A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced Solid Tumors

Phase 1

Active, not recruiting

• Conditions: HER2-positive advanced solid tumours
• Interventions: Drug: ZN-A-1041; Drug: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1b; Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1b; Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1b; Drug: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1c; Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1c; Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1c

• Registration Number: 2023-508459-37-00
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This will be a Phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination in participants with HER2-positive advanced solid tumors with or without brain metastases.

The study will consist of three phases: Phase 1a (dose escalation with ZN-A-1041 monotherapy), Phase 1b (dose escalation with ZN-A-1041 combination therapy) and Phase 1c (dose expansion with ZN-A-1041 combination therapy).

Detailed Description

This study is composed of three parts designed to evaluate the safety and efficacy of ZN-A-1041 in participants with HER2-positive advanced solid tumors.

Phase 1a (Monotherapy Dose Escalation): In this first phase, participants will receive ZN-A-1041 alone. The study will begin with a low dose of ZN-A-1041, which will be gradually increased in new groups of participants to find the highest dose that can be given safely. This will establish the recommended dose for further study.

Phase 1b (Combination Dose Escalation): In the second phase, the study will evaluate the safety of giving ZN-A-1041 together with established standard-of-care therapies for HER2-positive breast cancer. Participants will be enrolled into one of three combination arms to receive ZN-A-1041 with either T-DM1, T-DXd, or a pertuzumab/trastuzumab-based regimen. This phase will identify the recommended dose for these combination therapies.

Phase 1c (Combination Dose Expansion): In the final phase, additional participants will be enrolled to receive ZN-A-1041 at the recommended combination doses identified in Phase 1b. This will allow for a more thorough evaluation of the safety and preliminary efficacy of these treatment regimens.

Throughout the study, participants will undergo screening, treatment, and follow-up periods to collect comprehensive data on the safety, tolerability, pharmacokinetics, and anti-tumor activity of ZN-A-1041, both as a single agent and in combination.

Study Timeline

• Study Start: 2020-09-03
• Study First Submitted: 2022-10-17
• Study First Submitted QC: 2022-10-22
• Study First Posted: 2022-10-25
• Status Verified: 2025-08
• Last Update Submitted: 2025-08-28
• Last Update Posted: 2025-09-04
• Primary Completion: 2025-10-30
• Study Completion: 2026-10-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 34

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 6 months, as determined by the investigator
• Histologically or cytologically confirmed with unresectable or metastatic HER2-positive advanced solid tumors
• Must be relapsed or refractory after prior treatment for metastatic disease that included a taxane and trastuzumab or must have received first-line induction therapy for advanced disease a pertuzumab plus trastuzumab-based regimen or a T-DXd-based regimen
• Participants with new, untreated, progressive, or stable brain metastases are eligible

Exclusion Criteria

• Participation in any other clinical study involving an investigational drug or device within 4 weeks prior to the first dose of study treatment
• Any intracranial lesion (brain metastasis) that requires immediate local therapy, such as surgery or radiation, or systemic corticosteroids at the time of enrollment

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
1a: ZN-A-1041	ZN-A-1041	Phase 1a: Participants will receive escalating doses of ZN-A-1041 orally twice a day (BID) at pre-defined dosing regimens to determine the maximum tolerated dose (MTD).
1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv.	ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1b	Phase 1b Arm1: 1. If the maximum tolerated dose (MTD) of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.	ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1b	Phase 1b Arm2: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
1b: ZN-A-1041 + PHESGO / Herceptin plus Perjeta	ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1b	Phase 1b Arm3: 1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2). 2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
1c: ZN-A-1041 + T-DM1 3.6 mg/kg iv.	ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1c	Phase 1c Arm1: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.
1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.	ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1c	Phase 1c Arm2: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.
1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO	ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1c	Phase 1c Arm3: The recommended dose combination for Phase 1c will be determined by the Investigator and the Sponsor based on the data from Phase 1b.

Primary Outcome Measures

Name	Time	Method
The Incidence of Treatment-emergent Adverse Events of ZN-A-1041 as a Monotherapy in Phase 1a	23 days	Dose at which no more than one out of six participant at the same dose level experiences a probable drug-related DLT.
The Incidence of Treatment-emergent Adverse Events of ZN-A-1041 in Combination with T-DM1 or with T-DXd, or in Combination with PHESGO or Herceptin plus Perjeta	21 days	Dose at which no more than one out of six participant at the same dose level experiences a probable drug-related DLT.
RP2D	Through study completion, an average of 1 year	To evaluate the safety of ZN-A-1041 in combination with T-DM1 or with T-DXd, or in combination with PHESGO or Herceptin plus Perjeta in participants on the RP2D.

Secondary Outcome Measures

Name	Time	Method
Plasma, Urine and Potentially Cerebrospinal Fluid (CSF) Level of ZN-A-1041 and its Main Metabolites	From baseline to cycle 9 (each cycel is 21 days)	To assess the PK of ZN-A-1041 and its major metabolites.
Serum Level of Combination Drugs in Phase 1c	Through study completion, an average of 2 year	To assess the serum concentration of combination drugs.
Anti-drug Antibodies (ADAs) Evaluation in Phase 1c	Through study completion, an average of 2 year	To assess the incidence of ADAs.
Overall Response Rate (ORR)	Through study completion, an average of 2 year	The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a, Phase 1b and 1c.
Progression Free Survival (PFS)	Through study completion, an average of 2 year	The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a, Phase 1b and 1c.

Trial Locations

Locations (36)

Arizona Clinical Research Center, Inc.;Hematology Oncology Physicians - Aoa; 🇺🇸 Tucson, Arizona, United States

TOI Clinical Research; 🇺🇸 Cerritos, California, United States

UCSF Helen Diller Family CCC; 🇺🇸 San Francisco, California, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

University of Michigan Hospital; 🇺🇸 Ann Arbor, Michigan, United States

Barbara Ann Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Duke University School of Medicine; 🇺🇸 Durham, North Carolina, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Geelong Hospital; 🇦🇺 Geelong, Victoria, Australia

Sunshine Hospital; 🇦🇺 St Albans, Victoria, Australia

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