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 (ATEZOGIST)

  • STATUS
    Recruiting
  • End date
    Jun 17, 2026
  • participants needed
    110
  • sponsor
    Centre Leon Berard
Updated on 17 May 2022

Summary

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.

Description

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.

Details
Condition Unresectable Gastrointestinal Stromal Tumor (GIST), Locally Advanced Gastrointestinal Stromal Tumor (GIST), Metastatic Gastrointestinal Stromal Tumor
Treatment Atezolizumab 1200 mg, Imatinib 400 MG
Clinical Study IdentifierNCT05152472
SponsorCentre Leon Berard
Last Modified on17 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

I1. Male or female ≥ 18 years at the day of consenting to the study
I2. Patients must have histologically confirmed diagnosis of GIST (within the French
Reference Network in Pathology of Sarcomas - RRePS network); archival tumor sample must be
made available for translational research program (in case there is no sufficient archival
tumor material available, a biopsy must be performed prior to treatment start); Nota Bene
mutational status and level of expression of PD1/PD-L1 will not be considered as selection
criteria but will be studied as endpoints for translational objectives
I3. Locally advanced or metastatic disease confirmed as measurable according to the RECIST
V1.1 (Appendix 1)
I4. Patients who previously failed to at least imatinib, sunitinib and then regorafenib
Failure is defined for Imatinib as progressive disease, and for sunitinib and regorafenib
as progressive disease and/or intolerance
I5. Performance Status of the ECOG of 0 or 1
I6. Adequate bone marrow and organ function defined by the following laboratory results
a. Bone marrow: i. Hemoglobin ≥ 9.0 g/dl, ii. Absolute Neutrophils Count (ANC) ≥ 1.5 G/l
iii. Lymphocytes count ≥ 0.5 G/l, iv. Platelets ≥ 100 G/l
b. Coagulation: i. Prothrombin time ≤ 1.5 x Upper Limit of the Normal (ULN) for patients
without therapeutic anticoagulation
Patients with therapeutic anticoagulation must have stable dose of treatment
c. Hepatic function: i. Total serum bilirubin ≤ 1.5 x ULN (except patients with Gilbert's
syndrome who must have total serum bilirubin ≤ 3.0 x ULN), ii. Transaminases (ASAT/ALAT) ≤
5 x ULN (or ≤ 5.0 x ULN in case of documented liver metastases) iii. Alkaline
Phosphatases ≤ 2.5 x ULN (or ≤ 5.0 x ULN in case of documented bone metastases)
d. Renal function: i. Serum creatinine ≤ 1.5 x ULN or Cr. Cl. ≥ 40ml/min/1.73m² (MDRD or
CKD-EPI formula)
I7. Willingness and ability to comply with the study requirements
I8. Signed and dated informed consent indicating that the patient has been informed of all
the aspects of the trial prior to enrolment
I9. Women of childbearing potential are required to have a negative serum pregnancy test
within 72 hours prior to study treatment start. A positive urine test must be confirmed by
a serum pregnancy test
I10. Women of childbearing potential and male patients must agree to use adequate highly
effective contraception for the duration of study participation (Appendix 3)
I11. Patient must be covered by a medical insurance

Exclusion Criteria

E1. Prior malignancy within the last 3 years except for locally curable disease with no
sign of relapse
E2. Patients in whom imatinib had been already reintroduced after sunitinib as second line
E3. Known D842V mutation in Exon 18 of PDGFRA
E4. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-cytotoxic T lymphocyte-associated protein 4 , anti-TIGIT, anti PD-1,and anti PD-L1
therapeutic antibodies
E5. Any approved anticancer therapy (chemotherapy, hormonal therapy or radiotherapy) or
treatment with any investigational product within 2 weeks or within 5 elimination
half-lives (whichever is longer) prior to study treatments start
E6. Residual adverse events from prior anticancer therapy that has not resolved to grade
≤1, except for alopecia and lab values (provided that inclusion criteria described in
section 6.1 are met)
E7. Symptomatic, untreated, or actively progressing central nervous system (CNS)
metastases
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the
following criteria are met
Measurable disease, per RECIST v1.1, must be present outside the CNS
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage
The patient has not undergone stereotactic radiotherapy within 7 days prior to
randomization, whole-brain radiotherapy within 14 days prior to randomization, or
neurosurgical resection within 28 days prior to randomization
The patient has no ongoing requirement for corticosteroids as therapy for CNS disease
Anticonvulsant therapy at a stable dose is permitted
Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metastases to the midbrain, pons, medulla, or spinal cord)
There is no evidence of interim progression between completion of CNS-directed therapy
and randomization
Spinal cord compression not definitively treated with surgery and/or radiation, and/or
previously diagnosed and treated spinal cord compression without evidence that disease
has been clinically stable for 2 weeks prior to screening
History of leptomeningeal disease
E8. Patients using or require to use while on the study of any prohibited concomitant
and/or concurrent medications (see section "Prohibited concomitant/concurrent treatments)
Live, attenuated vaccines within 28 days prior to enrolment. Examples of live vaccines
include, but are not limited to, the following: measles, mumps, rubella, chicken pox
yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however intranasal
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed
during the study active period
Treatment with systemic immunosuppressive medication (including, but not limited to
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-TNF-alpha agents) within 2 weeks prior to C1D1, or anticipation of need for
systemic immunosuppressive medication during study treatment, with the following
exceptions
Patients who receive acute, low-dose systemic immunosuppressant medication or a
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of
corticosteroids for a contrast allergy) are eligible for the study after Medical
Monitor confirmation
Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids for
chronic obstructive pulmonary disease or asthma, or low-dose corticosteroid
Systemic immunostimulatory agents (including, but not limited to, interferons and
IL-2) are prohibited within 4 weeks or five half-lives of the drug (whichever is
longer) prior to C1D1
Traditional herbal medicines since the ingredients of many herbal medicines are not
fully studied and their use may result in unanticipated drug-drug interactions that
may cause or confound assessment of toxicity
E9. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple
sclerosis (see Appendix 4 for a more comprehensive list of pre-existing autoimmune diseases
and immune deficiencies), with the following exceptions
Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are
eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are met
Rash must cover less than 10% of body surface area
Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
No occurrence of acute exacerbations of the underlying condition requiring psoralen
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12
months
E10. History of severe allergic / anaphylactic reaction or other hypersensitivity reactions
to
chimeric or humanized antibodies or fusion proteins
biopharmaceuticals produced in Chinese hamster ovary cells, any active substance or to
any of the chemical excipients of atezolizumab (refer to its IB) or imatinib (refer to
its respective SmPC)
E11. Patients with active infectious disease
severe infections within 4 weeks prior to randomisation including but not limited to
hospitalization for complications of infection, bacteraemia, or severe pneumonia
active infection requiring or have required treatment with therapeutic oral or IV
antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving
prophylactic antibiotics (e.g., to prevent a urinary tract infection) are eligible for
the study
active B or C hepatitis infection, Note: Patients with past Hepatitis B Virus (HBV)
infection or resolved HBV infection (defined as having a negative HBsAg test and a
positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible
Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if polymerase
chain reaction (PCR) is negative for HCV RNA
active tuberculosis
HIV infection
E12. Active or prior history of primary immunodeficiency
E13. Major surgical procedure within 28 days prior to study treatments start, or need for a
major surgery during the course of the study
E14. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
or within
months after the final dose of study treatment for patients included in the standard
arm (imatinib alone)
months after the final dose of study treatment for patients included in the
experimental arm (imatinib + atezolizumab) Women of childbearing potential must have a
negative pregnancy test result within 72 hours prior to treatment start (any urine
positive pregnancy test must be confirmed by a serum pregnancy test prior to treatment
start)
E15. Patient that impairs their ability to swallow and retain imatinib or with impairment
of gastrointestinal (GI) function or GI disease that may significantly alter the absorption
of imatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea
malabsorption syndrome, or small bowel resection)
E16. Clinically significant unrelated systemic illness (e.g., significant cardiac
pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability
to tolerate study treatment or would likely interfere with study procedures or results
E17. Patients under tutorship or curatorship
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