Study of Durvalumab in Combination with Gemcitabine and Cisplatin in Patients with First Line Advanced Biliary Tract Cancers (TOPAZ-1)

Phase 3

Completed

• Conditions: Intrahepatic bile duct carcinoma, (2) ICD-10 Condition: C23||Malignant neoplasm of gallbladder,

• Registration Number: CTRI/2020/08/027208
• Lead Sponsor: AstraZeneca AB

Brief Summary

This is a Phase III Randomized, Double-Blind, Placebo-Controlled,Multi-Regional, International Study of Durvalumab in Combination withGemcitabine plus Cisplatin versus Placebo in Combination with Gemcitabine plusCisplatin for Patients with First-Line Advanced Biliary Tract Cancers (BTC)

 Approximately 672 patientswith previously untreated, unresectable locally advanced or metastatic BTC willbe randomized in a 1:1 ratio to receive either Durvalumab plus Gemcitabine and Cisplatinor Placebo plus Gemcitabine and Cisplatin.

 The primary objective ofthe study is to confirm the superiority of Arm A compared to Arm B in terms ofoverall survival (OS) in patients with first-line advanced BTC.

 Patients will be stratifiedby disease status (initially unresectable versus recurrent) and primary tumoursite (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versusgallbladder cancer).

 Patients will receive Durvalumabplus cisplatin and gemcitabine (Arm A) or placebo plus cisplatin andgemcitabine (Arm B) via IV infusion q3w, starting on Cycle 1, for up to 8cycles. After treatment with gemcitabine/cisplatin is complete, the patientswill receive durvalumab (Arm A) or placebo (Arm B) via IV infusion q4w untilclinical progression or RECIST 1.1-defined radiological PD, unless there isunacceptable toxicity, withdrawal of consent, or another discontinuationcriterion is met.

 During the treatmentperiod, patients who are clinically stable at an initial RECIST 1.1-definedradiological PD may continue to receive study treatment at the discretion ofthe Investigator and patient. A follow-up scan is to be collected after theinitial RECIST 1.1-defined radiological PD, preferably at the next (and nolater than the next) scheduled imaging visit and no less than 4 weeks after theprior assessment of PD.

 Patients with RECIST1.1-defined radiological PD who continue to receive their assigned treatment atthe discretion of the Investigator and patient (following consultation withsponsor) can receive treatment until no longer having clinical benefit, andimaging for tumour assessments should continue on their regular imagingschedule for the duration of treatment.

 All randomized patientsshould be followed up for survival.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-08-21
• Last Update Posted: 2024-06-21

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 672

Inclusion Criteria

• Informed consent 1.Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• 2.Provision of a signed and dated written ICF prior to any mandatory study-specific procedures, sampling, and analyses.
• 3.Provision of a signed and dated written informed consent prior to the collection of sample for optional genetic analysis Age 4.Age ≥18 years at the time of screening Type of patient and disease characteristics 5.Histologically confirmed, unresectable advanced or metastatic adenocarcinoma of biliary tract, including cholangiocarcinoma (intrahepatic or extrahepatic) and gallbladder carcinoma.
• 6.Patients with previously untreated disease if unresectable or metastatic at initial diagnosis will be eligible.
• 7.Patients who developed recurrent disease >6 months after surgery with curative intent and, if given, >6 months after the completion of adjuvant therapy (chemotherapy and/or radiation) will be eligible.
• 8.A World Health Organization (WHO)/ECOG PS of 0 or 1 at enrollment.
• 9.At least 1 lesion that qualifies as a RECIST 1.1 Target Lesion (TL) at baseline.
• 10.No prior exposure to immune-mediated therapy, including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
• 11.Adequate organ and marrow function, as defined below: a.
• Hemoglobin ≥9.0 g/dL.
• Absolute neutrophil count ≥1.5 × 109 /L.
• Platelet count ≥100 × 109/L.
• Serum bilirubin ≤2.0 × the upper limit of normal (ULN); This will not apply to e.
• patients with confirmed Gilbert’s syndrome.
• Any clinically significant biliary f.
• obstruction should be resolved before randomization.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN.
• Creatinine clearance (CL) >50 mL/min per 24hr urine or as calculated by Cockcroft-Gault 12.Patients must have a life expectancy of at least 12 weeks at the time of screening Sex 14.
• Male and/or female.
• Other 15.Patients must provide a recent tumor biopsy or an available unstained archived tumor tissue sample in a quantity sufficient to allow for analysis (taken ≤3 years prior to screening).
• The tumor lesions to be used for biopsy should not be those used as RECIST TLs, unless there are no other lesions suitable for biopsy.
• 16.Patients with HBV infection (as characterized by positive hepatitis B surface antigen [HBsAg] and/or anti-hepatitis B core antibodies (anti-HBc) with detectable HBV deoxyribonucleic acid (DNA) [≥10 IU/mL or above the limit of detection per local laboratory]) must receive antiviral therapy prior to randomization per institutional practice to ensure adequate viral suppression.
• Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
• Patients who test positive for anti-HBc with undetectable HBV DNA (<10 IU/mL or under the limit of detection per local laboratory) do not require antiviral therapy unless HBV DNA exceeds 10IU/mL or reaches detectable limits per local laboratory during the course of treatment.
• Patients with active co-infection of HBV and HCV as evidenced by positive anti-HCV antibody and actively co-infected with HBV and hepatitis D virus are not eligible.

Exclusion Criteria

• Medical conditions 1.Ampullary carcinoma.
• 2.History of allogeneic organ transplantation.
• 3.Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, 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]).
• The following are exceptions to this criterion: a.
• Patients with vitiligo or alopecia.
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
• Any chronic skin condition that does not require systemic therapy.
• Patients without an active disease in the last 5 years may be included but only after consultation with the Study Physician.
• Patients with celiac disease controlled by diet alone.
• 4.Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring AEs, or compromise the ability of the patient to give written informed consent.
• 5.History of another primary malignancy, except for: a.
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of investigational product (IP) and of low potential risk for recurrence.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in situ without evidence of disease.
• 6.History of leptomeningeal carcinomatosis.
• 7.History of active primary immunodeficiency.
• 8.Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), or human immunodeficiency virus (positive HIV 1/2 antibodies).
• 9.Any unresolved toxicity NCI Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥2 from a previous anticancer therapy, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• 10.Brain metastases or spinal cord compression (including asymptomatic and adequately treated disease).
• Patients with suspected brain metastases at screening should have an MRI (preferred) or CT scan, each preferably with IV contrast, of the brain prior to study entry.
• 11.Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Prior/concomitant therapy 12.Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• 13.Radiation therapy, including palliative radiation, is not allowed before the study, with an exception of radiation given in an adjuvant setting.
• 14.Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.
• Note that patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP.
• 15.Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
• Note that minor surgery of isolated lesions for palliative intent is acceptable if performed more than 14 days prior to the first dose of IP.
• 16.Patients who have received prior immune-mediated therapy, including, but not limited to, other anti-PD-1, anti PD-L1, or anti CTLA-4.
• 17.Prior locoregional therapy such as radioembolization.
• 18.Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab.
• Intranasal, inhaled, or topical steroids or local steroid injections (eg, intra-articular injection).
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
• c Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
• Prior/concurrent clinical study experience 19.Participation in another clinical study with an IP administered in the last 3 months.
• 20.Previous IP assignment in the present study.
• 21.Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• 22.Prior randomization or treatment in a previous durvalumab clinical study, regardless of treatment arm assignment.
• Other exclusions 23.Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to use effective birth control from screening to 180 days after the last dose of gemcitabine/cisplatin or 90 days after the last dose of durvalumab/placebo monotherapy.
• 24.Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
• 25.Genetic research study (optional).
• Previous allogeneic bone marrow transplant.
• Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection.
• Patients who test positive for hepatitis C (HCV) antibody may be enrolled if HCV RNA is undetectable.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To assess the efficacy of Arm A compared to Arm B in terms of OS (overall survival) in patients with first-line advanced BTC	It will be assessed at the following time points: | 1. Interim Analysis-2: Approximately 347 OS events have occurred across Arm A and Arm B (52% maturity) and | 2. Final Analysis: Approximately 496 OS events have occurred across Arm A and Arm B (74% maturity).

Secondary Outcome Measures

Name	Time	Method
To further assess the efficacy of Arm A compared to Arm B in terms of ORR and DoR in patients with first-line advanced BTC	Interim Analysis -1: When at least 200 patients (100 patients in the each arm) have had the opportunity to be followed for at least 32 weeks or the last patient has been randomized to the global cohort whichever comes later.
For interim analysis 1: to summarise the efficacy of Arm A compared to Arm B in terms of ORR and DoR in patients with first-line advanced BTC	Interim Analysis -1: When at least 200 patients (100 patients in the each arm) have had the opportunity to be followed for at least 32 weeks or the last patient has been randomized to the global cohort whichever comes later.
To assess the efficacy of Arm A compared to Arm B by PD-L1 expression	It will be assessed at the following time points:
To assess the PK of durvalumab when used in combination with cisplatin / gemcitabine	It will be assessed at the following time points:
To investigate the immunogenicity of durvalumab	It will be assessed at the following time points:
PROs (secondary):	It will be assessed at the following time points:
Safety objective:	To assess the safety and tolerability profile of Arm A compared to Arm B in patients with first-line advanced BTC
Exploratory objectives:	1. To investigate the efficacy of Arm A compared to Arm B by candidate biomarkers (for example but not limited to TMB and MSI) that may correlate with drug activity or identify patients likely to respond to treatment
2. To evaluate circulatory-based biomarkers and associations with efficacy parameters, including, but not limited to, ctDNA	It will be assessed at the following time points:
3. To explore the impact of treatment and disease on healthcare resource use	It will be assessed at the following time points:
4. PROs (exploratory):	To assess patient-reported treatment tolerability using PRO-CTCAE and global assessment of treatment tolerability
To assess the patients’ global impression of the severity of cancer symptoms	It will be assessed at the following time points:
To explore the impact of treatment and disease state on health state utility using the EQ-5D-5L	It will be assessed at the following time points:

Trial Locations

Locations (8)

Action Cancer Hospital; 🇮🇳 Delhi, DELHI, India

Artemis Hospitals; 🇮🇳 Gurgaon, HARYANA, India

Indraprastha Apollo Hospitals Sarita Vihar; 🇮🇳 Delhi, DELHI, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Shettys Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Sri Venkateshwara Hospitals; 🇮🇳 Bangalore, KARNATAKA, India

Tata Medical Centre Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

Tata Memorial Hospital; 🇮🇳 Mumbai, MAHARASHTRA, India

Action Cancer Hospital

🇮🇳Delhi, DELHI, India

Dr Sushant Mittal

Principal investigator

01149222222

sushantmittal80@gmail.com