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

Sponsor

Institut Bergonié (Other)

Overall Status

Recruiting

CT.gov ID

NCT03475953

Collaborator

Bayer (Industry), Merck KGaA, Darmstadt, Germany (Industry)

482

Enrollment

Locations

Arms

55.9

Anticipated Duration (Months)

68.9

Patients Per Site

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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).

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

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Phase 1 : Regorafenib Drug: Phase 1 : Avelumab Drug: Phase 2 : Regorafenib Drug: Phase 2 : Avelumab Drug: Phase 2: low-dose Regorafenib	Phase 1/Phase 2

Detailed Description

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)

Study Design

Study Type:

Interventional

Anticipated Enrollment :

482 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention 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 11 phase II trials : to evaluate the association of Regorafenib at the RP2D with Avelumab in 10 distinct disease settings (advanced or metastatic tumors). to evaluate the association of a low-dose of regorafenib with avelumab in advanced or metastatic colorectal cancerThis 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 11 phase II trials :to evaluate the association of Regorafenib at the RP2D with Avelumab in 10 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)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 4, 2018

Actual Primary Completion Date :

Dec 31, 2020

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1 : Regorafenib + Avelumab 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.	Drug: Phase 1 : Regorafenib 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. Drug: Phase 1 : Avelumab 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).
Experimental: Phase 2 : cohort A Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort B Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort C Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort D Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort E Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort F Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort G Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort H Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort I Regorafenib + Avelumab 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.	Drug: Phase 2 : Regorafenib 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. Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial.
Experimental: Phase 2 : cohort A' Regorafenib low-dose + Avelumab 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.	Drug: Phase 2 : Avelumab Phase 2 : Avelumab - All patients will be treated with avelumab with the same schedule as in the phase 1 trial. Drug: Phase 2: low-dose Regorafenib Phase 2 : Regorafenib - All patients will be treated at a fixed low-dose of regorafenib of 80 mg/day

Outcome Measures

Primary Outcome Measures

PHASE I : Recommended phase II dose (RP2D) [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 (7 phase II cohorts) : Assessment of the antitumor activity of regorafenib [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 (cohort H and I): Assessment of the antitumor activity of regorafenib [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 [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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria :

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),
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.

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 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
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

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
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,
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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Bergonié	Bordeaux	France	33076
2	Centre Hospitalier Régional Universitaire - CHU Morvan	Brest	France	29200
3	Centre Léon Bérard	Lyon	France	69008
4	Institut de Cancérologie de Montpellier	Montpellier	France	34298
5	Institut Curie	Paris	France	75248
6	IUCT Oncopôle - Institut Claudius Regaud	Toulouse	France	31059
7	Institut Gustave Roussy	Villejuif	France	94800