Neoplasms

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Behaviors and Mental Disorders

Rare Diseases

Gastrointestinal Stromal Tumors

Disease Progression

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Quality of Life

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Immunomodulating Agents

Atezolizumab

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Imatinib per os 400 mg daily continuously associated with intravenous administrations of atezolizumab at the fixed dose of 1 200 mg every 3 weeks (up to 12 months)

Imatinib alone, per os 400 mg daily continuously (up to 12 months)

Atezolizumab 1200 mg

Imatinib 400 MG

Julien GAUTIER

Mehdi BRAHMI, MD

Antoine ITALIANO

Loïc LEBELLEC

Florence DUFFAUD, MD

Agnès DUCOULOMBIER

Nicolas ISAMBERT

Olivier BOUCHE, MD

Marc PRACHT

Emmanuelle BOMPAS

Justine GANTZER, MD

Axel LE CESNE, MD

This trial is a prospective, randomized (1:1 ratio), multicenter, comparative and phase II study, conducted in patients with unresectable advanced gastrointestinal stromal tumors (GIST) after failure of imatinib (disease progression),sunitinib and regorafenib (either disease progression or intolerance)

In the first arm, patients will be treated with imatinib + atezolizumab (experimental arm), whereas in the second arm, patients will be treated with imatinib alone (control arm).

The comparison between this two arms will allow to compare whether or not atezolizumab and imatinib is efficient for disease control, in terms of Progression-Free Survival improvement.

This is a prospective, randomized (1:1 ratio), multicenter, comparative and phase II trial.

Patients with unresectable advanced gastrointestinal stromal tumors (GIST) will be accrued after the failure of standard treatments (imatinib, sunitinib and regorafenib) :

* For imatinib, failure is defined as disease progression
* For sunitinib and regorafenib, failure is defined as disease progression and/or intolerance

Randomization (1:1 ratio) will be stratified according to:

* The tumor KIT (exon 11) mutational status: wild type or mutated

STUDY TREATMENTS :

During the treatment period (12 months maximum), all patients will receive either:

* Imatinib per os 400 mg daily continuously associated with intravenous administrations of atezolizumab at the fixed dose of 1200 mg every 3 weeks (experimental arm)
* Or imatinib alone, per os 400 mg daily continuously (control arm)

The comparison between this two arms will allow to compare whether or not atezolizumab and imatinib is efficient for disease control, in terms of Progression-Free Survival improvement.

STATISTICAL ANALYSIS :

A total of 110 patients will be randomized (55 per arm).

It is expected a 6-month PFS rate of 10% in the standard arm (imatinib alone). Thus, a 6-month PFS-rate of 30% is a clinically significant target for patient treated with imatinib associated to immunotherapy.

An interim safety analysis is planned to be conducted after 6-month follow-up of the 12th patient has been randomized (approximately 6 patients by arm).

PFS will be estimated using the Kaplan-Meier method, and will be described in terms of median PFS along with the associated 2-sided 95% CIs for the estimates.

PFS distributions will be compared between the 2 study arms using a stratified Log-Rank test by tumor mutational status of KIT - exon 11 (stratification factors used for the randomisation).

DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING :

All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. Serious adverse event (SAE) and Adverse Event of Specific Interest (AESI) reporting will be also paper-based by e-mail and/or Fax.

The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

A Prospective, Randomized, Multicenter, Comparative Study of the Efficacy of Imatinib Resumption Combined With Atezolizumab Versus Imatinib Resumption Alone in Patients With Unresectable Advanced Gastrointestinal Stromal Tumors (GIST) After Failure of Standard Treatments

Time from the date of randomization to the date of first disease progression, or death from any cause, whichever occurs first

The best response from randomization : Complete Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD)

The proportion of patients with a best overall response of CR or PR during the study

The time from the date of randomization to the date of permanent study treatments discontinuation (any cause, including death, progression, discontinuation of treatment due to progression, toxicity or start of a new anticancer therapy and withdrawal of consent)

The time from the date of randomization to the date of death due to any cause

Assessed using the EORTC QLQ-C30 questionnaire

Described through the incidence and severity of drug-related AEs (AE, SAE, SUSAR, new safety issue) according to the National Cancer Institute Common Terminology Criteria for Adverse Event Version 5 (NCI-CTC AE V5.0)

Centre Leon Berard

Gland and Hormone Related Diseases

Thyroid Diseases

Carcinoma

Thyroid Neoplasms

Neoplasms, Glandular and Epithelial

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Daily oral administration of pazopanib 800mg (28 days cycles) from randomization until progression (according to RECIST 1.1) under treatment, after an initial period of 6 cycles (28 days) of daily administration of pazopanib 800mg from inclusion until randomization

Temporary discontinuation of pazopanib at randomization, after an initial period of 6 cycles (28 days) of daily administration of pazopanib 800mg from inclusion until randomization. Pazopanib will be reintroduced for 6 cycles of 28 days, with daily administration of pazopanib 800mg, as soon as the patient relapses (progressive disease according to RECIST 1.1). At the end of this additional 6 cycles, study drug will be stopped a second time.

This sequential scheme will be maintained until the patient experiences "on-treatment" progression

Continuous pazopanib (Arm A)

Intermittent pazopanib (Arm B)

Christelle De La Fouchardière, MD

The objective of this study is to determine the feasibility of pazopanib treatment interruption with reintroduction at progression in iodine refractory progressive Differentiated Thyroid Cancer (DTC) patients as compared to pazopanib continuous administration.

Total or near-total thyroidectomy is the primary treatment for differentiated thyroid carcinoma. Postoperatively, DTC are treated with radioiodine (131I) and thyroid stimulating hormone (TSH) suppressive levothyroxine therapy.

But 5% to 20% of patients with DTC develop distant metastases; some of them become refractory to 131I therapy.

Targeted therapies have been studied in iodine refractory DTC for several years but none of these treatments has yet been approved in DTC and clinicians continue to enroll patients in clinical trials. The agents used so far in thyroid cancer are small molecules sharing the property to inhibit various tyrosine kinase receptors such as Vascular Endothelial Growth Factor Receptor (VEGFR), Epidermal Growth Factor Receptor (EGFR), RET or c-met.

The VEGF (Vascular Endothelial Growth Factor) is one of the several pro angiogenic molecules that play a pivotal role in angiogenesis, one of the mechanisms involved in tumor growth and dissemination.

VEGF expression is highly prevalent in Papillary Thyroid Carcinoma (PTCs) (79%), Follicular Thyroid Carcinoma (FTCs) (50%) or Poorly Differentiated Thyroid Carcinoma (PDTCs) (37%) and VEGFR is respectively expressed in 76%, 83% and 25% for VEGRF-1 and 68%, 56% and 37% for VEGRF-2.

Pazopanib (GW786034 - GlaxoSmithKline) is an orally administered, potent multitarget tyrosine kinase inhibitor of VEGFR in particular (but also of PDGFR-α and -β, and stem cell factor receptor c-Kit).

The results obtained in metastatic or locally advanced refractory DTC are currently available (phase II study of 39 patients with metastatic, rapidly progressive RAI-refractory DTC, treated with pazopanib 800mg daily, were published in Lancet Oncology in 2010 by KC Bible), demonstrating the efficacy of these therapies in this indication. However, no clear data is yet available indicating the optimal duration of treatment in first line therapy: patients are currently treated until progression or until drug discontinuation due to toxicity. Indeed, patients may have some difficulties to manage the chronic mild to moderate (grade 1-2) side-effects related to long-term treatment, leading some asymptomatic patients in whom tumor is controlled by TKI treatment to ask for treatment interruption.

The intermittent administration should avoid the occurrence of long-term adverse event and subsequent dose reductions or discontinuation, thus allowing a longer control of underlying disease.

All these considerations led our reflexion in the design of the present study, that is to say to determine the feasibility of pazopanib treatment interruption with reintroduction at progression in iodine refractory progressive DTC patients as compared to pazopanib continuous administration, after 6 initial cycles of pazopanib 800 mg daily for all patients included in the study, with a strong rationale for intermittent administration of pazopanib.

Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma

A Randomized, Multicenter, Open-label, Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma

To study the correlation between clinical response and biomarkers (serum and tissue).

To perform gene expression profiling and to identify potential candidate genes.

TTF is the time to permanent treatment discontinuation due to any cause after randomization in each arm

Proportion of patients with a best overall response of Complete Response (CR) or a Partial Response (PR) at the end of the first 6 cycles, according to RECIST criteria 1.1

Proportion of patients with a best overall response of Complete Response, Partial Response or Stable Disease at the end of the first 6 cycles, according to RECIST criteria 1.1

Time from date of randomization to the date of event defined as the first documented progression under treatment or death due to any cause.

Best response observed from date of randomization

Time from the first documented response (CR or PR) to the first documented disease progression or death due to any cause, applies only to patients whose best overall response is CR or PR

Time from date of randomization to the date of death due to any cause

Proportion of patients with a CR or a PR after 6 cycles from randomization.

The proportion of patients with a SD, PR or CR after 6 cycles from randomization.

Adverse events (AE) experienced throughout the study and assessed according the NCI-CTC AE version 4.0.

The score obtained at the EORTC Quality of Life Questionnaire C30

GlaxoSmithKline

Osteosarcoma

Sarcoma

Neoplasms, Bone Tissue

Soft Tissue Sarcoma

Treatment will be divided in 28 days cycles, including a 21-day period of treatment by regorafenib and best supportive care followed by a 7-day period of rest.

In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC).

Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).

Treatment will be divided in 28 days cycles, including a 21-day period of treatment by placebo and best supportive care followed by a 7-day period of rest.

In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC).

Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).

Treatment for 13 cycles (12 months) maximum.

During each cycle :

* patients ≥ 16 years old and patients \<16 old with Body Surface Area (BSA) ≥ 1,70 m2 will take 3 tablets, once a day, corresponding to a total of 120 mg Regorafenib, during 21 days, followed by 7 days without treatment.
* patients \< 16 years old with a 1,30 m2 ≤ BSA ≥ 1,70 m2 will take 2 tablets, once a day, corresponding to a total of 80 mg Regorafenib, during 21 days, followed by 7 days without treatment

Treatment by regorafenib and best supportive care

Treatment for 13 cycles (12 months) maximum.

During each cycle :

* patients ≥ 16 years old and patients \<16 old with Body Surface Area (BSA) ≥ 1,70 m2 will take 3 tablets, once a day, corresponding to a total of 120 mg Placebo, during 21 days, followed by 7 days without treatment.
* patients \< 16 years old with a 1,30 m2 ≤ BSA ≥ 1,70 m2 will take 2 tablets, once a day, corresponding to a total of 80 mg Placebo, during 21 days, followed by 7 days without treatment

Treatment by placebo and best supportive care

Loïc CHAIGNEAU

Maud TOULMONDE

Alice HERVIEUX

Nicolas PENEL

Mehdi BRAHMI

Nelly FIRMIN

Morgane CLEIREC

Sophie PIPERNO-NEUMANN

Pascaline BOUDOU-ROUQUETTE

Claire BERGER

Natacha ENTZ WERLE

Justine GANTZER

Thibaud VALENTIN

Nathalie GASPAR

This is a randomized, double-blinded, 2 arms study concerning patients with high-grade bone sarcoma (HGBS) without complete remission after standard treatment at diagnosis or first relapse.

In the first arm, patients will be treated with regorafenib + best supportive care (BSC) for a maximum of 12 months as maintenance therapy after standard line therapy completion, whereas in the second arm, patients will be treated with placebo + BSC (standard of care).

The comparison between this two arms will allow to determine whether or not regorafenib and BSC is efficient for disease control, in terms of Progression-Free Survival improvement.

This is a randomized, placebo-controlled, double-blinded, prospective, comparative, multicentre phase II study.

Patients with measurable unresectable residual disease will be accrued after they completed standard of care, consisting of:

* At diagnosis: multimodal treatment with neoadjuvant chemotherapy, surgery and adjuvant chemotherapy
* At relapse: chemotherapy

Patients who meet the eligibility criteria will be randomly assigned (1:1) into one of the following treatment groups:

* Experimental arm: regorafenib + best supportive care (BSC) maintenance (12 months maximum)
* Standard arm: placebo + BSC (12 months maximum)

A randomization procedure (centralized implementation of concealed random permuted blocks) will be used to obtain a balanced distribution of the setting of the disease (stratification factor): residual disease at diagnosis or at relapse after standard multimodal treatment.

After their eligibility has been confirmed, patients will receive regorafenib or its matching placebo until disease progression, or for a maximum of 12 months, or unacceptable toxicity or willingness to stop, whichever occurs first.

In case of radiological disease progression during treatment period, patients from the standard arm (placebo) who have unresectable disease will be allow to switch to experimental arm (regorafenib). After the switch, patients will be treated with regorafenib until disease progression or unacceptable toxicity or willingness to stop which occurs first.

After the completion of the maintenance therapy (12 months) patients will be followed-up until the first radiological disease progression, unless a premature disease progression occurred. All patients will be followed-up until the data cut-off (12 months after the last randomization).

The vital status will be updated once for all patients at the end of the study, based on patient's medical file.

The end of the study will be 24 months after the last randomisation or at the end of treatment of the last patient under treatment (either blinded or open label) whichever occurs last.

Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients

A Randomized, Placebo-controlled, Double-blinded, Phase II Study of Efficacy of Regorafenib as Maintenance Treatment in Patients With High Grade Bone Sarcomas at Diagnosis or Relapse and Without Complete Remission After Standard Treatment

The Progression-Free Survival (PFS) will be defined as the time from the date of randomization to the date of first documented disease progression (according to the RECIST V1.1) or the date of death due to any cause.

Patients alive and progression-free at the time of data cut-off will be censored at the time of the latest tumour evaluation.

In patients from the placebo arm who switched into the active treatment group, PFS will be studied from regorafenib initiation: PFS from switch will be defined as the time from the date of switch to the date of first documented disease progression (according to the RECIST V1.1) post-switch or the date of death due to any cause.

The Objective Response Rate (ORR) will be defined as the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) (RECIST V1.1)

In patients from the placebo arm who switched into the active treatment group, the ORR will be studied from regorafenib initiation:

The ORR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of Complete Response (CR) or Partial Response (PR) from regorafenib initiation.

The Disease Control Rate (DCR) will be defined as the proportion of patients with a best overall response of CR, PR or Stable Disease (SD) (RECIST V1.1) 2 months after randomization

The Disease Control Rate (DCR) will be defined as the proportion of patients with a best overall response of CR, PR or Stable Disease (SD) (RECIST V1.1) 4 months after randomization

In patients from the placebo arm who switched into the active treatment group, the DCR will be studied from regorafenib initiation:

The DCR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of CR, PR or Stable Disease (SD) 2 months after regorafenib initiation.

In patients from the placebo arm who switched into the active treatment group, the DCR will be studied from regorafenib initiation:

The DCR from switch will be defined as the proportion of patients in the placebo arm with a best overall response of CR, PR or Stable Disease (SD) 4 months after regorafenib initiation.

The Time to Treatment Failure (TTF) will be defined as the time from the date of randomization to the date of permanent discontinuation of the study treatment, whichever is the cause. Patient not known to have withdrawn treatment before 12 months (study treatment duration) will be censored at the time of treatment stop.

The Overall Survival (OS) will be defined as the time from date of randomization to the date of death, from any cause. 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.

In patients from the placebo arm who switched into the active treatment group, the OS will be studied from regorafenib initiation:

The Overall Survival (OS) from switch will be defined as the time from date of switch to the date of death, from any cause. 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 patient's Quality of Life (QoL) will be assessed using the EORTC Quality Of Life Questionnaire (QLQ)-C30 file. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point. Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant.

The safety will be described mainly on the frequency of adverse events (AE) coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. AE will be coded according to the MedDRA®.

Histiocytoma, Malignant Fibrous

Sarcoma, Ewing

Chondrosarcoma

Hemangiosarcoma

Leiomyosarcoma

Histiocytoma

Neoplasms, Vascular Tissue

Neoplasms, Fibrous Tissue

Undifferentiated Pleomorphic Sarcoma

Ewing Sarcoma

Treatment will be divided in 28 days cycles, including a 21-day period of treatment by regorafenib followed by a 7-day period of rest.

In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC).

Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).

Treatment will be divided in 28 days cycles, including a 21-day period of treatment by placebo followed by a 7-day period of rest.

In case of toxicity, dose can be reduced or treatment interrupted according to Specific Product Characteristics (SPC).

Patients can receive up to a maximum of 13 cycles (maximum treatment period : 12 Months).

Treatment for 13 cycles (12 months) maximum.

During each cycle, patient will take once a day, during 21 days, followed by 7 days without treatment :

* 3 tablets daily, corresponding to a total of 120 mg of Regorafenib (3 weeks out of 4 weeks) in patients ≥ 16 years old and patients \< 16 years old with BSA ≥ 1.70m²;
* 2 tablets daily corresponding to a total of 80 mg of Regorafenib (3 weeks out of 4 weeks) in patients \< 16 years old with 1.30m² ≤ BSA \< 1.70m²;

Treatment by Regorafenib

Treatment for 13 cycles (12 months) maximum.

During each cycle, patient will take once a day, during 21 days, followed by 7 days without placebo treatment :

* 3 placebo tablets (3 weeks out of 4 weeks) in patients ≥ 16 years old and patients \< 16 years old with BSA ≥ 1.70m²;
* 2 placebo tablets (3 weeks out of 4 weeks) in patients \< 16 years old with 1.30m² ≤ BSA \< 1.70m²;

Treatment by Placebo

Cyril LERVAT

Jean-Yves BLAY

Florence DUFFAUD

Pierre FOURNEL

Natacha ENTZ-WERLE

Maria RIOS

Benjamin VERRET

This is a randomized, double-blinded, 2 arms study concerning patients with bone sarcoma after the first line therapy.

In the first arm, patients will be treated with regorafenib for a maximum of 12 months as maintenance therapy after first line therapy, whereas in the second arm, patients will be treated with placebo (standard of care).

The comparison between this two arms will allow to determine whether or not regorafenib is efficient for disease control, in terms of Relapse-Free Survival improvement.

Bone sarcomas are rare primary bone cancers, although, their frequency has been increasing by 0.3% per year over the last decade. They include a very large number of tumour types belonging to the family of primary malignant bone tumours and originate from bone as Osteosarcomas (OS), Chondrosarcomas (CS), Fibrosarcomas, Chordomas, ...

Current conventional treatments for OS combine chemotherapy and surgery. Chemotherapy treatment is commonly given for OS over a period of 6-10 months, with a period of preoperative chemotherapy, to facilitate local surgical treatment. The conventional cocktail used in OS is composed by a minimum of three drugs (reference combination: methotrexate, doxorubicin and cisplatin (MAP)).

The currently recommended treatments for Ewing sarcomas (for both localized and metastatic diseases) consist of multimodal approaches including surgery and/or radiotherapy associated to neoadjuvant and adjuvant chemotherapy, comprising respectively from 3 to 6, and then from 6 to 10 cycles. Doxorubicin, cyclophosphamide, ifosfamide, vincristine, dactinomycin and etoposide are considered as the most active substances. Current trials require combination chemotherapies, and most of them are based on the combination of 5-6 of these substances.

Concerning chondrosarcomas, the treatment is adapted according to the subtype. Thus, the treatment regimen for mesenchymal chondrosarcomas and dedifferentiated chondrosarcomas differs. Indeed, an Ewing-type chemotherapy regimen is usually suggested to treat mesenchymal chondrosarcomas while dedifferentiated chondrosarcomas are often treated as high-grade bone sarcoma, with systemic and local therapies.

Compared with surgery alone, multimodal treatment of high-grade sarcomas increases disease-free survival probabilities from only 10%-20% to 50-65% depending on the bone sarcoma type. In general, despite second-line treatment, the prognosis of recurrent disease has remained poor, with long-term post-relapse survival of \<20%.

The outcome of bone sarcoma has been dramatically improved by the addition of chemotherapy in the 70' and 80' but has remained remarkably stable in the last 3 decades, with a survival rate largely plateaued, despite introduction of novel regimens, both in localized and metastatic disease, in children and in adults. Primary bone cancer presented challenges in new drug development partly because of their rarity and heterogeneity. Thus, improving treatments for these diseases is a high priority, but advances have been few in recent years. In this context, maintenance therapy may be an interesting option as a way to prolong the benefit of first-line chemotherapy.

Regorafenib may play a role in the maintenance setting for bone sarcomas (as improved Progression-Free Survival and sustained responses were observed in the REGOBONE study) in maintaining the initial response to standard treatments and delaying the need for further treatment at relapse, while exerting a manageable associated toxicity and minimal negative impact on health-related quality of life.

Currently there is no available agent used as maintenance therapy after first-line treatments. In the context of a clinical trial with close monitoring, it is, thus, acceptable to consider a placebo-control group.

On this basis, this study propose to conduct a double-blinded randomized controlled trial to evaluate the efficacy of regorafenib versus placebo in the treatment of patients with bone sarcomas, who have no evidence of disease after standard multimodal treatments based on the histological subtype.

The main goal of the present study is then to explore whether sequential addition of regorafenib after completion of a standard treatment in patients with bone sarcomas would improve outcomes in term of event-free-survival (EFS) defined by local or distant recurrence of the disease.

Results will be stratified on the "high-risk" versus "low-risk" of relapse. As response to neoadjuvant chemotherapy and metastatic status at time of diagnosis are known to be important on patient's outcome, stratification will rely on a combined criteria taking into account these two factors. Thus, "high-risk" of relapse will be defined by the group of patients who are poor responders to neoadjuvant chemotherapy and/or in metastatic setting at diagnosis, whereas "low-risk" of relapse will be defined by the group of patients who have no metastatic disease at time of diagnosis and are good responders to neoadjuvant chemotherapy.

Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

A Randomized, Placebo-controlled, Double-blinded, Multicentre Study Evaluating the Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas

RFS will be defined as the time from randomization to relapse, or death from any cause, whichever occurs first. Patients alive without relapse at the time of the analysis will be censored at the date of last tumour assessment. The Kaplan-Meier approach will be used to estimate median RFS for each study arm. The two-sided log-rank test, stratified on randomization stratification factors, will be used to compare RFS between the investigational arm and the control arm. The stratified Cox-regression (with proportional hazards) will be used to estimate the hazard ratio and to calculate the 95% confidence intervals of the hazard ratio.

TTF will be defined as the time from the date of randomization to the date of permanent discontinuation of the study treatment, whichever is the cause. Patient not known to have withdrawn treatment before 12 months (study treatment duration) will be censored at the time of treatment stop. TTF survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.

OS will be defined as the time from date of randomization to the date of death, from any cause. 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. OS survival will be estimated using the Kaplan-Meier method, and will be described in terms of medians along with the associated 2-sided 95% confidence interval for the estimates.

The patient's Quality of Life will be assessed using the EORTC QLQ-C30. Scores will be calculated at each time point according to the scoring manuals. Descriptive statistics will be used to evaluate baseline scores and evolution of scores from baseline to each time point (Every 3 months since baseline, then every 4 months after second year surveillance). Data will be compared between arms using the Student's t-test. The QoL data will also be presented graphically if deemed relevant.

The safety will be described mainly on the frequency of adverse events coded using the common toxicity criteria (NCI-CTCAE v5.0) grade. Descriptive statistics will be provided for characterizing and assessing patient tolerance to treatment. Adverse events will be coded according to the MedDRA®.

The compliance to treatment will be described using the proportion of patients requiring dose reduction and temporary or permanent treatment discontinuation.

Nivolumab

Ipilimumab

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, Dr

Armelle DUFRESNE, Dr

Hélène VANACKER, Dr

Jean-Yves BLAY, Dr

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
A Prospective, Randomized, Multicenter, Comparative Study of the Efficacy of Imatinib Resumption Combined With Atezolizumab Versus Imatinib Resumption Alone in Patients With Unresectable Advanced Gastrointestinal Stromal Tumors (GIST) After Failure of Standard Treatments	NCT05152472	Unresectable Ga... Locally Advance... Metastatic Gast...	Atezolizumab 12... Imatinib 400 MG	18 Years -	Centre Leon Berard
Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma	NCT01813136	Thyroid Carcino...	Continuous pazo... Intermittent pa...	18 Years -	Centre Leon Berard
Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients	NCT04698785	Bone Sarcoma Osteosarcoma	Treatment by re... Treatment by pl...	12 Years -	Centre Leon Berard
Efficacy and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas	NCT04055220	Bone Sarcoma Osteosarcoma Ewing Sarcoma Chondrosarcoma Undifferentiate... Leiomyosarcoma Angiosarcoma	Treatment by Re... Treatment by Pl...	12 Years -	Centre Leon Berard
Efficacy of Regorafenib Combined With Best Supportive Care as Maintenance Treatment in High Grade Bone Sarcomas Patients	NCT04698785	Bone Sarcoma Osteosarcoma	Treatment by re... Treatment by pl...	12 Years -	Centre Leon Berard
Phase II Study of the Optimal Scheme of Administration of Pazopanib in Thyroid Carcinoma	NCT01813136	Thyroid Carcino...	Continuous pazo... Intermittent pa...	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 and Safety of Regorafenib as Maintenance Therapy After First-line Treatment in Patients With Bone Sarcomas	NCT04055220	Bone Sarcoma Osteosarcoma Ewing Sarcoma Chondrosarcoma Undifferentiate... Leiomyosarcoma Angiosarcoma	Treatment by Re... Treatment by Pl...	12 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

Spots Global Cancer Trial Database for time to treatment failure