Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART): Eligibility, Screening & Treatment

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1 Renal Adjuvant MultiPle Arm Randomised Trial (RAMPART): Eligibility, Screening & Treatment Sponsor: University College London Lead Trials Unit: MRC CTU at UCL Chief Investigator: Dr James Larkin Independent Scientific Peer Review and Funding: Kidney Cancer UK Educational Grant: AstraZeneca

2 So where are we now? Unlike most other cancers, no adjuvant therapy has proven benefit Global SOC after surgery active monitoring Observation by clinical and radiological means FDA approval (Nov-2017) of sunitinib in adjuvant RCC (high risk) Immunotherapy becoming a promising research avenue Growing experience in conducting efficient trial designs Multi-Arm Multi-Stage (MAMS)

3 Cancer Immunotherapy Immune checkpoint inhibitors Target molecules that serve as checks on immune responses Treatment works by: Blocking inhibitory molecules Activating stimulatory molecules Unleash or enhance pre-existing anti-cancer immune response

4 Trials of Adjuvant Immunotherapy for RCC Author Treatment N 1 o EP Outcome Pizzocaro et al IFN-α vs observation 247 5yr DFS No difference in 5yr DFS or OS Messing et al IFN-α vs observation 283 5yr OS No difference in 5yr DFS or OS Clarke et al IL-2 vs observation 138 2yr DFS No difference in 2yr DFS or OS Atzpodien et al Il-2/IFN-α/5-FU vs observation 203 2yr DFS No difference in 2yr DFS or OS

5 Potential T-cell Targets in Immuno-regulatory anti-body therapy Mellman et al. Nature 2011: 480

6 Immunity Cycle for Therapeutic Intervention The cancer immunity cycle is a series of stepwise events leading to effective killing of cancer cells Various treatments target the different steps promoting the activity of the cycle Chen et al. Immunity 2013;39:1 10

7 What have we learned so far? Nivolumab and Pembrolizumab (anti-pd1 agents) have approval in a number of indications in the US and EU Nivolumab is approved for use in advanced RCC (patients who have failed on anti-angiogenics) FDA approved and recommended in the UK by NICE Ipilimumab (anti-ctla-4) as adjuvant therapy for melanoma Combination of Nivolumab and Ipilimumab Approved for use in the UK for patients with metastatic melanoma Response rates of approx. 40% in advanced RCC CA trial assessing the combination vs sunitininb in advanced or metastatic RCC

8 What have we learned so far? Anti-PD-1 and anti-pd-l1 agents Comparable safety and efficacy data Multiple tumour types Same is true for the two anti-ctla-4 agents in late-stage development Immunogenic nature of RCC (Il-2, IFNa) Immune checkpoint inhibitors have shown activity in patients with advanced RCC and other tumour types Timely research question Is adjuvant immunotherapy effective in RCC?

9 Trial Schema Patients with confirmed RCC, high or intermediate (up to year 3 or 25%) Leibovich score eligible for randomisation into the study Randomisation Patients will initially be allocated in a ratio of 3:2:2 between arms A, B and C. Arm A active monitoring for 1 year Arm B durvalumab 1500mg q4w for 1 year Arm C durvalumab 1500mg q4w for 1y tremelimumab 75mg at day 1 and week 4 Arm D to be decided

10 Durvalumab Durvalumab is a selective, high affinity human IgG monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 Durvalumab binds to PD-L1 and allows T cells to recognise and kill tumour cells PD-L1 inhibits cancer immunity Zou et al. Nature Rev Immunology 2008;8:467-77

11 Tremelimumab Tremelimumab is an IgG 2 kappa isotype mab directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) It is an immune checkpoint blocker CTLA-4 inhibits the killing of cancer cells Ribas et al. The Oncologist, July 2007, 12:

12 Rationale for combination treatment PD-1 and CTLA-4 activation mechanisms are non-redundant Potential for additive or synergistic effects Supporting evidence from trials in other disease areas Melanoma (ipi + nivo) Lung cancer (phase 1b * ) Antonia S et al, Lancet Oncology, Feb-2016

13 Inclusion Criteria Histologically proven RCC No residual macroscopic disease Leibovich score 3-11 Nephrectomy days prior randomisation Post-operative scans should be performed within 28 days prior to randomisation WHO PS 0-1 FFPE tissue available Haemoglobin 9.0g/dL Neutrophil count 1.5 x 10 9 /L Platelet count 100 x 10 9 Bilirubin 1.5 ULN AST/ALT 2.5 ULN Creatinine clearance > 40mL/min 12-lead ECG QtcF <450ms 18 years of age Following trial s contraception policy

14 Intermediate and High-Risk Patients Intermediate risk (IR) patients (LS 3-5) will be capped at 25% of the trial population (or 3 years from start of recruitment) Clinically and ethically important to include patients in this risk group Events from this group will take longer to accrue Will contribute to the primary DFS analysis Rationale for targeting OS in high-risk pts competing causes of death in the IR group potentially large enough to dilute any treatment effect on OS

15 Exclusion Criteria Previous diagnosis of RCC Metastatic or residual macroscopic disease Single pulmonary nodule 5mm (unless benign) Prior anti-cancer treatment Any unresolved toxicity CTCAE Grade 2 History of another primary malignancy Previous malignancy with estimated risk of recurrence in 5 years > 5% Concurrent enrolment in other RCT Major surgical procedure within 28 days prior randomisation History of leptomeningeal carcinomatosis Current or prior use of immunosuppressive therapy within 14 days prior to first dose of trial IMP Active or prior autoimmune or inflammatory disorder History of immunodeficiency syndrome History of allogeneic organ transplant

16 Exclusion Criteria Uncontrolled intercurrent illness, including Ongoing or active infection Symptomatic congestive heart failure Uncontrolled hypertension Unstable angina pectoris Uncontrolled cardiac arrhythmia Active peptic ulcer disease or gastratis Active bleeding diatheses Psychiatric illness or social situation that would limit compliance Active infection (i.e. TB, HIV, Hep B, Hep C) Received of live attenuated vaccine within 30 days prior to randomisation Pregnant or breastfeeding 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 to durvalumab or tremelimumab

17 Screening Procedures Review of eligibility criteria Medical history Complete physical exam Assess baseline symptoms WHO Performance Status Vitals signs Weight and height Review of prior and concomitant medications 12-lead ECG on which QTcF must be <470 ms. In case of clinically significant ECG abnormalities, including a QTcF value >470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding. Post-operative imaging of disease by CT with contrast of chest, abdomen and pelvis Haematology Clinical chemistry Coagulation parameters (PT, PTT, International Normalised Ratio [INR]) Hepatitis serologies (Hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody) Urine HCG or serum HCG test (women of childbearing potential only). To be completed prior to randomisation within 28 days 14 days 7 days Table 2 on study protocol

18 Screening Lab Tests Haematology Assessments Basophils Eosinophils Haematocrit Haemoglobin Lymphocytes Mean Corpuscular Haemoglobin Mean Corpuscular Haemoglobin Concentration Mean Corpuscular Volume Monocytes Neutrophils Platelet count Red blood cell count Total white cell count

19 Screening Lab Tests Clinical Biochemistry Assessments Albumin Alkaline phosphatase Alanine aminotransferase Amylase Aspartate aminotransferase Bicarbonate Calcium Chloride Creatinine Creatinine clearance Gamma glutamyltransferase Glucose Hepatitis serologies

20 Screening Lab Tests Clinical Biochemistry Assessments Lactate dehydrogenase Lipase Magnesium Potassium Random cortisol Sodium Thyroid stimulating hormone Total bilirubin Total protein Urea or blood urea nitrogen Uric acid For more information, see protocol section 3.5.2

21 Contraception Contraception methods described in Protocol Section Female participant or partner of male participant must: Be on highly effective contraception method for 90 days after last durvalumab infusion Barrier or Intrauterine Methods - Copper T intrauterine device - Levonorgesterel-releasing intrauterine system (e.g., Mirena) B Hormonal methods - Etonogestrel implants: e.g., Implanon or Norplan - Intravaginal device: e.g., ethinylestradiol and etonogestrel - Medroxyprogesterone injection: e.g., Depo-Provera - Normal and low dose combined oral contraceptive pill - Norelgestromin/ethinylestradiol transdermal system - Cerazette (desogestrel)

22 Treatment Schedule Both trial medications Supplied by AstraZeneca Administered via infusion Treatment must be started within 14 days from randomisation Additional safety visits: weeks 2 and 6

23 Durvalumab Administration (Arm B and C) Year 1: 1 cycle every 28 days for 1 year (13 cycles max) 3 days administrative delay allowed If time between infusions >8 weeks, treatment to be permanently discontinued If single infusion missed, resume treatment at next visit (no more than 1 year of treatment allowed) Durvalumab administered at each visit (arms B and C) 1500mg per infusion Over 60 minutes (<55min = deviation) Vital signs monitoring before, during (every 30 min) and after administration Additional safety visits: weeks 2 and 6

24 Tremelimumab Administration (Arm C) Year 1: Tremelimumab given at day 1 and week 4 (2 cycles max) Over 60 minutes (<55min = deviation) Tremelimumab should be administered first 1 st cycle: durvalumab administered after 1hr observation 2 nd cycle: if no reactions observed, administer durva after 30min Vital signs monitoring before, during (every 30 min) and after administration Additional safety visits: weeks 2 and 6

25 Toxicity Management There are a number of known side-effects for both drugs some can be quite severe Detailed toxicity management guidelines provided in study protocol Safety will be monitored closely, with a safety review after approx. 20 patients have been randomised to the research arms

26 Toxicity Management If infusion-related reaction occurs, stop treatment immediately G3 toxicity permanent treatment discontinuation

27 Wk 16 Wk 32 Wk 52 DFS Event As Clinically Required Patient FU and Assessments: Year 1 (Arm A) Arm A patients radiologically assessed at Week 16 Week 32 Week 52 Lab tests assessment at each timepoint Protocol Section 6 Clinical Assessments Physical Examination Vital Signs ECG Concomitant Medications AEs WHO Performance Status Radiology CT Scan Laboratory Tests Haematology Clinical Chemistry Questionnaires EQ-5D (optional) QLQ-C30 (optional) PAIR Study Questionnaire (optional)

28 Patient FU and Assessments: Year 1 (Arm B & C) Arm B and C visits Day 1 2 weekly until week 8 Every 4 weeks throughout treatment Lab tests required at each visit (see table 13 & 14 of trial protocol) Radiologically assessed at same timepoints as Arm A Week 16 Week 32 Week 52 Protocol Section 6

29 Day 1 Wk 2 Wk 4 Wk 6 Wk 8 Wk12 Wk 16 Wk 20 Wk 24 Wk 28 Wk 32 Wk 36 Wk 40 Wk 44 Wk 48 Wk 52 DFS Event As Clinically Required Patient FU and Assessments: Year 1 (Arm B & C) Clinical Assessments Physical Examination Vital Signs Weight ECG Concomitant Medications AEs WHO Performance Status Radiology CT Scan Laboratory Tests Haematology Clinical Chemistry Pregnancy Test Urine or serum HCG pregnancy Test Questionnaires EQ-5D (optional) QLQ-C30 (optional) PAIR Study Questionnaire (optional)

30 Wk 52 M 15 M 18 M 21 M 24 M 27 M 30 M 33 M 36 M 48 M 60 M 84 M 120 DFS Event As Clinically Required Year 1 Year 2 Year 3 Year 4 Year 5 year 7 Year 10 Patient FU and Assessments: after Year 1 Clinical Assessments Physical Examination Concomitant Medications AEs WHO Performance Status Radiology CT Scan Laboratory Tests Haematology Clinical Chemistry Questionnaires EQ-5D (optional) QLQ-C30 (optional) PAIR Study Questionnaire (optional)

31 Safety reporting Adverse Events up to M15 * Adverse Events of Special Interest Serious Adverse Events Serious Adverse Reaction SUSAR up to M15 up to M15 indefinitely indefinitely *Up to 120 days after last protocol treatment

32 Safety reporting An event is serious if Results in death Is life-threatening * Requires hospitalisation or prolongation of existing hospitalisation ** Results in persistent or significant disability or incapacity Consists of a congenital anomaly or birth defect Is another important medical condition *** *life threatening at the time of the event ** defined as inpatient admission (excluding selective hospitalisation) *** exercise medical judgements; new primaries need to be reported on SAE form