MEK Inhibitor and a PDL1 Inhibitor Patients With Locally Advanced and/or Metastatic Soft Tissue Sarcoma (COTESARC)

  • STATUS
    Recruiting
  • End date
    Feb 1, 2024
  • participants needed
    120
  • sponsor
    Centre Leon Berard
Updated on 23 April 2022
cancer
measurable disease
neutrophil count
cancer chemotherapy
angiosarcoma
immunomodulators
soft tissue sarcoma
liposarcoma
metastatic soft tissue sarcoma
myxoid liposarcoma
alveolar soft part sarcoma
epithelioid sarcoma
mpnst

Summary

The proposed study is a two-step trial with 1) a safety run in part conducted in pediatric patients and 2) a Phase II part in adult and pediatric patients aiming to evaluate the safety and clinical activity of atezolizumab + cobimetinib in advanced/metastatic soft tissue sarcomas.

Description

The hypothesis of the proposed combination is as follows: cobimetinib via MEK1/2 inhibition could modify the tumor microenvironment and improve the response of T cells against tumor cells. Therefore, the addition of cobimetinib to atezolizumab may improve immune recognition and result in improved anti-tumour activity.

The combination of cobimetinib and atezolizumab showed clinical activity in a Phase I trial in patients with metastatic colorectal cancer (Atezolizumab 840 mg every 2 weeks and Cobimetinib 60 mg/d) with a disease control rate of 31%. Atezolizumab and cobimetinib are currently being tested in pediatrics in the iMatrix clinical trial with no major safety concerns to date.

A molecular screening step is mandatory for all patients enrolled in this trial in order to document MAPK pathway status and Tumor Mutational Burden (TMB) using FoundationOne test (FOne Heme).

Details
Condition Sarcoma,Soft Tissue
Treatment Cobimetinib, Atezolizumab
Clinical Study IdentifierNCT04216953
SponsorCentre Leon Berard
Last Modified on23 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

I1. Male or female patients aged of at least
Adult-Young Adult cohort: 12 years on day of signing informed consent
Pediatric Cohort: 6 months and maximum 11 years on day of signing informed consent
I2. Histologically-confirmed diagnosis of soft tissue sarcomas, confirmed by a pathologist
from RRePS Network, among the 4 cohorts
Rhabdomyosarcomas (RMS)
Malign Peripheral Nerve Sheath Tumors (MPNST)
Complex genomics sarcomas including Undifferentiated Pleomorphic Sarcomas (UPS)
leiomyosarcomas (LMS), Pleomorphic liposarcomas, angiosarcoma, myxofibrosarcomas
Single genomic sarcoma including Well and de-differentiated liposarcoma, myxoid
liposarcoma, synovialsarcoma, alveolar soft part sarcoma, epithelioid sarcomas, and
malignant rhabdoïd tumors
I3. Availability of a representative formalin-fixed paraffin-embedded (FFPE) primary and/or
metastatic tumor tissue with an associated pathology report for molecular prescreening i.e
either an archival block or a dedicated freshly collected de novo tumor biopsy
I4. Documented MAPK pathway status and known Tumor Mutational Burden (TMB) before C1D1
I5. Previous treatment with anthracycline-based chemotherapy (in the neoadjuvant, adjuvant
or metastatic setting). Note: this criteria not mandatory for rhabdomyosarcoma
I6. Previous treatment by at least one line of chemotherapy in the advanced/metastatic
setting before C1D1
I7. Documented radiological disease progression as per RECIST V1.1 before C1D1
I8. At least one measurable lesion according to RECIST v1.1 before C1D1
I9. Mandatory for adult patients only - Presence of at least one tumor lesion visible by
medical imaging and accessible to repeatable percutaneous sampling that permits core needle
biopsy without unacceptable risk of a significant procedural complications, and suitable
for retrieval of 4 cores using a 16-gauge diameter needle or larger
Lansky Play score for pediatric patients <12 years of age ≥ 70%
I10. Performance status
Karnofsky performance status for pediatric patients ≥12 years of age ≥ 70%
PS ECOG for adult patients: 0 or 1
I12. Demonstrate adequate organ function based on screening laboratory tests performed
I11. Life expectancy of at least 16 weeks
within 7 days prior C1D1: Absolute neutrophil count ≥1.5 10 exp. 9/L; Platelets ≥100 10
exp. 9/L; Hemoglobin ≥9 g/dL; Serum creatinine OR Creatinine clearance according to CKD-EPI
for adult and C-KID formula for pediatric patients ≤1.5 X ULN OR ≥ 30 mL/min/1.73m2 for
patient with creatinine levels > 1.5 ULN; Serum total bilirubin ≤ 1.5 X ULN OR Direct
bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN; ASAT and ALAT and ALP ≤
X ULN; INR and Activated Partial Thromboplastin Time (aPTT)≤1.5 X ULN
I13. Resolution (i.e. ≤ Grade 1 with the exception of alopecia all grades and Grade 2 for
neuropathy, lab values presented in criteria I12.) of any toxicities related to previous
anti-cancer treatment
I14. Women patient of child-bearing potential must have a negative serum pregnancy test
before C1D1 and must agree to use effective forms of contraception from the time of the
negative pregnancy test up to 6 months after the last dose of study drugs
I15. Sexually active and fertile men must agree to use contraceptive measures up to 5
months after the last study drugs
I16. Written informed consent from patient, parents if applicable/legal representative
before any study-specific screening procedures, and willingness to comply to study visits
and procedures
I17. Patients must be covered by a medical insurance

Exclusion Criteria

NI1. Soft tissue sarcoma disease considered curable with surgery or radiotherapy
NI2. Prior treatment with cobimetinib or other MEK inhibitors. NI3. Prior treatment with
immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, or anti-PD-L1
therapeutic antibodies
NI4. Patients with history of severe allergic or other hypersensitivity reactions to
NI5. History of malabsorption syndrome or other condition that would interfere with the
absorption of oral medications
Chimeric or humanized antibodies or fusion proteins
NI6. Symptomatic, untreated, or actively progressing central nervous system (CNS)
Biopharmaceuticals produced in Chinese hamster ovary cells, or
metastases
Any component of the atezolizumab formulation
Note: Asymptomatic patients with treated CNS lesions are eligible, provided that all of the
Any component of Cobimetinib formulation
following criteria are met
Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metastases to the midbrain, pons, medulla, or spinal cord)
No stereotactic radiotherapy within 7 days prior to initiation of study treatments
whole-brain radiotherapy within 14 days prior to initiation of study treatment
Measurable disease, per RECIST v1.1, must be present outside the CNS
neurosurgical resection within 28 days prior to initiation of study treatments
No history of intracranial hemorrhage or spinal cord hemorrhage
No evidence of interim progression between completion of CNS-directed therapy and
initiation of study treatments
No ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant
therapy at a stable dose is permitted
NI7. History of or evidence of retinal pathology on ophthalmologic examination that is
considered a risk factor for neurosensory retinal detachment, central serous
chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration
NI8. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal
(according to age) or < 50%
NI9. History of congenital long QT syndrome or corrected QT interval (QTc) > 450 ms
NI10. Patients using, or requirement to use while on the study, or not respecting the
minimal wash-out period of medications listed below
Any approved anti-cancer systemic treatment including chemotherapy, hormonotherapy
biological therapy, or immunotherapy: 2 weeks; any investigational agents: 4 weeks
Radiotherapy: 3 weeks; major surgical procedure, open biopsy, or significant traumatic
injury: 4 weeks; abdominal surgery, abdominal interventions or significant abdominal
traumatic injury : 60 days; live vaccines : 4 weeks; systemic immunostimulatory agents
including but not limited to IFN-α, IFN-γ, or IL-2 : 4 weeks; immunosuppressive medications
with the exceptions of intranasal, inhaled, or topical corticosteroids or systemic
corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or
an equivalent corticosteroid: 2 weeks; P-gp inhibitors : None; Strong or moderate
inhibitors of CYP3A4 : None; Strong CYP3A4 inducers: None; oral or IV antibiotics : 2
weeks
NI11. Patients with a malignancy other than STS within 5 years prior to C1D1 with the
exception of those with a negligible risk of metastasis or death and treated with expected
curative outcome
NI12. History of autoimmune disease including but not limited to myasthenia gravis
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis
inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome
Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, multiple sclerosis
vasculitis, or glomerulonephritis with the following exceptions
patients with a history of autoimmune-related hypothyroidism who are on stable thyroid
replacement hormone therapy
patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
excluded) are eligible provided that they meet the following conditions
patients with controlled Type 1 diabetes mellitus
disease is well controlled at baseline and only requiring low potency topical
rash must cover less than 10% of body surface area (BSA)
steroids
no acute exacerbations of underlying condition within the previous 12 months requiring
PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, high potency or oral steroids
NI13. Patients with HIV, active B or C hepatitis infection, or any other active infection
Active hepatitis C i.e. Patients positive for hepatitis C virus (HCV) antibody are eligible
only if PCR is negative for HCV RNA at screening
NI14. Patients with active tuberculosis. NI15. Prior allogeneic bone marrow transplantation
or solid organ transplant for another malignancy in the past
NI16. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing
pneumonia), or evidence of active pneumonitis on screening chest CT scan
NI17. Patients with a high-risk of hemorrhage or history of coagulopathy. NI18. Pregnant or
breastfeeding women
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