CheckpOiNt Blockade For Inhibition of Relapsed Mesothelioma

NCT03063450 | Completed Phase 3 DMC

• 4 other identifiers: 228642016-003111-35CA209-841A21400
• Study Type: interventional
• Target: 332
• Locations: 1 country
• Sites: 24

Brief Summary

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 second or third relapse following a platinum based chemotherapy treatment.

Conditions

Mesothelioma

Keywords

anti PD-L1; nivolumab; immunotherapy; RECIST; quality of life; survival; immune checkpoint inhibition

Outcome Measures

Primary Outcomes (2)

• Overall survival

  Length of time participants are alive

  Time from randomisation to date of death from any cause or time of censoring

• Progression free survival

  Length of time participants are free of disease progression

  Time from randomisation to investigator-reported progression, death, or end of study (max. 12 months from last participant randomised)

Secondary Outcomes (5)

• Overall response rate (modified RECIST or RECIST 1.1)

  From randomisation and while on treatment

• EQ-5D-5L

  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

  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

  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.

• Progression-free survival (RECIST)

  From randomisation until 28 days after completing treatment (max. 12 months), progression, or death

Other Outcomes (1)

• Translational

  Samples collected at baseline and optional sample at progression (assessed up to 51 months from randomisation)

Study Arms (2)

Nivolumab

EXPERIMENTAL

Nivolumab 240mg flat dose Q2W over 30 minutes IV until disease progression, to a maximum of 12 months

Drug: Nivolumab

Placebo

PLACEBO COMPARATOR

Sterile 0.9% sodium chloride Q2W over 30 minutes IV until disease progression, to a maximum of 12 months

Other: Placebo

Interventions

Nivolumab DRUG

Nivolumab at a dose of 240mg as a 30-minute IV infusion, on Day 1 of every 14 day treatment cycle

Also known as: Opdivo

Nivolumab

Placebo OTHER

Placebo consisting of sterile 0.9% sodium chloride as a 30-minute IV infusion, on Day 1 of every 14 day treatment cycle

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 one prior line of treatment. Prior maintenance therapy (e.g. avastin) is allowed and will not count as a line of therapy. Prior lines of antineoplastic therapy, including chemotherapy, surgical resection of lesions, radiation therapy, must be completed within 14 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).
• 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 10\^9/L ii) Neutrophils ≥1.5 x 10\^9/L iii) Platelets ≥ 100 X10\^9/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 10\^9/L
• Reproductive status
• 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.

You may not qualify if:

• Target Disease Exceptions
• 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.
• Patients with carcinomatous meningitis are excluded.
• Physical and Laboratory Test Findings
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• 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
• Patients with active, known or suspected autoimmune disease.
• 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.
• Other active malignancy requiring concurrent intervention.
• 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.
• 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.
• 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.

Sponsors & Collaborators

• University of Southampton: lead
• Bristol-Myers Squibb: collaborator

Study Sites (24)

Ulster Hospital

Dundonald, Belfast, BT16 1RH, United Kingdom

Location

Raigmore Hospital

Inverness, Inverness, IV2 3UJ, United Kingdom

Location

East Kent Hospitals University Foundation Trust

Canterbury, Kent, CT1 3NG, United Kingdom

Location

Northumbria Healthcare NHS Foundation Trust

Newcastle upon Tyne, Northumberland, NE12 8EW, United Kingdom

Location

Aberdeen Royal Infirmary

Aberdeen, United Kingdom

Location

Basildon University Hospital

Basildon, United Kingdom

Location

Belfast City Hospital

Belfast, United Kingdom

Location

Royal Bournemouth Hospital

Bournemouth, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

Velindre Cancer Centre

Cardiff, United Kingdom

Location

Ninewells Hospital

Dundee, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

Location

Harrogate District Hospital

Harrogate, United Kingdom

Location

University Hospitals Morecambe Bay

Lancaster, United Kingdom

Location

Leicester Royal Infirmary

Leicester, United Kingdom

Location

Barts Cancer Institute

London, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Location

Wythenshawe Hospital

Manchester, United Kingdom

Location

Mount Vernon Cancer Centre

Northwood, United Kingdom

Location

Churchill Hopsital

Oxford, United Kingdom

Location

Southampton General Hospital

Southampton, United Kingdom

Location

Southend Hospital

Southend-on-Sea, United Kingdom

Location

Lister Hospital

Stevenage, United Kingdom

Location

Musgrove Park Hospital

Taunton, United Kingdom

Location

Related Publications (2)

• Fennell DA, Kirkpatrick E, Cozens K, Nye M, Lester J, Hanna G, Steele N, Szlosarek P, Danson S, Lord J, Ottensmeier C, Barnes D, Hill S, Kalevras M, Maishman T, Griffiths G. CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial. Trials. 2018 Apr 18;19(1):233. doi: 10.1186/s13063-018-2602-y.

  PMID: 29669604 BACKGROUND

• Fennell DA, Ewings S, Ottensmeier C, Califano R, Hanna GG, Hill K, Danson S, Steele N, Nye M, Johnson L, Lord J, Middleton C, Szlosarek P, Chan S, Gaba A, Darlison L, Wells-Jordan P, Richards C, Poile C, Lester JF, Griffiths G; CONFIRM trial investigators. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1530-1540. doi: 10.1016/S1470-2045(21)00471-X. Epub 2021 Oct 14.

  PMID: 34656227 DERIVED

Related Links

• Preliminary data for the trial

MeSH Terms

Conditions

Mesothelioma

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Dean Fennell

  University of Leicester

  PRINCIPAL INVESTIGATOR

• Gareth Griffiths

  Southampton Clinical Trials Unit, University of Southampton

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2017
• First Posted: February 24, 2017
• Study Start: March 28, 2017
• Primary Completion: February 7, 2023
• Study Completion: February 7, 2023
• Last Updated: April 10, 2025

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be shared once all parties have signed relevant data sharing documentation, from three months following publication of the final analysis.
• Access Criteria: Completion of data access request via Southampton CTU website.

Locations

GB (24)