Phase III Randomized Controlled Trial of Adjuvant Durvalumab and Tremelimumab in Resected High-Risk Renal Cell Carcinoma
- Trial ID
- 2024-513219-29-00
- Sponsor
- University College London
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART) is to evaluate the efficacy of **durvalumab** alone or in combination with **tremelimumab** in delaying the recurrence of renal cell carcinoma (RCC) in patients who have undergone surgery and are at intermediate or high risk of relapse. Additionally, the trial aims to determine whether these treatments can increase life expectancy compared to the current standard-of-care, which is active monitoring. This is clinically relevant as it addresses the need for effective adjuvant therapies in RCC to improve patient outcomes and survival rates.
Secondary objectives include assessing whether treatment with durvalumab alone or in combination with tremelimumab can delay the spread of cancer beyond the kidneys and reduce mortality rates in kidney cancer patients. The study also aims to evaluate the impact of these treatments on patients' quality of life, identify any side effects experienced, and understand patient preferences regarding immune system-affecting treatments. These objectives are crucial for comprehensively understanding the benefits and risks associated with the treatments, thereby informing clinical decision-making and patient care strategies.
Participants
The clinical trial involves a total of **587 participants** diagnosed with **Renal Cell Carcinoma**. The study population includes both male and female subjects, aged **18 years and older**, who have undergone surgery and are at intermediate or high risk of cancer recurrence. Participants were selected based on specific inclusion criteria, such as having histologically proven renal cell carcinoma, adequate organ and marrow function, and no evidence of residual macroscopic disease on post-operative CT scans. The trial does not include a vulnerable population. Participants are required to adhere to trial policies on contraception during and after the treatment phase. The general health status of participants is monitored, ensuring they have a **WHO Performance Status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is a **randomized**, **controlled**, and **double-blind** study designed to evaluate the efficacy of adjuvant therapy in patients with resected primary **renal cell carcinoma** (RCC) at high or intermediate risk of relapse. The trial aims to determine whether treatment with **durvalumab** alone or in combination with **tremelimumab** can delay cancer recurrence and increase life expectancy compared to the current standard-of-care, which is active monitoring. The study is structured as a multi-arm, multi-stage platform trial, allowing for the evaluation of multiple treatment regimens within the same framework.
The trial is expected to run until June 2033, with recruitment having commenced in July 2021. Participants will be involved in the study for a maximum treatment period of 12 months, depending on the assigned treatment arm. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The primary endpoints are disease-free survival and overall survival, while secondary endpoints include metastasis-free survival, RCC-specific survival, quality of life, toxicity, and patient preferences for adjuvant immunotherapy.
Participants will be randomly assigned to receive either durvalumab alone, a combination of durvalumab and tremelimumab, or standard-of-care monitoring. The inclusion criteria require participants to have histologically proven RCC, adequate organ and marrow function, and a WHO performance status of 0 or 1, among other criteria. Participants must be at least 18 years old and provide written informed consent. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, withdrawal of consent, or any condition that, in the investigator's opinion, warrants discontinuation for the participant's safety.
Treatment
The clinical trial involves the administration of two experimental medications: **IMJUDO** and **IMFINZI**. **IMJUDO** is a concentrate for solution for infusion, containing the active substance **tremelimumab**. It is provided in a concentration of 20 mg/mL and is administered via infusion. The maximum daily dose of **tremelimumab** is 75 mg, with a total maximum dose of 150 mg over the treatment period. The treatment period for **IMJUDO** is up to 8 weeks. The pharmaceutical form is a sterile concentrate, and the product is manufactured by AstraZeneca AB. The active substance, **tremelimumab**, is a protein of non-specific origin, classified under the ATC code L01FX20.
**IMFINZI** is also a concentrate for solution for infusion, containing the active substance **durvalumab**. It is provided in a concentration of 50 mg/mL and is administered via infusion. The maximum daily dose of **durvalumab** is 1500 mg, with a total maximum dose of 19500 mg over the treatment period. The treatment period for **IMFINZI** is up to 12 weeks. The pharmaceutical form is a concentrate for solution for infusion, and the product is manufactured by AstraZeneca AB. The active substance, **durvalumab**, is a protein of non-specific origin, classified under the ATC code L01XC28. **Durvalumab** is also known by the synonym MEDI4736.
In this trial, the experimental treatments are compared against the current standard-of-care, which involves active monitoring. The trial aims to evaluate whether treatment with either **durvalumab** alone or in combination with **tremelimumab** can delay cancer recurrence and increase life expectancy in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the RAMPART trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Disease Free Survival** (DFS) and **Overall Survival** (OS). DFS is defined as the interval from randomization to the first evidence of local recurrence, new primary renal cell carcinoma (RCC), distant metastases, or death from any cause, whichever occurs first. OS is defined as all-cause mortality, measuring the time from randomization to death from any cause, including RCC.
Secondary endpoints will further evaluate efficacy through **Metastasis Free Survival** (MFS), RCC-specific survival time, quality of life, toxicity, and patient preferences for adjuvant immunotherapy. MFS is defined as the interval from randomization to the first evidence of metastases or death from RCC. RCC-specific survival time measures the time from randomization to death specifically from RCC.
The trial will involve the administration of durvalumab alone or in combination with **tremelimumab** to assess their impact on delaying cancer recurrence and increasing life expectancy compared to the current standard-of-care, which is active monitoring. The trial is designed to include patients with resected primary RCC at high or intermediate risk of relapse, and it will be conducted over an estimated period ending in June 2033. Efficacy assessments will be conducted at various timepoints throughout the trial to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically proven RCC (all cell types of RCC are eligible, except for pure oncocytoma, collecting duct, medullary and transitional cell cancer [TCC]); no evidence of residual macroscopic disease on post-operative CT scan after resection of RCC. Patients with treated bilateral synchronous RCCs are eligible.
- At the start of recruitment patients with Leibovich score 3-11 will be eligible for randomisation. MRC CTU at UCL will monitor accrual and stop recruiting intermediate risk patients (Leibovich Score 3-5) once agreed by the RAMPART TMG. Intermediate risk patients will contribute up to 25% of the total accrual target. Recruitment of patients with Leibovich Score 6-11 will continue until the accrual target is reached.
- Patients with synchronous ipsilateral adrenal metastases will be eligible, provided they are fully resected (adrenal metastectomy) at the time of nephrectomy and there is no evidence of residual macroscopic disease on post-operative CT scans.
- Patients with a single soft tissue metastasis developing at any organ site will be eligible, provided they are fully resected (metastectomy) between 6-24 months after nephrectomy and there is no evidence of residual macroscopic disease on post-metastectomy CT scans.
- Patients should have had surgery (nephrectomy or metastectomy) at least 28 days but no more than 91 days prior to their randomisation date.
- Post-operative scans should be performed within 28 days prior to randomisation.
- Patients with microscopically positive resection margins after radical nephrectomy at the nephrectomy bed, renal vein or inferior vena cava are eligible provided the post-operative CT scan shows no evidence of residual macroscopic disease.
- WHO Performance Status 0 or 1.
- Patient has archival FFPE pathology tissue available, and agrees to provide at least one sample (FFPE tumour block from nephrectomy and where applicable the adrenal metastectomy, or a minimum of 10 unstained slides), as well as baseline CPDA and PAXgene blood samples for future translational research
- Adequate normal organ and marrow function a. Haemoglobin ≥9.0g/dL (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria). b. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500 per mm3). c. Platelet count ≥100 x 109 (≥100,000 per mm3). d. Bilirubin ≤1.5 x ULN (This will not apply to subjects with confirmed Gilbert’s syndrome (i.e., persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), who will be allowed only in consultation with their physician). e. AST/ALT ≤2.5 x ULN. f. Calculated Creatinine Clearance level >40mL/min by Cockcroft Gault formula (using actual body weight): Males: Creatinine CL (mL/min) = 1.23x Weight (kg) x (140 – Age) serum creatinine (μmol/L) Females: Creatinine CL (mL/min) = 1.04 x Weight (kg) x (140 – Age) serum creatinine (μmol/L)
- Subjects must be ≥18 years of age.
- Written informed consent obtained from the patient.
- Both men and women enrolled in this trial must be in agreement with trial policy on contraception (Section 5.8.4) during the treatment phase of the study and 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided.
- Evidence of post-menopausal status or negative serum HCG pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply: a. Women <50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy). b. Women ≥50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).
Exclusion Criteria
- Previous diagnosis of RCC.
- Metastatic disease except: MRC|CTU|UCL RAMPART Protocol v7.0 XX-Xxx-2023 Page 39 of 153 a. Synchronous ipsilateral adrenal metastases which are fully resected at the time of nephrectomy b. A single soft tissue metastasis developing at any organ site that has been fully resected between 6-24 months after radical nephrectomy
- Macroscopic residual disease following nephrectomy.
- Patients with positive resection margins after partial nephrectomy. If multiple resection margins are taken, the patient will be considered eligible as long as the last margin is negative.
- Patients with a single pulmonary nodule ≥5mm diameter are not eligible unless the nodule has had a definite benign diagnosis. Patients with multiple small, less than 5 mm nodules may be eligible if nodules have been shown to be radiologically stable for at least 8 weeks.
- Prior anticancer treatment (other than nephrectomy) for RCC.
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
- Previous invasive or non-invasive malignancy except: a. Basal cell carcinoma where treatment consisted of resection alone or radiotherapy. b. Low grade non-muscle-invasive bladder carcinoma where treatment consisted of endoscopic resection alone or with a single installation of intravesical chemotherapy or with BCG treatment. c. Ductal carcinoma in situ of breast where treatment consisted of resection alone. d. Cervical carcinoma in situ where treatment consisted of resection alone. e. Previously treated clinically localized low or intermediate risk prostate cancer with undetectable PSA after surgery or stable PSA for radiation therapy. f. Malignancy treated with curative intent and with no known active disease > 5 years before the first dose of IP and of low potential risk of recurrence. g. Other cancers with very low potential of recurrence can be discussed with MRC CTU at UCL where eligibility will be considered on an individual basis.
- History of leptomeningeal carcinomatosis.
- Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the start of treatment. Local surgery of isolated lesions for palliative intent is acceptable.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: a. Patients with vitiligo or alopecia b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Patients without active disease in the last 5 years may be included but only after consultation with the RAMPART Trial Management Team, Patients with coeliac disease controlled by diet alone
- history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty.
- History of allogeneic organ transplant
- Uncontrolled intercurrent illness including, but not limited to: a. Ongoing or active infection of any kind (patients who are exhibiting symptoms consistent with COVID-19, or who have tested positive, should not be randomised into the study until they are asymptomatic and at least 14 days after a positive test) b. Symptomatic congestive heart failure c. Uncontrolled hypertension d. Unstable angina pectoris e. Uncontrolled cardiac arrhythmia f. Active peptic ulcer disease or gastritis g. Active bleeding diatheses h. Psychiatric illness or social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
- Active infection including a. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice) b. Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. c. Hepatitis C d. Human immunodeficiency virus (positive HIV 1/2 antibodies). Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- Receipt of live attenuated vaccine within 30 days prior to the start of treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving investigational medicinal product and up to 30 days after the last dose of investigational medicinal product
- Pregnant or breastfeeding patients.
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
- Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients.
- Previous investigational medicinal product assignment in the present study.
- Clinically significant pneumonitis or fibrosis.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 22 Jul 2021 | 170 |
 Spain | Not Yet Recruiting | 22 Jul 2021 | 33 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
IMFINZI 50 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 1500 | 12 | PRD6651398 |
IMJUDO 20 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION (STERILE CONCENTRATE). | INFUSION | 75 | 8 | PRD10239824 |