Clinical trial NCT03929666: A Safety and Efficacy Study of ZW25 (Zanidatamab) Plus Combination Chemotherapy in HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer
Official title: Phase 2 Study of ZW25 Plus First-line Combination Chemotherapy in HER2-Expressing Gastrointestinal (GI) Cancers, Including Gastroesophageal Adenocarcinoma (GEA), Biliary Tract Cancer (BTC), and Colorectal Cancer (CRC)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer
Keywords: HER2
Bispecific antibody
Biparatopic antibody
Immunotherapy
Gastric cancers
Esophageal cancers
Gastroesophageal junction (GEJ) cancers
Chemotherapy
FP
mFOLFOX6
Capecitabine
Cisplatin
5-FU
Leucovorin (folinic acid)
Oxaliplatin
XELOX
Gastrointestinal cancers
Gastroesophageal adenocarcinoma
Biliary tract cancer
Colorectal cancer
Intrahepatic cholangiocarcinoma
Extrahepatic cholangiocarcinoma
Gall bladder
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2019-04-29
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multicenter, global, Phase 2, open-label, 2-part, first-line study to investigate the safety, tolerability, and anti-tumor activity of ZW25 (zanidatamab) plus standard first-line combination chemotherapy regimens for selected gastrointestinal (GI) cancers. Eligible patients include those with unresectable, locally advanced, recurrent or metastatic HER2-expressing gastroesophageal adenocarcinoma (GEA), biliary tract cancer (BTC), or colorectal cancer (CRC).

Detailed description: Part 1 of the study will first evaluate the safety and tolerability of ZW25 plus standard first-line combination chemotherapy (XELOX, FP, or mFOLFOX6 for GEA; mFOLFOX6 with or without bevacizumab for CRC; and CisGem for BTC) and will confirm the recommended dosage (RD) of ZW25 when administered in combination with each of these multi-agent chemotherapy regimens. Then, Part 2 of the study will evaluate the anti-tumor activity of ZW25 plus combination chemotherapy in HER2-expressing GEA, BTC, and CRC.

Eligibility criteria: Inclusion:

* Disease diagnosis:

  * Part 1:
  * GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA (IHC 3+ or 2+ with or without gene amplification based upon local assessment or central assessment)
  * BTC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing BTC (including intrahepatic cholangiocarcinoma \[ICC\], extrahepatic cholangiocarcinoma \[ECC\], or gallbladder cancer \[GBC\]) (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification, based upon central assessment)
  * CRC: Unresectable, locally advanced, recurrent or metastatic HER2-expressing CRC (IHC 3+ with or without gene amplification; or IHC 0, 1+ or 2+ with gene amplification, based upon central assessment). Patients will be required to be extended RAS (KRAS and NRAS) and BRAF wild-type based upon central assessment.
  * Part 2:
  * GEA: Unresectable, locally advanced, recurrent or metastatic HER2-expressing GEA (IHC 3+, or IHC 2+ and FISH+ by central assessment)
  * BTC: Same as Part 1
  * CRC: Same as Part 1
* Tumor measurements as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1:

  * Part 1: Measurable or non-measurable disease
  * Part 2: Measurable disease
* An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
* Adequate organ function
* Adequate cardiac left ventricular function, as defined by a LVEF \>/= institutional standard of normal

Exclusion:

* Prior treatment with a HER2-targeted agent
* Prior systemic anti-cancer therapy (including investigational products) except prior adjuvant/neoadjuvant therapy, which must be completed at least 6 months prior to first study treatment dosing. For subjects with BTC and CRC the following additional exceptions apply:

  * BTC: patients may have started therapy for advanced disease but may not have received more than one cycle of any standard gemcitabine-based chemotherapy regimen.
  * CRC: patients may have started therapy for advanced disease but may not have received more than one cycle of 5-FU-based chemotherapy (\< 1 month of therapy).
* Patients with certain contraindications to bevacizumab cannot be enrolled on the mFOLFOX6-2 with bevacizumab arm.
* Palliative radiotherapy is allowed if completed at least 2 weeks prior to first study treatment dosing
* Untreated known brain metastases (patients with treated brain metastases who are off steroids, off antiseizure medications, and stable for at least 1 month at the time of screening are eligible)
* Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF). Patients with known myocardial infarction or unstable angina within 6 months prior to randomization are also excluded.
* QTc Fridericia (QTcF) \> 470 ms. For patients with longer QTcF on initial electrocardiogram (ECG), follow-up ECG may be performed in triplicate to determine eligibility
* Peripheral neuropathy \> Grade 1 per NCI-CTCAE v5.0
* Clinically significant interstitial lung disease
* Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
* Active hepatitis B or hepatitis C infection or infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well controlled HIV \[e.g., CD4 \> 350/mm3 and undetectable viral load\] are eligible)

Primary outcomes:
measure: Incidence of dose-limiting toxicities (DLTs) (Part 1)
timeFrame: Up to 6 weeks
measure: Incidence of adverse events (Part 1)
timeFrame: Up to 11 months
measure: Incidence of lab abnormalities (Part 1)
timeFrame: Up to 11 months
measure: Objective response rate (ORR) (Part 2)
timeFrame: Up to 10 months
Secondary outcomes:
measure: Objective response rate (ORR) (Part 1)
timeFrame: Up to 10 months
measure: Disease control rate (Parts 1 and 2)
timeFrame: Up to 10 months
measure: Duration of response (Parts 1 and 2)
timeFrame: Up to 2 years
measure: Clinical benefit rate (Parts 1 and 2)
timeFrame: Up to 2 years
measure: Progression-free survival (Parts 1 and 2)
timeFrame: Up to 2 years
measure: Overall survival (Parts 1 and 2)
timeFrame: Up to 2 years
measure: Incidence of anti-drug antibodies (ADAs) (Parts 1 and 2)
timeFrame: Up to 11 months
measure: End of infusion concentration of ZW25 (Parts 1 and 2)
timeFrame: Up to 11 months
measure: Maximum serum concentration of ZW25 (Parts 1 and 2)
timeFrame: Up to 11 months
measure: Trough concentration of ZW25 (Parts 1 and 2)
timeFrame: Up to 11 months
measure: Incidence of adverse events (Part 2)
timeFrame: Up to 11 months
measure: Incidence of lab abnormalities (Part 2)
timeFrame: Up to 11 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Grand Rapids
country: United States
facility: The Cancer and Hematology Centers
state: Michigan
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Santiago
country: Chile
facility: Centro de Investigacion Clinica SAGA
city: Santiago
country: Chile
facility: Icegclinic Research & Care
city: Santiago
country: Chile
facility: CECIM Biocinetic
city: Santiago
country: Chile
facility: Centro Internacional de Estudios Clínicos
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Pusan National University
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
Study officials:
affiliation: Jazz Pharmaceuticals
name: Phillip Garfin, MD, PhD
role: STUDY_DIRECTOR
References: