PEMBROCABOSARC : Combination of pembrolizumab and cabozantinib in patients with advanced sarcomas

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Apr 2022 → ongoing

Decision date (initial)

2024-10-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509496-16-00

EudraCT number

2020-002366-13

ClinicalTrials.gov

NCT05182164

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Pharmacodynamic, Safety, Efficacy, Therapy

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 objectives 5

1. 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).
2. Assessment of the safety profile of the treatment strategy using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0.
3. 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.
4. Assessment of the efficacy of the treatment strategy in terms of 6-month non-progression according to iRECIST (Seymour 2017; central radiological review data)
5. Translational research on blood and tumor samples obtained at baseline and several time points during treatment for: - pharmacodynamic (PD)/mechanism of action (MOA) analysis assessing angiogenic and immunologic biomarkers in blood, - identification of biomarkers predictive of treatment response on tumor samples.

Conditions and MedDRA coding

Advanced /metastatic sarcomas: undifferentiated pleomorphic sarcoma, osteosarcoma and Ewing sarcoma.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 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),
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 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,
6. No more of three previous lines of systemic therapy for advanced disease,
7. Age ≥ 18 years,
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm,
10. Life expectancy > 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 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,
19. Voluntary signed and dated written informed consents prior to any specific study procedure,
20. Patients with a social security in compliance with the French Law.

Exclusion criteria 28

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 (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.
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. History of stem cell 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’ 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,
20. 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.
21. 21. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
22. 21. 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)
23. 21. 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.
24. 21. 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
25. 21. 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.
26. 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.
27. 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.
28. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. 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).
2. Non-progression: complete response, partial response or stable disease more than 24 weeks as per RECIST evaluation criteria v1.1.
3. Objective response: complete response or partial response as per RECIST evaluation criteria v1.1.
4. 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 analysis will be based on the central radiological review data. o Each patient will be assigned one of the following categories: Complete response, Partial response, Stable disease, Progression, not evaluated for response.

Secondary endpoints 13

1. Best overall response defined as per RECIST v1.1 criteria.
2. 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.
3. 1-year overall survival (OS): OS is defined as the time from study treatment initiation to death (of any cause).
4. 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.
5. Toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0.
6. Immune-related response is defined according to iRECIST (Seymour 2017). Analysis will be based on data centrally reviewed by an expert radiologist.
7. 7. 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.
8. 7. a) Blood samples will be mandatory collected at predefined timepoints for assessment of
9. 7. b) Serum/plasma cytokines levels (TNFγ, TNFα, TGFβ, IL2, 4, 6, 10), VEGF, HGF, sMET, sVEGFR2 (ELISA)
10. 7. c) Treg, CD4+ CD8+ and DR lymphocytes subpopulations monitoring, CD8+/Treg ratio (flow cytometry)
11. 7. d) Plasma levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS)
12. 7. e) 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 collected (optional) 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),
13. 7. e) as well as MET and phosphoMET, Ki67 expression by IHC. Frozen samples will be analysed by (but not limited to) RNA sequencing in search for a predictive signature for response. * biopsy at C2D8 will be collected under patient agreement end with discernment.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine ITALIANO

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore Barthod Malat

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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