Caire : Combining Epigenetic and Immune Therapy to Beat Cancer

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

5 Jul 2021 → 17 Jul 2025

Decision date (initial)

2024-10-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509501-72-00

EudraCT number

2019-003303-35

ClinicalTrials.gov

NCT04705818

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacogenomic, Pharmacodynamic, Therapy

 To investigate the antitumor activity of durvalumab when prescribed in association with tazemetostat independently for 4 populations of participants :
o [Cohort A] Participants with pancreatic cancer,
o [Cohort B] Participants with colorectal cancer not MSI-H or MMR-deficient,
o [Cohort C] Participants with metastatic solid tumors with positive interferon gamma signature and/or tertiary lymphoid structure positive,
o [Cohort D] Participants with soft-tissue sarcoma.
 Antitumor activity will be assessed in terms of:
o [Cohorts A, B] Disease control rate within 24 weeks of treatment onset.
o [Cohort C] Objective response rate within 24 weeks of treatment onset.
o [Cohort D] 6-month progression-free rate.

Secondary objectives 3

1. To investigate the antitumor activity of durvalumab when prescribed in association with tazemetostat in terms of additional endpoints (independently for each cohort of participants): o Cohorts A, B, C: 6-month progression-free status, 6-month objective response, best overall response under treatment, growth modulation index (GMI), 1-year progression-free survival (PFS) and 1 year overall survival (OS). o Cohort D: Objective response within 24 weeks of treatment onset, 6-month objective response, best overall response under treatment, growth modulation index (GMI), 1-year progression-free survival (PFS) and 1 year overall survival (OS).
2. To evaluate the safety profile of Durvalumab when prescribed in association with Tazemetostat (NCI-CTCAE v5).
3. To perform pharmacodynamics (PD) / mechanisms of action (MOA) biomarker analysis as well as analysis of predictive biomarkers (levels of immunologic biomarkers in blood / tissue at baseline and different time points.

Conditions and MedDRA coding

Adult participants with metastatic or unresectable locally advanced solid tumors.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Histology: histologically confirmed pancreatic cancer (cohort A), non MSI-H or MMR-deficient colorectal cancer (cohort B), solid tumor with positive IFNG gene expression signature and/or tertiary lymphoid structure positive (cohort C), soft-tissue sarcomas (Cohort D). Other solid tumor types may be included through future amendment of the current version of the study protocol. Note: for cohort C, IFNG gene expression and/or presence of tertiary lymphoid structure will be centrally assessed. Cohort D, diagnosis must be confirmed and reviewed by the RRePS Network.as recommended by the French NCI (Inca).
2. For cohort C, availability of archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample for IFNG gene expression assessment and/or determination of the presence of tertiary lymphoid structure.
3. Advanced disease defined as metastatic or unresectable locally advanced disease.
4. Age ≥ 18 years.
5. ECOG, Performance status ≤ 1.
6. Measurable disease according to RECIST (lesion in previously irradiated field can be considered as measurable if progressive at inclusion according to RECIST v1.1). At least one site of disease must be uni-dimensionally ≥ 10 mm.
7. Life expectancy > 3 months.
8. Participants must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgment.
9. Adequate hematological, renal, metabolic and hepatic functions: a. Hemoglobin ≥ 9 g/dl (participants may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 G/l and platelet count ≥ 100 G/l, b. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement and/or liver metastasis for AP exclusively and ≤ 5 x ULN in case of liver metastasis for AST and ALT). c. Total serum bilirubin ≤ 1.5 x ULN d. Albumin ≥ 25 g/l e. Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula) f. Deleted at MSA 1. g. Lipase ≤ 1.5 X ULN.
10. 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.
11. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy.
12. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event - NCI-CTCAE, v5).
13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to inclusion. Note that pregnancy test must be repeated within 72 hours prior to receiving the first dose of study medication.
14. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for at least nine months after discontinuation of treatment for women and six months after discontinuation of treatment for men. Acceptable methods for contraception are described in protocol.
15. Voluntary signed and dated written informed consents prior to any specific study procedure.
16. Participants with a social security in compliance with the French law.

Exclusion criteria 37

1. Previous treatment with durvalumab or tazemetostat.
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 ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
3. EGFR/ALK/ROS mutated NSCLC.
4. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases.
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days.
6. Previous enrolment in the present study.
7. Participant unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons.
8. Known hypersensitivity to any involved study drug or of its formulation components.
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a.Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day c. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment.
11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan or interstitial lung disease with ongoing signs and symptoms at inclusion. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
12. Has known active tuberculosis, hepatitis B or hepatitis C.
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS).
14. Persistent proteinuria > 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCI-CTCAE v5).
15. Major surgical procedure or significant traumatic injury within 28 days before inclusion.
16. Non-healing wound, non-healing ulcer, or non-healing bone fracture.
17. Participants with evidence or history of any bleeding diathesis, irrespective of severity.
18. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to inclusion.
19. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before inclusion (except for adequately treated catheter-related venous thrombosis occurring more than one month before inclusion).
20. Ongoing infection > Grade 2 as per NCI CTCAE v5.
21. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management.
22. Congestive heart failure ≥ New York Heart Association (NHYA) class 2.
23. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
24. Myocardial infarction less than 6 months before inclusion.
25. Uncontrolled cardiac arrhythmias.
26. Pregnant or breast-feeding participants.
27. Individuals deprived of liberty or placed under legal guardianship.
28. Prior organ transplantation, including allogeneic stem cell transplantation.
29. Known alcohol or drug abuse.
30. Participants with any condition that impairs their ability to swallow and retain tablets.
31. Other severe acute or chronic medical conditions including immune inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study
32. Participant with anti-Vitamine K oral anticoagulation therapy.
33. Suspected or known intraabdominal fistula.
34. Screening QTc interval > 480 msec is excluded (corrected by Fredericia or Bazett formula). In the event that a single QTc is > 480 msec, the subject may enroll if the average QTc for the 3 ECGs is < 480 msec.
35. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMistR) are live attenuated vaccines and are not allowed.
36. Participants with a prior history of myeloid malignancies, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
37. Participants with a prior history of T-cell lymphoblastic lymphoma (T-LBL) / T-cell lymphoblastic leukemia (T-ALL).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Participants with pancreatic cancer [Cohort A]: Disease control rate within 24 weeks of treatment onset is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR), unconfirmed partial response (PRu) or stable disease (SD), as per RECIST v1.1 criteria, observed within 24 weeks of treatment onset (while treated with the investigational product).
2. Participants with colorectal cancer not MSI-H or MMR-deficient [Cohort B]: Same primary endpoint as for cohort A.
3. Participants with metastatic solid tumors with positive interferon gamma signature and/or tertiary lymphoid structure positive [Cohort C]: Objective response rate within 24 weeks of treatment onset is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu), as per RECIST v1.1 criteria, observed within 24 weeks of treatment onset (while treated with the IP)
4. Participants with soft-tissue sarcomas [Cohort D] : 6-month progression-free rate is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu) or stable disease (SD) more than 24 weeks as per RECIST v1.1 criteria, observed within 6 months following treatment onset.

Secondary endpoints 9

1. 6-month objective response rate is defined as the proportion of participants with confirmed complete response (CR), unconfirmed complete response (CRu), confirmed partial response (PR) or unconfirmed partial response (PRu) as per RECIST v1.1 criteria.
2. Best overall response under treatment: best response (as per RECIST v1.1 criteria) recorded from the start of the study treatment until the end of treatment.
3. Growth modulation index (GMI) is defined for each participant as the ratio of the PFS on the current treatment strategy to the PFS on the previous line of therapy (Von Hoff, 1998), in participants with documented progression at inclusion.
4. Progression-free survival (PFS) is defined as the delay between the start date of treatment and the date of progression (as per RECIST v1.1) or death (from any cause), whichever occurs first. 6-month PFS and 1- year PFS rates will be reported.
5. Overall survival (OS) is defined as the delay between the start date of treatment and the date of death (of any cause). 1-year OS rate will be reported.
6. Safety profile of durvalumab in association with tazemetostat. Events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
7. Pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of immunologic biomarkers in blood/tissue at baseline and different study time points): Fresh tumor samples will be collected before tazemetostat dosing, after 3 weeks of treatment with tazemetostat (C2D1) and then at C3D1 (1 cycle of combo treatment).
8. 7a) Formalin-fixed, paraffin-embedded biopsy samples will be analyzed for (but not limited to) H3K27 (PD marker of tazemetostat), CD4, CD8, PDL1, CSF-1R, CD68/CD163, CD68/MHC class II, and other exploratory markers.
9. 7b) Gene profiling: We will perform on all pre-treatment tumor samples whole-exome sequencing and RNA sequencing in order to identify :  Differences in point mutation and indel status in driver genes between responders and non-responders  Differences in mutational load between responders and non-responders  Differences in copy number alterations between responders and non-responders  Differences in expression profiling between responders and non responders.

Investigational products

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

Test 2

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 · 3 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 6 files

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

Application history

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