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

Official title

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

Overview

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).

Detailed 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 (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.

Interventions

• Drug AVZO-021
  AVZO-021 is an oral selective CDK2 inhibitor
• Drug Fulvestrant
  Antineoplastic agent, estrogen receptor antagonist
• Drug Letrozole
  Antineoplastic agent, aromatase inhibitor
• Drug AVZO-023
  AVZO-023 is an oral selective CDK4 inhibitor

Primary outcome measures

• Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1) [Time frame: Cycle 1 (28 Days)]
• Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 1) [Time frame: From baseline until end of study treatment or study completion (approximately 2 years)]
• Determine the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) (Phase 1) [Time frame: Approximately 16 months]
• Objective Response Rate (ORR) (Phase 2) [Time frame: From baseline through disease progression or study completion (approximately 2 years)]

Secondary outcome measures (12)

• Objective Response Rate (ORR) (Phase 1) [Time frame: From baseline through disease progression or study completion (approximately 2 years)]
• Duration of response (DOR) (Phase 1 and Phase 2) [Time frame: From baseline through time to event on study or study completion (approximately 2 years)]
• Progression Free Survival (PFS) (Phase 1 and Phase 2) [Time frame: From baseline through time to event on study or study completion (approximately 2 years)]
• Overall Survival (OS) (Phase 1 and Phase 2) [Time frame: Approximately 76 months]
• Disease control rate (DCR) (Phase 1 and Phase 2) [Time frame: From baseline through disease progression or study completion (approximately 2 years)]
• Clinical benefit rate (CBR) (Phase 1 and Phase 2) [Time frame: From baseline through disease progression or study completion (approximately 2 years)]
• PK Parameters: Maximum plasma concentration (Cmax) (Phase 1) [Time frame: Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)]
• PK Parameters: Time to maximum plasma concentration (Tmax) (Phase 1) [Time frame: Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)]
• PK Parameters: Elimination half-life (t1/2) (Phase 1) [Time frame: Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)]
• PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-last) (Phase 1) [Time frame: Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)]
• Determination of RP2D (Phase 2) [Time frame: Approximately 16 months]
• Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 2) [Time frame: From baseline until end of study treatment or study completion (approximately 2 years)]

Eligibility criteria

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

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 15 centers

• Avenzo Therapeutics Recruiting Site — Los Angeles
• Avenzo Therapeutics Recruiting Site — Los Angeles
• Avenzo Therapeutics Recruiting Site — New Haven
• Avenzo Therapeutics Recruiting Site — Orlando
• Avenzo Therapeutics Recruiting Site — Sarasota
• Avenzo Therapeutics Recruiting Site — Tampa
• Avenzo Therapeutics Recruiting Site — Boston
• Avenzo Therapeutics Recruiting Site — New York
• … and 7 more centers

Identifiers

NCT: NCT06998407 · AVZO-023-1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗