Status: Open
Specialty: Renal
Date Opened: 08/07/2021
Planned Close Date: 30/06/2023
Sponsor: University College London
Principal Investigator: Dr Natalie Charnley
Study Title: Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART): An international investigator-led phase III multi-arm multi-stage randomised controlled platform trial of adjuvant therapy in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse
Renal cell carcinoma is a type of kidney cancer that starts from the kidneys. It is the 8th most common cancer in the UK and an increase of new cases of 2% has been seen in the last twenty years. About half of the new cases of kidney cancer are among people aged 70 and above.
Patients whose disease has not spread outside the kidneys typically have surgery to remove a part or all of their kidney (called a partial or radical nephrectomy). After surgery, patients are seen by their doctor with regular check-ups to look for signs of the cancer coming back or spreading to other parts of the body; this is generally called ‘active monitoring’ or ‘active surveillance’. Unfortunately, it is estimated that the cancer will return in 30-40% of the patients who have undergone surgery.
Many clinical studies have been carried out to find if a new treatment after surgery might slow the cancer coming back or prevent it from coming back altogether. However, to date no treatment is available. Immunotherapy is a type of cancer treatment that ‘wakes up’ the patient’s own immune system so it can fight the cancer. New drugs which act in this way have worked well in patients with skin cancer (melanoma), lung cancer and in patients with kidney cancer that has spread outside the kidney.
RAMPART is a study looking at two new immunotherapy treatments. We aim to find out whether taking one drug (durvalumab) or a combination of two drugs (durvalumab and tremelimumab) for one year can prevent or delay kidney cancer from coming back compared to the current standard of care (active monitoring after surgery).
Durvalumab is sometimes referred to as an anti-PDL1 drug, and it is currently being tested (alone or in combination with other drugs) in many types of cancer. Tremelimumab is sometimes called anti-CTLA4 drug. It is also being tested in different types of cancer. Like all drugs, these treatments have side effects and patients will have regular blood tests, scans and appointments with their study doctor and nurse.
Around 1,750 patients from the UK, Australia, France and the US will join the study. It will take approximately 5.5 years to reach this number. The first results from the study are expected 6.5 years after the study starts, with more results following later. If positive, the results of the study will change the current standard of care for the treatment of kidney cancer after surgery.
1.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.
2.At the start of recruitment patients with Leibovich score 3-11 will be eligible for randomisation. MRC CTU will monitor accrual and stop recruiting intermediate risk patients (Leibovich Score 3-5) after three years or when intermediate risk patients contribute 25% of the total accrual target, whichever is earlier. Recruitment of patients with Leibovich Score 6 11 will continue until the accrual target is reached.
3.Patients should have had surgery at least 28 days but no more than 91 days prior to randomisation date.
4. Post-operative scans should be performed within 28 days prior to randomisation
5.WHO Performance Status 0 or 1.
6.Patient has archival FFPE pathology tissue available, and agrees to provide at least one sample (FFPE tumour block from nephrectomy, or a minimum of 10 unstained slides), as well as a baseline EDTA blood sample for future translational research
7.Adequate normal organ and marrow function
a.Haemoglobin > = 9.0g/dL (transfusions will be allowed within 2 weeks of 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
8.12-lead ECG on which QTcF must be < 470 ms. In case of clinically significant ECG abnormalities, including a QTcF value > = 470 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding.
9. Patient must weight > = 30Kg at the time of randomisation
10.Subjects must be > = 18 years in age.
11.Written Informed Consent obtained from the patient
12.Both men and women enrolled in this trial must use adequate contraception during the treatment phase of the study and for 6 months afterwards. Egg donation, sperm donation and breastfeeding must be avoided.
13. Evidence of post-menopausal status or negative urinary or serum 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).
1.Previous diagnosis of RCC.
2.Metastatic or macroscopic residual disease.
3.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.
4.Prior anticancer treatment (other than nephrectomy) for RCC.
5. 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.
6. History of another primary malignancy except for:
a) Malignancy treated with curative intent and with no known active disease > = 5 years before the first dose of IP and of low potential risk for recurrence.
b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c) Adequately treated carcinoma in situ without evidence of disease.
7. History of leptomeningeal carcinomatosis.
8. 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.
9. 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.
10. 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.
11. 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
e. Patients with coeliac disease controlled by diet alone
12. A history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty.
13. History of allogeneic organ transplant.
14. Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection
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.
15.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)
c. Hepatitis C
d. Human immunodeficiency virus (positive HIV 1/2 antibodies). 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.
Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
16. 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.
17. Pregnant or breastfeeding patients.
18. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
19. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients.
20. Previous investigational medicinal product assignment in the present study.
Research Nurse: Carolyn Hatch (x3921) Carolyn.Hatch@lthtr.nhs.uk
Administrator: Rob Speirs (x8475)
Link to EDGE