Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University College London

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Oct 2024 → ongoing

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AstraZeneca

External identifiers

EU CT number

2024-513219-29-00

EudraCT number

2017-002329-39

ClinicalTrials.gov

NCT03288532

ISRCTN

ISRCTN53348826

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The RAMPART trial is aiming to address two research questions:
1. Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab delay the cancer
from coming back compared with the current standard-of-care (active monitoring) in patients with kidney cancer who
underwent surgery and are at intermediate or high risk of recurrence?
2. Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab increase life
expectancy compared with current standard-of-care (active monitoring) in patients with kidney cancer who underwent
surgery and are at intermediate or high risk of recurrence?

Secondary objectives 5

1. Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab delay the cancer from spreading outside the kidneys?
2. Does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab reduces the chances of dying from kidney cancer?
3. How does treatment with either durvalumab alone or a combination of durvalumab and tremelimumab affect the quality of life of patients?
4. What side effects are experienced in patients undergoing treatment with either durvalumab alone or a combination of durvalumab and tremelimumab?
5. What are patients' preferences when it comes to treatments affecting the immune system?

Conditions and MedDRA coding

Renal Cell Carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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 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.
3. 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.
4. 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.
5. Patients should have had surgery (nephrectomy or metastectomy) at least 28 days but no more than 91 days prior to their randomisation date.
6. Post-operative scans should be performed within 28 days prior to randomisation.
7. 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.
8. WHO Performance Status 0 or 1.
9. 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
10. 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)
11. Subjects must be ≥18 years of age.
12. Written informed consent obtained from the patient.
13. 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.
14. 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 23

1. Previous diagnosis of RCC.
2. 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
3. Macroscopic residual disease following nephrectomy.
4. 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.
5. 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.
6. Prior anticancer treatment (other than nephrectomy) for RCC.
7. 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.
8. 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.
9. History of leptomeningeal carcinomatosis.
10. 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.
11. 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.
12. 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.
13. 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
14. history of immunodeficiency syndrome. Please consult the MRC CTU at UCL on an individual basis if there is any uncertainty.
15. History of allogeneic organ transplant
16. 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.
17. 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.
18. 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
19. Pregnant or breastfeeding patients.
20. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
21. Known allergy or hypersensitivity to durvalumab or tremelimumab, or any of their excipients.
22. Previous investigational medicinal product assignment in the present study.
23. Clinically significant pneumonitis or fibrosis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Disease Free Survival - defined as the interval from randomisation to first evidence of local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first.
2. Overall Survival - defined as all-cause mortality, the time from randomisation to death from any cause (including RCC).

Secondary endpoints 5

1. Metastasis Free Survival (MFS), defined as the interval from randomisation to first evidence of metastases or death from RCC.
2. RCC specific survival time, defined as the time from randomisation to death from RCC.
3. Quality of life
4. Toxicity
5. Patient preferences for adjuvant immunotherapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University College London

Sponsor organisation

University College London

Address

19 Torrington Place, Gower Street Gower Street

City

London

Postcode

WC1E 6BT

Country

United Kingdom

Scientific contact point

Organisation

University College London

Contact name

Angela Meade

Public contact point

Organisation

University College London

Contact name

Angela Meade

Locations

2 EU/EEA countries · 32 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications