Combining Epigenetic And Immune Therapy to Beat Cancer. (CAIRE)

Combining Epigenetic And Immune Therapy to Beat Cancer. CAIRE Study

Umbrella study structure to independently and simultaneously assess the effects of the association of durvalumab and tazemetostat in multiple solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Adult Solid Tumor; Advanced Solid Tumor; Advanced Pancreatic Adenocarcinoma; Advanced Colorectal Carcinoma; Advanced Soft-tissue Sarcoma
• Intervention / Treatment: Drug: Durvalumab; Drug: Tazemetostat

Detailed Description

4 independant, multicenter, prospective, signle-arm phase II trials, based on 2-stage Simon's optimal design, will be conducted in parallel to assess the efficacy of durvalumab when prescribed with tazemetostat, separately, in distinct cohorts of solid tumors:

• cohort A: patients with pancreatic cancer
• cohort B: patients with colorectal cancer not MSI-H or MMR-deficient
• cohort C: patients with metastatic solid tumors with positive interferon gamma signature and/or tertiary lymphoid structure positive
• cohort D: patients with soft-tissue sarcoma

• Study Type: Interventional
• Enrollment (Anticipated): 173
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Recruiting
    • Institut Bergonié
  • Brest, France, 29200
    • Recruiting
    • CHRU Brest
  • Poitiers, France, 86000
    • Recruiting
    • CHU Poitiers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histology: histologically confirmed solid tumors including 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 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
7. Life expectancy > 3 months,
8. 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 judgment,
9. Adequate hematological, renal, metabolic and hepatic functions
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
13. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to inclusion.
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.
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:

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 CTLA-4 antibody,
3. EGFR/ALK/ROS mutated NSCLC,
4. Evidence of progressive or symptomatic central nervous system 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
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 or known acquired immunodeficiency syndrome,
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 class 2,
23. Unstable angina, 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,
35. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: pancreatic cancer; Patients with pancreatic cancer will be treated by durvalumab prescribed in association with tazemetostat	Drug: Durvalumab; Durvalumab will be administered by intraveinous infusion (1120 mg) on day 1, every 3 weeks. Treatment by durvalumab will start on Day 22 (i.e., day 1 of cycle 2); Drug: Tazemetostat; Tazemetostat will be administered per-os, twice daily (800 mg x 2), continuously. Treatment by tazemetostat will start on day 1 (of cycle1).
Experimental: Cohort B: not MSI-H or MMR-deficient colorectal cancer; Patients with colorectal cancer will be treated bydurvalumab prescribed in association with tazemetostat	Drug: Durvalumab; Durvalumab will be administered by intraveinous infusion (1120 mg) on day 1, every 3 weeks. Treatment by durvalumab will start on Day 22 (i.e., day 1 of cycle 2); Drug: Tazemetostat; Tazemetostat will be administered per-os, twice daily (800 mg x 2), continuously. Treatment by tazemetostat will start on day 1 (of cycle1).
Experimental: Cohort C: metastatic solid tumor; Patients with metastatic solid with positive interferon gamma signature and/or presence of tertiary lymphoid structurestumor will be treated bydurvalumab prescribed in association with tazemetostat	Drug: Durvalumab; Durvalumab will be administered by intraveinous infusion (1120 mg) on day 1, every 3 weeks. Treatment by durvalumab will start on Day 22 (i.e., day 1 of cycle 2); Drug: Tazemetostat; Tazemetostat will be administered per-os, twice daily (800 mg x 2), continuously. Treatment by tazemetostat will start on day 1 (of cycle1).
Experimental: Cohort D: soft-tissue sarcoma; Patients with soft-tissue sarcoma will be treated by durvalumab prescribed in association with tazemetostat	Drug: Durvalumab; Durvalumab will be administered by intraveinous infusion (1120 mg) on day 1, every 3 weeks. Treatment by durvalumab will start on Day 22 (i.e., day 1 of cycle 2); Drug: Tazemetostat; Tazemetostat will be administered per-os, twice daily (800 mg x 2), continuously. Treatment by tazemetostat will start on day 1 (of cycle1).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort A	Antitumor activity will be assessed in terms of disease control rate, defined as complete response (CR), partial response (PR) and stable disease (SD) as per RECIST v1.1 criteria	Within 6 months of treatment onset
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort B	Antitumor activity will be assessed in terms of disease control rate, defined as CR, PR and SD as per RECIST v1.1 criteria	Within 6 months of treatment onset
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort C	Antitumor activity will be assessed in terms of objective response rate, defined as CR and PR as per RECIST v1.1 criteria	Within 6 months of treatment onset
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort D	Antitumor activity will be assessed in terms of 6-months progression-free rate, defined as CR, PR and SD as per RECIST v1.1 criteria	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort D	Antitumor activity will be assessed in terms of objective response rate, defined as CR and PR as per RECIST v1.1 criteria	Within 6 months of treatment onset
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort A	Antitumor activity will be assessed in terms of 6-months progression-free rate, defined as CR, PR and SD as per RECIST v1.1 criteria	6 months
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort B	Antitumor activity will be assessed in terms of 6-months progression-free rate, defined as CR, PR and SD as per RECIST v1.1 criteria	6 months
Assessment of antitumor activity of durvalumab combined with tazemetostat for cohort C	Antitumor activity will be assessed in terms of 6-months progression-free rate, defined as CR, PR and SD as per RECIST v1.1 criteria	6 months
6-month objective response (OR) independently for each population	Objective response is defined as the proportion of patients with complete response (CR) or partial response (PR) observed at 6 months, based on RECIST 1.1 criteria	6 months
Best overall response, independently for each population	Best overall response is defined as the best response across all time points (RECIST 1.1). The best overall response is determinded once all the data for the patient is known (RECIST 1.1)	Throughout the treatment period, an expected average of 6 months
1-year progression-free survival, independently for each population	Progression-free survival is defined as the delay between the start date of treatment and the date of progression (as per RECIST 1.1) or death (from any cause), whichever occurs first	1 year
1-year overall survival, independently for each population	Overall survival is defined as the delay between the start date of treatment and the date of death (of any cause)	1 year
Safety profile, independently for each population: Common Terminology Criteria for adverse events version 5	Toxicity graded using the Common Terminology Criteria for Adverse Events vers 5	Throughout the treatment period, an expected average of 6 months
Tumor immune cell levels	Levels of immune cells in tumors will be measured by immunohistochemistry	before treatment onset, cycle 2 day 1 and cycle 3 day 1 (each cycle is 21 days)
Blood cytokines level	Levels of cytokines in blood will be measured by ELISA	before treatment onset, cycle 2 day 1, cycle 3 day 1 and treatment discontinuation (each cycle is 21 days)
Blood lymphocytes level	Levels of lymphocytes in blood will be measured by flow cytometry	before treatment onset, cycle 2 day 1, cycle 3 day 1 and treatment discontinuation (each cycle is 21 days)
Blood kynurenin level	Levels of kynurenin in blood will be measured by ELISA	before treatment onset, cycle 2 day 1, cycle 3 day 1 and treatment discontinuation (each cycle is 21 days)

Collaborators and Investigators

• Sponsor: Institut Bergonié
• Collaborators: Epizyme, Inc.; AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2021
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): January 1, 2025

Study Registration Dates

• First Submitted: January 11, 2021
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 12, 2021

Study Record Updates

• Last Update Posted (Actual): March 1, 2023
• Last Update Submitted That Met QC Criteria: February 28, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: colorectal cancer; immunotherapy; soft-tissue sarcoma; pancreatic cancer; solid tumor; tertiary lymphoid structure; epigenetic
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms; Sarcoma; Colorectal Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab
• Other Study ID Numbers: IB2019-04; 2019-003303-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No