RAMPART: Renal Adjuvant MultiPle Arm Randomised Trial

Sponsor

University College, London (Other)

Overall Status

Recruiting

CT.gov ID

NCT03288532

Collaborator

AstraZeneca (Industry), Kidney Cancer UK (Other), Cancer Research UK (Other)

1,750

Enrollment

Locations

Arms

196.4

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma	Drug: Durvalumab Drug: Tremelimumab	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1750 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Multi-Arm Multi-Stage DesignMulti-Arm Multi-Stage Design

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An International Investigator-led Phase III Multi Arm Multi Stage Multi-centre Randomised Controlled Platform Trial of Adjuvant Therapy in Patients With Resected Primary Renal Cell Carcinoma (RCC) at High or Intermediate Risk of Relapse

Actual Study Start Date :

Jul 19, 2018

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Dec 1, 2034

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Arm A (active monitoring) 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
Experimental: Arm B (durvalumab monotherapy) Participants randomised to Arm B will receive durvalumab (1500mg) 4 weekly for 1 year (13 cycles maximum)	Drug: Durvalumab controlled infusion via an infusion pump into a peripheral or central vein
Experimental: Arm C (durvalumab + tremelimumab) 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 controlled infusion via an infusion pump into a peripheral or central vein Drug: Tremelimumab controlled infusion via an infusion pump into a peripheral or central vein

Arm

Intervention/Treatment

No Intervention: Arm A (active monitoring)

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

Experimental: Arm B (durvalumab monotherapy)

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

Drug: Durvalumab

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

Experimental: Arm C (durvalumab + tremelimumab)

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

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

Drug: Tremelimumab

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

Outcome Measures

Primary Outcome Measures

Disease Free Survival (DFS): Arm C vs A [6.25 years]
Interval from randomisation to first evidence of local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first.
Disease Free Survival (DFS): Arm B vs A [10.54 years]
Interval from randomisation to first evidence of local recurrence, new primary RCC, distant metastases, or death from any cause, whichever occurs first.
Overall Survival (OS): Arm C vs A (high risk patients only) [13.25 years]
All-cause mortality, the time from randomisation to death from any cause (including RCC).
Overall Survival (OS): Arm B vs A (high risk patients only) [20.5 years]
All-cause mortality, the time from randomisation to death from any cause (including RCC).

Secondary Outcome Measures

Metastasis-free survival (MFS): Arm C vs A [6.25 years]
Interval from randomisation to first evidence of metastases or death from RCC
Metastasis-free survival (MFS): Arm B vs A [10.54 years]
Interval from randomisation to first evidence of metastases or death from RCC
RCC specific survival time: Arm C vs A [13.25 years]
Time from randomisation to death from RCC
RCC specific survival time: Arm C vs A [20.5 years]
Time from randomisation to death from RCC

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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) 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).
12-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
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 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:
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).
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 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.
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
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.
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:
Patients with vitiligo or alopecia
Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
Any chronic skin condition that does not require systemic therapy
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
A 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:
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)
Symptomatic congestive heart failure
Uncontrolled hypertension
Unstable angina pectoris
Uncontrolled cardiac arrhythmia
Active peptic ulcer disease or gastritis
Active bleeding diatheses
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
Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
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.
Hepatitis C
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aberdeen Royal Infirmary	Aberdeen	United Kingdom	AB25 2ZN
2	Ysbyty Gwynedd	Bangor	United Kingdom	LL57 2PW
3	Royal Bournemouth Hospital	Bournemouth	United Kingdom	BH7 7DW
4	Bristol Haematology and Oncology Centre	Bristol	United Kingdom	BS2 8ED
5	Addenbrookes Hospital	Cambridge	United Kingdom	CB2 0QQ
6	Velindre Cancer Centre	Cardiff	United Kingdom	CF14 2TL
7	Broomfield Hospital	Chelmsford	United Kingdom	CM1 7ET
8	Cheltenham General Hospital	Cheltenham	United Kingdom	GL53 7AN
9	Colchester General Hospital	Colchester	United Kingdom	CO4 5JL
10	University Hospital Coventry & Warwickshire	Coventry	United Kingdom	CV2 2DX
11	Western General Hospital	Edinburgh	United Kingdom	EH4 2XU
12	Beatson West of Scotland Cancer Centre	Glasgow	United Kingdom	G12 0YN
13	Diana Princess of Wales Hospital	Grimsby	United Kingdom	DN33 2BA
14	Castle Hill Hospital	Hull	United Kingdom	HU16 5JQ
15	Raigmore Hospital	Inverness	United Kingdom	IV2 3UJ
16	St James University Hospital	Leeds	United Kingdom	LS9 7TF
17	Leicester Royal Infirmary	Leicester	United Kingdom	LE1 5WW
18	Clatterbridge Cancer Centre	Liverpool	United Kingdom	L9 7AL
19	St Bartholomew's Hospital	London	United Kingdom	EC1A 7BE
20	Mount Vernon Hospital	London	United Kingdom	HA6 2RN
21	Royal Free Hospital	London	United Kingdom	NW3 2QG
22	Guy's Hospital	London	United Kingdom	SE1 9RT
23	Royal Marsden Hospital	London	United Kingdom	SW3 6JJ
24	Charing Cross Hospital	London	United Kingdom	W6 8RF
25	The Christie	Manchester	United Kingdom	M20 4BX
26	Nottingham University Hospital	Nottingham	United Kingdom	NG5 1PB
27	Churchill Hospital	Oxford	United Kingdom	OX3 7LE
28	Glan Clwyd Hospital	Rhyl	United Kingdom	LL18 5UJ
29	Scunthorpe General Hospital	Scunthorpe	United Kingdom	DN15 7BH
30	Weston Park Hospital	Sheffield	United Kingdom	S10 2SJ
31	South Tyneside District Hospital	South Shields	United Kingdom	NE34 0PL
32	Southend University Hospital	Southend-on-Sea	United Kingdom	SS0 0RY
33	Sunderland Royal Hospital	Sunderland	United Kingdom	SR4 7TP
34	Royal Marsden Hospital	Sutton	United Kingdom	SM2 5PT
35	Torbay Hospital	Torquay	United Kingdom	TQ2 7AA