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A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination in Patients With HER2-Positive Advanced Solid Tumors

PHASE1RECRUITING

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 patients 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).

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Study details:

Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7 planned dose levels. Patients with HER2-positive advanced solid tumor (including those with brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041 followed by multiple-dose administration of ZN-A-1041. Phase 1b of the study will adopt the "traditional 3+3" dose escalation design.

The dose levels will be based on the results of the Phase 1a study and the results of a food effect study. In Phase 1b, patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis will be enrolled in three arms: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd. Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta and 4-8-cycle treatment of taxane.

Patients will be assessed for an appropriate arm by the sponsor and the investigator at the time of consent. Patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis are planned to be enrolled in Phase 1c of the study: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd; Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta or T-DXd based induction regimen. Patients will be assessed for an appropriate arm by the sponsor and the investigator at the time of consent.

Arm1 of Phase 1c can start independently after the DLT observation period of the last patient in Phase 1b Arm1. Arm 2 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 2. Arm 3 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 3.

The dose levels used in Phase 1c will be based on the recommended doses obtained from the Phase 1b study. Each phase of the study includes a screening period (from 28 days prior to the first administration of the study drug), a treatment period (until there are no clinical benefits as deemed by the Investigator, disease progression, death, intolerable toxicity, withdrawal of informed consent, loss of follow-up, or the start of new anti-tumor treatment), and a follow-up period (until 28 days after the last administration of the study drug). During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as monotherapy and in combination in the subjects will be collected and analyzed, thereby providing RP2D for subsequent future clinical trials.

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Eligibility criteria

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Inclusion criteria

ECOG performance status of 0 to 1

HER2 positive is defined as Immunohistochemistry (IHC) (++) and Fluorescence In Situ Hybridization (FISH) positive, or IHC (+++).

Phase 1a study will enroll patients with unresectable or metastatic HER2-positive advanced solid tumor.

For patients who have received previous tyrosine kinase inhibitor (TKI) treatment, chemotherapy, antibody, or antibody-drug conjugate (ADC), the interval between the last treatment and the first administration of the study drug in this trial should be at least 2 weeks.

Phase 1b and Phase 1c study will enroll patients with unresectable locally advanced or metastatic HER2+ breast cancer.

Suspected or confirmed leptomeningeal metastasis are allowed.

Exclusion criteria

Subjects who have participated in any clinical study or received any clinical study drug within 4 weeks prior to the first administration except for on-going Herceptin, Perjeta or PHESGO in arm3

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2020-10-15

Primary completion: 2025-10-30

Study completion finish: 2026-10-30

Study type

TREATMENT

Phase

PHASE1

Trial ID

NCT05593094

Intervention or treatment

DRUG: ZN-A-1041 50mg BID

DRUG: ZN-A-1041 100mg BID

DRUG: ZN-A-1041 200mg BID

DRUG: ZN-A-1041 400mg BID

DRUG: ZN-A-1041 600mg BID

DRUG: ZN-A-1041 800mg BID

DRUG: ZN-A-1041 1000mg BID

DRUG: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1b

DRUG: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1b

DRUG: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1b

DRUG: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1c

DRUG: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1c

DRUG: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1c

Conditions

• Advanced Solid Tumors
• HER2-positive Breast Cancer

Condition: Advanced Solid Tumors, HER2-positive Breast Cancer
DRUG: ZN-A-1041 50mg BID and other drugs
Geelong, Victoria, Australia and more
Sponsor: Suzhou Zanrong Pharma Limited

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Find a site

Closest Location:

Andrew Love Cancer Center

Research sites nearby

Select from list below to view details:

Andrew Love Cancer Center
Geelong, Victoria, Australia
Sunshine Hospital - Australia
St Albans, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: ZN-A-1041 50mg Phase 1a: Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 50mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 100mg Phase 1a: Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 100mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 200mg Phase 1a: Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 200mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 400mg Phase 1a: Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 400mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 600mg Phase 1a: Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 600mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 800mg Phase 1a: Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 800mg BID twice a day (BID) via oral administration
EXPERIMENTAL: ZN-A-1041 1000mg Phase 1a: Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle	DRUG: ZN-A-1041 1000mg BID twice a day (BID) via oral administration
EXPERIMENTAL: 1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv. Phase 1b Arm1: 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.	DRUG: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1b ZN-A-1041: twice a day (BID) via oral administration T-DM1: 3.6 mg/kg given as an intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
EXPERIMENTAL: 1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. 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.	DRUG: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1b ZN-A-1041: twice a day (BID) via oral administration T-DXd: 5.4 mg/kg given as an intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
EXPERIMENTAL: 1b: ZN-A-1041 + PHESGO / Herceptin plus Perjeta 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.	DRUG: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1b ZN-A-1041: twice a day (BID) via oral administration PHESGO dose is 600 mg pertuzumab/600 mg trastuzumab/2000 unites hyaluronidase every 3 weeks for subcutaneous administrations (21-day cycle) Perjeta is 420 mg administered as an intravenous infusion Herceptin is 6 mg/kg administered as an intravenous infusion
EXPERIMENTAL: 1c: ZN-A-1041 + T-DM1 3.6 mg/kg iv. Phase 1c Arm1: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.	DRUG: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1c ZN-A-1041: twice a day (BID) via oral administration T-DM1: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
EXPERIMENTAL: 1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. Phase 1c Arm2: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.	DRUG: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1c ZN-A-1041: twice a day (BID) via oral administration T-DXd: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
EXPERIMENTAL: 1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO Phase 1c Arm3: The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.	DRUG: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1c ZN-A-1041: twice a day (BID) via oral administration PHESGO: every 3 weeks for subcutaneous administrations (21-day cycle) Perjeta: intravenous infusion Herceptin: intravenous infusion

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
The Incidence of Treatment-Emergent Adverse Events of ZN-A-1041 as a monotherapy in Phase 1a	Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.	23 days
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	Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.	21 days
RP2D Dose	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 patients on the RP2D Dose	through study completion, an average of 1 year

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Plasma, urine and potentially CSF level of ZN-A-1041 and its main metabolites	To assess the PK of ZN-A-1041 and its major metabolites	From baseline to Cycle 9 (each cycel is 21 days)
Serum level of combination drugs in phase 1c	To assess the serum concentration of combination drugs	through study completion, an average of 2 year
Anti-drug antibodies (ADAs) evaluation in Phase 1c	To assess the incidence of ADAs	through study completion, an average of 2 year
overall Response Rate (ORR)	The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c	through study completion, an average of 2 year
Progression free survival(PFS)	The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c	through study completion, an average of 2 year

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References

Clinical Trials Gov: A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination in Patients With HER2-Positive Advanced Solid Tumors