Clinical Trials /

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

NCT03475953

Description:

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

Related Conditions:
  • Bile Duct Carcinoma
  • Colorectal Carcinoma
  • Esophagogastric Carcinoma
  • Gastrointestinal Stromal Tumor
  • Hepatocellular Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase I/II Study of Regorafenib Plus Avelumab in Digestive Tumors
  • Official Title: A Phase I/II Study of Regorafenib Plus Avelumab in Digestive Tumors

Clinical Trial IDs

  • ORG STUDY ID: IB 2017-01
  • SECONDARY ID: 2016-005175-27
  • NCT ID: NCT03475953

Conditions

  • Colorectal Cancer Not MSI-H or MMR-deficient
  • GIST
  • Oesophageal or Gastric Carcinoma
  • Biliary Tract Cancer
  • Hepatocellular Carcinoma

Interventions

DrugSynonymsArms
Phase 1 : RegorafenibPhase 1 : Regorafenib + Avelumab
Phase 1 : AvelumabPhase 1 : Regorafenib + Avelumab
Phase 2 : RegorafenibPhase 2 : Regorafenib + Avelumab
Phase 2 : AvelumabPhase 2 : Regorafenib + Avelumab

Purpose

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

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 a phase II trial to evaluate the association of
      Regorafenib at the RP2D with Avelumab in 4 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
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 : Regorafenib + AvelumabExperimentalAvelumab 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 1 : Regorafenib
  • Phase 1 : Avelumab
Phase 2 : Regorafenib + AvelumabExperimentalAvelumab 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 : Regorafenib
  • Phase 2 : Avelumab

Eligibility Criteria

        Inclusion Criteria :

          1. Histology:

               -  Dose escalation part: histologically confirmed non MSI-H or deficient-MMR
                  colorectal cancer, or GIST, or esophageal or gastric carcinoma or hepatobiliary
                  cancers,

               -  Expansion cohort : histologically confirmed non MSI-H or deficient-MMR colorectal
                  cancer (cohort A), or GIST (cohort B), or esophageal or gastric carcinoma (cohort
                  C) or hepatobiliary cancers (cohort D), 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.

          2. Advanced non resectable / metastatic disease,

          3. 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,

          4. Age ≥ 18 years,

          5. ECOG, Performance status ≤ 1,

          6. Measurable disease according to RECIST (outside any previously irradiated field). At
             least one site of disease must be uni-dimensionally ≥ 10 mm,

          7. Life expectancy > 3 months,

          8. ≥ 1 previous line (s) of systemic therapy,

          9. Adequate hematological, renal, metabolic and hepatic functions:

               1. 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.

               2. 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).

               3. Total bilirubin ≤ 1.5 x ULN.

               4. Albumin ≥ 25g/l.

               5. Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and
                  Gault formula).

               6. Creatine phosphokinase (CPK) ≤ 2.5 x ULN.

               7. 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.

               8. 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.

               9. Lipase ≤ 1.5 X ULN.

              10. Cohort specific criteria: Patients with hepatocellular carcinoma must have a
                  correct hepatocellular function, id est Child-Pugh A.

         10. 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,

         11. At least three weeks since last chemotherapy, immunotherapy or any other
             pharmacological treatment and/or radiotherapy,

         12. 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)),

         13. Women of childbearing potential must have a negative serum pregnancy test within 72
             hours prior to receiving the first dose of study medication,

         14. 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,

         15. Voluntary signed and dated written informed consents prior to any specific study
             procedure,

         16. Patients with a social security in compliance with the French law.

        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 :

               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

         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 < 3.5 g/24 hours measured by urine protein-creatinine ratio
             from a random urine sample (≥ Grade 3, NCI-CTCCAE v 4.0),

         15. Major surgical procedure or significant traumatic injury within 28 days before start
             of study medication,

         16. Non-healing wound, non-healing ulcer, or non-healing bone fracture,

         17. Patients with evidence or history of any bleeding diathesis, irrespective of severity,

         18. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of
             study medication,

         19. 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),

         20. Ongoing infection > 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 angina (begun within the last 3
             months),

         24. Myocardial infarction less than 6 months bedfore start of study drug,

         25. Uncontrolled cardiac arrhythmias,

         26. Pregnant or breast-feeding patients,

         27. Individuals deprived of liberty or placed under legal guardianship,

         28. Prior organ transplantation, including allogeneic stem-cell transplantation,

         29. Known alcohol or drug abuse,

         30. Vaccination within 4 weeks of the first dose of Avelumab and while on trial is
             prohibited except for administration of inactivated vaccines,

         31. Patients with any condition that impairs their ability to swallow and retain tablets,

         32. 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,

         33. Patient with oral anticoagulation therapy,

         34. Suspected or known intraabdominal fistula.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:PHASE I : Recommended phase II dose (RP2D)
Time Frame:During the first cycle (28 days)
Safety Issue:
Description:Recommended phase II dose (RP2D) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.

Secondary Outcome Measures

Measure:PHASE I : Maximum Tolerated Dose (MTD)
Time Frame:During the first cycle (28 days)
Safety Issue:
Description:Maximum Tolerated Dose (MTD) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
Measure:PHASE I : Dose Limiting Toxicities (DLT)
Time Frame:During the first cycle (28 days)
Safety Issue:
Description:Dose Limiting Toxicities (DLT) evaluated on the first cycle (Day 1 to Day 28) of regorafenib when prescribed in association with avelumab.
Measure:PHASE I : Toxicity
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description:Toxicity graded using the common toxicity criteria from the NCI v4.03.
Measure:PHASE I : Assessment of the antitumor activity of regorafenib - Best overall response
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description:Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of best overall response as per RECIST v1.1.
Measure: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
Safety Issue:
Description: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.
Measure:PHASE I :Assessment of the antitumor activity of regorafenib - objective response rate
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description: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.
Measure:PHASE I :Assessment of the antitumor activity of regorafenib - non-progression
Time Frame:6 months
Safety Issue:
Description: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
Measure:PHASE I :Assessment of the antitumor activity of regorafenib - progression-free survival (PFS)
Time Frame:1 year
Safety Issue:
Description: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.
Measure:PHASE I : Assessment of the antitumor activity of regorafenib - overall survival (OS)
Time Frame:1 year
Safety Issue:
Description: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.
Measure:PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time Frame:Day 15 of cycle 1 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measure:PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time Frame:Day 1 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measure:PHASE I :Pharmacocinetics (PK) - Area Under Curve (AUC)
Time Frame:Day 15 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as Area Under Curve (AUC) for regorafenib.
Measure:PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time Frame:Day 15 of cycle 1 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as half-life for regorafenib.
Measure:PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time Frame:Day 1 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as half-life for regorafenib.
Measure:PHASE I :Pharmacocinetics (PK) - half-life for regorafenib.
Time Frame:Day 15 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as half-life for regorafenib.
Measure:PHASE I :PK - concentration peak for regorafenib.
Time Frame:Day 15 of cycle 1 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as concentration peak for regorafenib
Measure:PHASE I :PK - concentration peak for regorafenib.
Time Frame:Day 1 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as concentration peak for regorafenib
Measure:PHASE I :PK - concentration peak for regorafenib.
Time Frame:Day 15 of cycle 2 (Each cycle is 28 days)
Safety Issue:
Description:PK measurement expressed as concentration peak for regorafenib
Measure:Phase I: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
Time Frame:day 1 of cycles 1, 2, 4, 6 and at progression
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in blood
Measure:Phase I: Predictive blood biomarkers analysis (lymphocytes) by flow cytmetry.
Time Frame:day 1 of cycles 1, 2, 4, 6 and at progression
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in blood
Measure:Phase I: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
Time Frame:day 1 of cycle 1 and day 1 of cycle 2
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in tissue
Measure:Phase I: Adverses events graded using the common toxicity criteria from the NCI v4.03 to determine the safety profile of regorafenib plus avelumab.
Time Frame:throughouth the treatment period, an average of 6 months
Safety Issue:
Description:Toxicity graded using the common toxicity criteria from the NCI v4.03.
Measure:PHASE II : Assessment of the antitumor activity of regorafenib - Best overall response
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description:Assessment of the antitumor activity of regorafenib when prescribed in association with avelumab in terms of best overall response as per RECIST v1.1.
Measure:PHASE II : Assessment of the antitumor activity of regorafenib - objective response rate
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description: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.
Measure:PHASE II :Assessment of the antitumor activity of regorafenib - non progression
Time Frame:6 months
Safety Issue:
Description: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.
Measure:PHASE II : Assessment of the antitumor activity of regorafenib - Progression-Free Survival (PFS)
Time Frame:1 year
Safety Issue:
Description: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.
Measure:PHASE II : Assessment of the antitumor activity of regorafenib - Overall Survival
Time Frame:1 year
Safety Issue:
Description: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.
Measure:Phase II: Predictive blood biomarkers analysis (cytokines levels) by ELISA.
Time Frame:day 1 of cycles 1, 2, 4, 6 and at progression
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in blood
Measure:Phase II: Predictive blood biomarkers analysis (lymphocytes) by flow cytmetry.
Time Frame:day 1 of cycles 1, 2, 4, 6 and at progression
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in blood
Measure:Phase II: Predictive tumor growth factor biomarkers analysis by immunohistochemistry.
Time Frame:day 1 of cycle 1 and day 1 of cycle 2
Safety Issue:
Description:levels of angiogenic and immunologic biomarkers in tissue

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institut Bergonié

Trial 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

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