REGORAFENIB for Advanced or metastatic solid tumors

Inclusion criteria

• {"criterion_text":"- 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.\n- 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.\n- 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,\n- At least four weeks or 5 half-lives, whichever is shorter since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,\n- 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)),\n- Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.\n- 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.\n- Voluntary signed and dated written informed consents prior to any specific study procedure,\n- Patients with a social security in compliance with the French law.\n- 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.\n- Cancelled (MSA6)\n- Phase II trials : histologically confirmed : \tnon MSI-H or MMR-deficient colorectal cancer (cohort A). \tnon 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. \tor 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. \tor oesophageal or gastric carcinoma (cohort C) \tor hepatobiliary cancers (cohort D) \tor 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 \tor Radioiodine-Refractory Differentiated Thyroid Cancer (RR-DTC) (cohort F) \tor Neuroendocrine gastroenteropancreatic tumors (GEP-NETs) grade 2 and 3 (cohort G), \tor Non-small cell lung cancer (cohort H), \tor 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. \tor urothelial cancer (cohort J) \tor HPV-associated cancer (cohort K) with molecular confirmation of p16 positive status. \tor triple negative breast cancer (cohort L) \tor TMB-high solid tumors (cohort M) with TMB-high status already known \tor MSI-high solid tumors (cohort N) with MSI-high status already known \tor Non clear-cell renal carcinoma (cohort O) \tor Malignant pleural mesothelioma (cohort P) \tor 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. \tor 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.\n- 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.\n- 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.\n- 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\n- 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\n- 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.\n- For TMB-High cancer patients (Cohort M): - TMB-High is defined as TMB score > 16 mutations /megabase on tissue or blood sample\n- 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.\n- 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.\n- Advanced non resectable / metastatic disease. For cohort Q, metastatic disease.\n- Patients for which either there is no further established therapy that is known to provide clinical benefit,\n- Age ≥ 18 years,\n- ECOG, Performance status ≤ 1,\n- Measurable disease according to RECIST v1.1,\n- Life expectancy > 3 months,\n- Except for cohorts F (RR-DTC), ≥ 1 previous line (s) of systemic therapy."}

Exclusion criteria

• {"criterion_text":"- Previous treatment with Avelumab or Regorafenib,\n- 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.\n- 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.\n- Has known hepatitis B or hepatitis C, active and/or treated by antiviral therapy.\n- Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS).\n- 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).\n- 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.\n- Non-healing wound, non-healing ulcer, or non-healing bone fracture requiring orthopedic treatment.\n- Patients with evidence or history of any bleeding diathesis, irrespective of severity.\n- Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication.\n- 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).\n- 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),\n- Ongoing infection > Grade 2 as per NCI CTCAE v5.0.\n- Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management.\n- History of myocarditis or congestive heart failure ≥ New York Heart Association (NHYA) class 2.\n- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).\n- Myocardial infarction less than 6 months before start of study drug.\n- Uncontrolled cardiac arrhythmias.\n- Pregnant or breast-feeding patients.\n- Individuals deprived of liberty or placed under legal guardianship.\n- Prior organ transplantation, including allogeneic stem-cell transplantation.\n- Known alcohol or drug abuse.\n- 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,\n- Vaccination within 4 weeks of the first dose of Avelumab and while on trial is prohibited except for administration of inactivated vaccines.\n- Patients with any condition that impairs their ability to swallow and retain tablets.\n- 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.\n- Patient with anti-Vitamine K therapy.\n- Suspected or known intraabdominal fistula.\n- 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.\n- Men or women of childbearing potential who are not using an effective method of contraception as previously described.\n- Participation to a study involving a medical or therapeutic intervention in the last 30 days.\n- Previous enrolment in the present study.\n- Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons.\n- Known hypersensitivity to any involved study drug or of its formulation components.\n- 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."}

Primary endpoints

• {"endpoint_text":"- Phase I : Toxicity graded using the common toxicity criteria from the NC-CTCAE v5.","definition_or_measurement_approach":"Toxicity will be graded using the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5."}
• {"endpoint_text":"- Phase I : Incidence rate of DLT at each dose level during the first 28 days.","definition_or_measurement_approach":"Dose-limiting toxicities (DLT) incidence rate assessed at each dose level during the first 28 days (first cycle)."}
• {"endpoint_text":"- Phase II-Cohorts A,C,D,E,F,G: Antitumor activity will be assessed in terms of objective response under treatment based on adapted RECIST 1.1 criteria, and after centralized radiological review:","definition_or_measurement_approach":"Objective response assessed using adapted RECIST v1.1 criteria with centralized radiological review."}
• {"endpoint_text":"- 3a) Objective response under treatment is defined as patients with confirmed complete response (CR) or partial response, as per RECIST v1.1 criteria, observed during treatment with the investigational product(s).","definition_or_measurement_approach":"Objective response defined as confirmed CR or PR per RECIST v1.1 observed during treatment."}
• {"endpoint_text":"- 3b) As per RECIST v1.1 criteria, to be considered as “confirmed”, complete and partial responses will have to be confirmed at least 4 weeks later to ensure responses identified are not the result of measurement errors. If the new imaging to confirm response is not performed after 4 weeks, complete or partial responses will be considered as unconfirmed responses.","definition_or_measurement_approach":"Responses (CR/PR) require confirmation on re-imaging at least 4 weeks after initial response to be considered confirmed; otherwise considered unconfirmed."}
• {"endpoint_text":"- 3c) Objective response rate (ORR) under treatment is defined as the proportion of patients with objective response (confirmed or unconfirmed) under treatment based on adapted RECIST 1.1.","definition_or_measurement_approach":"ORR = proportion of patients with confirmed or unconfirmed CR or PR per adapted RECIST v1.1."}
• {"endpoint_text":"- Phase II-Cohorts B,H,I,M,N,O,P,R: 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. 6-month PFR is defined as the proportion of patients with progression-free status at 6 months. Progression-free status is defined as complete response (confirmed or unconfirmed), partial response (confirmed or unconfirmed) or stable disease more than 24 weeks as defined as per RECIST v1.1 criteria.","definition_or_measurement_approach":"6-month PFR = proportion of patients progression-free at 6 months (CR/PR confirmed or unconfirmed or stable disease >24 weeks) assessed by RECIST v1.1 with centralized review."}
• {"endpoint_text":"- Phase II-Cohort A': antitumor activity will be assessed in terms of 4- month progression-free rate (4-month PFR) based on RECIST 1.1 criteria after centralized radiological review. 4-month PFR is defined as the proportion of patients with progression-free status at 4 months. Progression-free status is defined as complete response (confirmed or unconfirmed), partial response (confirmed or unconfirmed) or stable disease more than 24 weeks as defined as per RECIST v1.1 criteria.","definition_or_measurement_approach":"4-month PFR = proportion of patients progression-free at 4 months (CR/PR confirmed or unconfirmed or stable disease >24 weeks) assessed by RECIST v1.1 with centralized review."}
• {"endpoint_text":"- Phase II-Cohorts J,K,L:antitumor activity will be assessed in terms of disease control rate at 6-month based on RECIST 1.1 criteria after centralized radiological review. 6-month DCR rate is defined as the proportion of participants with confirmed complete response, unconfirmed complete response, confirmed partial response or unconfirmed partial response within 24 weeks of treatment onset (while treated with the investigational product), or stable disease at 6 months, as per adapted RECIST v1.1.","definition_or_measurement_approach":"6-month DCR = proportion with CR/CRu/PR/PRu within 24 weeks or stable disease at 6 months, per adapted RECIST v1.1 with centralized review."}
• {"endpoint_text":"- Phase II-Cohort Q: 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]. 6-month rPFR is defined as the proportion of patients with radiographic progression-free status at 6 months. Radiographic progression is defined as per RECIST/PCWG3 criteria as soft-tissue and/or bone progression as follows :","definition_or_measurement_approach":"6-month rPFR assessed by RECIST v1.1 for soft-tissue lesions and PCWG3 for bone lesions after centralized radiological review; rPFR = proportion radiographic progression-free at 6 months."}
• {"endpoint_text":"- 10a) Soft tissue: Radiographic progression is defined as an increase in measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).","definition_or_measurement_approach":"Soft-tissue progression defined per RECIST v1.1 (increase in measurable disease)."}
• {"endpoint_text":"- 10b) Bone: Bone progression is defined by the occurrence of at least 2 new lesions.","definition_or_measurement_approach":"Bone progression defined as occurrence of ≥2 new bone lesions (per PCWG3 criteria as applicable)."}

Secondary endpoints

• {"endpoint_text":"- Phase I secondary endpoints : Preliminary signs of antitumor activity in terms of:","definition_or_measurement_approach":"Descriptive listing of preliminary anti-tumour activity metrics (see subsequent secondary endpoints)."}
• {"endpoint_text":"- 1a) 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.","definition_or_measurement_approach":"Best overall response = best RECIST v1.1 response from treatment start to end, accounting for confirmation requirements."}
• {"endpoint_text":"- 1b) 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.","definition_or_measurement_approach":"ORR = proportion of patients with CR or PR per RECIST v1.1; reported overall and at 6 months."}
• {"endpoint_text":"- 1c) 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.","definition_or_measurement_approach":"6-month PFR = proportion with CR/PR or stable disease ≥24 weeks per RECIST v1.1."}
• {"endpoint_text":"- 1d) 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.","definition_or_measurement_approach":"PFS = time from treatment start to progression or death; 1-year PFS rate and median PFS to be reported."}
• {"endpoint_text":"- 1e) 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.","definition_or_measurement_approach":"OS = time from treatment start to death; 1-year OS rate and median OS to be reported."}
• {"endpoint_text":"- 1f) 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.","definition_or_measurement_approach":"GMI = (PFS on study treatment) / (PFS on previous therapy); effectiveness suggested if GMI > 1.3."}
• {"endpoint_text":"- Phase I secondary endpoints :PK measurements expressed as AUC, half-life and concentration peak for Regorafenib","definition_or_measurement_approach":"Pharmacokinetic measurements for Regorafenib including AUC, half-life (t1/2) and Cmax."}
• {"endpoint_text":"- Phase I secondary endpoints : 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:","definition_or_measurement_approach":"PD assessments in blood for angiogenic and immunologic biomarkers at baseline and defined timepoints."}
• {"endpoint_text":"- 9a) Serum/plasma cytokines levels (ELISA)","definition_or_measurement_approach":"Measurement of serum/plasma cytokine concentrations by ELISA."}
• {"endpoint_text":"- 9b) Treg, CD4+, CD8+ and DR lymphocytes subpopulations (flow cytometry)","definition_or_measurement_approach":"Lymphocyte subpopulation analysis by flow cytometry (Treg, CD4+, CD8+, HLA-DR)."}
• {"endpoint_text":"- 9c) Archived tumor tissue will be collected for assessment of tumor VEGFR, PDGFR, HIF1alpha expression and lymphocytes, TAM and MDSC tumor infiltrates (IHC)","definition_or_measurement_approach":"IHC assessment on archived tumor tissue for VEGFR, PDGFR, HIF1alpha and immune infiltrates (TAM, MDSC, lymphocytes)."}
• {"endpoint_text":"- 9d) In additional, for all patients, optional biopsy at baseline and after 4 weeks of treatment will be proposed for mechanisms of action documentation: tumor VEGFR, PDGFR, HIF1alpha expression as well as PD-L1/PD1, lymphocytes, TAM, MDSC tumor infiltrates (IHC) and mutational burden.","definition_or_measurement_approach":"Optional paired biopsies (baseline and at 4 weeks) for IHC and mutational burden analyses to document mechanisms of action."}
• {"endpoint_text":"- Phase II secondary endpoints [All cohorts, except cohort Q]: Best overall response is defined as the best response across all time points (RECIST v1.1). Following RECIST v1.1 recommendations:","definition_or_measurement_approach":"Best overall response per RECIST v1.1 across all timepoints (see RECIST confirmation rules)."}
• {"endpoint_text":"- 14a) The best overall response is determined once all the data for the patient is known.","definition_or_measurement_approach":"Best overall response determined post-hoc once complete patient data are available."}
• {"endpoint_text":"- 14b) The best overall response will be classified as confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR), unconfirmed partial response (PRu), stable disease or progressive disease, as per RECIST v1.1 criteria.","definition_or_measurement_approach":"Classification of best overall response into CR/CRu/PR/PRu/stable/progressive per RECIST v1.1."}
• {"endpoint_text":"- 14c) As per RECIST v1.1 criteria, to be considered as “confirmed”, complete and partial responses will have to be confirmed at least 4 weeks later to ensure responses identified are not the result of measurement errors.","definition_or_measurement_approach":"Confirmation rule: CR/PR require repeat imaging ≥4 weeks after initial response to be confirmed."}
• {"endpoint_text":"- Phase II [All cohorts, except cohort Q]: Objective response rate at 6 months (6-month ORR) is defined as the proportion of patients with objective response (confirmed or unconfirmed) at 6 months.","definition_or_measurement_approach":"6-month ORR = proportion with CR/PR (confirmed or unconfirmed) at 6 months per RECIST v1.1."}
• {"endpoint_text":"- Phase II [All cohorts, except cohort Q]: Progression-free status is defined as complete response (confirmed or unconfirmed), partial response (confirmed or unconfirmed) or stable disease more than 24 weeks as defined as per RECIST v1.1 criteria (appendix 3). 6-month progression-free rate (6-month PFR) is defined as the proportion of patients with progression-free status at 6 months. 4- month progression-free rate is defined as the proportion of patients with progression-free status at 4 months.","definition_or_measurement_approach":"PFR definitions as per RECIST v1.1; 6-month and 4-month PFR calculated accordingly."}
• {"endpoint_text":"- Phase II Cohort Q : PSA response rate is defined as the percentage of patients reaching a PSA decline from baseline ≥ 50% with PSA confirmation ≥ 3 weeks after the first documented reduction in PSA of ≥ 50%. The PSA response rate will be calculated as the proportion of participants with a PSA response in the PSA response-evaluable population.","definition_or_measurement_approach":"PSA response = ≥50% decline from baseline with confirmation ≥3 weeks later; rate calculated in PSA-evaluable population."}
• {"endpoint_text":"- Phase II Cohort Q : The 1-year PSA response rate will be calculated as the proportion of participants with a PSA response at one year. after the first documented reduction in PSA","definition_or_measurement_approach":"1-year PSA response rate = proportion with confirmed PSA response at 1 year."}
• {"endpoint_text":"- Phase II Cohort Q : PSA-Progression Free Survival (PSA-PFS) is defined as the time from treatment initiation until first evidence of PSA progression or until death from any cause, whichever comes first. PSA progression is defined by the criteria of the Prostate Cancer Clinical Trials Working Group (PCWG 3) as follows:","definition_or_measurement_approach":"PSA-PFS = time from treatment start to PSA progression or death; PSA progression defined per PCWG3 criteria."}
• {"endpoint_text":"- 22a) For patients with a PSA decrease observed after baseline: PSA progression is defined as the first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 1 week later (i.e., a confirmed rising trend). The date of progression corresponds to the date of the first PSA increase that is ≥ 25% and ≥ 2 ng/mL above the nadir.","definition_or_measurement_approach":"For patients with PSA decrease: progression = first PSA increase ≥25% and ≥2 ng/mL above nadir confirmed by a second value ≥1 week later; progression date = date of first qualifying increase."}
• {"endpoint_text":"- 22b) For patients without a PSA decrease observed after baseline: PSA progression is defined as PSA progression ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.","definition_or_measurement_approach":"For patients without PSA decrease: progression = ≥25% and ≥2 ng/mL increase from baseline after 12 weeks."}
• {"endpoint_text":"- Phase II : Growth modulation index (GMI): GMI is 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 anticancer agent should be considered effective if the GMI is greater than 1.3.","definition_or_measurement_approach":"GMI = PFS on study / PFS on previous line; effectiveness threshold considered >1.3."}
• {"endpoint_text":"- Phase II : Progression-free survival (PFS) is 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.","definition_or_measurement_approach":"PFS defined as time from treatment start to progression or death; 1-year PFS rate and median PFS reported."}
• {"endpoint_text":"- Phase II : Overall Survival (OS) is defined as the time from study treatment initiation to death (of any cause). 1-year OS rate and median OS will be reported.","definition_or_measurement_approach":"OS defined as time from treatment start to death; 1-year OS rate and median OS reported."}
• {"endpoint_text":"- Phase II : Safety profile of the association Regorafenib + Avelumab: Toxicity will be graded using the common toxicity criteria from the NCI v5.0.","definition_or_measurement_approach":"Safety/toxicity graded per NCI-CTCAE v5.0."}
• {"endpoint_text":"- Phase II : Pharmacodynamic activity: o archived tumor tissue will be collected for assessment of the tumor microenvironment. o to perform integrative assessment of biomarkers of efficacy (genetic, metabolomics profiling in blood/tissue at baseline and different study time points) and its prognostic value on efficacy.","definition_or_measurement_approach":"PD assessments include archived tissue microenvironment analyses and integrative biomarker profiling (genetic, metabolomics) at baseline and defined time points."}
• {"endpoint_text":"- Phase II Cohort B : To evaluate the antitumor activity based on Choi criteria in terms of non-progression at 6 months.","definition_or_measurement_approach":"For Cohort B (GIST) antitumor activity evaluated by Choi criteria for non-progression at 6 months."}

France

Earliest CTIS Part Ii Submission Date

13-08-2024

Latest Decision Or Authorization Date

21-11-2025

Processing Time Days

465

Number Of Sites

7

Number Of Participants

827

Primary sponsor

Full Name

Institut Bergonie

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France