Durvalumab Plus Tremelimumab Combination Immunotherapy With or Without Weekly Paclitaxel in Patients With Advanced Biliary Tract Carcinoma (BTC) After Failure of Platinum-based Chemotherapy (IMMUNO-BIL)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2022
  • participants needed
    106
  • sponsor
    GERCOR - Multidisciplinary Oncology Cooperative Group
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Updated on 1 February 2022
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Summary

IMMUNO-BIL is a non-comparative randomized 1:1 phase II study. This study will assess the efficacy and safety of the combination of durvalumab plus tremelimumab with or without weekly paclitaxel in patients with advanced BTC after failure of platinum-based chemotherapy.

On the 25th June 2019, the maximum DLT event number was reached (6/10) in the durvalumab plus tremelimumab combination with paclitaxel Arm (Arm B). According to the Pocock boundary described in the protocol, GERCOR has updated the study to discontinue enrollment in Arm B (durvalumab plus tremelimumab with paclitaxel) . No safety concerns were raised by the IDMC in Arm A. Consequently, the study will resume with Arm A (durvalumab plus tremelimumab) only, without randomization.

Discontinuation of ARM B(June 2019): Durvalumab plus tremelimumab plus paclitaxel

One cycle equals 4 weeks (D1=D28); Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent.

Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles. Paclitaxel: 80 mg/m2, every week for 3 weeks (D1-D8-D15), by IV infusion, until progression or unacceptable toxicity or withdrawal of consent (at least 6 cycles, at the discretion of the investigator).

December 2020: Tremelimumab dosage modification based on the results of the Study 22 study (Kelley RK, et al. ASCO20 Virtual Scientific Program 2020) showing increased efficacy (response rate and progression-free survival) without safety concerns with one dose of tremelimumab 300 mg (cycle 1) instead of four doses of 75 mg (cycle 1 to cycle 4) in combination with durvalumab 1,500 mg Q4W in hepatocellular carcinoma. Following these results, we have changed the tremelimumab 75 mg x 4 schedule for the 300 mg x 1 schedule. The inclusion of 106 additional patients will be required to adequately evaluate the efficacy of this administration schedule.

ARM A : Durvalumab plus tremelimumab ( patients included before 31/12/2020) One cycle equals 4 weeks (D1=D28);

Durvalumab: 1,500 mg by IV infusion on D1, until progression or unacceptable toxicity or withdrawal of consent.

Tremelimumab: 75 mg by IV infusion on D1 for the first 4 cycles.

Description

Biliary tract carcinoma (BTC, adenocarcinoma in more than 90% of cases) is the second primary liver tumor in incidence after hepatocellular carcinoma (2,000 new cases/year in France).

The prognosis of biliary malignancies is poor, with a 5-year overall survival rate (OS) of about 10-15%, most often due to late diagnosis, at an advanced stage.

In advanced BTC, the gemcitabine plus platinum (cisplatin [GEMCIS] or oxaliplatin [GEMOX]) doublet of chemotherapy is the standard first-line treatment and no targeted therapy has been validated in this indication to date. There is no second-line therapeutic standard; chemotherapy (mainly, 5-FU-based combination) yields limited median progression-free survival (PFS) and OS of abouty 2-3 months and 6-7 months respectively, justifying the exploration of new therapeutic options.

Immune therapies (mainly, immune checkpoint inhibitors [ICI]) have opened new opportunities in cancer therapy. Hence, anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb) have demonstrated robust clinical activity and obtained FDA approval in several cancers. Recent data showed encouraging results with anti-PD-1 mAb as a monotherapy in PD-L1-positive pre-treated advanced BTC. The effects of ICI in combination with second-line chemotherapy in patients with advanced BTC have not been explored to date.

Platinum salts can induce "immunogenic cell death". Therefore, previous treatment with platinum may increase tumor immunogenicity and sensitivity to immune therapy, particularly, ICI. The second-line setting after failure of platinum-based chemotherapy may then be an optimal biological context for testing immune therapy in advanced BTC.

Durvalumab is a human immunoglobulin (Ig) G1 kappa (IgG1) anti-PD-L1 mAb. Tremelimumab is a human IgG2 anti-CTLA-4 mAb. Paclitaxel is a chemotherapy belonging to the taxane family. Taxanes may enhance the effect of immunotherapy by increasing the sensitivity of the tumor and activating the immune system. Taxanes are used in some patients with advanced biliary cancer.

These data suggest that BTC may be a good candidate for immune therapy. The combination of anti-CTL4 and anti-PD1/PD-L1 mAb is expected to be active in both immune-inflamed and non-inflamed BTC, and in PD-L1 high and low tumors.

Details
Condition Advanced Biliary Tract Carcinoma
Treatment Paclitaxel, tremelimumab, durvalumab
Clinical Study IdentifierNCT03704480
SponsorGERCOR - Multidisciplinary Oncology Cooperative Group
Last Modified on1 February 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Patients with Grade 2 neuropathy will be excluded
Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician
History of allogenic organ transplantation
Any systemic steroid therapy (> 10 mg daily dose of prednisone or equivalent) whatever the duration of this corticotherapy
Note: The following are exceptions to this criterion
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). 10. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies) Note: Patients with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [HBc] antibody test) are eligible
Note: Patients positive for HCV antibody are eligible only if polymerase chain
reaction testing is negative for HCV ribonucleic acid (RNA)
\. Diagnosis of any second malignancy within the last 5 years, except for
adequately treated basal cell or squamous cell skin cancer, or in situ
carcinoma of the cervix uteri
\. Prior treatment with taxane or any immune ICI, including durvalumab and
tremelimumab or any other anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4
antibody
\. Known active central nervous system metastases and/or carcinomatous
meningitis; patients with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at
least 4 weeks prior to the first dose of trial treatment and any neurologic
symptoms have returned to baseline), have no evidence of new or enlarging
brain metastases, and are not using steroids > 10 mg/day of prednisone or
equivalent for at least 14 days prior to trial treatment
\. Uncontrolled massive pleural effusion or massive ascites
\. Active or prior documented autoimmune or inflammatory disorders
(including inflammatory bowel disease [e.g., colitis or Crohn's disease]
diverticulitis [with the exception of diverticulosis], systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis
etc]), that has required systemic treatment (i.e. with use of disease
modifying agents, corticosteroids or immunosuppressive drugs) Note: Patients
with vitiligo, alopecia, or any chronic skin condition that does not require
systemic therapy are exception to this criterion
Note: History of autoimmune-related hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible
Note: Controlled Type 1 diabetes mellitus on a stable insulin regimen may be
eligible
\. Uncontrolled intercurrent illness, including but not limited to, ongoing
or active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung
disease, serious chronic gastrointestinal conditions associated with diarrhea
or psychiatric illness/social situations that would limit compliance with
study requirement, substantially increase risk of incurring AEs or compromise
the ability of the patient to give written informed consent
\. Live vaccine administration within 30 days prior to the first dose of
study treatment Note: Patients, if enrolled, should not receive live vaccine
whilst receiving investigational product and up to 30 days after the last dose
of investigational product
\. Known or suspected allergy or hypersensitivity to any of the study drugs
or any of the study drug excipients (taxane, durvalumab, or tremelimumab)
\. Mean QT interval corrected for heart rate using Fridericia's formula
(QTcF) 470 ms
\. History or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with
participation for the full duration of the trial, or is not in the best
interest of the participant, in the opinion of the treating investigator
\. Radiotherapy treatment to more than 30% of the bone marrow or with a wide
field of radiation within 4 weeks of the first dose of study drug
\. Major surgical procedure (as defined by the Investigator) within 28 days
prior to the first dose of investigational product Note: Local surgery of
isolated lesions for palliative intent is acceptable
\. Pregnancy/lactation
\. Tutelage or guardianship

Exclusion Criteria

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) or supportive care clinical study or during the follow-up period of an interventional study
Receipt of the last dose of anticancer therapy (investigational product, chemotherapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) 21 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetics properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator
Mixed histology (hepatocholangiocarcinoma)
Extensive tumor massively replacing both entire lobes
Obstructive jaundice (bilirubin > 1.5 ULN) without adequate biliary drainage
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