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REGOMUNE : A phase I/II study of Regorafenib plus Avelumab in solid tumors
EU CTIS ID: 2023-509500-15-00
What this study is testing
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 19 cohorts of patients : Colorectal cancer not MSIH or MMR-deficient (Cohorts A and A’ with immune signature (based on low tumor-associated macrophages infiltrate level), GIST (Cohort B), Oesophageal or gastric carcinoma (Cohort C), Biliary tract cancer, hepatocellular carcinoma (Cohort D), Soft Tissue Sarcoma (STS – Cohort E), Radioiodine-Refractory Differentiated Thyroid Cancer (RR-DTC – Cohort F), Neuroendocrine gastroenteropancreatic tumors (GEP-NETs – Cohort G), Non-small cell lung cancer (NSCLC - Cohort H), Solid tumors (including Soft Tissue Sarcoma) with immune signature (TLS+) (Cohort I), urothelial cancer (Cohort J), HPV-associated cancer (Cohort K), triple negative breast cancer (L), TMB-high solid tumors (Cohort M), MSI-high solid tumors (Cohort N), non clear-cell renal carcinoma (Cohort O), malignant pleural mesothelioma (Cohort P), metastatic castration resistant prostate cancer (Cohort Q) with immune signature (TLS+) and neuroendocrine prostate cancer (Cohort R). For cohorts A (Colorectal cancer not MSI-H or MMR-deficient [standard dose]), C (Oesophageal or gastric carcinoma), D (Biliary tract cancer, hepatocellular carcinoma), E (Soft Tissue Sarcoma [STS]), F (Radioiodine-Refractory Differentiated Thyroid Cancer), G (Neuroendocrine gastroenteropancreatic tumors):: antitumoral activity will be assessed in terms of objective response under treatment based on adapted RECIST 1.1 criteria after centralized radiological review (see endpoints section). For cohorts B (GIST), H (NSCLC), I (Solid tumors -TLS+), M (TMB-high solid tumors), N (MSI-high solid tumors), O (non clear-cell renal carcinoma), P (malignant pleural mesothelioma) and R (neuroendocrine prostate cancer), antitumor activity will be assessed in terms of 6-month progression-free rate (6-month PFR) based on RECIST 1.1 criteria after centralized radiological review (see endpoints, section 9). For cohort A’ with immune signature (based on low tumor-associated macrophages infiltrate level, antitumor activity will be assessed in terms of 4-month progressionfree rate (4-month PFR) based on RECIST 1.1 criteria after centralized radiological review (see endpoints, section 9). For cohorts J, K and L, antitumor activity will be assessed in terms of disease control rate at 6-month (6-month DCR) based on RECIST 1.1 criteria after centralized radiological review (see endpoints, section 9). For cohort Q (metastatic castration resistant prostate cancer with immune signature [TLS+]), antitumor activity will be assessed in terms of 6-month radiographic progression-free rate (6-month rPFR), after centralized radiological review, as per RECIST 1.1 for extra-skeletal lesions and PCWG3 for skeletal lesions criteria response criteria [88] (see endpoints, section 9).
- Phase I and Phase II (Integrated)- Other
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- Phase I - Histology : - Dose escalation part: histologically confirmed non MSI-H or MMR-deficient colorectal cancer, or GIST, or oesophageal or gastric carcinoma or hepatobiliary cancers.
- 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. 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 and/or liver metastasis for AP 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 or PT ≤ 1.5 x ULN h. aPTT ≤ 1.5 X ULN. 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. k. Cohort Q: serum testosterone < 50 ng/dL.
- No prior or concurrent malignant disease diagnosed or treated in the last 3 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 four weeks or 5 half-lives, whichever is shorter 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.
You likely can't join if
- Previous treatment with Avelumab or Regorafenib,
- 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. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours).
See the full eligibility criteria
Who can join
- Phase I - Histology : - Dose escalation part: histologically confirmed non MSI-H or MMR-deficient colorectal cancer, or GIST, or oesophageal or gastric carcinoma or hepatobiliary cancers.
- 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. 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 and/or liver metastasis for AP 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 or PT ≤ 1.5 x ULN h. aPTT ≤ 1.5 X ULN. 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. k. Cohort Q: serum testosterone < 50 ng/dL.
- No prior or concurrent malignant disease diagnosed or treated in the last 3 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 four weeks or 5 half-lives, whichever is shorter 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 seven months (210 days) in WOCBP or four months (120 days) in men sexually active with WOCBP after discontinuation of treatment. Acceptable methods for contraception are described in 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 patient of cohorts 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 at less than 6 months in the period of 12 months prior to inclusion. - For patient 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.
- Cancelled (MSA6)
- Phase II trials : histologically confirmed : non MSI-H or MMR-deficient colorectal cancer (cohort A). non MSI-H or MMR-deficient colorectal cancer with immune signature (cohort A’), i.e. low tumor-associated macrophages infiltrate level as determined by central review. Except if the low level of tumor-associated macrophages infiltrate level has been already confirmed by Biopathological platform at Bergonié Institute, the low level of tumor-associated macrophages infiltrate level should be confirmed by central review based on FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose). Note that the level of tumor-associated macrophages infiltrate could be determined by central analysis if not available before. or GIST (cohort B) : as recommended by INCa, patients must have diagnosis histologically confirmed by central review, except if it has been already confirmed by the RRePS Network. or oesophageal or gastric carcinoma (cohort C) or hepatobiliary cancers (cohort D) or Soft Tissue Sarcoma (STS) (cohort E) : as recommended by INCa, patients must have diagnosis 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 (GEP-NETs) grade 2 and 3 (cohort G), or Non-small cell lung cancer (cohort H), or Solid tumors including soft-tissue sarcoma with immune signature (cohort I), i.e. presence of mature tertiary lymphoid structures (TLS). Except if presence of TLS has been already confirmed by Biopathological platform at Bergonié Institute, presence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose). Note that the presence of TLS could be determined by central analysis if not available before. or urothelial cancer (cohort J) or HPV-associated cancer (cohort K) with molecular confirmation of p16 positive status. or triple negative breast cancer (cohort L) or TMB-high solid tumors (cohort M) with TMB-high status already known or MSI-high solid tumors (cohort N) with MSI-high status already known or Non clear-cell renal carcinoma (cohort O) or Malignant pleural mesothelioma (cohort P) or Metastatic castration resistant prostate cancer (cohort Q) with immune signature i.e., presence of mature tertiary lymphoid structures (TLS). TLS status determination can be centrally performed by Biopathological platform at Bergonié Institute or on each investigation site by a pathologist specifically trained by a representative of Biopathological platform at Bergonié Institute. or neuroendocrine prostate cancer (cohort R) defined by the presence of 50% or more of neuroendocrine subtype in the tumor or the presence of 2 of the 3 subsequent genomic alterations: PTEN loss, RB1 mutation, TP53 mutation detected by NGS on tissue and/or blood samples.
- For patients with non-small cell lung cancer (cohort H): - Subjects with histologically or cytologically confirmed diagnosis of nonsquamous NSCLC. - Documented disease progression based on radiographic imaging, during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/Stage IV or metastatic disease. Two components of treatment must have been received in the same line or as separate lines of therapy : A maximum of 1 line of platinum-containing chemotherapy regimen in the metastatic setting, and 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. o No EGFR, ALK, ROS1 positive tumor mutations o 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) MSIhigh solid tumors (cohort N), Non clear-cell renal carcinoma (cohort O): - A maximum of 1 line of PD(L)1 mAb containing regimen, and - Patients must have received at least 4 months of PD(L1) in the case they received this treatment
- For malignant pleural mesothelioma (Cohort P): - A maximum of 1 line of PD(L)1/CTLA-4 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. Except if CPS<10, an anterior line of PD(L)1 mAb is not mandatory.
- For TMB-High cancer patients (Cohort M): - TMB-High is defined as TMB score > 16 mutations /megabase on tissue or blood sample
- For cohort Q: - progressive disease documented at inclusion either a PSA progression defined by a minimum of 2 rising PSA values of more than 2.0ng/mL with an interval of at least 1 week between the measurements OR bone disease progression as defined by PCWG3 criteria OR soft tissue disease progression as defined by RECIST 1.1 criteria . - Previous exposure to at least one new-hormone therapy (eg. abiraterone/enzalutamide/apalutamide/darolutamide). Patients may have received radionucleide-based therapies, or taxane based therapies.
- For cohort R: previous exposure to a platinum-based chemotherapy (CT) or one new-hormone therapy (eg. abiraterone/enzalutamide/apalutamide/darolutamide). - If platinum-based CT was administered for localized disease, relapse and/or progression should occured within 12 months after the last CT administration to allow inclusion in the REGOMUNE study. Otherwise, platinum-based CT must be reintroduced before a potential inclusion in the REGOMUNE study. - If platinum-based CT was administered for advanced/metastatic disease, patient can be enrolled in the REGOMUNE study without delays.
- Advanced non resectable / metastatic disease. For cohort Q, metastatic disease.
- Patients for which either there is no further established therapy that is known to provide clinical benefit,
- Age ≥ 18 years,
- ECOG, Performance status ≤ 1,
- Measurable disease according to RECIST v1.1,
- Life expectancy > 3 months,
- Except for cohorts F (RR-DTC), ≥ 1 previous line (s) of systemic therapy,
What rules you out
- Previous treatment with Avelumab or Regorafenib,
- 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. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours).
- Major surgical procedure or significant traumatic injury within 28 days before start of study medication. Note: If a patient had major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
- 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).
- For cohorts A to G and A’: Has received prior therapy with an anti-PD-1, anti-PDL1, 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 co-stimulation or checkpoint pathways),
- 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.
- History of myocarditis or 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 before 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.
- Evidence of progressive or symptomatic or newly diagnosed central nervous system (CNS) or leptomeningeal metastases. Participants with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks before the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 7 days before study treatment,
- 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 anti-Vitamine K therapy.
- Suspected or known intraabdominal fistula.
- For cohort H (NSCLC): - Received > 2 prior lines of therapy for NSCLC, including subjects with BRAF molecular alterations, - Subjects with known EGFR/ALK/ROS1 molecular alterations are excluded from participation in this study.
- 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: 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.
The study team makes the final eligibility decision.
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 65+ years, 18-64 years. The study team makes the final eligibility decision.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.