Subjects with HER2-amplified, inoperable and advanced or metastatic Biliary Tract Cancer (BTC), ZW25 in Subjects with Advanced or Metastatic HER2-Amplified Biliary Tract Cancer
Conditions
Sponsors
Zymeworks Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Histologically- or cytologically-confirmed BTC, including ICC, ECC or GBC. 2.Locally advanced or metastatic BTC and not eligible for curative resection, transplantation, or ablative therapies. 3.Received at least 1 prior regimen of systemic therapy for advanced disease, including 1 gemcitabine containing regimen, and experienced disease progression after or developed intolerance to the most recent prior therapy. For subjects who have received prior adjuvant or neoadjuvant treatment, if progression has occurred <6 months from completion of the adjuvant or neoadjuvant therapy, this regimen will be considered as 1 prior line of therapy for advanced disease. 4.Subjects must have at least 1 measurable target lesion by RECIST 1.1. Subjects who have received prior local therapy (embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of the treatment field or is within the treatment field and has shown =20% growth in size since post-treatment assessments. 5.Subjects must test positive for HER2 amplification by in situ hybridization (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. 6.Male or female, =18 years of age (or the legal age of adulthood per country-specific regulations). 7.Eastern Cooperative Oncology Group (ECOG) performance status (PS) =1. 8.Adequate hematologic function, defined as absolute neutrophil count (ANC) =1.5 x 109/L, platelet count =75 x 109/L (not requiring transfusion support), and hemoglobin (Hgb) =9 g/dL (subjects with chronic anemia that is supported by intermittent red blood cell [RBC] transfusions are eligible). 9.Liver function: serum bilirubin =1.5 x the upper limit of normal (ULN) or =3 x ULN for subjects with Gilbert’s disease, aspartate aminotransferase (AST) =3 x ULN, and alanine aminotransferase (ALT) =3 x ULN. For subjects with liver involvement, AST and ALT =5.0 x ULN is acceptable. 10.Adequate cardiac function, as defined by left ventricular ejection fraction (LVEF) =50%. 11.Kidney function: glomerular filtration rate (GFR) =30 mL/min as estimated by the Modification of Diet in Renal Disease (MDRD) equation . 12.Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (ß hCG) pregnancy test result within 3 days prior to the first dose of ZW25. Females with false positive urine test results can be enrolled if subsequent serum testing is negative . 13.For female subjects who are not surgically sterile or post-menopausal and for male subjects with a partner of child-bearing potential, willingness for the couple to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 12 months after the last dose of ZW25. These include, but are not limited to, established use of oral, implanted, or injected hormonal contraceptives or placement of intra-uterine device or intra-uterine system 14.Male subjects must agree to not donate sperm and female subjects must agree to not donate oocytes starting at screening and throughout the study period, and for at least 12 months after the last dose of ZW25 15.The subject or subject’s legally acceptable representative must provide written i
Exclusion criteria
Exclusion criteria: 1.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. 2.Had major surgery within 4 weeks of the first dose of ZW25. 3.Prior treatment with HER2-targeted agents. 4.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). 5.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. 6.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, biloma or abscess. Any complications should be resolved within 2 weeks prior to the first dose of ZW25. 7.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. 8.Significant acute infection or chronic infections that have not stabilized with treatment. 9.Active hepatitis, including the following: a.Acute or chronic hepatitis B (Exception: subjects who are hepatitis B surface antigen positive are eligible if they have HBV DNA less than 500 IU/mL) b.Infection with hepatitis C (Exception [i] subjects who have no history of curative viral treatment and are documented to be viral load negative are eligible; [ii] subjects who have completed curative viral therapy =12 weeks prior to enrollment, and viral load is negative are eligible) 10.Infection with human immunodeficiency virus (HIV)-1 or HIV-2 (Exception: subjects with well-controlled HIV [e.g., CD4 >350/mm3 and undetectable viral load] are eligible). 11.Females who are breastfeeding or pregnant, and females and males planning a pregnancy. 12.History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of ZW25. 13.Treatment with anthracyclines within 90 days before first dose of ZW25 and/or total lifetime load exceeding 360 mg/m2 Adriamycin® or equivalent. 14.Use of corticosteroids administered at doses equivalent to >15 mg per day of prednisone within 2 weeks of first ZW25 dosing unless otherwise approved by the medical monitor. Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids are permitted. 15.Ongoing, clinically significant toxicity (Grade 2 or higher) associated with prior cancer therapies, with the following exceptions: a.Alopecia b.Congestive heart failure (CHF), which must have been = Grade 1 at the time of occurrence and which must have completely resolved 16.QTc Fridericia (QTcF) >470 ms. 17.History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic CHF. 18.Acute or chronic un
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the anti-tumor activity of ZW25 monotherapy in subjects with advanced or metastatic HER2-amplified biliary tract cancers (BTC) ;Secondary Objective: To further evaluate the anti-tumor activity of ZW25 monotherapy in subjects with advanced or metastatic HER2-amplified BTC To evaluate the safety and tolerability of ZW25 monotherapy in subjects with advanced or metastatic HER2-amplified BTC To evaluate the pharmacokinetics (PK) of ZW25 To evaluate the immunogenicity of ZW25 Exploratory: To evaluate the anti-tumor activity of ZW25 monotherapy by BTC anatomical subtype To evaluate the utility of potential serum and tumor biomarkers To evaluate the effect of ZW25 treatment on quality of life (QOL) To evaluate the effect of ZW25 treatment on disease-related pain and opioid use for pain control ;Primary end point(s): Confirmed objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), assessed by independent central review (ICR);Timepoint(s) of evaluation of this end point: Disease response will be assessed according to RECIST 1.1 by ICR; responses are to be confirmed 4 weeks following initial documentation of objective response by the investigator. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Duration of response (DOR) by RECIST 1.1 assessed by ICR Proportion of subjects with a DOR =16 weeks by RECIST 1.1 assessed by ICR Disease control rate (DCR) by RECIST 1.1 assessed by ICR Progression-free survival (PFS) by RECIST 1.1 assessed by ICR ORR by RECIST 1.1 assessed by investigator DOR by RECIST 1.1 assessed by investigator Proportion of subjects with a DOR =16 weeks by RECIST 1.1 assessed by investigator DCR by RECIST 1.1 assessed by investigator PFS by RECIST 1.1 assessed by investigator Overall survival (OS) Frequency and severity of adverse events (AEs) Frequency of serious adverse events (SAEs) and deaths Frequency and severity of clinical laboratory abnormalities Frequency of dose modifications of ZW25 Serum concentrations of ZW25 as a function of time post-dosing PK parameters for single (first) dose and multiple doses Frequency, duration, and time of onset of anti-drug antibodies (ADA) and neutralizing antibodies, if applicable Exploratory Confirmed ORR and DOR by RECIST 1.1 and BTC anatomical subtype, as assessed by ICR Potential biomarkers predictive of response Patient-reported outcomes (PRO) per the European Quality of Life 5-Dimensions 5-level questionnaire (EQ-5D-5L) Change from baseline in opioid use Change from baseline in Brief Pain Inventory (BPI) domain scores ;Timepoint(s) of evaluation of this end point: Disease response (DOR,DCR,ORR, PFS) assessed according to RECIST 1.1 by PI. Responses 4 weeks following initial documentation of objective response by PI. Safety will be monitored by recording the type, frequency, and severity of AEs as well as SAEs and deaths. ZW25 Serum concentrations as a function of time post-dosing ADA on day 1 & 15 Cycle 1 & 2, and day 1 Cycle 4 and every even cycle thereafter Extensive PK day 1, 2, 5 & 15 Cycle 1, days 1 & 15 Cycle 2, day 1 of every even cycle thereafter, and EoT with less than 6 treatment months Sparse PK day 1 an&d 15 Cycle 1, and day | — |
Countries
Canada, Chile, China, France, Italy, Korea, Republic of, Spain, United Kingdom, United States
Contacts
Public ContactDenis Ushakov
PPD
Outcome results
None listed