Sequence Strategy of Immuneoncology (IO-IO) vs IO-tyrosine kinase inhibitors (TKI) followed by TKI in metastatic renal cell carcinoma (mRCC): A randomized phase 3 study Meet uro and FICOG trial. COMBO-Seq trial.

Prior treatment

• Receipt of other investigational drugs within 28 days prior to enrollment.
• Significant cardiac disease within 6 months prior to first dose of the study intervention such as congestive heart failure New York Heart Association Class III or IV, unstable angina, myocardial infarction, cerebral vascular accident, uncontrolled cardiac arrhythmia. Medically controlled arrhythmia is permitted.
• Diagnosis or treatment for another malignancy within 3 years prior to enrollment, except for complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or prostate cancer Gleason 6 (3+3).
• Active and clinically significant hematuria, hematemesis, or hemoptysis within 3 weeks prior to first dose of study drug.
• History of significant bleeding 3 months prior to randomization.
• Major surgery within 3 weeks prior to first dose of study drug, to minimize potential bleeding or late tissue healing due to tyrosine kinase inhibitors (TKIs).
• Untreated Central Nervous System metastasis. Patients with treated brain metastases are eligible if clinically stable and receiving ≤10 mg prednisone-equivalent/day.
• Prior radiation therapy to target lesions. Palliative radiotherapy is permitted.
• Prior immunotherapy, except for adjuvant immunotherapy if completed more than 6 months prior to randomization.
• Prior systemic treatment for locally advanced or metastatic renal cell carcinoma.
• At screening, any ECG abnormality must be documented by the investigator as not clinically significant prior to study entry.
• At screening, any ECHO or MUGA scan abnormality must be documented by the investigator as not clinically significant prior to study entry.

Other illness

• History of allogeneic tissue or solid organ transplant.
• Any condition that is unstable or could jeopardize patient safety or compliance with the study.
• Active infection requiring systemic therapy.
• Absolute contraindication to immunotherapy, including active autoimmune disease that requires systemic treatment (prednisone ≤10 mg/day is permitted).
• Non-infection pneumonitis that requires systemic therapy.
• History of interstitial lung disease.
• Serious medical or psychiatric illness likely to interfere with participation in the study.

Lab values

• Female subjects who are pregnant or breastfeeding. Non-pregnancy must be confirmed by a negative serum β-human chorionic gonadotropin (β-hCG) test within 14 days prior to the administration of the first study treatment. Pregnancy testing is not required for postmenopausal or surgically sterilized women.
• Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or administration of study treatment or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment.

Age

• Less than 18 years old.

Other

• Incapacitated participants - as not all requirements set in Article 31 of Reg. EU 536/2014 are met, especially letter (e).

• Age > 18
• Patients receiving bone resorptive therapy are eligible.
• Availability of archival tumor tissue sample.
• Absolute neutrophil count (ANC) > 1000/mm³, platelets > 100,000/mm³, Hgb > 8 g/dL. Values must be obtained without need for myeloid growth factor or platelet transfusion support within 14 days before randomization.
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN); AST and ALT ≤ 2.5 × ULN. AST and/or ALT may be ≤ 5 × ULN in patients with known liver metastases.
• For patients receiving palliative radiation therapy, a minimum interval of 7 days must be observed between the last radiation treatment and randomization.
• Patients must be accessible for treatment and follow up and must be willing and capable to comply with the requirements of the study.
• Female subject must be either post-menopausal for at least one year before the screening visit, or surgically sterilized, or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the treatment and for up to 5 months after the last dose of study treatment.
• Male subject, even if surgically sterilized (i.e., status post-vasectomy), must agree to use an acceptable method for contraception during the entire study treatment period through 7 months after the last dose of study treatment.
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Histologically confirmed diagnosis of Renal cell Carcinoma (RCC) with or without sarcomatoid features. Clear cell renal cell carcinoma and non-clear cell renal cell carcinoma are eligible except for collecting duct carcinoma and renal medullary carcinoma.
• Diagnosis of locally advanced or metastatic disease according to American Joint Committee on Cancer (AJCC) VIII edition criteria.
• No prior systemic therapy for metastatic or advanced RCC. Adjuvant immunotherapy is permitted if completed more than 6 months prior to randomization.
• At least one measurable lesion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
• Intermediate- or poor-risk mRCC as defined by IMDC classification. Favorable risk patients could be enrolled in an observational cohort and will receive treatment according to investigator’s choice.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Karnofsky Performance Status (KPS) > 50%.