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

Conditions: HER2-expressing Gastrointestinal Cancers, Including Gastroesophageal Adenocarcinoma, Biliary Tract Cancer, and Colorectal Cancer

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).

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)

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