ORION-1: Study of AVZO-023 as a Single Agent and in Combination With AVZO-021, and/or Endocrine Therapy in Advanced Solid Tumors

A Phase 1/2, First-in-human Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of AVZO-023 as a Single Agent, and in Combination With AVZO-021 and/or Endocrine Therapy in Patients With Advanced Solid Tumors

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).

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 (NCT05867251).

In Phase 1, the safety and tolerability of AVZO-023 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.

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. Bone only disease is allowed in dose escalation.
• 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 any prior selective investigational 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. Patients who received radiation of >25% of bone marrow are excluded.
• 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
• Confirmed loss of function mutation or deletion of Rb1 gene
• Previous high-dose chemotherapy requiring stem cell rescue