Efficacy of Pembrolizumab and Cabozantinib in Advanced Undifferentiated Pleomorphic Sarcoma, Osteosarcoma, and Ewing Sarcoma: A Clinical Trial Evaluation
- Trial ID
- 2023-509496-16-00
- Protocol
- IB 2020-02
- Sponsor
- Institut Bergonie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of the combination of Pembrolizumab and Cabozantinib in terms of 6-month non-progression, as per RECIST v1.1 criteria, in patients with advanced sarcomas. This evaluation is conducted independently across three specific strata: advanced undifferentiated pleomorphic soft-tissue sarcoma, advanced osteosarcoma, and advanced Ewing sarcoma. The clinical relevance of this objective lies in determining the potential of this combination therapy to halt disease progression in these aggressive and difficult-to-treat sarcomas, thereby providing insights into new therapeutic avenues.
Secondary objectives include: - Assessment of the efficacy of the treatment strategy in terms of best overall response, 1-year progression-free survival (PFS), and 1-year overall survival (OS) according to RECIST v1.1 criteria. - Evaluation 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 as the ratio of PFS on the current treatment to PFS on the previous line of therapy, in patients with documented progression under a previous line at inclusion. - Evaluation of the efficacy of the treatment strategy in terms of 6-month non-progression according to iRECIST, based on central radiological review data. - Conducting translational research on blood and tumor samples obtained at baseline and during treatment to analyze pharmacodynamic and mechanism of action biomarkers, and to identify biomarkers predictive of treatment response.
Participants
The clinical trial involves participants diagnosed with **advanced/metastatic sarcomas**, specifically undifferentiated pleomorphic sarcoma, osteosarcoma, and Ewing sarcoma. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a life expectancy greater than three months and must not be candidates for other approved therapeutic regimens that provide significant clinical benefit. The trial does not include a vulnerable population. Participants must have advanced disease and meet specific health criteria, including adequate hematological, renal, metabolic, and hepatic function. Lifestyle considerations such as diet and physical activity are not specified. The selection process for the trial population is not detailed, as the sponsor has not provided information on the total number of participants. Key inclusion criteria include having measurable disease according to RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Exclusion criteria include symptomatic central nervous system disease and chronic use of glucocorticoids. Participants must have recovered from any adverse events from previous treatments to a grade of 1 or less, except for certain conditions. The trial requires participants to have provided a tissue sample from a tumor lesion and to have documented disease progression according to RECIST criteria.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **pembrolizumab** and **cabozantinib** in patients with advanced sarcomas, specifically undifferentiated pleomorphic sarcoma, osteosarcoma, and Ewing sarcoma. This is a Phase II, randomized, double-blind, controlled trial. The trial will assess the 6-month non-progression rate as per RECIST v1.1 criteria across three strata of sarcomas. The trial is expected to last until September 2028, with recruitment having commenced in April 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histological confirmation of sarcoma type, adequate organ function, and absence of symptomatic central nervous system disease. Following the screening, participants will be randomized to receive either the investigational treatment or a control. The treatment period will last up to 24 months, with regular follow-up visits to monitor efficacy and safety, including assessments of disease progression and adverse events.
The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The expected length of participant involvement is approximately 24 months, contingent upon individual response and tolerance to the treatment. The trial will also include secondary endpoints such as overall survival, progression-free survival, and biomarker analysis to further understand the treatment's impact.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **PD-1/PDL-1 inhibitor**. This experimental medication is provided as a 25 mg/mL concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous route**. The maximum daily dose is 200 mg, with a total maximum dose of 7000 mg over a treatment period of up to 24 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The product is labeled for clinical trial use and is manufactured by Merck Sharp & Dohme B.V.
In addition to pembrolizumab, the trial includes the administration of **CABOMETYX** (cabozantinib), a **tyrosine kinase inhibitor**. CABOMETYX is available in two dosages: 20 mg and 40 mg film-coated tablets. The medication is administered orally. The maximum daily dose for the 20 mg tablets is 20 mg, with a total maximum dose of 14400 mg, while for the 40 mg tablets, the maximum daily dose is 40 mg, with a total maximum dose of 28800 mg. Both dosages are intended for a treatment period of up to 24 months. Cabozantinib is a chemically synthesized compound, and its ATC classification is L01EX07. The product is labeled for clinical trial use and is manufactured by Ipsen Pharma.
Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed treatment regimen. No non-experimental treatments, such as standard-of-care therapy or placebo, are specified in this study. The trial aims to assess the efficacy of the combination of pembrolizumab and cabozantinib in patients with advanced sarcomas, including advanced undifferentiated pleomorphic soft-tissue sarcoma, advanced osteosarcoma, and advanced Ewing sarcoma, based on 6-month non-progression criteria as per RECIST v1.1.
Efficacy
The efficacy of the combination of **Pembrolizumab** and **Cabozantinib** in patients with advanced sarcomas will be assessed through a primary endpoint of 6-month non-progression, evaluated according to RECIST v1.1 criteria. This endpoint will be independently measured for three strata: advanced undifferentiated pleomorphic soft-tissue sarcoma, advanced osteosarcoma, and advanced Ewing sarcoma. Non-progression is defined as complete response, partial response, or stable disease lasting more than 24 weeks. Objective responses, including complete and partial responses, will be confirmed at least four weeks later, and 6-month radiological data will be reviewed by an independent expert radiologist. The primary efficacy analysis will rely on central radiological review data, categorizing each patient as having a complete response, partial response, stable disease, progression, or not evaluated for response.
Secondary endpoints include the best overall response as per RECIST v1.1 criteria, 1-year progression-free survival (PFS), and 1-year overall survival (OS). PFS is defined as the time from study treatment initiation to the first occurrence of disease progression or death, while OS is the time from study treatment initiation to death from any cause. Additional analyses will include the growth modulation index (GMI) and toxicity graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Immune-related responses will be assessed according to iRECIST, with data centrally reviewed by an expert radiologist.
Pharmacodynamic and predictive biomarker analyses will be conducted on blood and tumor tissue at baseline and various study time points. Blood samples will be collected at predefined intervals to assess serum/plasma cytokine levels, Treg, CD4+, CD8+ lymphocyte subpopulations, and plasma levels of Kynurenine. Tumor samples will be analyzed for CD8+ effectors, macrophage infiltrates, and other markers such as PDL1 and MET. These analyses aim to identify predictive signatures for response through RNA sequencing and other methods.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histology: undifferentiated pleomorphic sarcoma (stratum 1), bone osteosarcoma (stratum 2), bone or or extraskeletal Ewing sarcoma (stratum 3). Diagnosis must be reviewed or confirmed by the RRePS/RESOS Network as recommended by the French NCI (Inca),
- Advanced non resectable / metastatic disease,
- Recurrent disease or progression after standard therapy,
- 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,
- Have provided tissue of a tumor lesion from < 3 months old archival tissue sample obtained on locally advanced disease, or metastatis with no subsequent treatment since or presence of a tumor lesion that can be biopsied,
- No more of three previous lines of systemic therapy for advanced disease,
- Age ≥ 18 years,
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
- Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm,
- Life expectancy > 3 months,
- 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,
- No symptomatic central nervous system disease,
- No chronic use of glucocorticoids.
- 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,
- 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,
- At least three weeks since last chemotherapy, immunotherapy and two weeks for any other pharmacological treatment and/or radiotherapy,
- 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,
- Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Both women and men must agree to use 2 medically acceptable methods of contraception throughout the treatment period and for 6 months after discontinuation of treatment. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year,
- Voluntary signed and dated written informed consents prior to any specific study procedure,
- Patients with a social security in compliance with the French Law.
Exclusion Criteria
- Previous treatment with Pembrolizumab or Cabozantinib,
- 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),
- Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
- 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,
- Participation to a study involving a medical or therapeutic intervention in the last 21 days,
- Previous enrolment in the present study,
- Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons,
- Patient unable to swallow,
- Known hypersensitivity to any involved study drug or of its formulation components,
- 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 (at doses ≤ 10 mg or 10 mg equivalent prednisone per day) replacement therapy for adrenal or pituitary insufficiency, etc…) is not considered a form of systemic treatment and is allowed.
- 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,
- 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,
- 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.
- Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies) and/or of active TB (Bacillus Tuberculosis),
- Treatment with anticoagulants such as anti-Vitamin K, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel),
- History of stem cell or solid organ transplantation,
- Has an active infection requiring systemic treatment at study entry,
- 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,
- 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’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product,
- The subject has experienced any of the following: a. Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment b. Hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment c. Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment d. The subject has radiographic evidence of cavitating pulmonary lesion(s). e. The subject has tumor in contact with, invading or encasing any major blood vessels. f. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
- The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
- a) Cardiovascular disorders including: - Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening - Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment - Any history of congenital long QT syndrome - Any of the following within 6 months before the first dose of study treatment: Unstable angina pectoris Clinically-significant cardiac arrhythmias Stroke (including TIA, or other ischemic event) Myocardial infarction Thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study)
- b) Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: - Any of the following within 28 days before the first dose of study treatment Intra-abdominal tumor/metastases invading GI mucosa Any evidence of active peptic ulcer disease, patients must be completely recovered Any evidence of inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, patients must be completely recovered from these conditions Malabsorption syndrome - Any of the following within 6 months before the first dose of study treatment: Abdominal fistula Gastrointestinal perforation Bowel obstruction or gastric outlet obstruction Intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment.
- c) Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy
- d) Other clinically significant disorders such as: - Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment - Serious non-healing wound/ulcer/bone fracture within 7 days before the first dose of study treatment - Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. - Subjects with clinically relevant ongoing complications or non complete wound healing from prior surgery are not eligible.
- Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Note: Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
- Has an history or current evidence of any condition, therapy, or laboratory abnormality that might counfound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
- The subject is planning to have oral surgery/invasive dental procedure within the projected duration of the study, starting with the screening visit through 3 months after the last dose of study treatment or had such a procedure within 3 months of first dose of study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 25 Apr 2022 | 99 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CABOMETYX 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 40 | 24 | PRD4382703 |
CABOMETYX 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 20 | 24 | PRD4381882 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 200 | 24 | PRD4323105 |