A clinical trial to look at how ZN-A-1041 alone or ZN-A-1041 plus some approved drugs works to reduce tumor size and how safe these drugs are at different doses.

Phase 1

Recruiting

Conditions: HER2-positive advanced solid tumours

Interventions: 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

Registration Number: 2023-508459-37-00

Lead Sponsor: Suzhou Zanrong Pharma Limited

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 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 34

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
ZN-A-1041 50mg	ZN-A-1041 50mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle
ZN-A-1041 100mg	ZN-A-1041 100mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle
ZN-A-1041 200mg	ZN-A-1041 200mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle
ZN-A-1041 400mg	ZN-A-1041 400mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle
ZN-A-1041 600mg	ZN-A-1041 600mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle
ZN-A-1041 800mg	ZN-A-1041 800mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle
ZN-A-1041 1000mg	ZN-A-1041 1000mg BID	Phase 1a: Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle
1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv.	ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1b	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.
1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.	ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1b	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 Phase1b	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 Phase1c	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.
1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.	ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1c	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.
1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO	ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1c	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.

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 patient at the same dose level experiences a probable drug-related dose limiting toxicity.
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 patient at the same dose level experiences a probable drug-related dose limiting toxicity.
RP2D Dose	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 patients on the RP2D Dose

Secondary Outcome Measures

Name	Time	Method
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
Plasma, urine and potentially 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
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 (25): Centr Georges Francois Leclerc
🇫🇷
Dijon, France
Centre Leon Berard
🇫🇷
Lyon, France
Centre Oscar Lambret
🇫🇷
Lille, France
Institut Gustave Roussy
🇫🇷
Villejuif, France
Institut Paoli-Calmettes
🇫🇷
Marseille, France
Institut Universitaire Du Cancer Toulouse-Oncopole
🇫🇷
Toulouse, France
Institut De Cancerologie De L Ouest
🇫🇷
St Herblain, France
Hospital Clinico Universitario De Valencia
🇪🇸
Valencia, Spain
University Hospital Virgen Del Rocio S.L.
🇪🇸
Sevilla, Spain
Hospital Beata Maria Ana
🇪🇸
Madrid, Spain
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Centr Georges Francois Leclerc
🇫🇷Dijon, France
Isabelle DESMOULINS
Site contact
+33380737528
idesmoulins@cgfl.fr