Advanced Solid Tumors, HER2-positive Breast Cancer
Conditions
Keywords
Phase 1, Advanced Solid Tumors, HER2 postive, Brain metastases, Herceptin, Perjeta, PHESGO, First Line, 1st Line
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.
Interventions
DRUGZN-A-1041
ZN-A-1041: escalating doses orally BID at pre-defined dosing regimens to determine the MTD
DRUGZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1b
ZN-A-1041: 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)
DRUGZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1b
ZN-A-1041: 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)
DRUGZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1b
ZN-A-1041: 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
DRUGZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase 1c
ZN-A-1041: BID via oral administration T-DM1: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
DRUGZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase 1c
ZN-A-1041: BID via oral administration T-DXd: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
DRUGZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase 1c
ZN-A-1041: BID via oral administration PHESGO: every 3 weeks for subcutaneous administrations (21-day cycle) Perjeta: intravenous infusion Herceptin: intravenous infusion
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Australia, France, Italy, New Zealand, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed