Neoplasms

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Sarcoma

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Soft Tissue Sarcoma

Antineoplastic Agents

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Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Arm A (Experimental arm).

* Nivolumab 3 mg/kg
* Ipilimumab 1 mg/kg

Arm B (Control arm). Pazopanib 800 mg/day

The combination of Nivolumab+Ipilimumab will be given to patients as follows:

* Nivolumab: 3 mg/kg IV over 30 minutes every 2 weeks for 4 cycles.
* Ipilimumab 1 mg/kg IV over 60 minutes every 6 weeks for 4 cycles. After completion of 4 courses with ipilimumab, patients continue receiving nivolumab IV at the dose of 480 mg Q4W in the absence of disease progression or unacceptable toxicity for a maximum of 18 months.

Nota Bene: A cycle is defined as a 6-weeks period.

The planned treatment period is 24 months

Nivolumab and Ipilimumab must be injected the same day every 6 weeks (Q6W). In case of toxicity, dose will be delayed, but will not be reduced.

Nivolumab and IPILIMUMAB

Treatment by pazopanib 800 mg/day per os, continuously during a maximum 24 months.

In case of toxicity, dose will be delayed and reduced.

Pazopanib Oral Tablet [Votrient]

Séverine METZGER

Mehdi BRAHMI

Justine GANTZER

Mehdi BRAHMI, Dr

Armelle DUFRESNE, Dr

Hélène VANACKER, Dr

Jean-Yves BLAY, Dr

Loïc CHAIGNEAU

Antoine Italiano, MD

Alice Hervieu, MD

Nicolas Penel, MD

François Bertucci, MD

Agnès Ducoulombier, MD

Camille Tlemsani, MD

Nicolas Isambert, MD

Christophe Perrin, MD

Thibaud Valentin, MD

Benjamin Verret, MD

This is a randomized open label study, with 2 arms treatments conducted in patients with metastatic or unresectable advanced sarcoma of rare subtype; previously treated by anthracycline-based regimen except for whom standard therapy does not exist or is not considered appropriate by the Investigator.

In the experimental arm, patients will receive the combination of Nivolumab + Ipilimumab for a maximum of 24 months, whereas in the control arm, patients will receive Pazopanib alone.

The purpose of the study is to know if the combination of nivolumab + ipilimumab can be more efficient than Pazopanib in terms of Progression-Free Survival.

This is a randomized open label, comparative, prospective, multicentre phase III study.

The patients who meet the eligibility criteria will be randomly assigned (1:1) into one of the following treatments groups:

* Experimental arm: Nivolumab + Ipilimumab (24 months maximum)
* Control arm: Pazopanib alone (24 months maximum)

A randomization procedure will be used to obtain a balanced distribution of stratifications factors:

* The number of previous lines of treatment in advanced/metastatic setting: ≤1 line or \>1 line (a treatment line is defined as a treatment initiation whatever the reason)
* The lymphocytes count at baseline: \<1 g/L or ≥1 g/L.

After their eligibility has been confirmed, patients will be treated with:

* The combination of Nivolumab + Ipilimumab for 4 cycles. After completion of 4 cycles with Ipilimumab, patients continue receiving nivolumab IV (480 mg Q4W) in the absence of disease progression or unacceptable toxicity. A cycle is defined as a 6-weeks period.
* Or Pazopanib until disease progression or unacceptable toxicity. The planned treatment duration in both arm is maximum 24 months.

After the completion of treatment, patients will be followed up within 30 days after the last study treatment administration. The survival and disease status will be updated for all patients at the time of the end of the study.

The overall end of the study will be the Last Patient Last Visit (LPLV), defined as the End Of Treatment (EOT) visit of the last active patient.

Efficacy of the Combination of Nivolumab and Ipilimumab as a Treatment in Patients With Sarcoma of Rare Subtype

A Randomised, Comparative, Prospective, Multicentre Study of the Efficacy of Nivolumab + Ipilimumab Versus Pazopanib Alone in Patients With Metastatic or Unresectable Advanced Sarcoma of Rare Subtype (RAR-Immune)

The Progression-Free Survival defined as the time from the date of randomisation to the date of first documented progression or death due to any cause. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment.

The Best Overall Response will be defined as the best among all overall responses during the trial.

The Objective Response Rate will be defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) during the trial.

in the patients whose BOR is either CR or PR, the DOR will be defined as the time from the date of first documented tumour response to the date of first documented disease progression or death due to underlying cancer. Patients with no event at the time of the analysis will be censored.

The Time to Treatment Failure will be defined as the time from the date of randomisation to the date of permanent study treatments discontinuation (any cause, including disease progression, treatment toxicity, adverse event, start of any new anticancer therapy, withdrawal of consent and death). Patients without treatment failure at the time of the analysis will be censored at the date of last tumour

The Overall Survival will be defined as the time from the date of randomisation to the date of death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.

The Quality of Life will be assessed using the EORTC QLQ-C30 questionnaire.

The Tolerance profile will be described through the incidence and severity of drug-related AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) (v5.0)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy of the Combination of Nivolumab and Ipilimumab as a Treatment in Patients With Sarcoma of Rare Subtype	NCT04741438	Sarcoma	Nivolumab and I... Pazopanib Oral ...	18 Years -	Centre Leon Berard
Efficacy of the Combination of Nivolumab and Ipilimumab as a Treatment in Patients With Sarcoma of Rare Subtype	NCT04741438	Sarcoma	Nivolumab and I... Pazopanib Oral ...	18 Years -	Centre Leon Berard
Efficacy of the Combination of Nivolumab and Ipilimumab as a Treatment in Patients With Sarcoma of Rare Subtype	NCT04741438	Sarcoma	Nivolumab and I... Pazopanib Oral ...	18 Years -	Centre Leon Berard

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