TAC T-cells for the Treatment of HER2-positive Solid Tumors (TACTIC-2)

• ClinicalTrials.gov Identifier: NCT04727151
• Recruitment Status: Active, not recruiting
• First Posted: January 27, 2021
• Last Update Posted: February 9, 2024
• Sponsor: Triumvira Immunologics, Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Triumvira Immunologics, Inc.

Tracking Information

• First Submitted Date: January 20, 2021
• First Posted Date: January 27, 2021
• Last Update Posted Date: February 9, 2024
• Actual Study Start Date: April 19, 2021
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 13, 2023)

• Phase 1: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 24 months ]
  Document incidence of DLTs; Type, frequency, and severity of AEs (including clinically significant laboratory abnormalities).
• Phase 2: Evaluate Overall Response Rate (ORR) [ Time Frame: 24 months ]
  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.
• Phase 2: Evaluate Duration of Response (DoR) [ Time Frame: 24 months ]
  Defined as time from first response to disease progression, end of study, start of another anticancer therapy, or death
• Phase 2: Evaluate Overall survival (OS) [ Time Frame: 24 months ]
  Defined as time from infusion to death from any cause
• Phase 2: Evaluate Disease control rate (DCR) [ Time Frame: 24 months ]
  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.
• Phase 2: Evaluate Progression-Free survival (PFS) or Time to progression (TTP) [ Time Frame: 24 months ]
  Defined as time from infusion to disease progression or death from any cause

Original Primary Outcome Measures (submitted: January 26, 2021)

Incidence of Treatment-Emergent Adverse Events [ Time Frame: 24 Months ]

Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 5 and American Society for Transplantation and Cellular Therapy (ASTCT) 2018 criteria.

Current Secondary Outcome Measures (submitted: September 13, 2023)

• Phase 1: Determine MTD or RP2D for TAC01-HER2 monotherapy and pembrolizumab combination therapy [ Time Frame: Up to 29 Days Post TAC01-HER2 infusion ]
  Document incidence of Dose-Limiting Toxicities.
• Phase 1: Evaluate Overall Response Rate (ORR) [ Time Frame: 24 months ]
  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.
• Phase 1: Evaluate Duration of Response (DoR) [ Time Frame: 24 months ]
  Defined as time from first response to disease progression, end of study, start of another anticancer therapy, or death
• Phase 1: Evaluate Overall survival (OS) [ Time Frame: 24 months ]
  Defined as time from infusion to death from any cause
• Phase 1: Evaluate Disease control rate (DCR) [ Time Frame: 24 months ]
  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.
• Phase 1: Evaluate Progression-Free survival (PFS) or Time to progression (TTP) [ Time Frame: 24 months ]
  Defined as time from infusion to disease progression or death from any cause
• Phase 2: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 24 Months ]
  Document type, frequency, and severity of AEs (including clinically significant laboratory abnormalities).
• Phase 1 and Phase 2: Cmax of TAC01-HER2 (pharmacokinetics; PK) [ Time Frame: 24 Months ]
  Defined as the maximum concentration of TAC T cells after infusion; assessed by vector copy number
• Phase 1 and Phase 2: Tmax of TAC01-HER2 (PK) [ Time Frame: 24 Months ]
  Defined as the the first study day the Cmax is reached; assessed by vector copy number
• Phase 1 and Phase 2: area under the concentration time curve (AUC) of TAC01-HER2 (PK) [ Time Frame: 24 Months ]
  Calculated using the trapezoid rule; assessed by vector copy number
• Phase 1 and Phase 2: Duration of persistence of TAC T cells (PK) [ Time Frame: 24 Months ]
  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
• Phase 1 and Phase 2: Human anti-mouse antibody (HAMA) detection [ Time Frame: Up to 29 Days Post TAC01-HER2 infusion ]
  Correlation of HAMA detection with TAC PK and subject response
• Phase 1 and Phase 2: Cytokine level detection [ Time Frame: 24 Months ]
  Correlation with adverse events and subject response

Original Secondary Outcome Measures (submitted: January 26, 2021)

• Determine MTD or RP2D [ Time Frame: 28-42 Days Post-Treatment ]
  Assessed by incidence of Dose-Limiting Toxicities.
• Determine expansion of TAC01-HER2 [ Time Frame: 24 Months ]
  Assessed by vector copy number.
• Determine persistence of TAC01-HER2 [ Time Frame: 24 Months ]
  Assessed by vector copy number.
• Evaluate Overall Response Rate (ORR) [ Time Frame: 1, 3, 6, 9, 12, 18 and 24 months ]
  Assessed by imaging using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria Version 1.1.
• Evaluate Overall Survival (OS) [ Time Frame: 24 Months ]
  Defined as the time between the date of TAC01-HER2 infusion and death due to any cause.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: TAC T-cells for the Treatment of HER2-positive Solid Tumors
• Official Title: 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

Brief Summary

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.

Detailed Description

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).

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• HER2 Positive Gastric Cancer
• Metastatic HER2 Positive Gastroesophageal Junction Cancer

Intervention

• Biological: TAC01-HER2

  TAC01-HER2 and:

  • fludarabine and cyclophosphamide, or
  • clofarabine and cyclophosphamide, or
  • bendamustine, or
  • cyclophosphamide
• Biological: TAC01-HER2 plus pembrolizumab

  TAC01-HER2 plus pembrolizumab and:

  • fludarabine and cyclophosphamide, or
  • clofarabine and cyclophosphamide, or
  • bendamustine, or
  • cyclophosphamide
  Other Name: Keytruda

Study Arms

• Experimental: TAC01-HER2
  Lymphodepletion followed by TAC01-HER2 as a single IV infusion, with a potential for a second dose administration.
  Intervention: Biological: TAC01-HER2
• Experimental: TAC01-HER2 plus pembrolizumab
  Lymphodepletion followed by TAC01-HER2 as a single IV infusion, followed by pembrolizumab administration.
  Intervention: Biological: TAC01-HER2 plus pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: September 13, 2023): 110
• Original Estimated Enrollment (submitted: January 26, 2021): 70
• Estimated Study Completion Date: June 2027
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Written informed consent.
2. Age ≥ 18 years at the time of informed consent.

3. For Phase 1 and Phase 2:

   • Phase 1 monotherapy (completed): HER2 1+, 2+, 3+ by IHC by central laboratory confirmation
   • Phase 1 combination therapy and Phase 2: HER2 2+, 3+ by IHC and FISH by central laboratory confirmation

4. Histologically confirmed advanced, metastatic, unresectable solid tumors (regardless of PD-L1 expression levels; Phase 1 monotherapy) and histologically confirmed advanced, metastatic, unresectable gastric or esophageal adenocarcinoma (regardless of PD-L1 expression levels for Phase 1 combination therapy and Phase 2) after at least 2 prior lines of therapy (Phase 1) or after at least 2 and no more than 4 prior lines of therapy (Phase 2).

   1. HER2+ incurable malignancies for which no standard-of-care HER2 targeted therapy exists may be enrolled regardless of the number of prior treatment lines, as long as in the opinion of the investigator the subject would be unlikely to tolerate or derive clinically meaningful benefit from other available treatment options.
   2. For breast cancer subjects, both prior lines of therapy must have included HER2-targeted agents per current standard-of-care.
   3. Subjects with solid tumors with genetic alterations and mutations (such as BRAF, BRCA, EGFR mutations, and ALK translocation) where approved targeted therapies were available to their specific cancers must have been previously treated with such approved therapies or refused such approved targeted therapy for their cancers prior to enrollment, or in the opinion of the investigator would be unlikely to tolerate or derive clinically meaningful benefit from these standard-of-care therapies.
5. Measurable disease per RECIST 1.1 at time of enrollment.
6. ECOG performance status of 0 or 1 at Screening.
7. Life expectancy of at least 12 weeks.
8. Adequate organ and bone marrow reserve function.
9. Recovery to Grade ≤1 or Baseline for any toxicities due to previous therapy.
10. Adequate vascular access for leukapheresis.
11. Negative pregnancy test and use of highly effective contraception.
12. Undetectable HBV viral load.
13. HCV viral load is undetectable.

Exclusion Criteria:

1. Intolerant to any component of TAC01-HER2.

2. Prior treatment with any of the following:

   1. Adoptive cell transfer of any kind, including CAR T cells
   2. Gene therapy
3. Investigational medicinal product within 5 half-lives or 21 days prior to leukapheresis, whichever is shorter.
4. Receipt of a live or live-attenuated vaccine within 30 days prior to study treatment.
5. Monoclonal antibody (mAb), including PD-1 and PD-L1, therapies within 21 days prior to leukapheresis.
6. Radiation within 28 days prior to enrollment. Palliative radiation is allowed up to 14 days prior to enrollment if non-irradiated lesions are present.
7. Chemotherapy or targeted small molecule therapy within 14 days prior to leukapheresis, or within 7 days prior to leukapheresis for erlotinib, gefitinib, afatinib, or crizotinib.
8. Colony stimulating factors, including granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and other hematopoietic cytokines, within 14 days prior to leukapheresis.
9. Immunosuppressive medication within 14 days or corticosteroid treatment < 72 hours prior to enrollment.
10. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. (Brain metastasis - non-progressive or previously treated and currently stable - are permitted.)
11. Active inflammatory neurological disorders (e.g., Guillain-Barre Syndrome, amyotrophic lateral sclerosis, multiple sclerosis).
12. Active autoimmune disease (e.g., lupus, rheumatoid arthritis, Sjogren's syndrome) requiring systemic disease modifying agents in the past 2 years.
13. Active or uncontrolled hepatitis B or C (HCV ribonucleic acid [RNA] positive) infection or any history of or active human immunodeficiency virus (HIV) infection.
14. Uncontrolled, acute, or life-threatening bacterial, viral, or fungal infection. Subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible if no evidence of active infection.
15. Class III or IV heart failure (as defined by the New York Heart Association - NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease within 6 months prior to Screening.
16. Cardiac arrhythmia not controlled by medical management.
17. Clinically significant thrombotic events within 6 months prior to leukapheresis and/or inability to stop anti-coagulation for at least 2 weeks prior to TAC01-HER2 infusion.
18. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, non-metastatic squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
19. Pregnant or lactating.
20. As determined by the Investigator, any uncontrolled medical, psychological, familial, sociological, or geographical condition(s) that do(es) not permit compliance with the protocol.
21. Participation in or has participated in a study using an investigational device within 4 weeks prior to study treatment..
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the subject's participation for the full duration of the study, such that it is not in the best interest of the subject to participate, in the opinion of the treating investigator.

23. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

    Combination Arm Only Specific Exclusions:

24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE).
26. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
27. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of trial treatment.
28. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
29. Has history of an allogeneic stem cell transplant or a solid organ transplant.
30. Has a history of radiation pneumonitis. (Note: Cannot receive prior radiotherapy within 2 weeks of start of pembrolizumab. Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation [≤2 weeks of radiotherapy] to non-CNS disease).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT04727151
• Other Study ID Numbers: TAC01-HER2-03; KEYNOTE-E77 ( Other Identifier: Merck Sharp & Dohme, LLC )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Triumvira Immunologics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Triumvira Immunologics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Not Provided
• PRS Account: Triumvira Immunologics, Inc.
• Verification Date: February 2024