Neoadjuvant Belzutifan Plus Pembrolizumab in High-Risk, Locally Advanced Clear Cell Renal Cell Carcinoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Therapeutic effects of belzutifan with and without pembrolizumab on the proportion of viable tumour cells in the neoadjuvant setting
研究概览
简要总结
The purpose of this study is to compare the safety and effectiveness of two new treatments: belzutifan alone or belzutifan in combination with pembrolizumab before kidney surgery and followed by a combination of belzutifan and pembrolizumab treatment post-surgery.
Belzutifan is a small molecule drug that specifically blocks a protein called Hypoxia-Inducible Factor 2 alpha (HIF-2α) and slows down or stops the growth of cancer. Belzutifan has been shown to provide better treatment results in kidney cancer compared to other drugs that target similar proteins to stop cancer growth.
Pembrolizumab is a type of medicine called an immunotherapy drug. It helps the immune system spot and attack kidney cancer cells by blocking a "stop sign" that the cancer uses to hide and help slow down or shrink the cancer.
The combined use of molecules similar to belzutifan and pembrolizumab has shown promising results in treating kidney cancer, although effectiveness depends on the specific combination. This treatment combination is experimental and is not approved to treat kidney cancer in Australia. This means that it must be tested to see if it is an effective treatment combination for kidney cancer prior to kidney surgery.
详细描述
This is a prospective, open label, single site, phase II, randomised, clinical trial, evaluating neoadjuvant belzutifan with or without pembrolizumab prior to nephrectomy, follow by adjuvant belzutifan plus pembrolizumab.
Patients identified as potential candidates for the NEBULA study will be asked to sign a Pre-Screening Patient Information and Consent Form (PICF) before undergoing a biopsy. The biopsy will be used to establish a diagnosis of ccRCC as per standard of care and for the collection of pre-treatment tissue samples for translational research for this trial. Patients with a confirmed diagnosis of ccRCC and found to fulfill the remaining eligibility criteria will be invited to participate in the NEBULA study. Patients without a confirmed diagnosis of ccRCC will be deemed ineligible.
Approximately 30 eligible patients will be randomised for neoadjuvant treatment to receive one of the following: Arm A: Belzutifan alone for 2 cycles. Arm B: Belzutifan and pembrolizumab for 2 cycles. All patients will undergo nephrectomy after completion of Cycle 2 neoadjuvant treatment. Both a nephron sparing (partial) or total nephrectomy is an acceptable standard of care and choice of approach is at the surgeon's discretion. After nephrectomy, patients will receive adjuvant treatment with belzutifan and pembrolizumab for up to 9 cycles in Arm A and 7 cycles in Arm B.
At the time of treatment discontinuation for any reason, visits will be conducted. Patients with non-progressive disease will then enter the follow-up phase of the trial. Patients with progressive disease or start a new anti-ccRCC therapy at any time will complete a progression visit and will subsequently be followed only for survival and start of new anti-ccRCC therapy. All patients will be followed for 2 years after the last patient has been randomised.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •1. Patient has provided written informed consent using the NEBULA Main PICF.
- •Adults aged 18 years or older at the time of written informed consent.
- •3. Histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (8th edition), with or without sarcomatoid features.
- •4. Patients who in the opinion of the treating surgeon require nephrectomy.
- •Patient has high risk ccRCC as defined by the following pathological tumour-node metastasis and tumour grading: • cT2b, Nany, Gany • cT3-cT4, N0, Gany • cTany, cN1, Gany
- •Patient has evaluable primary tumour disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST1.1).
- •7. Patients has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to randomisation.
- •8. Patient has a Karnofsky performance score of at least 70% within 10 days prior to randomisation.
- •9. Patients must have adequate bone marrow, hepatic and renal function documented within 10 days prior to randomisation, defined as: • Haemoglobin (Hgb) ≥ 100 g/L. Criteria must be met without erythropoietin dependency and without peripheral red blood cell transfusion within 4 weeks before the haematology screening assessment. • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. • Platelets ≥ 100 x 109/L. • Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 30 mL/min calculated using the Cockcroft-Gault equation (Appendix 1) or 24-hour urine collection. • Total bilirubin ≤ 1.5 x ULN ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 × ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 × ULN for patients with liver metastases). • International normalisation ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy as long as INR/PT or aPTT is within therapeutic range of intended use of anticoagulants.
- •10. Women of childbearing potential (WCBP) must agree to use a highly effective contraceptive method (with a failure rate of < 1%) as outlined in Section 9.10.1 during study treatment and for 30 days after the last dose of belzutifan or 120 days after the last dose of pembrolizumab, whichever occurs last and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period.
- •11. A WCBP must have a negative highly sensitive urine or serum pregnancy (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to randomisation.
- •12. Male patients are eligible to participate if they agree to the following during the treatment period and for at least 7 days after the last dose of belzutifan: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration. • Male patients must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.
- •13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing surgery, treatment, scheduled visits, and examinations.
排除标准
- •Presence of extensive tumour thrombus that necessitates early surgical intervention as per primary treating urologist.
- •cT1 or cT2a Gany.
- •Metastatic disease, or resected M1 disease.
- •Has received prior systemic therapy for ccRCC.
- •Has received prior radiotherapy for ccRCC.
- •Has any of the following: • Pulse oximeter reading < 92% at rest. • Requires intermittent supplemental oxygen. • Requires chronic supplemental oxygen.
- •Has clinically significant cardiovascular disease within 6 months prior to randomisation, including NYHA III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, undergone coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, or cardiac arrhythmia. Note: Medically controlled arrhythmia stable on medication is permitted.
- •Has other clinically significant disorders such as: • Serious active nonhealing wound/ulcer/bone fracture. • Requirement for haemodialysis or peritoneal dialysis.
- •Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy exceeding 10 mg daily dose of prednisone or equivalent or any other form of immunosuppressive therapy within 7 days prior to randomisation.
- •Has an active autoimmune disease that has required systemic treatment in the last 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
- •Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ, such as breast cancer in situ, that has undergone potentially curative therapy are not excluded.
- •Has known active central nervous system metastases and/or carcinomatous meningitis.
- •Has received colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin or transfusion within 28 days prior to randomisation.
- •Is unable to swallow orally administered medication or has a history or current evidence of a gastrointestinal condition (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral study intervention.
- •15. Has a severe hypersensitivity (Grade ≥ 3) reaction to belzutifan or pembrolizumab and/or any of their excipients.
- •16. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- •17. Has an active infection, requiring systemic therapy.
- •Has a known history of human immunodeficiency virus (HIV) infection.
- •Has known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] RNA [qualitative] is detected) infection.
- •20. Has received a live virus vaccine or live-attenuated vaccine within 30 days prior to randomisation. Note: Administration of killed vaccines is allowed.
- •21. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the patient's participation for the full duration of the study, such that it is not in the best interest of the patient to participate, in the opinion of the treating investigator.
- •22. Has a known psychiatric or substance abuse disorder that would interfere with the patient's ability to cooperate with the requirements of the study.
- •23. Has had a prior solid organ transplant.
- •Is breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through to 30 days after the last dose of belzutifan or 120 days after the last dose of pembrolizumab, whichever occurs last.
- •25. Any contraindications for surgery.
研究组 & 干预措施
Belzutifan plus pembrolizumab
Belzutifan and pembrolizumab for 2 cycles during neoadjuvant treatment. Post nephrectomy, all patients will receive adjuvant treatment with belzutifan and pembrolizumab.
干预措施: Pembrolizumab (Drug)
Belzutifan plus pembrolizumab
Belzutifan and pembrolizumab for 2 cycles during neoadjuvant treatment. Post nephrectomy, all patients will receive adjuvant treatment with belzutifan and pembrolizumab.
干预措施: Belzutifan (Drug)
Belzutifan alone
Belzutifan alone for 2 cycles during neoadjuvant treatment. Post nephrectomy, all patients will receive adjuvant treatment with belzutifan and pembrolizumab.
干预措施: Belzutifan (Drug)
结局指标
主要结局
Therapeutic effects of belzutifan with and without pembrolizumab on the proportion of viable tumour cells in the neoadjuvant setting
时间窗: Up to 18 weeks. From randomisation to the completion of nephrectomy
The proportion of viable tumour cells per patient post-neoadjuvant therapy as assessed by pathology
次要结局
- EFS rates between belzutifan with and without pembrolizumab neoadjuvant treatment plus adjuvant treatment arms.(Up to 20 months. From randomisation to the first date of documented radiographic progression using conventional imaging, discontinuation of trial treatment, or death due to any cause, whichever occurs first.)
- Pathological response rates between belzutifan with and without pembrolizumab neoadjuvant treatment(Up to 18 weeks. From randomisation to the completion of nephrectomy)
- Safety of belzutifan with and without pembrolizumab in the neoadjuvant and adjuvant settings.(Up to 21 months. From randomisation until 30 days after the last dose of treatment)