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Digestive System Neoplasms

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Immune Checkpoint Inhibitors

Lymphodepletion followed by TAC01-HER2 as a single IV infusion, with a potential for a second dose administration.

Lymphodepletion followed by TAC01-HER2 as a single IV infusion, followed by pembrolizumab administration.

TAC01-HER2 and:

* fludarabine and cyclophosphamide, or
* clofarabine and cyclophosphamide, or
* bendamustine, or
* cyclophosphamide

TAC01-HER2

TAC01-HER2 plus pembrolizumab and:

* fludarabine and cyclophosphamide, or
* clofarabine and cyclophosphamide, or
* bendamustine, or
* cyclophosphamide

TAC01-HER2 plus pembrolizumab

TAC01-HER2 is a novel cell therapy that consists of genetically engineered autologous T cells expressing T-cell Antigen Coupler (TAC) that recognizes human epidermal growth factor receptor 2 (HER2). TAC directs T-cells to the targeted antigen (HER2), and once engaged with the target, activates them via the endogenous T cell receptor.

This is an open-label, multicenter Phase 1/2 study that aims to establish safety, maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), pharmacokinetic profile and efficacy of TAC01-HER2 as a monotherapy, and in combination with pembrolizumab, in subjects with HER2 positive gastric and gastroesophageal adenocarcinoma.

The TAC technology is a novel approach to modifying T cells, herein referred to as TAC T cells, and using them in the treatment of solid tumors. TAC T cells are produced through genetic engineering, incorporating TAC receptors into a patient's own T cells. This redirects these enhanced T cells to specific cancer antigens, and upon recognition, activates them through the natural signaling pathways of the endogenous TCR. In the TAC01-HER2 engineered T cell product; TAC T cells recognize the HER2 protein present on the surface of tumor cells, and eradicate them. Consequently, it is hypothesized TAC01-HER2 will be potentially safe and effective in treating patients with HER2+ solid tumors and provide a clinically meaningful therapeutic benefit in patient populations with high unmet medical need.

This is a first-in-human study investigating TAC01-HER2 to evaluate the safety, MTD or RP2D, PK, and efficacy in subjects with HER2+ solid tumors who have been treated after at least 2 lines of prior therapy in Phase 1 and after at least 2 lines and no more than 4 lines of prior therapy in Phase 2.

In Phase 1, escalating doses of TAC01-HER2 will be evaluated to identify the RP2D using the classic keyboard design method. The monotherapy arm will treat all subjects with HER2-positive solid tumors that meet the eligibility criteria (completed). The combination arm will treat all 2+ or 3+ HER2-positive subjects with gastric or gastroesophageal AC who meet the eligibility criteria.

In Phase 2, dose expansion groups will further evaluate the efficacy, safety, and PK of the MTD or RP2D for TAC01-CLDN18.2 in subjects with gastric and esophageal adenocarcinoma. In Phase 2, a Simon 3-stage design will be used to enroll up to 36 subjects in Group A (monotherapy arm) and 34 subjects in Group B (combination arm).

In summary:

* Phase I monotherapy arm: Dose escalation in any HER2-positive solid tumor (completed).
* Phase I combination therapy arm: Dose escalation in combination with pembrolizumab in 2+ or 3+ HER2-positive gastric and gastroesophageal adenocarcinoma
* Phase II: Dose expansion cohorts: 2+ or 3+ HER2-positive gastric or gastroesophageal adenocarcinoma treated with TAC01-HER2 as a monotherapy (Group A) or in combination with pembrolizumab (Group B).

In Phase 1, escalating doses of TAC01-HER2 will be evaluated to identify the RP2D of the monotherapy arm and the combination arm using the classic keyboard design. In Phase 2, dose expansion groups will further evaluate the safety, efficacy, and PK of the MTD or RP2D for TAC01-HER2 as a monotherapy and in combination with pembrolizumab in subjects with gastric and gastroesophageal adenocarcinoma.

TAC T-cells for the Treatment of HER2-positive Solid Tumors

A Phase 1/2 Trial Investigating the Safety and Efficacy of Autologous TAC T Cell Monotherapy, and TAC T Cells in Combination With Pembrolizumab, in Relapsed HER2-Positive Solid Tumors

Document incidence of DLTs; Type, frequency, and severity of AEs (including clinically significant laboratory abnormalities).

Defined as the percentage of treated subjects with a complete or partial response (CR or PR) as assessed by imaging using Response Evaluation Criteria in Solid Tumors (RECIST)Version 1.1.

Defined as time from first response to disease progression, end of study, start of another anticancer therapy, or death

Defined as time from infusion to death from any cause

Defined as the percentage of treated subjects with stable disease (SD), PR, and CR as assessed by imaging using Response Evaluation Criteria in Solid Tumors (RECIST)Version 1.1.

Defined as time from infusion to disease progression or death from any cause

Document incidence of Dose-Limiting Toxicities.

Document type, frequency, and severity of AEs (including clinically significant laboratory abnormalities).

Defined as the maximum concentration of TAC T cells after infusion; assessed by vector copy number

Defined as the the first study day the Cmax is reached; assessed by vector copy number

Calculated using the trapezoid rule; assessed by vector copy number

Defined as the time between the first measurement of transgene above the limit of detection until the last observed quantifiable level of transgene; assessed by vector copy number

Correlation of HAMA detection with TAC PK and subject response

Correlation with adverse events and subject response

Spots Global Cancer Trial Database for her2 positive gastroesophageal adenocarcinoma