TGW211 for Click-Cleavable Imaging in HER2-Positive Cancers.

NCT07009184 | Recruiting Early Phase 1

• 2 other identifiers: 1166502025-520673-39-00
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief Summary

In recent years, there is increasing interest in antibodies for imaging, antibody-drug conjugates (ADC) and targeted radionuclide therapy (TRT). With these techniques, antibodies are used as a vector to deliver a cytotoxic drug or radionuclide for therapy or nuclear medicine imaging. One such antibody-based vector suitable for delivering a cytotoxic drug or radionuclide is trastuzumab, which targets HER2 that is overexpressed in cancers such as breast, gastric and gastroesophageal junction carcinomas. Unfortunately, antibodies generally have a very long circulation time (\>20-30 days) that often result in unfavorable background noise in the healthy organs in imaging or toxicity when trastuzumab is bound to a therapeutic radionuclide for radioimmunotherapy. There is thus a need to increase the speed of excretion of antibodies or release the antibody from its payload. Ideally, the clinician would like to appropriately time the elimination of radioactivity to achieve an optimal tumor to non-tumor ratio. To this aim, Tagworks Pharmaceuticals developed a new class of chemically cleavable radiolabeled conjugates that release the radiolabel on demand upon reaction with a small molecule "the trigger" (TRG001).

Conditions

HER2 Positive Solid Tumor

Outcome Measures

Primary Outcomes (1)

• Frequency and severity of Adverse Events using the CTCAE version 5.0.

  From enrollment to end of treatment at 14 days after last dose of investigational product.

Study Arms (1)

Click-chemistry using [111In]In-DOTA-TCO-trastuzumab and trigger component TRG001 (TGW211)

EXPERIMENTAL

The goal and main intervention are to demonstrate safety and tolerability of click-chemistry using the intravenously administered radiolabeled (Indium-111) imaging tracer \[111In\]In-DOTA-TCO-trastuzumab in combination with an intravenously injected trigger component (TRG001). Following a cold pre dose trastuzumab to minimize antibody-sink effect, a radioactivity dose of 150 ± 20% MBq \[111In\]In-DOTA-TCO-trastuzumab is administered using a fixed microdose of protein up to 4.5 mg (\< 30 nM). This is followed by intravenous administration of TRG001 in escalating dose levels. TRG001 cleaves \[111In\]In-DOTA-TCO-trastuzumab at the TCO-linker level. In subsequent cohorts the TRG001 dose level is escalated using a traditional 3+3 dose escalation design (38). After cleavage, the \[111In\]In-DOTA fragment is excreted via the urine.

Drug: [111In]In-DOTA-TCO-trastuzumab; Drug: Small molecule tetrazine trigger component

Interventions

[111In]In-DOTA-TCO-trastuzumab DRUG

\[111In\]In-DOTA-TCO-trastuzumab is a chemically cleavable \[111In\]In-labeled trastuzumab conjugate that is administered first to the patient, it accumulates in HER2-positive tumors and internalizes in HER2-expressing tumor cells.

Click-chemistry using [111In]In-DOTA-TCO-trastuzumab and trigger component TRG001 (TGW211)

Small molecule tetrazine trigger component DRUG

TRG001 is a small molecule tetrazine trigger that reacts with \[111In\]In-TGW211-DC in blood and extracellular space thus releasing a fast clearing \[111In\]In-DOTA containing fragment which is rapidly eliminated via the kidney. Because of its non-cell permeable nature, TRG001 does not reach \[111In\]In-TGW211-DC inside tumor cells and therefore the radioactivity inside tumor cells is retained by the tumor.

Click-chemistry using [111In]In-DOTA-TCO-trastuzumab and trigger component TRG001 (TGW211)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed, written informed consent and willing and able to comply with study requirements.
• Male or Female aged ≥ 18 years.
• Histologically confirmed HER2-positive cancer (IHC 3+ or IHC 2+ AND FISH+) with at least 1 measurable target lesion of at least 10 mm on CT or MRI based on RECIST v1.1, assessed by the investigator to enable adequate SPECT/CT imaging.
• WHO performance status (ECOG) of 0 or 1.
• Adequate organ and bone marrow function, evidenced by the following laboratory results:
• Absolute neutrophil count ≥ 1.5 x 10\^9 /l;
• Platelet count ≥ 100 x 10\^9 /l;
• Hemoglobin ≥ 9.0 g/dl or 5.6 mmol/l;
• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN);
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases);
• Serum creatinine ≤ 1.5 x ULN; - Estimated Glomerular Filtration Rate (eGFR)\* ≥ 60 ml/min/1.73 m2 ; \*preferably calculated with CKD-EPI formula.

You may not qualify if:

• Medical history of myocardial infarction within 6 months before participation or symptomatic CHF (New York Heart Association Class III to IV).
• QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec on screening ECG or congenital long QT syndrome.
• Has a history of (non-infectious) ILD/pneumonitis that required steroids or has current or suspected ILD/pneumonitis.
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g, pulmonary embolism within 3 months of trial participation, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.).
• Has an uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals.
• Participation in another clinical study with an investigational product during the past 6 weeks.
• Concurrent enrolment in another clinical study unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study.
• Pregnant or breastfeeding women, where pregnancy is defined as the time between conception and termination of gestation, confirmed by a positive urinary or serum pregnancy test.
• Women of childbearing potential (WOCBP), defined as women physiologically capable of becoming pregnant and no evidence of post-menopausal status, unless they use highly effective methods of contraception or abstain from sexual activity for 30 days after investigational drug administration. Male partners of female patients should also use a condom during intercourse for 30 days after investigational drug administration to the partner to prevent them from fathering a child.
• Male patients in the reproductive age, not willing or able to use a condom or abstain from sexual activity for 30 days after investigational drug administration. WOCBP partners of sexually active male patients should also use a highly effective contraception method during intercourse for 30 days after investigational drug administration of the partner.
• Known allergy or hypersensitivity to any of the investigational drugs or its excipients.
• Any condition which, in the opinion of the investigator, would preclude participation in the study.
• Second active malignancy.

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Tagworks Pharmaceuticals BV: collaborator

Study Sites (1)

Radboud University Medical Center

Nijmegen, Gelderland, 6525 GS, Netherlands

RECRUITING

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2025
• First Posted: June 6, 2025
• Study Start: December 10, 2025
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: November 18, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)