The UK has the highest incidence of mesothelioma. The incidence has risen by 497% since the late 1970's and is increasing worldwide due to continued mining and use of asbestos. For patients with mesothelioma who have relapsed after taking pemetrexed and cisplatin, there is currently no standard treatment, making this an urgent unmet need. Recent trials in this area have not found an effective treatment that improves overall survival.
Following a debate in the House of Lords, a national survey assessing the research priorities in mesothelioma found that 'exploiting the potential of immunotherapy' was a top priority. This trial was designed in response to that survey. It uses the immunotherapy agent nivolumab which blocks programmed cell death 1 (PD-1) receptor on activated T-cells (a type of white blood cell forming part of the immune system). Early research has found a dependency of mesothelioma on the PD-1 checkpoint. By attaching to PD-1, nivolumab blocks its action (checkpoint inhibition), preventing it from turning off the T-cell, and therefore allowing the immune system to work. PD-1 checkpoint inhibition has revolutionised the treatment of melanoma and it is hoped to be as effective in mesothelioma.
This trial is a randomised, double blind placebo controlled trial of patients with mesothelioma who are third relapse following a platinum based chemotherapy treatment. Patients will be randomised in a 2:1 ratio (nivolumab: placebo).
336 patients will be recruited from 25 UK centres over a four-year period with the last patient having a minimum of 6 months follow up. All patients will be on treatment for 12 months unless they progress or withdrawal prior to this. Clinic visits will occur every 12 weeks, mirroring standard care. Data following progression will be obtained from the NHS Information Centre.
|First Received Date||February 10, 2017|
|Last Changed Date||June 22, 2017|
|Start Date||March 28, 2017|
|Anticipated Primary Completion Date||June 2021|
|Primary Outcome Measures||
Overall survival [Time Frame: Time from randomisation to date of death from any cause through study completion up to a maximum of 5 years]
|Secondary Outcome Measures||
modified RECIST or RECIST 1.1 - progression free survival [Time Frame: Time from randomisation to progression through study completion up to a maximum of 5 years]
modified RECIST or RECIST 1.1 - overall response rate [Time Frame: Time from randomisation to progression through study completion up to a maximum of 5 years]
EQ-5D-5L [Time Frame: Up to max. 24 months. At baseline, after cycles 3 and 6 (each cycle is 14 days) and 1, 6 and 12 months post progression/treatment discontinuation.]
CTCAE V4.03 [Time Frame: Up to max. 13 months. At baseline, after each treatment cycle (each cycle is 14 days) and each follow up visit. Up to 30 days post progression/treatment discontinuation.]
Health resource use questionnaire [Time Frame: Up to max. 24 months. At baseline, after cycles 3 and 6 (each cycle is 14 days) and 1, 6 and 12 months post progression/treatment discontinuation.]
|Study Arms / Comparison Groups||2 / 0|
|Ages||18 Years - N/A|
|Accepts Healthy Volunteers||No|
Phone: 023 8120 3785
- Signed and dated a REC-approved written informed consent form in accordance with regulatory and institutional guidelines. Must be obtained before the performance of any protocol-related procedures that are not part of normal patient care.
- Consent to provide tissue and blood samples for research
- Must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study
- Histological confirmation of mesothelioma (any subtype, pleural or peritoneal).
- Must have received treatment with at least two prior lines of chemotherapy. Prior maintenance therapy (e.g. avastin) is allowed and will not count as a line of therapy.
- Patients enrolled into the CRUK VIM trial as second line therapy who are randomised to best supportive care, will be eligible to enrol into CONFIRM upon disease progression.
- Prior lines of antineoplastic therapy, including chemotherapy, surgical resection of lesions, radiation therapy, must be completed within 28 days of receiving nivolumab
- ECOG PS 0-1
- Age≥18 years
- Expected survival of at least 12 weeks
- Radiologically assessable disease by modified RECIST (pleural mesothelioma) or RECIST 1.1 (non-pleural mesothelioma or where measurements for mRECIST cannot be obtained). Must be performed within 28 days of first dose of study drug
- Evidence of disease progression by CT scan
- Prior palliative radiotherapy must have been completed at least 14 days prior to study drug administration
- Screening laboratory values must meet the following criteria within 48 hours prior to commencement of treatment:
i) White blood cells ≥ 2 x 109/L ii) Neutrophils ≥1.5 x 109/L iii) Platelets ≥ 100 X109/L iv) Haemoglobin ≥ 90 g/L v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl) > 50 mL/minute (using Cockcroft/Gault formula) vi) AST ≤ 3 X ULN vii) ALT ≤ 3 X ULN viii) Total bilirubin ≤ 1.5 X ULN (except patients with Gilbert Syndrome, who must have total bilirubin < 51.3 μmol/L) 2 x 109/L
- Reproductive status
1. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at enrolment and within 24 hours prior to the start of study drug.
2. Women must not be breastfeeding.
3. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with nivolumab plus 5 half-lives of nivolumab (5 x half-life=125 days) plus 30 days (duration of ovulatory cycle) for a total of 5 months post- treatment completion.
4. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
- Target Disease Exceptions
1. Patients with untreated, symptomatic CNS metastases are excluded. Participants are eligible if CNS metastases are adequately treated and participants are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to treatment assignment. In addition, participants must be either off corticosteroids, or on a stable or decreasing dose of
- 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to treatment.
2. Patients with carcinomatous meningitis are excluded.
- Physical and Laboratory Test Findings
1. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
2. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
- Allergies and Adverse Drug Reactions
a) History of severe hypersensitivity reactions to other monoclonal antibodies
- Medical History and Concurrent Diseases
1. Patients with active, known or suspected autoimmune disease.
2. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
3. Other active malignancy requiring concurrent intervention.
4. Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period.
5. Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the patient to receive protocol therapy.
6. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue not resolved to Grade 1 (NCI CTCAE version 4.03) or baseline before administration of study drug.
7. Patients who have not recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.
8. Known alcohol or drug abuse.
9. Patients who have received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or who have previously taken part in a randomised Bristol Myers Squibb (BMS) clinical trial for nivolumab or ipilimumab including study CA209-743 (CheckMate 172).
|Sponsor||University of Southampton|
|Verification Date||June 2017|