A multicentre trial evaluating the combination of a MEK inhibitor and a PDL1 inhibitor in pediatric and adult patients with locally advanced and/or metastatic soft tissue sarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Leon Berard

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Feb 2020 → ongoing

Decision date (initial)

2024-12-04

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-510712-75-00

EudraCT number

2019-000987-80

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Safety run in To confirm the safety of cobimetinib when combined with atezolizumab in pediatric STS patients (≥6 months to <12 years). Phase II part To assess the clinical activity of cobimetinib combined with atezolizumab in 4 independent and parallel cohorts (20 patients in each cohorts) based on histological types: Rhabdomyosarcoma (RMS), Malign Peripheral Nerve Sheath Tumors (MPNST), Complex genomics sarcomas: Single genomic sarcoma.

Secondary objectives 2

1. To further define the safety profile of the combination investigated
2. To further document the clinical activity of the combination investigated

Conditions and MedDRA coding

advanced / metastatic

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. I1. Male or female patients aged of at least : 12 years on day of signing informed consent.
2. I2. Histologically-confirmed diagnosis of soft tissue sarcomas, confirmed by a pathologist from RRePS Network (http://www.infosarcomes.org/reseau-dereference-en-pathologie-des-sarcomes-des-tissus-mous-et-des-visceres-rreps-tmv), among the 2 cohorts: oRhabdomyosarcomas (RMS), oMalign Peripheral Nerve Sheath Tumors (MPNST)
3. I3. Availability of a representative formalin-fixed paraffin-embedded (FFPE) primary and/or metastatic tumor tissue with an associated pathology report for molecular pre-screening i.e. either an archival block or a dedicated freshly collected de novo tumor biopsy. This tumor sample must meet the following quality/quantity control criteria: At least 20 % of tumor cells, a tumor surface area of at least 5mm2 and >90µm of depth
4. I4. Documented MAPK pathway status and known Tumor Mutational Burden (TMB) before C1D1.
5. I5. Previous treatment with anthracycline-based chemotherapy (in the neoadjuvant, adjuvant or metastatic setting). Note: this criteria not mandatory for rhabdomyosarcomas.
6. I6. Previous treatment by at least one line of chemotherapy in the advanced/metastatic setting before C1D1.
7. I7. Documented radiological disease progression as per RECIST V1.1 before C1D1.
8. I8. At least one measurable lesion according to RECIST v1.1 before C1D1.
9. 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.
10. I10. Performance status: oKarnofsky performance status for pediatric patients ≥12 years of age ≥ 70%; oPS ECOG for adult patients: 0 or 1.
11. I11. Life expectancy of at least 16 weeks
12. I12. Demonstrate adequate organ function based on screening laboratory tests performed within 7 days prior C1D1. * Absolute neutrophil count (≥1.5 109 /L) *Platelets (≥100 109 /L) *Hemoglobin (≥9 g/dL (without transfusion within 7 days)) *Serum creatinine OR Creatinine clearance according to CKD-EPI for adults or 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 (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 x ULN is acceptable) OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN) *ASAT and ALAT and ALP (≤ 3 X ULN (or up to 5ULN in case of liver metastasis or hepatic infiltration) *INR and Activated Partial Thromboplastin Time (aPTT) (≤1.5 X ULN Note: Patients receiving therapeutic anticoagulation must be on stable dose) *Troponin T or I (Negative (< ULN))
13. 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.
14. 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.
15. I15. Sexually active and fertile men must agree to use contraceptive measures up to 5 months after the last study drugs.
16. 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.
17. I17. Patients must be covered by a medical insurance.

Exclusion criteria 19

1. NI1. Soft tissue sarcoma disease considered curable with surgery or radiotherapy.
2. NI2. Prior treatment with cobimetinib or other MEK inhibitors.
3. NI3. Prior treatment with immune checkpoint blockade therapies, including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies.
4. 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.
5. NI5. History of malabsorption syndrome or other condition that would interfere with the absorption of oral medications.
6. 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 listed in the protocol.
7. 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.
8. NI8. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (according to age) or < 50%.
9. NI9. History of congenital long QT syndrome or corrected QT interval (QTc) > 450ms
10. NI10. Patients using, or requirement to use while on the study, or not respecting the minimal wash-ouions or significant abdominal traumatic injury (Minimal wash out period before C1D1: 60 days) *Live vaccines. Note - Influenza vaccination should be given durint period of medications listed below : *Any approved anti-cancer systemic treatment including chemotherapy, hormonotherapy, biological therapy, or immunotherapy (Minimal wash out period before C1D1: 2 weeks) *Any investigational agents (Minimal wash out period before C1D1: 4 weeks) *Radiotherapy Note: palliative radiotherapy on non-target lesions is allowed (Minimal wash out period before C1D1: 3 weeks) *Surgery ▪ Major surgical procedure, open biopsy, or significant traumatic injury (Minimal wash out period before C1D1: 4 weeks) *Surgery Abdominal surgery, abdominal interventg influenza season. Patients must not receive live attenuated influenza vaccine (e.g., FluMist®) (Minimal wash out period before C1D1: 4 weeks); *Systemic immunostimulatory agents, including but not limited to IFN-α, IFN-γ, or IL-2 (Minimal wash out period before C1D1: 4 weeks) *Immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) with the exceptions of intranasal, inhaled, or topical corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day (or 0.1 mg/kg in pediatric patients) of prednisone, or an equivalent corticosteroid (Minimal wash pout period before C1D1: 2 weeks) *P-gp inhibitors, Strong or moderate inhibitors of CYP3A4 and Strong CYP3A4 inducers (Non minial wash-out periode before C1D1) *Oral or IV antibiotics Note: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection, pneumocystis or chronic obstructive pulmonary disease exacerbation) are eligible (minimal wash out period before C1D1 2 weeks)
11. 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 (such as adequately treated in situ carcinoma of the cervix, basal or squamous cell skin cancer, localised prostate cancer or ductal in situ carcinoma treated surgically with curative intent).
12. 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 (see Appendix 17.3 for a more comprehensive list of pre-existing autoimmune diseases and immune deficiencies) with the following exceptions – listed in the protocol.
13. NI13. Patients with HIV, active B or C hepatitis infection or any other active infection.
14. NI14. Patients with active tuberculosis.
15. NI15. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past.
16. NI16. History of idiopathic pulmonary fibrosis (including pneumonitis), druginduced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
17. NI17. Patients with a high-risk of hemorrhage or history of coagulopathy
18. NI18. Pregnant or breastfeeding women.
19. NI19. Patients with a history of immune-mediated pericardial disorder (including pericarditis) related to immune-stimulatory anticancer agents.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety run in Incidence of severe toxicities (ST) during the 1st cycle of treatment
2. Phase II part Progression Free rate after 16 weeks of treatment (PFR16w)

Secondary endpoints 2

1. Nature, frequency and severity of AE according to NCI-CTCAE V5.0
2. ORR at 8 and 16 weeks according to RECIST V1.1 and iRECIST Duration of response; PFS; OS

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Leon Berard

Sponsor organisation

Centre Leon Berard

Address

28 Rue Laennec

City

Lyon

Postcode

69008

Country

France

Scientific contact point

Organisation

Centre Leon Berard

Contact name

Nadège CORRADINI

Public contact point

Organisation

Centre Leon Berard

Contact name

Project Manager

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications