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

NCT03202758 | Completed Phase 1

• 1 other identifier: MEDI-TREME-COLON
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 5

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.

Conditions

Colorectal Cancer Metastatic

Keywords

Durvalumab; Tremelimumab; FOLFOX; metastatic colorectal cancer

Outcome Measures

Primary Outcomes (1)

• Evaluation of the safety of Durvalumab plus Tremelimumab in combination with FOLFOX chemotherapy

  Criteria RECIST 1.1

  1 month

Study Arms (1)

Durvalumab + Tremelimumab + FOLFOX

OTHER

* Durvalumab for 12 months * Tremelimumab for up to 4 doses/cycles * FOLFOX

Drug: Durvalumab, Tremelimumab and ,FOLFOX

Interventions

Durvalumab, Tremelimumab and ,FOLFOX DRUG

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

Durvalumab + Tremelimumab + FOLFOX

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre Georges Francois Leclerc: lead
• AstraZeneca: collaborator

Study Sites (5)

CHRU Besançon

Besançon, France

Location

Centre Georges François Leclerc

Dijon, 21000, France

Location

CHU Nantes

Nantes, France

Location

Hôpital Europeen Georges Pompidou

Paris, France

Location

Hôpital Saint Antoine

Paris, France

Location

Related Publications (2)

• Thibaudin M, Fumet JD, Chibaudel B, Bennouna J, Borg C, Martin-Babau J, Cohen R, Fonck M, Taieb J, Limagne E, Blanc J, Ballot E, Hampe L, Bon M, Daumoine S, Peroz M, Mananet H, Derangere V, Boidot R, Michaud HA, Laheurte C, Adotevi O, Bertaut A, Truntzer C, Ghiringhelli F. First-line durvalumab and tremelimumab with chemotherapy in RAS-mutated metastatic colorectal cancer: a phase 1b/2 trial. Nat Med. 2023 Aug;29(8):2087-2098. doi: 10.1038/s41591-023-02497-z. Epub 2023 Aug 10.

  PMID: 37563240 DERIVED

• 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.

  PMID: 29942666 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

durvalumab; tremelimumab; Folfox protocol

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: June 7, 2017
• First Posted: June 29, 2017
• Study Start: August 29, 2017
• Primary Completion: January 9, 2023
• Study Completion: January 9, 2023
• Last Updated: February 10, 2023

Record last verified: 2019-03

Locations

FR (5)