Adult patients with advanced or metastatic digestive solid tumors MedDRA version: 20.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10051066 Term: Gastrointestinal stromal tumour System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: HLGT Classification cod
Conditions
Interventions
Product Name: AVELUMAB
Product Code: MSB0010718C
Pharmaceutical Form: Concentrate for solution for infusion
Trade Name: STIVARGA
Product Name: REGORAFENIB
Pharmaceutical Form: Tablet
Sponsors
Institut Bergonié
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histology: - Dose escalation part: histologically confirmed non MSI-H or MMR-deficient colorectal cancer, or GIST, or oesophageal or gastric carcinoma or hepatobiliary cancers, - Expansion cohort : histologically confirmed non MSI-H or MMR-deficient colorectal cancer (cohort A), or GIST (cohort B), or oesophageal or gastric carcinoma (cohort C) or hepatobiliary cancers (cohort D), As recommended by INCa, patients with GIST must have diagnosis histologically confirmed by central review, except if it has been already confirmed by the RRePS Network. 2. Advanced non resectable / metastatic disease, 3. Age = 18 years, 4. ECOG, Performance status = 1, 5. Measurable disease according to RECIST (outside any previously irradiated field). At least one site of disease must be uni-dimensionally = 10 mm, 6. Life expectancy > 3 months, 7. = 1 previous line (s) of systemic therapy 8. Adequate hematological, renal, metabolic and hepatic functions: a. 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. b. 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). c. Total bilirubin = 1.5 x ULN. d.Albumin = 25g/l. e. Calculated creatinine clearance (CrCl) = 30 ml/min (according to Cockroft and Gault formula). f. Creatine phosphokinase (CPK) = 2.5 x ULN g. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants h. aPTT = 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. i. Lipase = 1.5 X ULN j. Cohort specific criteria: Patients with hepatocellular carcinoma must have a correct hepatocellular function, id est Child-Pugh A. 9. 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, 10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy, 11. 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 4.0)), 12. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. 13. 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 include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized (e.g., vasectomy for males and hysterectomy for females) or have not been free from menses for = 1 year. 14. Voluntary signed and dated written informed consents prior to any specific study procedure, 15.
Exclusion criteria
Exclusion criteria: 1. Previous treatment with Avelumab or Regorafenib, 2. 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), 3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases, 4. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding, 5. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 6. Previous enrolment in the present study, 7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons, 8. Known hypersensitivity to any involved study drug or of its formulation components, 9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b. 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 c. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable 10. 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, 11. 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, 12. Has known active hepatitis B or hepatitis C, 13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS) 14. Persistent proteinuria Grade 2 as per NCI CTCAE v4.0, 21. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management, 22. Congestive heart failure = New York Heart Association (NHYA) class 2, 23. Unstable angina (angina symptoms at rest), new-onset ang
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I : Primary objective of the phase I trial is to establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities (DLT) of Regorafenib when prescribed in association with Avelumab (no dose escalation for Avelumab) in patients treated for advanced digestive solid tumors. Phase II : To investigate the antitumor activity of Regorafenib when prescribed in association with Avelumab, independently for 4 cohorts of patients (Colorectal cancer not MSIH or MMR-deficient / GIST / Oesophageal or gastric carcinoma / Biliary tract cancer, hepatocellular carcinoma). Antitumoral activity will be assessed in terms of objective response under treatment as per RECIST 1.1 after in-stream centralized radiological review.;Secondary Objective: Phase I : - Evaluate preliminary signs of anti-tumor activity of Regorafenib in association with Avelumab in terms of 6-month objective response, 6-month progression-free status, best overall response, objective response under treatment, growth modulation index, 1-year progression free survival and 1 year overall survival. - Describe the pharmacokinetics of Regorafenib in association with Avelumab. Phase II : - Evaluate the antitumor activity of Regorafenib in association with Avelumab in terms of 6-month objective response, 6-month progression-free status, best overall response, growth modulation index, 1-year progression-free survival and 1 year overall survival. - Evaluate the Regorafenib safety profile in association with Avelumab. Phase I and II : - Biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood/tissue at baseline and different study time points).;Primary end point(s): PHASE I TRIAL/ DOSE ESCALATION PART : - Toxicity graded using the common toxicity criteria from the NC-CTCAE v4.03 - Incidence rate of DLT at each dose level during the first | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PHASE I TRIAL/ DOSE ESCALATION PART : - Preliminary signs of antitumor activity in terms of : a. Best overall response defined as the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation as per RECIST v1.1 criteria. b. Objective response rate (ORR) defined as the proportion of patients with complete response or partial response, as per RECIST 1. ORR under treatment and 6-month ORR will be reported. c. Progression-free rate (PFR) at 6 months defined as the proportion of patients with complete response, partial response or stable disease more than 24 weeks as per RECIST v1.1 criteria. d. Progression-free survival (PFS) defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. 1-year PFS rate and median PFS will be reported. e. Overall Survival (OS) defined as the time from study treatment initiation to death (of any cause). 1-year OS rate and median OS will be reported. f. Growth modulation index (GMI): GMI will be defined for each patient as the ratio of its PFS on Regorafenib + Avelumab treatment to its PFS on the previous line of therapy. This method accounts for inter-patient variability, the patient serving as his/her own control and implies by the natural history of the disease that the PFS tends to become shorter in successive lines of therapy. It is thought that an anti-cancer agent should be considered effective if the GMI is greater than 1.3 - PK measurements expressed as AUC, half-life and concentration peak for Regorafenib - Pharmacodynamic activity: Predictive biomarkers analysis and pharmacodynamic (PD)/mechanism of action (MOA) in blood (levels of angiogenic and immunologic biomarkers in blood at baseline and different study time points), potentially including but not limited to : a. Serum/plasma cytokines levels (ELISA) b. Treg, CD4+, CD8+ an | — |
Countries
France
Contacts
Public ContactRegulatory Affairs Manager
Institut Bergonié
Outcome results
None listed