Ensayos clínicos

Inclusion Criteria:

• Signed Informed Consent Form.
• Age ≥ 18 years old.
• ECOG performance status of ≤ 1.
• Able to comply with the study protocol, in the investigator’s judgment.
• Pathologically confirmed RCC with a component of either clear cell histology or sarcomatoid histology (sarcomatoid differentiation regardless of the primary epithelial subtype) that has not been previously treated in the adjuvant or neoadjuvant setting
  • Patients with localized disease with T2 Grade 4, T3a Grade 3-4, T3b/c any grade, T4 any grade and TxN + any grade are eligible.
  • Patients with pulmonary (treated with sub-lobar or lobar resection), lymph node, or soft-tissue metachronous recurrence of disease occurring greater than 12 months following nephrectomy who undergo complete resection (R0; microscopically margin-negative resection in which no gross of microscopic disease remains) and have no evidence of disease following metastasectomy are eligible. Patients with resected CNS, bone or adrenal metastasis are not eligible. 
  • Patients with synchronous metastases who have  ndergone complete resection of residual disease are eligible in the following circumstances: isolated solitary ipsilateral or contralateral adrenal metastasis treated with adrenalectomy and lung metastases treatable with a sub-lobar or lobar resection within 12 weeks of nephrectomy.
  • Patients with resected CNS, bone or other soft-tissue metastasis are not eligible. 
  • Medical Monitor approval is necessary for patients with resected metachronous and synchronous metastasis. 
  • A TNM/grading high risk classification is not required for  patients with metachronous/synchronous recurrence.
• Radical or partial nephrectomy with lymphadenectomy in select patients
  • Surgeries may be performed by the open, laparoscopic, or robotic approach.
  • Nephrectomy should include a lymph node dissection in patients with suspected nodal metastases on preoperative imaging (e.g., 2 cm) rendering the patient surgically NED (no evidence of disease). For patients with clinical venous involvement or whose tumors are  clinically > 10 cm, a lymph node dissection is recommended but not required. The extent of the lymph node dissection will be at the discretion of the treating surgeon. 
  • For patients with no preoperative evidence of abdominal node involvement and those not at increased risk of nodal metastases, a lymph node dissection is not required.
  • Patients must have a negative surgical margin. Positive surgical margin is defined as tumor identified at the inked perinephric fat margin surrounding the nephrectomy specimen (R2), evidence of microscopic disease at the tumor margin (R1), or evidence of tumor histologically invading or adherent to the renal vein wall at the margin. Luminal thrombus without venous wall invasion is not considered a positive margin. The final surgical margin must be free of disease. Contact the Medical  Monitor if clarification is required.
  • For patients with evidence of thrombus involving the inferior vena cava and/or right atrium (i.e., cavoatrial involvement), a thrombectomy should be performed at the time of the radical nephrectomy.
• Representative formalin-fixed paraffin-embedded (FFPE) resected tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for central testing and determined to be evaluable for tumor PD-L1 expression prior to study enrollment.
  • Up to 5 unstained slides will be used to determine tumor PD-L1 expression. The remaining unstained slides will support exploratory biomarker analysis and objectives
  • Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible after discussion with the Medical Monitor.
  • Tumor tissue should be of good quality based on total and viable tumor content.  Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. For core-needle biopsy specimens, at least three cores hould be submitted for evaluation.
  • The tumor specimen must contain adequate viable tumor tissue to establish PD-L1 expression status.
  • Patients who have additional tissue samples from procedures performed at different times (e.g., nephrectomy and metastasectomy) during the course of their RCC will be requested (but not required) to also submit these samples for central testing.
  • In situations in which multiple specimens were received from different sites or at different times, the highest score will be used for eligibility.
• Absence of residual disease and absence of metastasis, as confirmed by a negative baseline computed tomography (CT) of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization (for patients with a contraindication to CT with contrast, see Section 4.5.5). Confirmation of disease-free status will be assessed by an independent central radiologic review of imaging data (see Appendix 9 for details on criteria for assessment of disease-free status by imaging).
• Absence of brain metastasis, as confirmed by a negative CT with contrast or MRI scan of the brain, no more than 4 weeks prior to randomization
  • Applicable only to patients who are eligible based upon completely resected metachronous lung, soft tissue or lymph node metastasis, or synchronous lung or adrenal metastasis
• Full recovery from nephrectomy or metastasectomy within 12 weeks from randomization following surgery.
  • Randomization should occur within 12 weeks after nephrectomy or metastasectomy.
• Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 28 days prior to randomization:
  • ANC ≥ 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
  • WBC counts > 2500/µL
  • Lymphocyte count ≥ 300/µL
  • Platelet count ≥ 100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
  • Hemoglobin ≥ 9.0 g/dL
  • Patients may be transfused or receive erythropoietic treatment to meet this criterion.
  • AST, ALT, and alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN)
  • Serum bilirubin ≤ 1.5 x ULN
  • Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
  • INR and aPTT ≤ 1.5 x ULN
  • This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  • Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula)
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period for at least 5 months after the last dose of study drug,  and agreement to refrain from donating eggs during this same period:
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
  • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established and proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and  withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Bilateral synchronous tumors with inheritable forms of RCC including von Hippel-Lindau.
• Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment.
  • Hormone-replacement therapy or oral contraceptives are allowed.
• Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days or five half-lives of the investigational agent, whichever is longer, prior to enrollment.
• CNS metastases or leptomeningeal disease.
• Malignancies other than RCC within 5 years prior to Cycle 1, Day 1.
  • Patients with low-risk prostate cancer (defined as Stage cT1/T2a, Gleason score ≤ 6 and PSA ≤ 10 ng/mL) who are treatment-naive or who have been treated definitively with surgery or radiation and who are currently undergoing surveillance are eligible.
  • Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death < 5% at 5 years) are eligible provided they meet all of the following criteria:
    • Malignancy treated with expected curative intent (e.g., adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated surgically with curative intent);
    • No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers.
• Life expectancy of < 24 weeks.
• Pregnancy or lactation, or intending to become pregnant during the study.
  • Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study drug.
• Serum albumin < 2.5 g/dL.
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
• History of autoimmune disease including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,  Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
  • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for this study.
  • Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study.
  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are permitted provided that they meet the following conditions:
    • Rash must cover less than 10% of body surface area (BSA);
    • Disease is well-controlled at baseline and only requiring low potency topical steroids;
    • No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids).
  • Patients with prior allogeneic stem cell or solid organ transplantation.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
  • History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class III or greater), myocardial infarction within 3 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina.
  • Patients with a known left ventricular ejection fraction (LVEF) < 40%.
  • Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Positive test for HIV.
  • Documentation of HIV testing is required. The most recent testing must have occurred within 3 months prior to randomization. If such testing has not been done, it must be performed during screening.
• Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
  • Documentation of HBsAg, hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis C virus (HCV) antibody testing is required. The most recent testing must have occurred within 3 months prior to randomization. If such  testing has not been done, it must be performed during screening;
  • Patients with a positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening are eligible. The HBV DNA test will be performed only for patients who have a positive total HBcAb test;
  • Patients with a positive HCV antibody test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• Active tuberculosis.
• Severe infections within 4 weeks prior to initiation of study treatment including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
  • Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease or for dental extraction) are eligible.
• Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
• Administration of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment.
  • Patients must agree not to receive live, attenuated influenza vaccine, or any other live, attenuated vaccine, within 28 days prior to initiation of study treatment, during treatment, or within 5 months after the last dose of study drug.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Prior treatment with CD137 agonists, anti-CTLA-4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferons or interleukin-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medications (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents) within 2 weeks prior to initiation of study treatment or anticipated need for systemic immunosuppressive medications during the study.
  • Patients who have received acute, low-dose (≤ 10 mg/day oral prednisone or equivalent), systemic immunosuppressant medications (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
  • The use of corticosteroids (≤ 10 mg oral prednisone or equivalent), physiologic replacement doses of glucocorticoids, and mineralocorticoids (e.g., fludrocortisone for non-autoimmune adrenal insufficiency) is allowed.