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ZW25 plus fluorouracil (5-FU) and cisplatin

ZW25 plus 5-FU, leucovorin, and oxaliplatin

ZW25 plus 5-FU, leucovorin, oxaliplatin, and bevacizumab

* Part 1: administered IV at dose levels and schedules determined by the Safety Monitoring Committee (SMC)
* Part 2: RD identified in Part 1

ZW25 (Zanidatamab)

Phillip Garfin, MD, PhD

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.

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

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)

Number of participants who experienced a DLT. DLTs include adverse events considered to be related to study treatment, including the evaluated dose level of ZW25, any component or combination of the components of a chemotherapy regimen, or the combination of ZW25 plus a chemotherapy regimen.

Number of participants who experienced an adverse event

Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology and chemistry. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Number of participants who achieved a best response of either complete response (CR) or partial response (PR) during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Number of participants who achieved a best response of either CR or PR during treatment per RECIST 1.1

Number of participants who achieved a best response of CR, PR, or stable disease (SD) during treatment per RECIST 1.1

Median duration of response (in months) and range (minimum, maximum)

Number of participants with SD for ≥ 24 weeks or a confirmed, best overall response of CR or PR per RECIST 1.1

Median progression-free survival (in months) and range (minimum, maximum)

Median overall survival (in months) and range (minimum, maximum)

Number of participants who experienced a maximum severity of Grade 3 or higher post-baseline laboratory abnormality, including either hematology and chemistry. Grades are defined using National Cancer Institute's CTCAE, version 5.0.

Jazz Pharmaceuticals

Symptoms and General Pathology

Recurrence

Head and Neck Neoplasms

Pembrolizumab

Immune Checkpoint Inhibitors

1-week lead in for PD-L1 CAR NK cell monotherapy followed by combination therapy of Pembrolizumab plus N-803

N-803 will be given via subcutaneous injection at a dose of 15 mcg/kg every 4 weeks (1 week after starting treatment with the PDL-1 CAR-NK cells).

N-803

Pembrolizumab 400 mg will be administered as a 30-minute IV infusion every 6 weeks. Pembrolizumab will be administered on the same day as the PD-L1 CAR-NK cells.

PD-L1 CAR NK cells (2x109) will be administered by IV infusion over approximately 30 minutes every week. After the week 6 treatment, these cells will be given every 2 weeks.

PD-L1 t-haNK

NCI Medical Oncology Referral Office

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Jason M Redman, M.D.

Background:

Immunotherapy is a powerful tool in the fight against cancer. It uses the body s own immune system to fight the cancer. Unfortunately, cancer cells can find ways to escape from destruction by the body s immune system, even when immunotherapy is used.

Natural killer (NK) cells are an important part of the body s immune system and can help fight cancer. In combination with immunotherapy, researchers are using engineered NK cells that recognize and kill cancer cells trying to escape destruction by the immune system.

Objective:

To test the effectiveness of irradiated PD-L1 CAR-NK cells, combined with pembrolizumab and N-803, in people with advanced forms of gastric or head and neck cancer.

Eligibility:

Adults ages 18 and older with advanced gastric or head and neck cancer who have already had standard cancer treatment.

Design:

Participants will be screened with a medical history and physical exam. Their symptoms and ability to do normal activities will be assessed. They will have blood and urine tests. They will have imaging scans of the chest, abdomen, and pelvis.

Participants will get PD-L1 CAR-NK cells by intravenous (IV) infusion. They will get the cells once a week for 6 weeks. Then they will get the cells once every 2 weeks. Before each infusion, an IV catheter will be placed in a large arm vein for infusion of these treatments.

Participants will get pembrolizumab by IV every 6 weeks. They will get N-803 under the skin every 4 weeks.

Participants will get the study drugs for up to 2 years. They will have study visits every 1-2 weeks during treatment. They will have a safety visit 28 days after treatment ends.

After treatment ends, participants will be contacted for follow-up every 2 months for a year. Then they will be contacted every 6 months. They will have tumor scans every 6-12 weeks until their cancer gets worse.

Background:

* Natural killer (NK) cells are an important component of an anti-tumor immune response.
* PD-L1 CAR-NK (PD-L1 t-haNKs) is an off the shelf, irradiated human, allogeneic, NK cell line that is frozen, shipped, thawed and then infused.
* PD-L1 CAR-NK cells have been engineered to have 3 adaptive modifications:

  * Expression of a chimeric antigen receptor (CAR) targeting the tumor-associated antigen PD-L1
  * Expression of the high-affinity variant (158V) of the human Fc \>= receptor (FcyRIIIa/CD16a)
  * An endoplasmic reticulum-retained version of the human interleukin-2 (ERIL-2) cytokine.
* To improve the safety profile, PD-L1 CAR-NK cells are irradiated, thus inhibiting proliferation while maintaining cytotoxicity.
* Irradiated PD-L1 CAR-NK cells are highly effective at lysing PD-L1 expressing tumor cells as well as PD-L1 null tumor cells (via expression of native NK cell receptors).
* Preliminary clinical data from 10 participants treated with PD-L1 CAR-NK cells (NCT04050709) suggest PD-L1 CAR-NK are well tolerated at a dose of 2x19\^9 cells intravenous (IV) twice per week. An additional 8 participants have received irradiated PDL1 CAR-NK under single patient INDs. PD-L1 CAR-NK cell treatment combined with PD-1 blockade and cytokine therapy may synergistically activate the T-cell and NK cell arms of the immune system and enhance anti-tumor activity.
* The combination of N-803 + PD-1/PD-L1 interaction blockade has a manageable safety profile

Objectives:

* Determine the 6-month progression free survival with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with gastric/GEJ cancer.
* Determine the clinical response rate (CR+PR) with irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with Head and neck squamous cell carcinoma.

Eligibility:

* Gastric/GEJ cancer Cohort

  * Participants must have metastatic or unresectable locally advanced Gastric/GEJ cancer.
  * Participants must have evaluable disease with or without measurable disease by RECISTv1.1.
  * Participants must have completed, had disease progression on, or been ineligible to receive first-line systemic chemotherapy for advanced/metastatic disease and anti-PD-1 therapy for advanced/metastatic disease.
  * Participants with HER2 positive disease must have received HER2-targeted systemic therapy.
* Head and neck squamous cell carcinoma Cohort

  * Participants must have metastatic or unresectable locally advanced HNSCC.
  * Participants must have measurable disease by RECISTv1.1. If the participant is one of the first six participants enrolled on study and is part of the safety-lead in, either measurable or evaluable (e.g., ascites, elevated tumor marker, or lesion visualized on imaging) disease will be permitted.
  * Participants must have received or been ineligible to receive first-line systemic chemotherapy and must have received systemic anti-PD-1 therapy (in the first-line or subsequent-line setting).
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
* Men or women, Age \>= 18 years

Design:

* This is an open label, single center, phase II trial using a safety lead-in to assess the safety and tolerability of irradiated PD-L1 CAR-NK cells in combination with N-803 plus pembrolizumab in participants with head and neck squamous cell carcinoma and/or gastric/GEJ cancer.
* The phase II objectives of this study is to assess 6-month progression free survival (PFS) and clinical response rate (CR+PR) in participants with gastric/GEJ cancer and head and neck squamous cell carcinoma, respectively.
* Participants will enroll and receive 1 dose of PD-L1 CAR-NK cell monotherapy (week -1) for PK/PD studies before starting the combined treatment of Pembrolizumab and N-803 one week later (week 0). PD-L1 CAR-NK cells (2x10\^9) will be given intravenously every week until week 6 and then every two weeks from 6 week onward.
* The accrual is 50 evaluable participants. To allow for a small number of inevaluable participants, the accrual ceiling will be set at 55 participants.

Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer

A Phase II Study of Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

The proportion of patients that have progressive disease after 18 months

The time when the proportion of patient's tumors shrunk after therapy

National Cancer Institute (NCI)

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Breast Neoplasms

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Ovarian Cancer

Ovarian Epithelial Cancer

* Dose Escalation: ZW49 administered intravenously at dose levels determined by the SMC
* Expansion: MTD or RD identified in the dose-escalation part of the study

ZW49

Joseph Woolery, PharmD, BCOP

This is a first-in-human, Phase 1, multicenter, open-label, dose-escalation study to establish the maximum-tolerated dose (MTD) or recommended dosage (RD) of ZW49, the investigational agent under study, and to assess the safety and tolerability of ZW49. Eligible patients include those with locally advanced (unresectable) or metastatic HER2-expressing cancers.

The study will use a 3+3 dose-escalation study design to evaluate the safety and tolerability of ZW49 and to determine the MTD or RD of ZW49 for further study. Selected expansion cohorts will be subsequently opened based upon Safety Monitoring Committee (SMC) recommendation and sponsor approval to further evaluate the safety and tolerability of ZW49 at the MTD or RD and to assess preliminary anti-tumor activity.

A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers

A Phase 1 Study of ZW49 in Patients With Locally Advanced (Unresectable) or Metastatic HER2-Expressing Cancers

Number of participants who experienced a DLT. DLTs are events that occur following administration of any amount of ZW49 and are considered related to ZW49 per the investigator. DLTs will include only events considered related to ZW49.

Number of participants who experienced an abnormal ECG or LVEF

Number of doses reduced and number of participants who require a dose reduction

End of infusion concentration, maximum serum concentration, and trough concentration of ZW49

Number of participants who achieved a best response of either complete or partial response during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Number of participants who achieved a best response of complete response, partial response, or stable disease during treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT03929666	HER2-expressing...	ZW25 (Zanidatam... Capecitabine Cisplatin Fluorouracil Leucovorin Oxaliplatin Bevacizumab Gemcitabine	18 Years -	Jazz Pharmaceuticals
Immunotherapy Combination: Irradiated PD-L1 CAR-NK Cells Plus Pembrolizumab Plus N-803 for Subjects With Recurrent/Metastatic Gastric or Head and Neck Cancer	NCT04847466	Gastroesophagea... Advanced HNSCC	N-803 Pembrolizumab PD-L1 t-haNK	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
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	NCT03929666	HER2-expressing...	ZW25 (Zanidatam... Capecitabine Cisplatin Fluorouracil Leucovorin Oxaliplatin Bevacizumab Gemcitabine	18 Years -	Jazz Pharmaceuticals
A Dose Finding Study of ZW49 in Patients With HER2-Positive Cancers	NCT03821233	HER2-expressing...	ZW49	18 Years -	Zymeworks BC Inc.

Spots Global Cancer Trial Database for gastroesophageal junction (gej) cancers