Study of AVZO-023 as a Single Agent and in Combination With AVZO-021, and/or Endocrine Therapy in Advanced Solid Tumors

Avenzo Therapeutics

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: HR+/HER2- Breast Cancer; Advanced Solid Tumor; CCND1 Gene Amplification; CDK Gene Mutation; CDK4 Gene Amplification; HR+, HER2-, Advanced Breast Cancer

Treatments: Drug: Fulvestrant; Drug: AVZO-023; Drug: Letrozole; Drug: AVZO-021

Study type: Interventional

Funder types: Industry

Identifiers

NCT06998407

AVZO-023-1001

Details and patient eligibility

About

This study, the first clinical trial of AVZO-023, aims to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, maximum tolerated dose, and anti-tumor effects of AVZO-023 in patients with advanced solid tumors. AVZO-023 is an oral medication that inhibits cyclin-dependent kinase 4 (CDK4).

Full description

AVZO-023 is an oral, potent, and selective inhibitor of CDK4. AVZO-021 is an oral, potent, and selective inhibitor of CDK2 that is currently being investigated in a global Phase 1/2 study in patients with advanced hormone receptive positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer and cyclin E1 protein (CCNE1)-amplified malignancies (NCT05867251).

In Phase 1, the safety and tolerability of AVZO-023 in patients with advanced solid tumors that are CDK4/CCND1 amplified and in patients with HR+/HER2- locally advanced or metastatic breast cancer (mBC) will be assessed. The goal of Phase 1 is to determine the MTD/preliminary RP2D of AVZO-023 for use as monotherapy and in combination with AVZO-021 with or without endocrine therapy (ET).

Phase 2 will assess the antitumor activity and confirm the RP2D of AVZO-023 in combination therapy in patients with HR+/HER2- locally advanced or mBC.

Enrollment: 380 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

• Male or female aged ≥ 18 years old at screening with Eastern Cooperative Oncology Group (ECOG) 0-1 and life expectancy > 3 months
• Patients with histologically or cytologically proven advanced malignancies of preferred indications
• Measurable disease (as assessed by investigator using RECIST v1.1) is preferred in Phase 1 dose escalation, unless otherwise specified in the protocol, and in all patients in Phase 2. For patients with HR+/HER2- breast cancer enrolled in dose escalation, bone only disease is allowed
• Agree to provide molecular test report results to confirm eligibility and archival tumor samples and/or fresh biopsy, as applicable
• Adequate renal, liver, and bone marrow function

Key Exclusion Criteria:

• Patients should not have received prior selective CDK (CDK2, CDK4, CDK2/4, CDK2/4/6) inhibitors
• Has known active brain metastasis (have either previously untreated intracranial CNS metastasis or previously treated intracranial central nervous system (CNS) metastasis with radiologically documented new or progressing CNS lesions) or leptomeningeal disease
• Other concurrent invasive malignancy or a prior invasive malignancy for which treatment was completed within 3 years before the first dose on study except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ, or colorectal adenomatous polyps
• Last anticancer treatment within 2 weeks (4 weeks for biologic, immunotherapy or ADC) or 5 half-lives of the drug, whichever is shorter, prior to first dose on study
• Major surgery within 4 weeks prior to first dose on study
• Have received radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have active radiation pneumonitis
• Strong or moderate CYP3A4 inhibitors or inducers within 2 weeks or 5 half-lives of the drug, whichever is shorter, prior to first dose on study
• History of serious cardiovascular conditions within 6 months prior to first dose on study
• Unresolved toxicities from prior therapy greater than Grade 1 (per CTCAE version 5.0) (with exceptions of alopecia, vitiligo, and ≤ Grade 2 peripheral neuropathy) prior to the first dose on study
• History of drug-induced pneumonitis/interstitial lung disease

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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380 participants in 4 patient groups

Phase 1, monotherapy (Part 1A) and food effect

Experimental group

Description:

Escalating doses of twice daily, oral AVZO-023 in 28-day cycles, with addition of fulvestrant for patients with HR+/HER2- mBC

Treatment:

Drug: AVZO-023

Drug: Fulvestrant

Phase 1, combination (Parts 1B)

Experimental group

Description:

Escalating doses of twice daily, oral AVZO-023 in combination with once daily, oral AVZO-021 in 28-day cycles, with addition of fulvestrant for patients with HR+/HER2- mBC

Treatment:

Drug: AVZO-021

Drug: AVZO-023

Drug: Fulvestrant

Phase 1, combination (Parts 1C)

Experimental group

Description:

Escalating doses of twice daily, oral AVZO-023 in combination with once daily, oral AVZO-021, with once daily, oral letrozole in 28-day cycles

Treatment:

Drug: AVZO-021

Drug: Letrozole

Drug: AVZO-023

Phase 2, combination (Cohorts 2A, 2B, 2C, and 2D)

Experimental group

Description:

Oral doses of AVZO-023 in 28-day cycles at the RP2D determined in Part 1B/1C, in combination with: 2A) letrozole 2B) fulvestrant 2C) AVZO-021 plus fulvestrant 2D) AVZO-021 plus letrozole

Treatment:

Drug: AVZO-021

Drug: Letrozole

Drug: AVZO-023

Drug: Fulvestrant