Clinical Trials /

Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC

NCT03202758

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of the Safety and the Tolerability of Durvalumab Plus Tremelimumab Combined With FOLFOX in mCRC
  • 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

Clinical Trial IDs

  • ORG STUDY ID: MEDI-TREME-COLON
  • NCT ID: NCT03202758

Conditions

  • Colorectal Cancer Metastatic

Interventions

DrugSynonymsArms
Durvalumab, Tremelimumab and ,FOLFOXDurvalumab + Tremelimumab + FOLFOX

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Durvalumab + Tremelimumab + FOLFOXOtherDurvalumab for 12 months Tremelimumab for up to 4 doses/cycles FOLFOX
  • Durvalumab, Tremelimumab and ,FOLFOX

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent and any locally-required authorization obtained from the
             subject prior to performing any protocol-related procedures, including screening
             evaluations

          2. Male or female age more than 18 years

          3. Performance status of 0 or 1 according to the ECOG and WHO

          4. Histologically confirmed diagnoses of colorectal cancer with positive mutated KRas.

          5. Patients with metastatic disease

          6. First line therapy

          7. Life expectancy of more than 12 weeks

          8. 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

          9. Tumour evaluation in the previous 4 weeks with presence of at least one measurable
             lesion according to RECIST 1.1 criteria

         10. At least 4 weeks since the last chemotherapy, immunotherapy or other drug therapy and
             / or radiotherapy

         11. Recovery to grade ≤ 1 from any AE derived from previous treatment according to the
             criteria of the NCI-CTCAE version 4.0

         12. Biopsable disease (for ancillary studies) or willingness to provide consent for use of
             archieved tissue for research purposes

         13. Female subjects must either be of non-reproductive potential or must have a negative
             serum pregnancy test upon study entry

         14. Patients must be affiliated to a social security system

         15. 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:

          1. 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

          2. Participation in another clinical study with an investigational product during the
             last 4 weeks

          3. Any previous treatment with a PD-1 or PD-L1 /CTLA-4 inhibitor, including durvalumab or
             tremelimumab

          4. 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

          5. 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.)

          6. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Frediricia's Correction

          7. 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

          8. Any history of hypersensitivity to durvalumab or tremelimumab, FOLFOX or their
             excipients

          9. 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)

         10. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE >Grade 1

         11. 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

         12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis)

         13. History of primary immunodeficiency

         14. History of organ transplant that requires use of immunosuppressive

         15. History of allogeneic organ transplant

         16. 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

         17. Sever concurrent disease, or co-morbidity that in the judgment of the investigator,
             would make the patient inappropriate for enrolment

         18. Ongoing treatment with CYP3A4 substrates or regularly taking of grapefruit juice

         19. Known history of active tuberculosis

         20. History of leptomeningeal carcinomatosis

         21. Brain metastases or spinal cord compression

         22. Receipt of live attenuated vaccination within 30 days prior to study entry or within
             30 days of receiving durvalumab

         23. 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

         24. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

         25. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
             of but not limited to surgery, radiation and/or corticosteroids

         26. Subjects with uncontrolled seizures,

         27. Subjects under guardianship, curatorship or judicial protection

         28. Known allergy or hypersensitivity to IP or any excipient
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Evaluation of the safety of Durvalumab plus Tremelimumab in combination with FOLFOX chemotherapy
Time Frame:1 month
Safety Issue:
Description:Criteria RECIST 1.1

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Georges Francois Leclerc

Trial Keywords

  • Durvalumab
  • Tremelimumab
  • FOLFOX
  • metastatic colorectal cancer

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