CheckpOiNt Blockade For Inhibition of Relapsed Mesothelioma (CONFIRM)

• ClinicalTrials.gov Identifier: NCT03063450
• Recruitment Status: Active, not recruiting
• First Posted: February 24, 2017
• Last Update Posted: November 17, 2022
• Sponsor: University of Southampton
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): University of Southampton

Tracking Information

• First Submitted Date: February 10, 2017
• First Posted Date: February 24, 2017
• Last Update Posted Date: November 17, 2022
• Actual Study Start Date: March 28, 2017
• Estimated Primary Completion Date: February 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 31, 2020)

• Overall survival [ Time Frame: Time from randomisation to date of death from any cause, assessed up to 51 months ]
• Progression free survival (modified RECIST or RECIST 1.1) [ Time Frame: Time from randomisation to progression, assessed up to 51 months ]
  Length of time patients are free from disease through study completion

• Original Primary Outcome Measures (submitted: February 20, 2017): Overall survival [ Time Frame: Time from randomisation to date of death from any cause through study completion up to a maximum of 5 years ]

Current Secondary Outcome Measures (submitted: January 31, 2020)

• Overall response rate (modified RECIST or RECIST 1.1) [ Time Frame: Time from randomisation to progression through study completion, assessed up to 51 months ]
  Response of disease to treatment
• Quality of life (EQ-5D-5L) [ Time Frame: At baseline, after cycles 3 and 6 (each cycle is 14 days) and 1, 6 and 12 months post progression/treatment discontinuation. ]
• Toxicity (CTCAE V4.03) [ Time Frame: At baseline, after each treatment cycle (each cycle is 14 days) and each follow up visit. Up to 30 days post progression/treatment discontinuation. ]
• Cost effectiveness (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. ]

Original Secondary Outcome Measures (submitted: February 20, 2017)

• 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 ]
  Length of time patients are free from disease
• 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 ]
  Response of disease to treatment
• 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. ]
  Quality of life
• 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. ]
  Toxicity
• 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. ]
  Cost effectiveness

Current Other Pre-specified Outcome Measures (submitted: January 31, 2020)

Transnational [ Time Frame: Samples collected at baseline and optional sample at progression (assessed up to 51 months from randomisation) ]

To correlate:

1. mutation burden with OS
2. immunosuppressive landscape (immune checkpoint expression and infiltration of immune cell) and nivolumab efficacy

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CheckpOiNt Blockade For Inhibition of Relapsed Mesothelioma
• Official Title: CheckpOiNt Blockade For Inhibition of Relapsed Mesothelioma (CONFIRM): A Phase III Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy of Nivolumab in Relapsed Mesothelioma

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. Patients will be randomised in a 2:1 ratio (nivolumab: placebo).

336 patients will be recruited from 25 UK centres 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Mesothelioma

Intervention

• Drug: Nivolumab
  Nivolumab at a dose of 240mg as a 30-minute IV infusion, on Day 1 of every 14 day treatment cycle
  Other Name: Opdivo
• Other: Placebo
  Placebo consisting of sterile 0.9% sodium chloride as a 30-minute IV infusion, on Day 1 of every 14 day treatment cycle

Study Arms

• Experimental: Nivolumab
  Nivolumab 240mg flat dose Q2W over 30 minutes IV until disease progression, to a maximum of 12 months
  Intervention: Drug: Nivolumab
• Placebo Comparator: Placebo
  Sterile 0.9% sodium chloride Q2W over 30 minutes IV until disease progression, to a maximum of 12 months
  Intervention: Other: Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 20, 2020): 332
• Original Estimated Enrollment (submitted: February 20, 2017): 336
• Estimated Study Completion Date: February 2023
• Estimated Primary Completion Date: February 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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

  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.
• Expected survival of at least 12 weeks.

Exclusion Criteria:

• 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) or in the CCTG trial of pembrolizumab (IND.227).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03063450
• Other Study ID Numbers: 22864; 2016-003111-35 ( EudraCT Number ); CA209-841 ( Other Grant/Funding Number: Bristol-Myers Squibb ); A21400 ( Other Grant/Funding Number: Cancer Research UK )
• 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
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: University of Southampton
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Southampton
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Principal Investigator: Dean Fennell; University of Leicester
• Principal Investigator: Gareth Griffiths; Southampton Clinical Trials Unit, University of Southampton

• PRS Account: University of Southampton
• Verification Date: November 2022