REFINE - a randomised control trial testing reduced intensity immunotherapy across different cancers

Phase 2

• Conditions: Treatment of multiple cancer types which are local advanced or metastatic using immune checkpoint inhibition therapies in adult patients already receiving immune checkpoint inhibitors; Cancer

• Registration Number: ISRCTN79455488
• Lead Sponsor: niversity College London

Brief Summary

2022 Protocol article in https://pubmed.ncbi.nlm.nih.gov/36519749/ (added 16/12/2022)

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2022-07-27
• Last Update Posted: 18 July 2023
• Study Completion: 2026-05-25

Recruitment & Eligibility

• Status: Ongoing
• Sex: All
• Target Recruitment: 360

Inclusion Criteria

1. Patients with locally advanced or metastatic cancers for which immune checkpoint inhibitors are standards-of-care and whose clinician has determined they are candidates for treatment with this approach (see also Cohort Specific Inclusion Criteria, below).
2. WHO Performance Status 0 or 1.
3. Patients aged =18 years.
4. Adequate normal organ and marrow function:
4.1. Haemoglobin =90g/L (transfusions will be allowed within 2 weeks prior to randomisation in order to achieve the entry criteria).
4.2. Absolute neutrophil count (ANC) =1.5 x 10^9/L (=1500 per mm³).
4.3. Platelet count =100 x 10^9/L (=100,000 per mm³).
4.4. Bilirubin =1.5 x ULN or patients with confirmed Gilbert’s syndrome (i.e. persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology).
4.5. AST/ALT =3 x ULN.
4.6. eGFR >40mL/min by CKD-EPI formula .
5. Resting 12-lead ECG on which QTcF must be <450 ms. This will usually have been performed prior to commencement of the initial 12 weeks ICI.
6. 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.
7. 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:
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).

Renal cohort specific inclusion criteria:
1. Patients with unresectable locally advanced or metastatic renal cell carcinoma (including clear cell and papillary histologies).
2. Intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria (prior to the initial 12 weeks treatment with ICI combination).
3. Patients have received induction ipilumumab (all four doses) and nivolumab as first-line treatment as planned.
4. No evidence of progression on ipilimumab and nivolumab induction therapy and due to commence maintenance nivolumab (i.e. response or stable disease on cross sectional imaging on completion of initial 12 weeks treatment with ICI combination).

Melanoma cohort specific inclusion criteria:
1. Patients with locally advanced or metastatic melanoma.

Exclusion Criteria

1. Patients who have received ICI in a prior line of treatment.
2. Patients 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).
3. Patients where 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.
4. History of another previous malignancy, except for:
4.1. Malignancy treated with curative intent and with no known active disease =5 years prior to the first dose of ICI.
4.2. Adequately treated non-melanoma skin cancer without evidence of current, active disease.
4.3. Adequately treated carcinoma in situ without evidence of current, active disease.
4.4. Non-muscle invasive bladder cancer.
5. Concurrent enrolment in another interventional clinical study, unless in the follow-up period, except where approved by the CTU (see co-enrolment section for further details).
6. 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.
7. Active infection including:
7.1. Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice).
7.2. 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.
7.3. Hepatitis C. Note: Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
7.4. Human immunodeficiency virus (positive HIV 1/2 antibodies).
8. 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.
9. Known allergy or hypersensitivity to immune checkpoint inhibitor.
10. Pregnant or breastfeeding patients.
11. Uncontrolled adrenal insufficiency.
12. 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.
13. 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).

Study & Design

• Study Type: Interventional
• Study Design: Not specified