Renal Adjuvant MultiPle Arm Randomised Trial

NCT03288532 | Recruiting Phase 3 DMC

• 1 other identifier: MRC RE06
• Study Type: interventional
• Target: 1,750
• Locations: 1 country
• Sites: 35

Brief Summary

RATIONALE: The current global standard of care after nephrectomy for localised RCC therefore remains active monitoring (i.e., observation by clinical and radiological means). 30-40% patients with initially localised RCC develop metastatic disease following nephrectomy. Need for adjuvant therapy is most marked in the high risk population where outcomes are predictably poor. However, the risk of recurrence in patients who are of intermediate risk of recurrence is not insignificant. Unfortunately, despite showing efficacy in advanced RCC, the results in the adjuvant setting, so far, are inconclusive. AIM: RAMPART is a phase III Multi-Arm Multi-Stage randomised controlled platform trial, initiated with three arms. The trial is assessing if durvalumab monotherapy or the combination of durvalumab and tremelimumab can improve Disease Free Survival (DFS) or Overall Survival (OS) compared to the current global standard-of-care (active monitoring). At the start of recruitment, patients with Leibovich scores 3 to 11 will be eligible for randomisation. Accrual of intermediate risk patients (Leibovich scores 3 5) will stop after 3 years or when intermediate risk patients contribute 25% of the total accrual target, whichever is earlier. Recruitment of patients with Leibovich scores 6 to 11 will continue until the accrual target is reached.

Conditions

Renal Cell Carcinoma

Keywords

Renal Cell Carcinoma; Immunotherapy; Multi-Arm Multi-Stage

Outcome Measures

Primary Outcomes (4)

• Disease Free Survival (DFS): Arm C vs A

  Interval from randomisation to first evidence of local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first.

  6.25 years

• Disease Free Survival (DFS): Arm B vs A

  Interval from randomisation to first evidence of local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first.

  10.54 years

• Overall Survival (OS): Arm C vs A (high risk patients only)

  All-cause mortality, the time from randomisation to death from any cause (including RCC).

  13.25 years

• Overall Survival (OS): Arm B vs A (high risk patients only)

  All-cause mortality, the time from randomisation to death from any cause (including RCC).

  20.5 years

Secondary Outcomes (4)

• Metastasis-free survival (MFS): Arm C vs A

  6.25 years

• Metastasis-free survival (MFS): Arm B vs A

  10.54 years

• RCC specific survival time: Arm C vs A

  13.25 years

• RCC specific survival time: Arm C vs A

  20.5 years

Study Arms (3)

Arm A (active monitoring)

NO INTERVENTION

Participants randomised to Arm A will be allocated to active monitoring for 1 year, in line with current standard-of-care in resected primary RCC at high or intermediate risk of relapse

Arm B (durvalumab monotherapy)

EXPERIMENTAL

Participants randomised to Arm B will receive durvalumab (1500mg) 4 weekly for 1 year (13 cycles maximum)

Drug: Durvalumab

Arm C (durvalumab + tremelimumab)

EXPERIMENTAL

Participants randomised to Arm C will receive durvalumab (administered as per arm B, i.e. 13 cycles maximum) and tremelimumab (75mg) on day 1 and week 4 visits (i.e. 2 cycles)

Drug: Durvalumab; Drug: Tremelimumab

Interventions

Durvalumab DRUG

controlled infusion via an infusion pump into a peripheral or central vein

Arm B (durvalumab monotherapy); Arm C (durvalumab + tremelimumab)

Tremelimumab DRUG

controlled infusion via an infusion pump into a peripheral or central vein

Arm C (durvalumab + tremelimumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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) 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.
• Patients should have had surgery 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, or a minimum of 10 unstained slides), as well as a baseline EDTA blood sample for future translational research).
• Adequate normal organ and marrow function
• Haemoglobin ≥9.0g/dL (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria).
• Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500 per mm3).
• Platelet count ≥100 x 109 (≥100,000 per mm3).
• 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).
• AST/ALT ≤2.5 x ULN.
• Calculated Creatinine Clearance level \>40mL/min by Cockcroft Gault formula (using actual body weight).
• lead ECG on which QTcF must be \<450 ms. In case of clinically significant ECG abnormalities, including a QTcF value ≥450 ms, two additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. Patients are only eligible if a QTcF of \<450ms is confirmed

You may not qualify if:

• Previous diagnosis of RCC.
• Metastatic or macroscopic residual disease.
• Patients with positive resection margins after partial nephrectomy.
• 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.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• 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.
• History of another primary malignancy except for:
• 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.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease.
• 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.

Sponsors & Collaborators

• University College, London: lead
• AstraZeneca: collaborator
• Kidney Cancer UK: collaborator
• Cancer Research UK: collaborator

Study Sites (35)

Aberdeen Royal Infirmary

Aberdeen, AB25 2ZN, United Kingdom

RECRUITING

Ysbyty Gwynedd

Bangor, LL57 2PW, United Kingdom

RECRUITING

Royal Bournemouth Hospital

Bournemouth, BH7 7DW, United Kingdom

RECRUITING

Bristol Haematology and Oncology Centre

Bristol, BS2 8ED, United Kingdom

RECRUITING

Addenbrookes Hospital

Cambridge, CB2 0QQ, United Kingdom

RECRUITING

Velindre Cancer Centre

Cardiff, CF14 2TL, United Kingdom

RECRUITING

Broomfield Hospital

Chelmsford, CM1 7ET, United Kingdom

RECRUITING

Cheltenham General Hospital

Cheltenham, GL53 7AN, United Kingdom

RECRUITING

Colchester General Hospital

Colchester, CO4 5JL, United Kingdom

RECRUITING

University Hospital Coventry & Warwickshire

Coventry, CV2 2DX, United Kingdom

RECRUITING

Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

RECRUITING

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

RECRUITING

Diana Princess of Wales Hospital

Grimsby, DN33 2BA, United Kingdom

RECRUITING

Castle Hill Hospital

Hull, HU16 5JQ, United Kingdom

RECRUITING

Raigmore Hospital

Inverness, IV2 3UJ, United Kingdom

RECRUITING

St James University Hospital

Leeds, LS9 7TF, United Kingdom

RECRUITING

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

RECRUITING

Clatterbridge Cancer Centre

Liverpool, L9 7AL, United Kingdom

RECRUITING

St Bartholomew's Hospital

London, EC1A 7BE, United Kingdom

RECRUITING

Mount Vernon Hospital

London, HA6 2RN, United Kingdom

RECRUITING

Royal Free Hospital

London, NW3 2QG, United Kingdom

RECRUITING

Guy's Hospital

London, SE1 9RT, United Kingdom

RECRUITING

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

RECRUITING

Charing Cross Hospital

London, W6 8RF, United Kingdom

RECRUITING

The Christie

Manchester, M20 4BX, United Kingdom

RECRUITING

Nottingham University Hospital

Nottingham, NG5 1PB, United Kingdom

RECRUITING

Churchill Hospital

Oxford, OX3 7LE, United Kingdom

RECRUITING

Glan Clwyd Hospital

Rhyl, LL18 5UJ, United Kingdom

RECRUITING

Scunthorpe General Hospital

Scunthorpe, DN15 7BH, United Kingdom

RECRUITING

Weston Park Hospital

Sheffield, S10 2SJ, United Kingdom

RECRUITING

South Tyneside District Hospital

South Shields, NE34 0PL, United Kingdom

RECRUITING

Southend University Hospital

Southend-on-Sea, SS0 0RY, United Kingdom

RECRUITING

Sunderland Royal Hospital

Sunderland, SR4 7TP, United Kingdom

RECRUITING

Royal Marsden Hospital

Sutton, SM2 5PT, United Kingdom

RECRUITING

Torbay Hospital

Torquay, TQ2 7AA, United Kingdom

RECRUITING

Related Publications (3)

• Oza B, Frangou E, Smith B, Bryant H, Kaplan R, Choodari-Oskooei B, Powles T, Stewart GD, Albiges L, Bex A, Choueiri TK, Davis ID, Eisen T, Fielding A, Harrison D, McWhirter A, Mulhere S, Nathan P, Rini B, Ritchie A, Scovell S, Shakeshaft C, Stockler MR, Thorogood N, Parmar MKB, Larkin J, Meade A. RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. Contemp Clin Trials. 2021 Sep;108:106482. doi: 10.1016/j.cct.2021.106482. Epub 2021 Sep 16.

  PMID: 34538402 DERIVED

• Meade A, Oza B, Frangou E, Smith B, Bryant H, Kaplan R, Choodari-Oskooei B, Powles T, Stewart GD, Albiges L, Bex A, Choueiri TK, Davis ID, Eisen T, Fielding A, Harrison DJ, McWhirter A, Mulhere S, Nathan P, Rini B, Ritchie A, Scovell S, Shakeshaft C, Stockler MR, Thorogood N, Larkin J, Parmar MKB. RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting. Contemp Clin Trials. 2021 Sep;108:106481. doi: 10.1016/j.cct.2021.106481. Epub 2021 Sep 16.

  PMID: 34538401 DERIVED

• Marconi L, Sun M, Beisland C, Klatte T, Ljungberg B, Stewart GD, Dabestani S, Choueiri TK, Bex A. Prevalence, Disease-free, and Overall Survival of Contemporary Patients With Renal Cell Carcinoma Eligible for Adjuvant Checkpoint Inhibitor Trials. Clin Genitourin Cancer. 2021 Apr;19(2):e92-e99. doi: 10.1016/j.clgc.2020.12.005. Epub 2021 Jan 7.

  PMID: 33526329 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• James Larkin

  Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Central Study Contacts

RAMPART Trial Management Team

CONTACT

0044(0)207 670; mrcctu.rampart@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multi-Arm Multi-Stage Design

Study Record Dates

• First Submitted: September 4, 2017
• First Posted: September 20, 2017
• Study Start: July 19, 2018
• Primary Completion: July 1, 2024
• Study Completion (Estimated): December 1, 2034
• Last Updated: September 7, 2020

Record last verified: 2020-09

Locations

GB (35)