Introduction
Methods & design
Study design
Study objectives
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Cost-effectiveness,
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The efficacy in terms of:
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Immune progression-free survival using iRECIST,
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Objective response rate at 12 and 24 months post-randomization,
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Overall survival,
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Duration of response at 12 months post-randomization,
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Quality of life (self-reported EORTC QLQ-C30 and EQ-5D-5L questionnaires),
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Anxiety and fear of relapse using specific questionnaires,
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Safety profile.
Primary endpoint
Secondary endpoints
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Incremental cost-effectiveness ratio (ICER) expressed as a cost per quality-adjusted life year (QALY) gained at 36 months.
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Efficacy
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Immune progression-free survival (iPFS) calculated from the date of randomization to the date of disease progression or death from to any cause, whichever occurs first. Immune progression will be determined locally by the investigator according to iRECIST v1.1 in case of lesions identified at baseline.
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Objective response rate (ORR) defined as the percentage of patients with a confirmed complete response (CR) or partial response (PR) at 12 and 24 months post-randomization considering patients who switch from study treatment to any other cancer treatment within 12 and 24 months post-randomization as failures.
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Overall survival (OS) calculated from the date of randomization to the date of death from any cause.
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Duration of response (DoR) defined as the time from randomization to first documented disease progression or death, whichever occurs first.
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Quality of life mean score of self-reported EORTC QLQ-C30 and EQ-5D-5L questionnaires at inclusion visit (pre-randomization), 3, 6, 9, 12, 15, 18, 24 and 36 months post-randomization.
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Evaluation of anxiety and fear of recurrence scores using specific questionnaires (HADS and Fear of Cancer Recurrence Inventory, Short Form) at 3, 6, 9, 12, 15, 18, 24 and 36 months post-randomization.
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Number, frequency and severity of adverse events according to CTCAE v5.0 at 12 months and 3 years post-randomization.
Study population
Inclusion criteria | Exclusion criteria |
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1. Patient must have signed a written informed consent form prior to any trial specific procedures 2. Patient aged ≥ 18 years old 3. Initial metastatic disease histologically confirmed including: lung cancer, renal cell cancer, head and neck cancer, bladder cancer, triple negative breast cancer, Merkel cancer, hepatocellular carcinoma, melanoma, colorectal carcinoma with microsatellite instability [MSI], or esophageal squamous cell carcinoma 4. Patients in partial or complete response after 6 months of standard immunotherapy (whatever the line of therapy) according to the RECIST criteria (confirmed by local radiological assessment). For metastatic melanoma only patients in partial response 5. Eligible to maintain the same standard IO treatment 6. Patient with ECOG performance status ≤ 1 7. Patients with brain metastases are allowed, provided they are stable according to the following definitions: treated with surgery or stereotactic radiosurgery and without evidence of progression prior to randomization and have no evidence of new or enlarging brain metastases 8. Patients treated by IO previously combined with chemotherapy are allowed 9. Patients with TKI-IO or pemetrexed-IO or bevacizumab-IO are allowed 10. Evidence of post-menopausal status, negative urinary, or serum pregnancy test for female pre-menopausal patients 11. Both sexually active women of childbearing potential and males (and their female partners) patients must agree to use adequate contraception method for the duration of the study treatment and after completing treatment according to the most recent version of the IO SmPC 12. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up 13. Patient must be affiliated to a Social Security System | 1. Metastatic melanoma in complete response 2. Metastatic renal cell carcinoma with IMDC favourable-risk treated TKI/IO combination 3. Hematologic malignancies (leukaemia, myeloma, lymphoma…) 4. Active infection requiring systemic therapy 5. Patients enrolled in another therapeutic study within 30 days before the inclusion in and during MOIO study 6. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study 7. Person deprived of their liberty or under protective custody or guardianship |
Inclusion criteria
Exclusion criteria
Randomization
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Response (CR vs PR),
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Metastatic tumor type (lung cancer, renal cell cancer, head and neck cancer, bladder cancer, triple negative breast cancer, Merkel cancer, hepatocellular carcinoma, melanoma, colorectal carcinoma with microsatellite instability [MSI], or esophageal squamous cell carcinoma).
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IO type (anti-PD-1 vs anti-PD-L1),
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Treatment line (first line vs others).
Treatment plan
Therapeutic regimens
Duration of treatment
Visit schedule and assessments (Supplementary Table 1)
Adverse events
Statistical analysis
Sample Size calculation
Statistical analyses
Analysis of the primary outcome
Interim analysis
Analysis of secondary outcomes
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Cost-effectiveness
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iPFS, DoR and ORR will be analyzed on the PP and the mITT population. Efficacy time-to-event outcomes will be censored on the date of last known follow up visit. In case of initiation of subsequent anticancer therapy before disease progression or death, individual iPFS and DoR data will be censored on the date of first initiation of subsequent anticancer therapy.
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ORR at 12 and 24 months post-randomization are defined as the percentage of patients with a confirmed CR or PR by considering patients who switch from study treatment to any other cancer therapy within 12 and 24 months post-randomization as treatment failures.
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Time-to-event outcomes will be summarized using Kaplan–Meier methods. Regression models with terms for the randomized arm, the tumor type, the IO type (anti-PD-1 vs anti-PD-L1), the therapy line (1st line vs others) and the response status 6 months after initiation of standard IO will be used to estimate the treatment effect (reduced IO vs standard IO) on secondary efficacy endpoints. Hazard ratios for iPFS, DoR and OS and odds ratio for ORRs will be estimated using Cox’s or logistic regression modelling, respectively.
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Analyses of self-reported questionnaires will be based on the mITT population set. Actual values and changes from pre-randomization visit in EORTC QLQ-C30, EQ-5D-5L, anxiety (HospitalAnxiety and Depression Scale) and fear of relapse. (Fear of Cancer Recurrence inventory short Form) specific questionnaires will be tabulated by treatment group using standard descriptive statistics. Differences in changes from pre-randomization visit between treatment arms will be estimated at specific time visit using robust linear regression methods for longitudinal data.
Data management and monitoring
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Effective protection of patients.
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Insure the ethical conduct of the trial.
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Benefit/risk ratio of the trial.
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Ensure the independent review of the scientific results during the trial and at the end of the trial.
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First analysis when 125 events are observed.
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Second analysis when 249 events are observed.
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The results of the interim analysis clearly show that the one-sided P-value for testing the hypothesis HR = 1 versus the alternative HR > 1 is less than 0.0192 (p value associated to an observed HR = 1.3 at mid-trial);
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An unacceptable toxicity.