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

Phase 1

Recruiting

Conditions: Hepatocellular Carcinoma
Colorectal Cancer Not MSI-H or MMR-deficient
GIST
Oesophageal or Gastric Carcinoma
Biliary Tract Cancer
Soft-tissue Sarcoma
Thyroid Cancer
Gastro-enteropancreatic Neuroendocrine Tumor
HPV-Related Carcinoma
Renal Carcinoma

Registration Number: NCT03475953

Lead Sponsor: Institut Bergonié

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.

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

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 747

Inclusion Criteria

Not provided

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 (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,
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 :
1. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
2. 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
3. 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

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Primary Outcome Measures

Name	Time	Method
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.
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 (7cohorts A, C, D, E, F and G) : 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 (cohorts B, H, I, M, N, O and P): 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.

Secondary Outcome Measures

Name	Time	Method
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 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 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 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 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 - 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

Trial Locations

Locations (7): Centre Léon Bérard
🇫🇷
Lyon, France
Institut Bergonié
🇫🇷
Bordeaux, France
Institut Gustave Roussy
🇫🇷
Villejuif, France
Institut de Cancérologie de Montpellier
🇫🇷
Montpellier, France
Institut Curie
🇫🇷
Paris, France
Centre Hospitalier Régional Universitaire - CHU Morvan
🇫🇷
Brest, France
IUCT Oncopôle - Institut Claudius Regaud
🇫🇷
Toulouse, France

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

Recruitment & Eligibility

Study & Design

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