|
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 rhabdod 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 obtained within 6 months |
|
|
|
|
|
before ICF signature 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 |
|
|
|
|
|
-gauge diameter needle or larger |
|
|
|
|
|
I10. Performance status |
|
|
|
|
|
Lansky Play score for pediatric patients <12 years of age 70% |
|
|
|
|
|
Karnofsky performance status for pediatric patients 12 years of age 70% |
|
|
|
|
|
PS ECOG for adult patients: 0 or 1 |
|
|
|
|
|
I11. Life expectancy of at least 16 weeks |
|
|
|
|
|
I12. Demonstrate adequate organ function based on screening laboratory tests |
|
|
|
|
|
performed 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 > |
|
|
|
|
|
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 3 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 |
|
|
|
|
|
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 antiCTLA-4
|
|
|
|
|
|
antiPD-1, or antiPD-L1 therapeutic antibodies
|
|
|
|
|
|
NI4. Patients with history of severe allergic or other hypersensitivity
|
|
|
|
|
|
reactions to
|
|
|
|
|
|
Chimeric or humanized antibodies or fusion proteins
|
|
|
|
|
|
Biopharmaceuticals produced in Chinese hamster ovary cells, or
|
|
|
|
|
|
Any component of the atezolizumab formulation
|
|
|
|
|
Any component of Cobimetinib formulation
|
|
|
|
|
|
NI5. History of malabsorption syndrome or other condition that would interfere
|
|
|
|
|
|
with the absorption of oral medications
|
|
|
|
|
|
NI6. Symptomatic, untreated, or actively progressing central nervous system
|
|
|
|
|
|
(CNS) metastases
|
|
|
|
|
|
Note: 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
|
|
|
|
|
|
No history of intracranial hemorrhage or spinal cord hemorrhage
|
|
|
|
|
|
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, neurosurgical resection within 28 days prior to initiation of study treatments
|
|
|
|
|
|
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) >
|
|
|
|
|
|
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
|
|
|
|
|
|
days; live vaccines : 4 weeks; systemic immunostimulatory agents, including
|
|
|
|
|
|
but not limited to IFN-, IFN-, 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, Sjgren'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 controlled Type 1 diabetes mellitus
|
|
|
|
|
|
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
|
|
|
|
|
|
rash must cover less than 10% of body surface area (BSA)
|
|
|
|
|
|
disease is well controlled at baseline and only requiring low potency topical 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
|
|
|
|