HER2-amplified Biliary Tract Cancers
Conditions
Keywords
HER2, Bispecific antibody, Biparatopic antibody, Immunotherapy, Biliary Tract Cancer, Intra-hepatic cholangiocarcinoma, Extra-hepatic cholangiocarcinoma, Gallbladder cancer, JZP598
Brief summary
This multicenter, open-label, single-arm trial will evaluate the anti-tumor activity of ZW25 (zanidatamab) monotherapy in subjects with human epidermal growth factor receptor 2 (HER2)-amplified, inoperable and advanced or metastatic biliary tract cancer (BTC), including intra-hepatic cholangiocarcinoma (ICC), extra-hepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC).
Interventions
Administered intravenously
Sponsors
BeiGene
Jazz Pharmaceuticals Ireland Limited
BeOne Medicines LTD
Jazz Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single-arm, open-label, multi-cohort, multicenter study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically- or cytologically-confirmed BTC, including ICC, ECC or GBC. * Locally advanced or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies. * Received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease, and experienced disease progression after or developed intolerance to the most recent prior therapy. For subjects who received gemcitabine in prior adjuvant or neoadjuvant treatment, if progression occurred \< 6 months from the latter of primary surgical resection or completion of gemcitabine-containing adjuvant therapy, they will be considered as having received 1 prior line of therapy for advanced disease. * Subjects must test positive for HER2 amplification by ISH-assay at a central laboratory on a new biopsy or archival tissue. Note that fine needle aspirates (FNAs; cytology samples) and biopsies from sites of bone metastases are not acceptable. Testing may occur at any time after diagnosis of advanced or metastatic disease and before study enrollment. * Male or female, ≥18 years of age (or the legal age of adulthood per country-specific regulations). * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. * Adequate organ function. * Adequate cardiac function, as defined by left ventricular ejection fraction ≥ 50%.
Exclusion criteria
* Received systemic anti-cancer therapy within 3 weeks of the first dose of ZW25. Received radiotherapy within 2 weeks of the first dose of ZW25. * Prior treatment with HER2-targeted agents. * Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as subjects 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). * Known leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline MRI, but is not suspected clinically by the investigator, the subject must be free of neurological symptoms of LMD. * 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 more than 2 weeks prior to the first dose of ZW25. * Prior or concurrent 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. * Active hepatitis * Infection with human immunodeficiency virus (HIV)-1 or HIV-2 * QTc Fridericia (QTcF) \> 470 ms. * History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease. * Acute or chronic uncontrolled pancreatitis or Child-Pugh Class C liver disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) by Independent Central Review (ICR) | Up to 34 months | Number of participants who achieved a confirmed best overall response (BOR) of either complete response (CR) or partial response (PR) during treatment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is defined as a disappearance of all target and non-target lesions and partial response (PR) is defined as at least a 30% decrease in the sum of diameters of all target lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DOR ≥ 16 Weeks by ICR | 24 weeks, up to 45 months | Proportion of subjects with a DOR ≥ 16 weeks per RECIST 1.1 |
| Disease Control Rate (DCR) by ICR | Up to 45 months | Number of subjects who achieved a best overall response of stable disease (SD), non-CR/non-PD, or confirmed CR or PR per RECIST 1.1 |
| Progression-free Survival (PFS) by ICR | Up to 45 months | The time from the first dose of study treatment to the date of documented disease progression (per RECIST 1.1), or death from any cause |
| ORR by Investigator Assessment | Up to 45 months | Number of subjects who achieved a confirmed BOR of either CR or PR during treatment per RECIST 1.1 |
| DOR by Investigator Assessment | Up to 45 months | The time from the first confirmed objective response (CR or PR) to documented progressive disease (PD) per RECIST 1.1, or death from any cause |
| DOR ≥ 16 Weeks by Investigator Assessment | 24 weeks, up to 45 months | Proportion of subjects with a DOR ≥ 16 weeks per RECIST 1.1 |
| DCR by Investigator Assessment | Up to 45 months | Number of subjects who achieved a best overall response of stable disease (SD), non-CR/non-PD, or confirmed CR or PR per RECIST 1.1 |
| Duration of Response (DOR) by ICR | Up to 45 months | The time from the first confirmed objective response (CR or PR) to documented progressive disease (PD) per RECIST 1.1, or death from any cause |
| Overall Survival | Up to 45 months | The time from the first dose of study treatment until the date of death from any cause |
| Incidence of Adverse Events (AEs) | Up to 45 months | Number of subjects who experienced AEs or serious adverse events |
| Incidence of Laboratory Abnormalities | Up to 45 months | Number of subjects who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 |
| Maximum Serum Concentration of ZW25 | Pre-dose, end of infusion, 2, 4, 8, 24 and 96 hours post dose | — |
| Trough Concentration of ZW25 | Pre-dose, end of infusion, 2, 4, 8, 24 and 96 hours post dose | Minimum observed serum concentration (trough) |
| Incidence of Anti-drug Antibodies (ADAs) | Up to 45 months | Number of subjects who develop ADAs |
| PFS by Investigator Assessment | Up to 45 months | The time from the first dose of study treatment to the date of documented disease progression (per RECIST 1.1), or death from any cause |
Countries
Canada, Chile, China, France, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 87 participants who met all eligibility criteria were enrolled and received treatment.
Pre-assignment details
Participants must have received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and experienced disease progression after or developed intolerance to the most recent prior therapy.
Participants by arm
| Arm | Count |
|---|---|
| Cohort I Participants with advanced or metastatic biliary tract cancer with HER2 amplification by in situ hybridization (ISH) and HER2 overexpression by immunohistochemistry (IHC) which includes IHC 2+ or 3+ | 80 |
| Cohort II Participants with advanced or metastatic biliary tract cancer with HER2 amplification by ISH and HER2 IHC 0 or 1+. | 7 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 60 | 6 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Study terminated by sponsor | 5 | 0 |
| Overall Study | Transitioned to Named Patient Supply (NPS) program | 5 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 1 |
Baseline characteristics
| Characteristic | Cohort I | Cohort II | Total |
|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 9.56 | 65.4 years STANDARD_DEVIATION 8.75 | 62.7 years STANDARD_DEVIATION 9.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 6 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 52 Participants | 5 Participants | 57 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 23 Participants | 2 Participants | 25 Participants |
| Sex: Female, Male Female | 45 Participants | 2 Participants | 47 Participants |
| Sex: Female, Male Male | 35 Participants | 5 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 60 / 80 | 6 / 7 |
| other Total, other adverse events | 78 / 80 | 5 / 7 |
| serious Total, serious adverse events | 43 / 80 | 3 / 7 |
Outcome results
Primary
Confirmed Objective Response Rate (ORR) by Independent Central Review (ICR)
Number of participants who achieved a confirmed best overall response (BOR) of either complete response (CR) or partial response (PR) during treatment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete response (CR) is defined as a disappearance of all target and non-target lesions and partial response (PR) is defined as at least a 30% decrease in the sum of diameters of all target lesions.
Time frame: Up to 34 months
Population: Assessed in participants with available data in the Efficacy Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | Confirmed Objective Response Rate (ORR) by Independent Central Review (ICR) | 33 Participants |
| Cohort II | Confirmed Objective Response Rate (ORR) by Independent Central Review (ICR) | 0 Participants |
Secondary
DCR by Investigator Assessment
Number of subjects who achieved a best overall response of stable disease (SD), non-CR/non-PD, or confirmed CR or PR per RECIST 1.1
Time frame: Up to 45 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | DCR by Investigator Assessment | 54 Participants |
| Cohort II | DCR by Investigator Assessment | 1 Participants |
Secondary
Disease Control Rate (DCR) by ICR
Number of subjects who achieved a best overall response of stable disease (SD), non-CR/non-PD, or confirmed CR or PR per RECIST 1.1
Time frame: Up to 45 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | Disease Control Rate (DCR) by ICR | 55 Participants |
| Cohort II | Disease Control Rate (DCR) by ICR | 3 Participants |
Secondary
DOR ≥ 16 Weeks by ICR
Proportion of subjects with a DOR ≥ 16 weeks per RECIST 1.1
Time frame: 24 weeks, up to 45 months
Population: Only participants with a response (a confirmed Complete Response (CR) or confirmed Partial Response (PR)), as evaluated by ICR, were evaluated for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | DOR ≥ 16 Weeks by ICR | 28 Participants |
Secondary
DOR ≥ 16 Weeks by Investigator Assessment
Proportion of subjects with a DOR ≥ 16 weeks per RECIST 1.1
Time frame: 24 weeks, up to 45 months
Population: Only participants with a response (a confirmed Complete Response (CR) or confirmed Partial Response (PR)) as per investigator assessment, were evaluated for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | DOR ≥ 16 Weeks by Investigator Assessment | 31 Participants |
Secondary
DOR by Investigator Assessment
The time from the first confirmed objective response (CR or PR) to documented progressive disease (PD) per RECIST 1.1, or death from any cause
Time frame: Up to 45 months
Population: Only participants with a response (a confirmed Complete Response (CR) or confirmed Partial Response (PR)) as per investigator assessment, were evaluated for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | DOR by Investigator Assessment | 11.10 months |
Secondary
Duration of Response (DOR) by ICR
The time from the first confirmed objective response (CR or PR) to documented progressive disease (PD) per RECIST 1.1, or death from any cause
Time frame: Up to 45 months
Population: Only participants with a response (a confirmed Complete Response (CR) or confirmed Partial Response (PR)), as evaluated by ICR, were evaluated for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | Duration of Response (DOR) by ICR | 14.92 months |
Secondary
Incidence of Adverse Events (AEs)
Number of subjects who experienced AEs or serious adverse events
Time frame: Up to 45 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort I | Incidence of Adverse Events (AEs) | Zanidatamab related TEAE resulting in treatment discontinuation | 2 Participants |
| Cohort I | Incidence of Adverse Events (AEs) | Any Treatment Emergent Adverse Event (TEAE) | 78 Participants |
| Cohort I | Incidence of Adverse Events (AEs) | Zanidatamab related TEAE | 61 Participants |
| Cohort I | Incidence of Adverse Events (AEs) | Any Treatment Emergent Serious Adverse Event | 43 Participants |
| Cohort I | Incidence of Adverse Events (AEs) | Zanidatamab related serious TEAE | 8 Participants |
| Cohort II | Incidence of Adverse Events (AEs) | Zanidatamab related serious TEAE | 0 Participants |
| Cohort II | Incidence of Adverse Events (AEs) | Any Treatment Emergent Serious Adverse Event | 3 Participants |
| Cohort II | Incidence of Adverse Events (AEs) | Any Treatment Emergent Adverse Event (TEAE) | 6 Participants |
| Cohort II | Incidence of Adverse Events (AEs) | Zanidatamab related TEAE resulting in treatment discontinuation | 0 Participants |
| Cohort II | Incidence of Adverse Events (AEs) | Zanidatamab related TEAE | 2 Participants |
Secondary
Incidence of Anti-drug Antibodies (ADAs)
Number of subjects who develop ADAs
Time frame: Up to 45 months
Population: All subjects who received any amount of zanidatamab and have both baseline anti-drug antibodies (ADA) and at least 1 post baseline ADA results available were included in this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | Incidence of Anti-drug Antibodies (ADAs) | 1 Participants |
| Cohort II | Incidence of Anti-drug Antibodies (ADAs) | 0 Participants |
Secondary
Incidence of Laboratory Abnormalities
Number of subjects who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology or chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
Time frame: Up to 45 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | Incidence of Laboratory Abnormalities | 37 Participants |
| Cohort II | Incidence of Laboratory Abnormalities | 7 Participants |
Secondary
Maximum Serum Concentration of ZW25
Time frame: Pre-dose, end of infusion, 2, 4, 8, 24 and 96 hours post dose
Population: All subjects who received any amount of zanidatamab and have at least 1 post-baseline PK assessment were included in this outcome
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I | Maximum Serum Concentration of ZW25 | 457.6 micrograms per milliliter | Geometric Coefficient of Variation 15.44 |
| Cohort II | Maximum Serum Concentration of ZW25 | 443.6 micrograms per milliliter | Geometric Coefficient of Variation 24.1 |
Secondary
ORR by Investigator Assessment
Number of subjects who achieved a confirmed BOR of either CR or PR during treatment per RECIST 1.1
Time frame: Up to 45 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort I | ORR by Investigator Assessment | 34 Participants |
| Cohort II | ORR by Investigator Assessment | 0 Participants |
Secondary
Overall Survival
The time from the first dose of study treatment until the date of death from any cause
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | Overall Survival | 15.54 months |
| Cohort II | Overall Survival | 5.52 months |
Secondary
PFS by Investigator Assessment
The time from the first dose of study treatment to the date of documented disease progression (per RECIST 1.1), or death from any cause
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | PFS by Investigator Assessment | 5.37 months |
| Cohort II | PFS by Investigator Assessment | 1.77 months |
Secondary
Progression-free Survival (PFS) by ICR
The time from the first dose of study treatment to the date of documented disease progression (per RECIST 1.1), or death from any cause
Time frame: Up to 45 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort I | Progression-free Survival (PFS) by ICR | 5.49 months |
| Cohort II | Progression-free Survival (PFS) by ICR | 1.87 months |
Secondary
Trough Concentration of ZW25
Minimum observed serum concentration (trough)
Time frame: Pre-dose, end of infusion, 2, 4, 8, 24 and 96 hours post dose
Population: All subjects who received any amount of zanidatamab and have at least 1 post-baseline pharmacokinetic (PK) assessment were included in this outcome.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort I | Trough Concentration of ZW25 | 73.4 micrograms per milliliter | Geometric Coefficient of Variation 42.1 |
| Cohort II | Trough Concentration of ZW25 | 46.5 micrograms per milliliter | Geometric Coefficient of Variation 18.66 |