, Biliary Tract Cancer, Hepatocellular Carcinoma, Soft-tissue Sarcoma
Being tested: Phase 1 : Regorafenib, Phase 1 : Avelumab, Phase 2 : Regorafenib, Phase 2 : Avelumab, Phase 2: low-dose Regorafenib
Keywords: Advanced solid tumor, Metastatic tumor, Phase Ib/II trial, Colorectal cancer not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma, Biliary Tract cancer, Hepatocellular Carcinoma, Soft-tissue sarcoma, Thyroid cancer, Neuroendocrine gastroenteropancreatic tumors, Non-small cell lung cancer, Tertiary lymphoid structures, triple negative brest cancer, urothelial cancer, HPV-associated cancer, malignant pleural mesothelioma, non clear-cell renal carcinoma, TMB-high solid tumors, MSI-high solid tumors
Medical subject headings: Turcot syndrome, Stomach Neoplasms, Biliary Tract Neoplasms, Carcinoma, Hepatocellular, Sarcoma, Thyroid Neoplasms, Gastro-enteropancreatic neuroendocrine tumor, Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Phase 1 : RegorafenibDrug
A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.). Patients will be allocated 3 dose levels of Regorafenib following a 3 + 3 design.
Phase 1 : AvelumabDrug
A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.). Avelumab will be administered on cycle 1 Day 15 as a 1-hour intravenous (IV) infusion (10mg/kg), repeated every two weeks thereafter (ie. Day 1 and Day 15 of each subsequent cycle, as a 1-hour intravenous infusion).
Phase 2 : RegorafenibDrug
Phase 2 : Regorafenib - All patients will be treated at the RP2D of regorafenib defined in the preliminary phase 1 trial with the same schedule as in the phase I.
Phase 2 : AvelumabDrug
Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Phase 2: low-dose RegorafenibDrug
Phase 2 : Regorafenib - All patients will be treated at a fixed low-dose of regorafenib of 80 mg/day

Study groups in NCT03475953
Study group	Role	What they receive
Phase 1 : Regorafenib + Avelumab	Experimental	Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 1 : Regorafenib; Drug: Phase 1 : Avelumab
Phase 2 : cohort A Regorafenib + Avelumab	Experimental	Treatment by Avelumab + Regorafenib Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort B Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort C Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort D Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort E Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort F Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort G Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort H Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort I Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort A' Regorafenib low-dose + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Avelumab; Drug: Phase 2: low-dose Regorafenib
Phase 2 : cohort J Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort K Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort L Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort M Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort N Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort O Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab
Phase 2 : cohort P Regorafenib + Avelumab	Experimental	Treatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off. Receives: Drug: Phase 2 : Regorafenib; Drug: Phase 2 : Avelumab

What is being measured

The primary outcome is the main question the study is designed to answer.

PHASE I : Recommended phase II dose (RP2D)
Recommended phase II dose (RP2D) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
Measured: During the first cycle (28 days)
PHASE II (7cohorts A, C, D, E, F and G) : Assessment of the antitumor activity of regorafenib
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on objective response under treatment defined as CR or PR following RECIST v1.1 criteria.
Measured: Throughout the treatment period, an average of 6 months
Phase II (cohorts B, H, I, M, N, O and P): Assessment of the antitumor activity of regorafenib
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on 6-month progression-free rate, defined as CR, PR and SD following RECIST v1.1 criteria.
Measured: 6 months
Phase II (cohort A'): Assessment of the antitumor activity of regorafenib
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on 4-months progression-free rate, defined as CR, PR and SD following RECIST v1.1 criteria.
Measured: 4 months

Secondary outcomes (33)

PHASE I : Maximum Tolerated Dose (MTD)
Maximum Tolerated Dose (MTD) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
Measured: During the first cycle (28 days)
PHASE I : Dose Limiting Toxicities (DLT)
Dose Limiting Toxicities (DLT) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
Measured: During the first cycle (28 days)
PHASE I : Toxicity
Toxicity graded using the common toxicity criteria from the NCI v5.
Measured: Throughout the treatment period, an average of 6 months
PHASE I : Assessment of the antitumor activity of regorafenib - Best overall response
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of best overall response as per RECIST v1.1.
Measured: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - objective response rate under treatment
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of objective response rate under treatment (ORR) defined as CR or PR as per RECIST v1.1.
Measured: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - objective response rate
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of objective response rate at 6-months (ORR) defined as CR or PR as per RECIST v1.1.
Measured: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - non-progression
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 6-months non-progression defined as CR, PR or SD as per RECIST v1.1
Measured: 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - progression-free survival (PFS)
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 1-year progression-free survival (PFS) as per RECIST v1.1.
Measured: 1 year
PHASE I : Assessment of the antitumor activity of regorafenib - overall survival (OS)
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 1-year overall survival (OS) as per RECIST v1.1.
Measured: 1 year
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measured: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measured: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measured: Day 15 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
PK measurement expressed as half-life for regorafenib.
Measured: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
PK measurement expressed as half-life for regorafenib.
Measured: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
PK measurement expressed as half-life for regorafenib.
Measured: Day 15 of cycle 2 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
PK measurement expressed as concentration peak for regorafenib
Measured: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
PK measurement expressed as concentration peak for regorafenib
Measured: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
PK measurement expressed as concentration peak for regorafenib
Measured: Day 15 of cycle 2 (Each cycle is 28 days)
Phase I: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
levels of angiogenic and immunologic biomarkers in blood
Measured: day 1 of cycles 1, 2, 4, 6 and at progression
Phase I: Predictive blood biomarkers analysis (lymphocytes) by flow cytmetry.
levels of angiogenic and immunologic biomarkers in blood
Measured: day 1 of cycles 1, 2, 4, 6 and at progression
Phase I: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
levels of angiogenic and immunologic biomarkers in tissue
Measured: day 1 of cycle 1 and day 1 of cycle 2
Phase I: Adverses events graded using the common toxicity criteria from the NCI v5 to determine the safety profile of regorafenib plus avelumab.
Toxicity graded using the common toxicity criteria from the NCI v5.
Measured: throughouth the treatment period, an average of 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - Best overall response
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of best overall response as per RECIST v1.1.
Measured: Throughout the treatment period, an average of 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - objective response rate
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of objective response rate at 6-months (ORR) defined as CR or PR as per RECIST v1.1.
Measured: Throughout the treatment period, an average of 6 months
PHASE II :Assessment of the antitumor activity of regorafenib - non progression
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 6-months non-progression defined as CR, PR or SD as per RECIST v1.1.
Measured: 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - Progression-Free Survival (PFS)
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 1-year progression-free survival (PFS) as per RECIST v1.1.
Measured: 1 year
PHASE II : Assessment of the antitumor activity of regorafenib - Overall Survival
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of 1-year overall survival (OS) as per RECIST v1.1.
Measured: 1 year
Phase II: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
levels of angiogenic and immunologic biomarkers in blood
Measured: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II: Predictive blood biomarkers analysis (lymphocytes) by flow cytometry.
levels of angiogenic and immunologic biomarkers in blood
Measured: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
levels of angiogenic and immunologic biomarkers in tissue
Measured: day 1 of cycle 1 and day 1 of cycle 2
Phase II: Adverses events graded using the common toxicity criteria from the NCI v5 to determine the safety profile of regorafenib plus avelumab
Toxicity graded using the common toxicity criteria from the NCI v5
Measured: throughouth the treatment period, an average of 6 months
Predictive metabolomic analysis by liquid chromatography-mass spectrometry
Levels of metabolites in blood
Measured: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II (cohort B): assessment of the antitumor activity of regorafenib
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on CHOI criteria
Measured: throughouth the treatment period, an average of 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

4 May 201831 Dec 2025

First posted23 Mar 2018
Study start4 May 2018
Primary completion31 Dec 2024 (estimated)
Study completion31 Dec 2025 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (4)Papers the sponsor has linked to this study.
Other trials for Colorectal Cancer Not MSI-H or MMR-deficientStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Model description: 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 solid tumors followed by 17 phase II trials : * to evaluate the association of Regorafenib at the RP2D with Avelumab in 16 distinct disease settings (advanced or metastatic tumors). * to evaluate the association of a low-dose of regorafenib with avelumab in advanced or metastatic colorectal cancer
Masking: None (open label)
Enrolment: 747 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03475953
Sponsor's protocol ID: IB 2017-01
Other IDs: 2016-005175-27, 2016
Acronym: REGOMUNE
Status last verified: Mar 2023
First submitted: 20 Feb 2018
Last updated: 3 Mar 2023
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No

Publications

Toulmonde M, Guegan JP, Spalato-Ceruso M, Valentin T, Bahleda R, Peyraud F, Rey C, Kind M, Cantarel C, Bellera C, Vanhersecke L, Bessede A, Italiano A. Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab. Signal Transduct Target Ther. 2025 Jun 27;10(1):202. doi: 10.1038/s41392-025-02278-9.
PubMed 40579407
Cousin S, Guegan JP, Palmieri LJ, Metges JP, Pernot S, Bellera CA, Assenat E, Korakis I, Cassier PA, Hollebecque A, Cantarel C, Kind M, Soubeyran I, Sokol H, Vanhersecke L, Bessede A, Italiano A. Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis. Nat Cancer. 2025 Apr;6(4):584-594. doi: 10.1038/s43018-025-00916-3. Epub 2025 Apr 9.
PubMed 40204996
Cousin S, Cantarel C, Guegan JP, Mazard T, Gomez-Roca C, Metges JP, Bellera C, Adenis A, Korakis I, Poureau PG, Bourcier K, Toulmonde M, Kind M, Rey C, Auzanneau C, Bessede A, Soubeyran I, Italiano A. Regorafenib-avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial. Eur J Cancer. 2022 Feb;162:161-169. doi: 10.1016/j.ejca.2021.11.012. Epub 2022 Jan 5.
PubMed 34998048
Toulmonde M, Brahmi M, Giraud A, Chakiba C, Bessede A, Kind M, Toulza E, Pulido M, Albert S, Guegan JP, Cousin S, Mathoulin-Pelissier S, Perret R, Croce S, Blay JY, Ray-Coquard I, Floquet A, Italiano A. Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study. Clin Cancer Res. 2022 May 2;28(9):1765-1772. doi: 10.1158/1078-0432.CCR-21-2258.
PubMed 34965951

Study at a glance

From the registry record, last updated by the sponsor on 3 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase I/II Study of Regorafenib Plus Avelumab in Solid Tumors
ClinicalTrials.gov ID: NCT03475953
Acronym / sponsor ID: REGOMUNE / IB 2017-01
Conditions: Colorectal Cancer Not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma, Biliary Tract Cancer, Hepatocellular Carcinoma, Soft-tissue Sarcoma
Keywords: Advanced solid tumor, Metastatic tumor, Phase Ib/II trial, Colorectal cancer not MSI-H or MMR-deficient, GIST, Oesophageal or Gastric Carcinoma, Biliary Tract cancer, Hepatocellular Carcinoma
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Unknown status
Enrolment: 747 participants (estimated)
Lead sponsor: Institut BergoniéUniversity, hospital or other
Collaborators: Bayer, Merck KGaA, Darmstadt, Germany
Study start: 4 May 2018 (actual)
Primary completion: 31 Dec 2024 (estimated)
Study completion: 31 Dec 2025 (estimated)
First posted: 23 Mar 2018 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

Detailed description

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)
Cohort J: urothelial cancer
cohort K: HPV-associated cancer with molecular confirmation p16 positive status
cohort L: triple netagtive brest cancer
cohort M: TMH-high solid tumors with status TMB-high already known
cohort N: MSI-high solid tumors with status MSI-high already known
cohort O: non clear-cell renal carcinoma
cohort P: malignant pleural mesothelioma

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 18
Model description: 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 solid tumors followed by 17 phase II trials : * to evaluate the association of Regorafenib at the RP2D with Avelumab in 16 distinct disease settings (advanced or metastatic tumors). * to evaluate the association of a low-dose of regorafenib with avelumab in advanced or metastatic colorectal cancer

Arm	Type	Receives
Phase 1 : Regorafenib + Avelumab	Experimental	Drug: Phase 1 : Regorafenib, Drug: Phase 1 : AvelumabAvelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort A Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab + Regorafenib Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort B Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort C Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort D Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort E Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort F Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort G Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort H Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort I Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort A' Regorafenib low-dose + Avelumab	Experimental	Drug: Phase 2 : Avelumab, Drug: Phase 2: low-dose RegorafenibTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort J Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort K Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort L Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort M Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort N Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort O Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.
Phase 2 : cohort P Regorafenib + Avelumab	Experimental	Drug: Phase 2 : Regorafenib, Drug: Phase 2 : AvelumabTreatment by Avelumab will be administrated by intravenous 1-hour infusion every 2 weeks starting at Cycle 1 Day 15. Regorafenib will be taken orally once daily for three weeks on/ one week off.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (59 listed)

Histology:
Advanced non resectable / metastatic disease,
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,
Age ≥ 18 years,
ECOG, Performance status ≤ 1,

Key exclusion criteria (38 listed)

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 (NSCLC), Cohort I (Solid tumors (including Soft Tissue Sarcoma) with immune signature (TLS+)) and cohort P (malignant pleural mesothelioma),
Evidence of progressive or symptomatic or newly diagnosed central nervous system (CNS) or leptomeningeal metastases,
Men or women of childbearing potential who are not using an effective method of contraception as previously described;
Participation to a study involving a medical or therapeutic intervention in the last 30 days,

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Phase 1 : RegorafenibA treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.). Patients will be allocated 3 dose levels of Regorafenib following a 3 + 3 design.	Drug	Phase 1 : Regorafenib + Avelumab
Phase 1 : AvelumabA treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.). Avelumab will be administered on cycle 1 Day 15 as a 1-hour intravenous (IV) infusion (10mg/kg), repeated every two weeks thereafter (ie. Day 1 and Day 15 of each subsequent cycle, as a 1-hour intravenous infusion).	Drug	Phase 1 : Regorafenib + Avelumab
Phase 2 : RegorafenibPhase 2 : Regorafenib - All patients will be treated at the RP2D of regorafenib defined in the preliminary phase 1 trial with the same schedule as in the phase I.	Drug	Phase 2 : cohort A Regorafenib + Avelumab, Phase 2 : cohort B Regorafenib + Avelumab, Phase 2 : cohort C Regorafenib + Avelumab, Phase 2 : cohort D Regorafenib + Avelumab, Phase 2 : cohort E Regorafenib + Avelumab, Phase 2 : cohort F Regorafenib + Avelumab, Phase 2 : cohort G Regorafenib + Avelumab, Phase 2 : cohort H Regorafenib + Avelumab, Phase 2 : cohort I Regorafenib + Avelumab, Phase 2 : cohort J Regorafenib + Avelumab, Phase 2 : cohort K Regorafenib + Avelumab, Phase 2 : cohort L Regorafenib + Avelumab, Phase 2 : cohort M Regorafenib + Avelumab, Phase 2 : cohort N Regorafenib + Avelumab, Phase 2 : cohort O Regorafenib + Avelumab, Phase 2 : cohort P Regorafenib + Avelumab
Phase 2 : AvelumabPhase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.	Drug	Phase 2 : cohort A Regorafenib + Avelumab, Phase 2 : cohort A' Regorafenib low-dose + Avelumab, Phase 2 : cohort B Regorafenib + Avelumab, Phase 2 : cohort C Regorafenib + Avelumab, Phase 2 : cohort D Regorafenib + Avelumab, Phase 2 : cohort E Regorafenib + Avelumab, Phase 2 : cohort F Regorafenib + Avelumab, Phase 2 : cohort G Regorafenib + Avelumab, Phase 2 : cohort H Regorafenib + Avelumab, Phase 2 : cohort I Regorafenib + Avelumab, Phase 2 : cohort J Regorafenib + Avelumab, Phase 2 : cohort K Regorafenib + Avelumab, Phase 2 : cohort L Regorafenib + Avelumab, Phase 2 : cohort M Regorafenib + Avelumab, Phase 2 : cohort N Regorafenib + Avelumab, Phase 2 : cohort O Regorafenib + Avelumab, Phase 2 : cohort P Regorafenib + Avelumab
Phase 2: low-dose RegorafenibPhase 2 : Regorafenib - All patients will be treated at a fixed low-dose of regorafenib of 80 mg/day	Drug	Phase 2 : cohort A' Regorafenib low-dose + Avelumab

Primary outcome

PHASE I : Recommended phase II dose (RP2D)
Time frame: During the first cycle (28 days)
Recommended phase II dose (RP2D) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
PHASE II (7cohorts A, C, D, E, F and G) : Assessment of the antitumor activity of regorafenib
Time frame: Throughout the treatment period, an average of 6 months
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on objective response under treatment defined as CR or PR following RECIST v1.1 criteria.
Phase II (cohorts B, H, I, M, N, O and P): Assessment of the antitumor activity of regorafenib
Time frame: 6 months
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on 6-month progression-free rate, defined as CR, PR and SD following RECIST v1.1 criteria.
Phase II (cohort A'): Assessment of the antitumor activity of regorafenib
Time frame: 4 months
Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab based on 4-months progression-free rate, defined as CR, PR and SD following RECIST v1.1 criteria.

33 secondary outcomes

PHASE I : Maximum Tolerated Dose (MTD)
Time frame: During the first cycle (28 days)
PHASE I : Dose Limiting Toxicities (DLT)
Time frame: During the first cycle (28 days)
PHASE I : Toxicity
Time frame: Throughout the treatment period, an average of 6 months
PHASE I : Assessment of the antitumor activity of regorafenib - Best overall response
Time frame: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - objective response rate under treatment
Time frame: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - objective response rate
Time frame: Throughout the treatment period, an average of 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - non-progression
Time frame: 6 months
PHASE I :Assessment of the antitumor activity of regorafenib - progression-free survival (PFS)
Time frame: 1 year
PHASE I : Assessment of the antitumor activity of regorafenib - overall survival (OS)
Time frame: 1 year
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time frame: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time frame: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time frame: Day 15 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time frame: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time frame: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time frame: Day 15 of cycle 2 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
Time frame: Day 15 of cycle 1 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
Time frame: Day 1 of cycle 2 (Each cycle is 28 days)
PHASE I :PK - concentration peak for regorafenib.
Time frame: Day 15 of cycle 2 (Each cycle is 28 days)
Phase I: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
Time frame: day 1 of cycles 1, 2, 4, 6 and at progression
Phase I: Predictive blood biomarkers analysis (lymphocytes) by flow cytmetry.
Time frame: day 1 of cycles 1, 2, 4, 6 and at progression
Phase I: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
Time frame: day 1 of cycle 1 and day 1 of cycle 2
Phase I: Adverses events graded using the common toxicity criteria from the NCI v5 to determine the safety profile of regorafenib plus avelumab.
Time frame: throughouth the treatment period, an average of 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - Best overall response
Time frame: Throughout the treatment period, an average of 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - objective response rate
Time frame: Throughout the treatment period, an average of 6 months
PHASE II :Assessment of the antitumor activity of regorafenib - non progression
Time frame: 6 months
PHASE II : Assessment of the antitumor activity of regorafenib - Progression-Free Survival (PFS)
Time frame: 1 year
PHASE II : Assessment of the antitumor activity of regorafenib - Overall Survival
Time frame: 1 year
Phase II: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
Time frame: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II: Predictive blood biomarkers analysis (lymphocytes) by flow cytometry.
Time frame: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
Time frame: day 1 of cycle 1 and day 1 of cycle 2
Phase II: Adverses events graded using the common toxicity criteria from the NCI v5 to determine the safety profile of regorafenib plus avelumab
Time frame: throughouth the treatment period, an average of 6 months
Predictive metabolomic analysis by liquid chromatography-mass spectrometry
Time frame: day 1 of cycles 1, 2, 4, 6 and at progression
Phase II (cohort B): assessment of the antitumor activity of regorafenib
Time frame: throughouth the treatment period, an average of 6 months

Results and safety

Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 3 Mar 2023.
Derived from this study: PubMed 40579407Toulmonde M, Guegan JP, Spalato-Ceruso M, Valentin T, Bahleda R, Peyraud F, Rey C, Kind M, Cantarel C, Bellera C, Vanhersecke L, Bessede A, Italiano A. Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab. Signal Transduct Target Ther. 2025 Jun 27;10(1):202. doi: 10.1038/s41392-025-02278-9.
Derived from this study: PubMed 40204996Cousin S, Guegan JP, Palmieri LJ, Metges JP, Pernot S, Bellera CA, Assenat E, Korakis I, Cassier PA, Hollebecque A, Cantarel C, Kind M, Soubeyran I, Sokol H, Vanhersecke L, Bessede A, Italiano A. Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis. Nat Cancer. 2025 Apr;6(4):584-594. doi: 10.1038/s43018-025-00916-3. Epub 2025 Apr 9.
Derived from this study: PubMed 34998048Cousin S, Cantarel C, Guegan JP, Mazard T, Gomez-Roca C, Metges JP, Bellera C, Adenis A, Korakis I, Poureau PG, Bourcier K, Toulmonde M, Kind M, Rey C, Auzanneau C, Bessede A, Soubeyran I, Italiano A. Regorafenib-avelumab combination in patients with biliary tract cancer (REGOMUNE): a single-arm, open-label, phase II trial. Eur J Cancer. 2022 Feb;162:161-169. doi: 10.1016/j.ejca.2021.11.012. Epub 2022 Jan 5.
Derived from this study: PubMed 34965951Toulmonde M, Brahmi M, Giraud A, Chakiba C, Bessede A, Kind M, Toulza E, Pulido M, Albert S, Guegan JP, Cousin S, Mathoulin-Pelissier S, Perret R, Croce S, Blay JY, Ray-Coquard I, Floquet A, Italiano A. Trabectedin plus Durvalumab in Patients with Advanced Pretreated Soft Tissue Sarcoma and Ovarian Carcinoma (TRAMUNE): An Open-Label, Multicenter Phase Ib Study. Clin Cancer Res. 2022 May 2;28(9):1765-1772. doi: 10.1158/1078-0432.CCR-21-2258.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Sophie COUSIN, MD contact

+33 5.56.33.33.33

s.cousin@bordeaux.unicancer.fr

Simone MATHOULIN-PELISSIER, MD, PhD contact

s.mathoulin@bordeaux.unicancer.fr

7 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 59 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 3 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Sophie COUSIN, MD (+33 5.56.33.33.33, s.cousin@bordeaux.unicancer.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

PHASE I : Recommended phase II dose (RP2D) (time frame: During the first cycle (28 days)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03475953, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2023.