CTRI/2024/08/072371 [Registered on: 12/08/2024] Trial Registered Prospectively
Last Modified On:
10/12/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Other
Public Title of Study
An open-label randomized trial of zanidatamab for advanced HER2-positive biliary tract cancer
Scientific Title of Study
An open-label randomized trial of the efficacy and safety of zanidatamab with standard-of-care therapy against standard-of-care therapy alone for advanced HER2-positive biliary tract cancer
Trial Acronym
NIL
Secondary IDs if Any
Secondary ID
Identifier
EU CTR No: 2023-508219-21-00
Other
IND: 142519
Other
JZP598-302_Amendment 1_20Oct2023
Protocol Number
NCT06282575
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Rashmi Chitgupi
Designation
Country Head - Clinical Management
Affiliation
PPD Pharmaceutical development Pvt Ltd.
Address
101, A Wing, Fulcrum
Hiranandani Business Park, Andheri
Mumbai MAHARASHTRA 400099 India
Phone
912266022900
Fax
Email
rashmi.chitgupi@ppd.com
Details of Contact Person Public Query
Name
Rashmi Chitgupi
Designation
Country Head - Clinical Management
Affiliation
PPD Pharmaceutical development Pvt Ltd.
Address
101, A Wing, Fulcrum
Hiranandani Business Park, Andheri
101 A Wing, Fulcrum, Hiranandani Business Park, Sahar Road, Andheri East,
Mumbai - 400099, Maharashtra, India
Countries of Recruitment
Belgium Brazil Chile China Czech Republic Finland France Germany India Israel Italy Portugal Republic of Korea Romania Serbia Spain Sweden Taiwan Turkey United Kingdom United States of America Argentina Canada Japan
AIG Hospitals (A Unit of Asian Institute of Gastroenterology)
B3, Oncology Department, 1-66/AIG/2 to 5 Mind Space Road, Gachibowli, Hyderabad-500032, India Hyderabad TELANGANA
9959778112
drmvkrishnaonco@gmail.com
Dr Mangesh Balasaheb Korde
Chopda Medicare & Research Centre Pvt. Ltd; Magnum Heart Institute
3/5, Patil Lane No. 1, Laxmi Nagar, Near K.B.H. Vidyalaya, Canada Corner, Nashik-422005 Nashik MAHARASHTRA
9168150942
drmangeshkorde@yahoo.in
Dr Ashok Kumar Diwan
Government Medical College and Hospital
Room No-85, Department of Radiation Oncology, Medical Square, Nagpur-440003  Nagpur MAHARASHTRA
9822816608
tinuad_07@hotmail.com
Dr Rohan Bhise
KLES Dr Prabhakar Kore Hospital & Medical Research Centre
Site Management Office, 2nd Floor, Nehrunagar, Belagavi- 590010 Belgaum KARNATAKA
9448866712
rohanbhise30@gmail.com
Dr Akhil Kapoor
Mahamana Pandit Madan Mohan Malaviya Cancer Centre,
(A Unit of Department of Atomic Energy, Govt. of India), D&T Block, 1st floor, Clinical Research Secretariat (CRS) department, Banaras Hindu University Campus, Sundar Bagiya Colony, Sundarpur, Varanasi-221005 Varanasi UTTAR PRADESH
7597364554
kapoorakhil1987@gmail.com
Dr Atul Sharma
Max Super Speciality Hospital, Saket (A Unit of Devki Devi Foundation)
2, Press Enclave Road, Saket, New Delhi 110017
New Delhi DELHI
9818548149
atul1@hotmail.com
Dr Venugopal Arroju
Pi Health Cancer Hospital
A Unit of B10 Health Technologies Private Limited, Plot 184, Survey No 110, Phase IV, HIG-B, DLF Road, Gachibowli, Hyderabad, Serilingampally, K. V. Rangareddy Hyderabad TELANGANA
9980707675
Venugopal.Arroju@picancerhospital.ai
Dr Vineet Talwar
Rajiv Gandhi Cancer Institute and Research Centre
Department of Clinical Trials, D block, Basement 1, Sector 5, Rohini, New Delhi – 110085 New Delhi DELHI
9810241512
drvineettalwar@yahoo.com
Dr Vikas Ostwal
Tata Memorial Hospital
Room No. 319, 3rd Floor, Homi Bhabha Block, Tata Memorial Centre, Dr. Ernest Borges Marg, Parel (East), Mumbai-400012 Mumbai MAHARASHTRA
Institutional Ethics Committee (IEC), Devki Devi Foundation
Approved
Institutional Ethics Committee IEC I/II,
Submittted/Under Review
Institutional Ethics Committee, Government Medical College and Hospital
Approved
Institutional Ethics Committee, KLE Academy of Higher Education & Research
Approved
Institutional Ethics Committee- Asian Institute of Gastroenterology
Approved
Institutional Review Board Rajiv Gandhi Cancer Institute and Research Centre
Approved
Magna-Care Ethics Committee
Submittted/Under Review
PI Health Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C249||Malignant neoplasm of biliary tract, unspecified,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Arm B: standard-of-care treatment with CisGem with or without a PD-1/L1 inhibitor.
On Day 1 of each 21-day cycle, when administration of the treatment components
coincides, a PD-1/L1 inhibitor (if given) is administered first, followed by CisGem (on Days 1 and 8).
Standard of care therapy dose and schedule:
Physician’s choice a of durvalumab or pembrolizumab
(where approved under local regulations)
Durvalumab-
a) Weight less than 30 kg: 20 mg/kg IV on Day 1 of each 21-day cycle
b) Weight 30kg and above: 1,500 mg IV on Day 1 of each 21-day cycle
Pembrolizumab-
c) 200 mg IV on Day 1 of each 21-day cycle
Standard-of-care chemotherapy dose and schedule:
Cisplatin 25 mg/m2 IV on Days 1 and 8 of each 21-day cycle
Gemcitabine 1000 mg/m2 IV on Days 1 and 8 of each 21-day cycle
Intervention
Arm A: zanidatamab in combination with CisGem, with or without a PD-1/L1
inhibitor.
On Day 1 of each 21-day cycle, when administration of the treatment
components coincides, zanidatamab is administered first, followed by a PD-1/L1
inhibitor (if given), and then CisGem (on Days 1 and 8).
Investigational dose and schedule:
Zanidatamab
a) Participant weight less than 70 kg: 1,800 mg IV on Day 1 of each 21-day cycle
b) Weight 70 kg and above: 2,400 mg IV on Day 1 of each 21-day cycle
Standard-of-care chemotherapy dose and schedule:
Cisplatin 25 mg/m2 IV on Days 1 and 8 of each 21-day cycle
Gemcitabine 1000 mg/m2 IV on Days 1 and 8 of each 21-day cycle
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
1. Histologically- or cytologically confirmed BTC, including GBC, ICC, or ECC.
2. Locally advanced unresectable or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies.
3. Received no more than 2 cycles of systemic therapy with gemcitabine and a platinum agent (eg, CisGem or GEMOX) with or without a PD-1/L1 inhibitor (physician’s choice
of durvalumab or pembrolizumab, where approved under local regulations) for advanced unresectable or metastatic disease. Participants who have received prior adjuvant or
neoadjuvant treatment (including investigational products) for earlier stage disease are permitted as long as therapy was completed more than 6 months prior to expected date of
C1D1
4. HER2-positive disease (defined as IHC 3+; or IHC 2+/ ISH+) by IHC and ISH assay (in participants with IHC 2+ tumors) at a central laboratory on new biopsy tissue or archival tissue from the most recent biopsy. Note that fine needle aspirates (FNAs; cytology samples) and biopsies from sites of bone metastases are not acceptable. Testing may occur with tissue obtained at any time after diagnosis of BTC and before expected date of randomization.
a. When the central laboratory is available, samples must be sent to the central laboratory prior to randomization for determination of HER2 status. If it has been confirmed with the medical monitor that a central laboratory is not available, sites may use local testing for HER2 to enroll participants with IHC 3+ tumors. In this case, samples still must be sent to the central laboratory for confirmatory analyses
once the central laboratory becomes available.
5. Assessable (measurable or non-measurable) disease as defined by RECIST 1.1, per investigator assessment.
6. Male or female 18 years and above, or age (or the legal age of adulthood per country-specific regulations)
7. ECOG performance status of 0 or 1.
8. Adequate hematologic function as follows:
a. Absolute neutrophil count (ANC) greater than or equal to 1.5 × 10 (to the power of 9)/L
b. Platelet count greater than or equal to 100 × 10 (to the power of 9)/L, not requiring transfusion support
c. Hemoglobin (Hgb) greater than or equal to 9 g/dL (participants with chronic anemia that is supported by intermittent red blood cell transfusions are eligible)
9. Adequate hepatic function, as defined by both:
a. Aspartate aminotransferase (AST) less than or equal to 3 × upper limit of normal (ULN), and alanine
aminotransferase (ALT) less than or equal to 3 × ULN. For participants with liver involvement, AST
and ALT less than or equal to 5 × ULN is acceptable.
b. Total bilirubin less than or equal 1.5 × ULN, or less than or equal to 3 × ULN for participants with Gilbert’s disease
10. Adequate renal function, as defined by estimated glomerular filtration rate (GFR) greater than 50 mL/min per local institutional standard method.
11. Left ventricular ejection fraction greater than or equal to 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA).
12. Females of childbearing potential must have a negative serum/plasma or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 3 days prior to expected date of C1D1. Females with false positive results can be enrolled if subsequent serum/plasma testing is negative.
13. Females of childbearing potential and males with a partner of childbearing potential must be willing to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab.
14. Females must agree to not donate oocytes starting at screening and throughout the study period, and for at least 14 months after the last dose of cisplatin, 6 months after the last dose of gemcitabine, 5 months after the last dose of zanidatamab, 4 months after the last dose of pembrolizumab, and 3 months after the last dose of durvalumab.
15. Males must agree to use condoms and not to donate sperm starting at screening and throughout the study period, and for at least 11 months after the last dose of cisplatin, 5 months after the last dose of zanidatamab, and 3 months after the last dose of
gemcitabine.
16. Participant has life expectancy of greater than 3 months, in the opinion of the investigator.
17. The participant must provide written informed consent. Participants who elect to be pre-screened for HER2 status must provide a separate written informed consent for collection, storage, and analysis of the tumor tissue.
ExclusionCriteria
Details
1. Prior treatment with a HER2-targeted agent, with the exception of participants who completed HER2-targeted treatment for breast cancer greater than 5 years prior to their diagnosis of BTC.
2. Prior treatment with check point inhibitors, other than durvalumab or pembrolizumab as part of the up to 2 cycles of systemic therapy allowed prior to expected date of C1D1 per Inclusion Criterion 3. Exclusionary checkpoint inhibitors include, but are not limited to
anti-PD-1, anti-PD-L1, anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 antibodies.
3. The following BTC histologic subtypes are excluded: small cell cancer, neuroendocrine tumors, lymphoma, sarcoma, mixed tumor histology, and mucinous cystic neoplasms detected in the biliary tract region.
4. Received radiotherapy within 2 weeks of expected date of C1D1.
5. Had major surgery within 4 weeks of expected date of C1D1.
6. Total lifetime load of anthracycline exceeding 360 mg/m2 doxorubicin or equivalent.
7. Use of systemic corticosteroids administered at doses equivalent to greater than 10 mg per day of prednisone within 2 weeks of expected date of C1D1. Topical, ocular, intra-articular, intranasal, and/or inhalation corticosteroids are permitted.
8. Brain metastases: Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of expected date of C1D1. Stable, treated brain metastases are allowed (defined as participants who are off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks at the time of screening).
9. Known history of or ongoing leptomeningeal disease (LMD). Participants will be eligible if LMD has been reported radiographically but is not suspected clinically by the investigator, and the participant does not have neurological symptoms of LMD.
10. Poorly controlled seizures in the judgment of the investigator.
11. Grade 2 or greater peripheral neuropathy.
12. Concurrent uncontrolled or active hepatobiliary disorders or untreated or ongoing complications after laparoscopic procedures or stent placement, including but not limited to active cholangitis, unresolved biliary obstruction, infected biloma, or abscess. Any
complications must be resolved at least 2 weeks prior to expected date of C1D1.
13. Prior or concurrent invasive malignancy whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen.
14. Severe chronic or active infections requiring systemic parenteral antibacterial, antifungal
or antiviral therapy; or any other potentially life-threatening viral or bacterial infection (participants on oral antibiotics must complete the planned course of treatment prior to expected date of C1D1).
15. Active hepatitis, including the following:
a. Acute or chronic hepatitis B (Exception: Participants who are hepatitis B surface
antigen [HBsAg] positive are eligible if they have hepatitis B virus (HBV) DNA less than 500 IU/mL or 2,500 copies/mL). Note: Participants with detectable HBsAg or detectable HBV DNA should be managed per institutional or local standards.
Participants beginning antiviral agents at screening should be treated for greater than 2 weeks prior to expected date of C1D1.
b. Infection with hepatitis C (Exceptions:
[i] Participants who have no history of curative viral treatment and are documented to be viral load negative are eligible;
[ii] Participants who have completed curative viral therapy greater than or equal to 12 weeks prior to
expected date of C1D1, and viral load is negative are eligible.)
16. Infection with human immunodeficiency virus (HIV)-1 or HIV-2. (Exception: Participants with well-controlled HIV [ie, CD4 greater than 350/mm3
and undetectable viral load] are eligible.)
17. Active tuberculosis.
18. History of allogeneic organ transplantation.
19. Active or prior autoimmune inflammatory conditions with the exception of:
a. Vitiligo or alopecia
b. Hypothyroidism stable on thyroid replacement
c. Chronic skin conditions that do not require systemic therapy
d. Celiac disease controlled by diet alone
e. Without active disease in the last 5 years after consultation with the treating physician
20. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant
proteins or excipients in the drug formulation of any of the agents in the trial (cisplatin,
gemcitabine, the selected PD-1/L1 inhibitor, or zanidatamab).
21. Known hypersensitivity to any components of the combination therapy.
22. Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with the exception of alopecia.
23. QTc Fridericia (QTcF) greater than 470 ms. Note: For participants with longer QTcF on initial
electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine eligibility.
24. Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy,
uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF).
Participants with known myocardial infarction or unstable angina within 6 months prior
to expected date of C1D1 are also excluded. Previous anticancer therapy-related CHF
must have been less than or equal to Grade 1 at the time of occurrence and must have completely resolved.
25. History of interstitial lung disease or non-infectious pneumonitis.
26. History of active primary immunodeficiency.
27. Participation in another clinical trial with an investigational medicinal product within the
last 3 months.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
Progression-free survival (PFS) per the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) in the immunohistochemistry (IHC) 3+ subgroup
The time from the date of randomization to the date of documented disease progression (per RECIST 1.1) per investigator, or death from any cause
Secondary Outcome
Outcome
TimePoints
a) Overall survival (OS) in the IHC 3+ subgroup
b) PFS per RECIST 1.1 in the overall population
c) OS in the overall population
The time from randomization to death due to any cause.
Confirmed objective response rate (cORR) per RECIST 1.1
The time from the date of randomization to the date of documented disease progression (per RECIST 1.1) per investigator, or death from any cause.
Duration of response (DOR) per RECIST 1.1
The time from the first objective response (CR or PR) that is subsequently confirmed to documented PD per RECIST 1.1 or death from any cause.
Frequency, severity, seriousness, and relatedness of treatment-emergent adverse events (AEs)
From the start of dosing of study drug to 30 days after the last dose of study drug.
Serum concentrations of zanidatamab as a function of time post-dosing
The time from the date of randomization pre dose to the End of Treatment date.
Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable, to zanidatamab
The time from the date of randomization pre dose to the End of Treatment date. If positive at EOT, retests to be performed approximately 3-month intervals until the ADA levels return to baseline or stabilize at a level acceptable to the investigator and sponsor.
Time to definitive deterioration (TDD) from baseline in the IHC 3+ subgroup in patient-reported PF domain score as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire – Core 30 (QLQ-C30)
Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death
TDD from baseline in the overall population in patient-reported PF domain score as measured by the EORTC QLQ-C30
Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.
TDD from baseline in IHC 3+ subgroup in patient-reported symptoms scores as measured by EORTC Quality of Life Questionnaire – Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21) (Pain, Jaundice, Abdominal Pain, and Pruritis)
Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.
TDD from baseline in the overall population in patient-reported symptoms scores as measured by the EORTC QLQ-BIL21 (Pain, Jaundice, Abdominal Pain, and Pruritis)
Time from randomization to the first confirmed clinical meaningful deterioration (ie, decrease in domain scores of ≥ 10 points from baseline) or death.
Target Sample Size
Total Sample Size="286" Sample Size from India="13" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is an open-label, randomized, multicenter, phase 3 study to investigate the efficacy and safety of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor (physician’s choice of either durvalumab or pembrolizumab, where approved under local regulations) as first-line treatment for participants with HER2-positive, locally advanced unresectable or metastatic BTC, including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC). Participants are allowed to receive up to 2 cycles of systemic therapy consisting of gemcitabine with a platinum agent (eg, CisGem or gemcitabine in combination with oxaliplatin [GEMOX]) with or without a PD-1/L1 inhibitor (physician’s choice of either durvalumab or pembrolizumab, where approved under local regulations) prior to randomization for their advanced or metastatic disease.
Upon enrollment, participants will be randomized in a 1:1 ratio to 1 of 2 arms:
Arm A (experimental arm): Zanidatamab plus CisGem (for up to 8 cycles) with or without a PD-1/L1 inhibitor
Arm B (control arm): CisGem (for up to 8 cycles) with or without a PD-1/L1 inhibitor
Study treatment may continue beyond the up to 8 cycles total of CisGem until investigator-assessed disease progression (per RECIST 1.1), although maximum treatment durations for the selected PD-1/L1 inhibitor (if given) per the locally approved package insert will apply.
Primary Objective: Compare the efficacy of zanidatamab plus CisGem with or without a PD-1/L1 inhibitor versus CisGem with or without a PD-1/L1 inhibitor in participants with advanced or metastatic HER2-positive BTC.