REduced Frequency ImmuNE Checkpoint Inhibition in Cancers (REFINE)

• ClinicalTrials.gov Identifier: NCT04913025
• Recruitment Status: Recruiting
• First Posted: June 4, 2021
• Last Update Posted: September 21, 2022
• Sponsor: University College, London
• Collaborator: JP Moulton Charitable Foundation
• Information provided by (Responsible Party): University College, London

Tracking Information

• First Submitted Date: May 13, 2021
• First Posted Date: June 4, 2021
• Last Update Posted Date: September 21, 2022
• Actual Study Start Date: May 26, 2022
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 2, 2021)

Progression Free Survival [ Time Frame: 1 year 9 months follow-up ]

Time to event

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 16, 2022)

• Overall survival [ Time Frame: 1 year 9 months follow-up ]
  Measured from date of randomisation until date of death or last follow-up
• Quality of Life (QoL) - Generic [ Time Frame: 1 year 9 months follow-up ]
  EQ-5D-5L questionnaire to assess generic quality of life
• Treatment-related toxicity [ Time Frame: 1 year 9 months follow-up ]
  Measured using severity of all AEs and/or ARs (serious and non-serious) with the toxicity scales in NCI CTCAE v5.0 reviewed at the end of each stage and reported until trial closure
• Mean incremental cost per patient [ Time Frame: 1 year 9 months follow-up ]
  Measured using unit costs from NHS Reference Costs, Personal Social Services Research Unit (PSSRU) and British National Formulary (BNF) prices, and applying them to health and social care resource use collected via the Client Service Receipt Inventory (CSRI), intervention medication CRF, additional treatment logs, and concomitant medication CRF, every 12 weeks starting at baseline, calculating the cost and taking the difference between arms to calculate mean incremental cost per patient (bootstrapped regression, adjusting for baseline values, jointly with QALYs).
• Mean incremental quality-adjusted life-years (QALYs) per patient [ Time Frame: 1 year 9 months follow-up ]
  Measured using utility scores calculated from EQ-5D-5L questionnaire responses collected every 12 weeks starting at baseline, and applying them to the relevant period of follow-up to calculate quality-adjusted life-years (QALYs), and taking the difference between arms to calculate mean incremental QALYs per patient (bootstrapped regression, adjusting for baseline values, jointly with costs).
• Cost-utility analysis [ Time Frame: 1 year 9 months follow-up ]
  Assessing cost-effectiveness of reduced vs. standard frequency administration with summary result expressed as the incremental cost-effectiveness ratio (ICER), i.e. incremental cost per QALY gained, calculated by dividing incremental costs by incremental QALYs; with sensitivity analysis expressed via cost-effectiveness planes and cost-effectiveness acceptability curves to indicate probability that the intervention is cost-effective compared to the standard of care for a range of values of the cost-effectiveness threshold
• Feasibility of recruitment to each cohort [ Time Frame: 1 year 9 months follow-up ]
  Measured by sites completing screening logs to identify number of treatment cycles
• Quality of Life (QoL) - Cancer-specific [ Time Frame: 1 year 9 months follow-up ]
  EORTC QLQ-C30 questionnaire to assess cancer-specific quality of life

Original Secondary Outcome Measures (submitted: June 2, 2021)

• Overall survival [ Time Frame: 1 year 9 months follow-up ]
  Overall survival
• Quality of Life (QoL) [ Time Frame: 1 year 9 months follow-up ]
  EQ-5D-5L questionnaires
• Overall Response Rate (ORR) [ Time Frame: 1 year 9 months follow-up ]
• Duration of Response [ Time Frame: 1 year 9 months follow-up ]
• Incidence of Treatment-Emergent Adverse Events [ Time Frame: 1 year 9 months follow-up ]
  Safety data analysis will be conducted on all subjects receiving at least one dose of study medication. The number and percentage of subjects experiencing an AE and the number of events will be summarized by arm. Information by severity will be examined with a focus on Grade 3-5 events using the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
• Health economic outcome: Mean incremental cost per patient [ Time Frame: 1 year 9 months follow-up ]
  Resource use will be collected via a modified version of the participant-completed Client Service Receipt Inventory (CSRI) and from treatment and concomitant medication data
• Health economic outcome: Mean incremental QALYs per patient [ Time Frame: 1 year 9 months follow-up ]
  QALYs will be calculated from the utility scores calculated from participant responses to the EQ-5D-5L, as the area under the curve, adjusting for baseline differences using regression analysis
• Health economic outcomes: Cost-utility analysis assessing cost-effectiveness of reduced vs. standard frequency administration [ Time Frame: 1 year 9 months follow-up ]
  CSRI questionnaire and Published NHS Reference Costs or Personal Social Services Research Unit (PSSRU) Unit Costs of Health and Social Care will be applied to service use information, and British National Formulary costs used where required for medications, with secondary analyses using any available information on patient access scheme discounts.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: REduced Frequency ImmuNE Checkpoint Inhibition in Cancers
• Official Title: REduced Frequency ImmuNE Checkpoint Inhibition in Cancers: A Multi Arm Phase II Basket Protocol Testing Reduced Intensity Immunotherapy Across Different Cancers
• Brief Summary: The REFINE trial aims to asses whether giving an immunotherapy drug less-often to patients with advanced cancer, results in fewer side effects whilst continuing to be an effective treatment. The question will be assessed in different tumour types by means of different cohorts within an overarching trial protocol.

Detailed Description

In stage I eligible participants will be randomly assigned to either the standard interval (either 4 or 6 weeks) or the extended interval (either 8 or 12 weeks) following an initial 12 weeks of standard of care immunotherapy. Disease recurrence and survival will be assessed, along with quality of life and health economic outcomes. The trial includes a feasibility outcome by which recruitment feasibility will be assessed.

Immunotherapy drugs are a standard treatment option for advanced kidney cancer, melanoma, and some lung cancers. These drugs work by stimulating the body's own immune system to fight against cancer cells. Clinical trials have proven the effectiveness of immunotherapy drugs, such as ipilimumab, nivolumab or pembrolizumab, in the treatment of different cancers. However the best way to give these drugs is not known.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Renal Cell Carcinoma
• Melanoma

Intervention

• Drug: Nivolumab
  60-minute IV infusion, as a flat dose of 480mg
• Drug: Pembrolizumab
  60-minute IV infusion, as a flat dose of 400mg

Study Arms

• Active Comparator: Standard interval
  Standard of care regimen Nivolumab administered as an approximate 60-minute IV infusion, as a flat dose of 480mg once every 4 weeks OR Pembrolizumab administered as an approximate 60-minute IV infusion, as a flat dose of 400mg once every 6 weeks
  Interventions:

  • Drug: Nivolumab
  • Drug: Pembrolizumab
• Experimental: Extended interval
  Nivolumab administered as an approximate 60-minute IV infusion, as a flat dose of 480mg once every 8 weeks OR Pembrolizumab administered as an approximate 60-minute IV infusion, as a flat dose of 400mg once every 12 weeks
  Interventions:

  • Drug: Nivolumab
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 2, 2021): 160
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Common Inclusion Criteria:

• WHO Performance Status 0 or 1.
• Patients with locally advanced or metastatic cancer whose clinician has determined they are candidates for treatment with standard of care immune checkpoint inhibitor.- Patients aged ≥18years.

• Adequate normal organ and marrow function:

  1. Haemoglobin ≥9.0g/dL (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria).
  2. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1500 per mm3).
  3. Platelet count ≥100 x 109/L (≥100,000 per mm3).
  4. 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 considered eligible only in consultation with their physician).
  5. AST/ALT ≤3 x ULN.
  6. eGFR >40mL/min by CKD-EPI formula .
• Both men and women enrolled in this trial must be in agreement with trial policy on contraception during the treatment phase of the study. Egg donation, sperm donation and breastfeeding must be avoided.

• Evidence of post-menopausal status or negative serum HCG pregnancy test for female pre/peri-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:

  1. Women <50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormone 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).
  2. 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).

Renal Cohort Inclusion Criteria:

• Patients with unresectable locally-advanced or metastatic renal cell carcinoma (including clear cell and papillary histologies).
• Intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria.
• Patient has received induction ipilimumab (all four doses) and nivolumab as first-line treatment as planned.
• Due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease on cross sectional imaging on completion of initial 12 weeks treatment with ICI).

Melanoma Cohort Inclusion Criteria

• Patients with locally-advanced or metastatic melanoma.
• Patients have received single agent pembrolizumab first-line for 3 months, with no evidence of progression (i.e. response or stable disease) on cross sectional imaging 12 weeks after initiation of ICI, and due to commence maintenance pembrolizumab every 6 weeks.

or Patients have received induction ipilimumab 1mg/kg and nivolumab 3mg/kg as first-line treatment, and due to commence maintenance nivolumab with no evidence of progression (i.e. response or stable disease) on cross sectional imaging 12 weeks after initiation of ICI.

Exclusion Criteria:

• Patients who have received ICI in a prior line of treatment.
• Patients whose planned treatment is the combination of anti-PD-1 and tyrosine kinase inhibitor e.g. pembrolizumab+axitinib or the combination of traditional cytotoxic chemotherapy and anti-PD-1.
• Patients with unresolved/untreated immune-related adverse events arising during the first 3 months treatment with standard of care ICI.

• History of another previous malignancy, except for:

  1. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP.
  2. Adequately treated non-melanoma skin cancer without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease.
  4. Superficial bladder cancer.
• 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.
• Current or prior use of immunosuppressive medication within 14 days of starting trial treatment, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10mg/day of prednisone, or an equivalent corticosteroid.

• Active infection including:

  1. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice).
  2. 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.
  3. Hepatitis C. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  4. Human immunodeficiency virus (positive HIV 1/2 antibodies).
• Receipt of a live attenuated vaccine within 30 days prior to the start of treatment.

Note: Patients, if enrolled, should not receive a live vaccine while receiving immune checkpoint inhibitor and up to 30 days after the last dose of immune checkpoint inhibitor.

• Known allergy or hypersensitivity to immune checkpoint inhibitor.
• Pregnant or breastfeeding patients.
• Uncontrolled adrenal insufficiency.
• Any serious or uncontrolled medical or psychiatric disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, interfere with participation and/or compliance in the trial, or interfere with the interpretation of study results.
• Participants who have undergone any prior systemic anti-cancer treatment (previous participation in adjuvant studies allowed, providing the patient was on the observation/ placebo arm - this may require un-blinding of the patient).
• Untreated brain metastases or brain metastases treated only with whole brain radiotherapy. (Patients are eligible if previous brain metastases treated with complete surgical resection, Stereotactic Brain Radiation Therapy (SBRT), or gamma knife with no subsequent evidence of progression and asymptomatic).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jonathan Badrock; 02076704602; mrcctu.refine@ucl.ac.uk

• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT04913025
• Other Study ID Numbers: RF01; 2021-002060-47 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University College, London
• Original Responsible Party: Same as current
• Current Study Sponsor: University College, London
• Original Study Sponsor: Same as current
• Collaborators: JP Moulton Charitable Foundation

Investigators

• Study Director: Duncan Gilbert; MRC CTU at UCL

• PRS Account: University College, London
• Verification Date: September 2022