Advanced /metastatic sarcomas: undifferentiated pleomorphic sarcoma, osteosarcoma and Ewing sarcoma MedDRA version: 20.0 Level: LLT Classification code 10039494 Term: Sarcoma NOS System Organ Class: 100000004864
Conditions
Interventions
Trade Name: KEYTRUDA
Product Name: PEMBROLIZUMAB
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Pembrolizumab
CAS Number: 1374853-91-4
Current Sponsor code: MK34
Sponsors
Institut Bergonié
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histology: undifferentiated pleomorphic sarcoma (stratum 1), osteosarcoma (stratum 2) or Ewing sarcoma (stratum 3). Diagnosis must be reviewed or confirmed by the RRePS Network as recommended by the French NCI (Inca), 2. Advanced non resectable / metastatic disease, 3. Recurrent disease or progression after standard therapy, 4. Documented progression according to RECIST criteria. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less than 6 months interval within the 12 months before inclusion, except if first line of recurrence, 5. Have provided tissue of a tumor lesion from 3 months, 11. Participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement, 12. No symptomatic central nervous system disease, 13. No chronic use of glucocorticoids. 14. Adequate hematological, renal, metabolic and hepatic function: a. Hemoglobin = 9 g/dl (without erythropoietin dependency and without red blood cel transfusion within the last two weeks); absolute neutrophil count (ANC) = 1.5 G/l, lymphocytes count = 0.5 G/l and platelet count = 100 G/l, b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 2.5 x upper limit of normality (ULN) (= 5 in case of liver metastasis). c. Total bilirubin = 1.5 x ULN OR Direct bilirubin = ULN for subjects with total bilirubin levels = 1.5 x ULN. d. Albumin = 25g/l. e. Serum creatinine = 1.5 x ULN OR Calculated creatinine clearance (CrCl) = 60 ml/min (calculated per institutional standard) for subject with creatinine levels = 1.5 x ULN. f. Creatine phosphokinase (CPK) = 2.5 x ULN g. International normalized ratio (INR) OR prothrombin time (PT), activated partial thromboplastine time (aPTT) = 1.5 x ULN., h. Lipase = 2 x ULN and no radiological or clinical evidence of pancreatitis, i. Urine protein/creatinine ratio (UPCR) = 1, 15. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma, 16. At least three weeks since last chemotherapy, immunotherapy and two weeks for any other pharmacological treatment and/or radiotherapy, 17. Recovery to grade = 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade, non-painful peripheral neuropathy grade = 2 and endocrine-related grade = 2 requiring treatment or hormone replacement) (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0). For patients previously treated by radiotherapy, they must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis, 18. Women of childbearing
Exclusion criteria
Exclusion criteria: 1. Previous treatment with Pembrolizumab or Cabozantinib, 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumabor any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways), 3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases, 4. Men or women of childbearing potential who are not using an effective method of contraception; women who are pregnant or breast feeding, men or women who are planning to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment, 5. Participation to a study involving a medical or therapeutic intervention in the last 21 days, 6. Previous enrolment in the present study, 7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons, 8. Patient unable to swallow, 9. Known hypersensitivity to any involved study drug or of its formulation components, 10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg. Thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc…) is not considered a form of systemic treatment and is allowed. 11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment, 12. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required steroids, current pneumonitis/interstitial lung disease, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted, 13. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 14. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies) and/or of active TB (Bacillus Tuberculosis), 15. Treatment with anticoagulants such as anti-Vitamin K, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel), 16. Previous allogenic bone marrow transplant or solid organ transplantation, 17. Has an active infection requiring systemic treatment at study entry, 18. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before treatment. Note: if initial QTcF is found to be > 500 ms, two additional ECGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is = 500 ms, the subject meets eligibility in this regard, 19. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians’ De
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Assessment of the efficacy of Pembrolizumab and Cabozantinib in terms of 6-month non-progression (as per RECIST v1.1 criteria) independently for 3 stratas: • Advanced undifferentiated pleomorphic soft-tissue sarcoma • Advanced osteosarcoma • Advanced Ewing sarcoma ;Secondary Objective: Each strata will be analysed independently. • Assessment of the efficacy of the treatment strategy in terms of best overall response (as per RECIST v1.1 criteria), 1-year Progression-free survival (PFS, as per RECIST v1.1 criteria), and 1-year overall survival (OS). • Assessment of the safety profile of the treatment strategy using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. • Assessment of the Growth modulation index (GMI), defined for each patient as the ratio of the PFS on the current treatment strategy to the PFS on the previous line of therapy (Von Hoff 1998), in patients with documented progression under a previous line at inclusion. • Assessment of the efficacy of the treatment strategy in terms of 6-month non-progression according to iRECIST (Seymour 2017; central radiological review data) • Translational research on blood and tumor samples obtained at baseline and several time points during treatment.;Primary end point(s): • The primary efficacy endpoint for advanced undifferentiated pleomorphic sarcoma (stratum 1), advanced osteosarcoma (stratum 2) and advanced Ewing sarcoma (stratum 3) is 6-month non-progression (as per RECIST evaluation criteria v1.1). • Non-progression: complete response, partial response or stable disease more than 24 weeks as per RECIST evaluation criteria v1.1. • Objective response: complete response or partial response as per RECIST evaluation criteria v1.1. • Following RECIST v1.1 recommendations: o claimed responses (complete or partial response) will have to be confirmed at least 4 weeks later; o 6-month radiological data will be reviewed by an independent expert radiologist. o Primary efficacy | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Best overall response defined as per RECIST v1.1 criteria. • 1-year progression-free survival (PFS): PFS is defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. • 1-year overall survival (OS): OS is defined as the time from study treatment initiation to death (of any cause). • Growth modulation index (GMI), defined for each patient as the ratio of the PFS on the current treatment strategy to the PFS on the previous line of therapy (Von Hoff, 1998), in patients with documented progression at inclusion. • Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. • Immune-related response is defined according to iRECIST (Seymour 2017). Analysis will be based on data centrally reviewed by an expert radiologist. • Performance of pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers) in blood and tumor tissue at baseline and different study time points. o Blood samples will be mandatory collected at predefined timepoints for assessment of: o Serum/plasma cytokines levels (TNF?, TNFa, TGFß, IL2, 4, 6, 10), VEGF, HGF, sMET, sVEGFR2 (ELISA) o Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, CD8+/Treg ratio (flow cytometry) o Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS) o Availability of a < 3 months, non subsequently treated or fresh tumor samples, with frozen material available will be mandatory at inclusion for baseline, and a second sampling will be mandatorily collected during treatment at C2Day8 (+/- 3 days). Formalin-fixed, paraffin-embedded biopsy samples will be analysed for (but not limited to) CD8+ effectors, CD68 and 163 Macrophages and FOXP3+ cells infiltrates as well as PDL1, IDO1, CD31 (microvessel density), as well as MET and ph | — |
Countries
France
Contacts
Public ContactRegulatory Affairs Management Desk
Institut Bergonié
Outcome results
None listed