Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC (MEDITREME)
Primary Purpose
Colorectal Cancer Metastatic
Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Durvalumab, Tremelimumab and ,FOLFOX
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Cancer Metastatic focused on measuring Durvalumab, Tremelimumab, FOLFOX, metastatic colorectal cancer
Eligibility Criteria
Inclusion Criteria:
- Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- Male or female age more than 18 years
- Performance status of 0 or 1 according to the ECOG and WHO
- Histologically confirmed diagnoses of colorectal cancer with positive mutated KRas.
- Patients with metastatic disease
- First line therapy
- Life expectancy of more than 12 weeks
Adequate normal organ and marrow function as defined below:
- Haemoglobin > 9.0 g/dL
- Absolute neutrophil count (ANC) > 1.5 x 109/L (>1500 per mm3)
- Platelet count > 100 x 109/L (>100,000 per mm3)
- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
- AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN
- Albumin > 30g/L
- Creatinine < 1.5 X institutional upper limit of normal (ULN)
- Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
- Tumour evaluation in the previous 4 weeks with presence of at least one measurable lesion according to RECIST 1.1 criteria
- At least 4 weeks since the last chemotherapy, immunotherapy or other drug therapy and / or radiotherapy
- Recovery to grade ≤ 1 from any AE derived from previous treatment according to the criteria of the NCI-CTCAE version 4.0
- Biopsable disease (for ancillary studies) or willingness to provide consent for use of archieved tissue for research purposes
- Female subjects must either be of non-reproductive potential or must have a negative serum pregnancy test upon study entry
- Patients must be affiliated to a social security system
- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Exclusion Criteria:
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrolment in the present study
- Participation in another clinical study with an investigational product during the last 4 weeks
- Any previous treatment with a PD-1 or PD-L1 /CTLA-4 inhibitor, including durvalumab or tremelimumab
History of another malignancy within the 5 previous years with low potential risk for recurrence other than :
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 28 days prior to the first dose of study drug (14 days prior to the first dose of study drug for subjects who have received prior TKIs (e.g., erlotinib, gefitinib and crizotinib) and within 6 weeks for nitrosourea or mitomycin C). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction
- Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Any history of hypersensitivity to durvalumab or tremelimumab, FOLFOX or their excipients
- Any unresolved toxicity (CTCAE grade >1) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
- Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
- Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
- History of primary immunodeficiency
- History of organ transplant that requires use of immunosuppressive
- History of allogeneic organ transplant
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; Clinically significant cardiovascular disease including: myocardial infarction within 6 months,, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia; history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, hypotension; rest limb claudication or ischemia within 6 months; active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
- Sever concurrent disease, or co-morbidity that in the judgment of the investigator, would make the patient inappropriate for enrolment
- Ongoing treatment with CYP3A4 substrates or regularly taking of grapefruit juice
- Known history of active tuberculosis
- History of leptomeningeal carcinomatosis
- Brain metastases or spinal cord compression
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
- Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
- Subjects with uncontrolled seizures,
- Subjects under guardianship, curatorship or judicial protection
- Known allergy or hypersensitivity to IP or any excipient
Sites / Locations
- CHRU Besançon
- Centre Georges François Leclerc
- CHU Nantes
- Hôpital Europeen Georges Pompidou
- Hôpital Saint Antoine
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Durvalumab + Tremelimumab + FOLFOX
Arm Description
Durvalumab for 12 months Tremelimumab for up to 4 doses/cycles FOLFOX
Outcomes
Primary Outcome Measures
Evaluation of the safety of Durvalumab plus Tremelimumab in combination with FOLFOX chemotherapy
Criteria RECIST 1.1
Secondary Outcome Measures
Full Information
NCT ID
NCT03202758
First Posted
June 7, 2017
Last Updated
February 9, 2023
Sponsor
Centre Georges Francois Leclerc
Collaborators
AstraZeneca
1. Study Identification
Unique Protocol Identification Number
NCT03202758
Brief Title
Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC
Acronym
MEDITREME
Official Title
Phase Ib/II Trial Evaluating the Safety, Tolerability and Immunological Activity of Durvalumab (MEDI4736) (Anti-PD-L1) Plus Tremelimumab (Anti-CTLA-4) Combined With FOLFOX in Patients With Metastatic Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
August 29, 2017 (Actual)
Primary Completion Date
January 9, 2023 (Actual)
Study Completion Date
January 9, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Georges Francois Leclerc
Collaborators
AstraZeneca
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
Colo-rectal cancer is still one of the leading causes of cancer death worldwide. In France, approximately 40 500 new cases are diagnosed each year. With more than 17 500 deaths in France in 2011, colo-rectal cancer is responsible for more than 12% of all cancer deaths, the overwhelming of deaths occurring in patients with metastatic disease.
Many studies highlight the fact that colo-rectal cancer has immunogenic properties and that host immune responses can influence survival. Recent data have provided a clearer understanding of the factors limiting the antitumor immune response in colo-rectal cancer. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) and PD ligand 1 (PD-L1) pathway.
PD-1 is expressed on activated immune cells and can link to PD-L1 express on Antigen-Presenting-Cell. Usually, this pathway is involved in promoting T-cells tolerance and preventing tissue damage in settings of chronic inflammation. In pathological context, the PD-1/PD-L1 pathway contributes to immune suppression and evasion. Many human solid tumors including colo-rectal cancer express PD-L1, and this expression is associated with a worse prognosis. The interaction of PD-1 with the ligand PD-L1 inhibits T-cell proliferation, survival, and effectors functions; induces apoptosis of tumor-specific T cells; promotes the differentiation of CD4+ T cells into immunosuppressive regulatory T cells; and increases the resistance of tumor cells to cytotoxic T lymphocytes attack. Thus, the blockage of the PD-1/PD-L1 interactions represents a logical target for cancer immunotherapy and in particular colo rectal cancer immunotherapy strategy.
Preclinical studies have shown that PD-L1 blockade improves the immune response by restoring T-cell effectors functions. Recent work in two in vivo tumor models shows a strong interest in using an anti-PD-L1 in combination with standard treatment of colo-rectal cancer (FOLFOX). In these models, the survival of mice that are treated with the combination therapy reached 40% when no mice were alive with FOLFOX treatment alone. This result may be explained, in one hand by cytotoxicity of 5FU and in the other hand by the restoration of anti-tumor immune activity of anti-PD-L1. These results suggest that the combination of chemotherapy with immunotherapy would act synergistically in patients with colo-rectal cancer.
Research Hypothesis: Combination of chemotherapy (FOLFOX) with immunotherapy association (anti-PD-L1 + anti-CTLA-4) would act synergistically in patients with colo-rectal cancer.
Detailed Description
Phase Ib primary objective (STEP 1): To determine the safety of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX
Phase II primary objective (STEP 2): To determine the efficacy of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX in terms of progression free survival (PFS).
Phase II secondary Objective: To determine efficacy of the combination of Durvalumab (Anti-PD-L1) + Tremelimumab (Anti-CTLA-4) + FOLFOX in terms of response to treatment and overall survival.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer Metastatic
Keywords
Durvalumab, Tremelimumab, FOLFOX, metastatic colorectal cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Step 1: Phase Ib with the aim to confirmed the safety of the association of Durvalumab (q2w 750mg) + Tremelimumab (q4w 75mg) + FOLFOX
Step 2: Phase II with the aim to assess efficacy of the association of Durvalumab (q2w 750mg) + Tremelimumab (q4w 75mg) + FOLFOX
Masking
None (Open Label)
Allocation
N/A
Enrollment
57 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Durvalumab + Tremelimumab + FOLFOX
Arm Type
Other
Arm Description
Durvalumab for 12 months
Tremelimumab for up to 4 doses/cycles
FOLFOX
Intervention Type
Drug
Intervention Name(s)
Durvalumab, Tremelimumab and ,FOLFOX
Intervention Description
Study will be performed in 2 step:
STEP 1 (phase Ib) will assess the safety of the combination of Durvalumab 750mg q2w + tremelimumab 75mg q4w + FOLFOX during the 2 first cycles of treatment (1 month)
STEP 2 (phase II) will assess the efficacy of the combination of Durvalumab 750mg q2w + tremelimumab 75mg q4w + FOLFOX
Primary Outcome Measure Information:
Title
Evaluation of the safety of Durvalumab plus Tremelimumab in combination with FOLFOX chemotherapy
Description
Criteria RECIST 1.1
Time Frame
1 month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
Male or female age more than 18 years
Performance status of 0 or 1 according to the ECOG and WHO
Histologically confirmed diagnoses of colorectal cancer with positive mutated KRas.
Patients with metastatic disease
First line therapy
Life expectancy of more than 12 weeks
Adequate normal organ and marrow function as defined below:
Haemoglobin > 9.0 g/dL
Absolute neutrophil count (ANC) > 1.5 x 109/L (>1500 per mm3)
Platelet count > 100 x 109/L (>100,000 per mm3)
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤ 5x ULN
Albumin > 30g/L
Creatinine < 1.5 X institutional upper limit of normal (ULN)
Serum creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
Tumour evaluation in the previous 4 weeks with presence of at least one measurable lesion according to RECIST 1.1 criteria
At least 4 weeks since the last chemotherapy, immunotherapy or other drug therapy and / or radiotherapy
Recovery to grade ≤ 1 from any AE derived from previous treatment according to the criteria of the NCI-CTCAE version 4.0
Biopsable disease (for ancillary studies) or willingness to provide consent for use of archieved tissue for research purposes
Female subjects must either be of non-reproductive potential or must have a negative serum pregnancy test upon study entry
Patients must be affiliated to a social security system
Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Exclusion Criteria:
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrolment in the present study
Participation in another clinical study with an investigational product during the last 4 weeks
Any previous treatment with a PD-1 or PD-L1 /CTLA-4 inhibitor, including durvalumab or tremelimumab
History of another malignancy within the 5 previous years with low potential risk for recurrence other than :
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ
Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) 28 days prior to the first dose of study drug (14 days prior to the first dose of study drug for subjects who have received prior TKIs (e.g., erlotinib, gefitinib and crizotinib) and within 6 weeks for nitrosourea or mitomycin C). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction
Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
Any history of hypersensitivity to durvalumab or tremelimumab, FOLFOX or their excipients
Any unresolved toxicity (CTCAE grade >1) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
History of primary immunodeficiency
History of organ transplant that requires use of immunosuppressive
History of allogeneic organ transplant
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; Clinically significant cardiovascular disease including: myocardial infarction within 6 months,, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia; history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, hypotension; rest limb claudication or ischemia within 6 months; active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
Sever concurrent disease, or co-morbidity that in the judgment of the investigator, would make the patient inappropriate for enrolment
Ongoing treatment with CYP3A4 substrates or regularly taking of grapefruit juice
Known history of active tuberculosis
History of leptomeningeal carcinomatosis
Brain metastases or spinal cord compression
Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
Subjects with uncontrolled seizures,
Subjects under guardianship, curatorship or judicial protection
Known allergy or hypersensitivity to IP or any excipient
Facility Information:
Facility Name
CHRU Besançon
City
Besançon
Country
France
Facility Name
Centre Georges François Leclerc
City
Dijon
ZIP/Postal Code
21000
Country
France
Facility Name
CHU Nantes
City
Nantes
Country
France
Facility Name
Hôpital Europeen Georges Pompidou
City
Paris
Country
France
Facility Name
Hôpital Saint Antoine
City
Paris
Country
France
12. IPD Sharing Statement
Citations:
PubMed Identifier
29942666
Citation
Fumet JD, Isambert N, Hervieu A, Zanetta S, Guion JF, Hennequin A, Rederstorff E, Bertaut A, Ghiringhelli F. Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer. ESMO Open. 2018 Jun 19;3(4):e000375. doi: 10.1136/esmoopen-2018-000375. eCollection 2018. Erratum In: ESMO Open. 2023 Apr;8(2):101185.
Results Reference
derived
Learn more about this trial
Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC
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