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

Phase 1

Not yet recruiting

• Conditions: Advanced Solid Tumor; HR+/HER2- Breast Cancer; HR+, HER2-, Advanced Breast Cancer; CDK Gene Mutation; CCND1 Gene Amplification; CDK4 Gene Amplification
• Interventions: Drug: AVZO-021; Drug: Fulvestrant; Drug: Letrozole; Drug: AVZO-023

• Registration Number: NCT06998407
• Lead Sponsor: Avenzo Therapeutics, Inc.

Brief Summary

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 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.

Study Timeline

• Status Verified: 2025-04
• Study First Submitted: 2025-05-22
• Study First Submitted QC: 2025-05-22
• Study First Posted: 2025-05-31
• Study Start: 2025-06
• Last Update Submitted: 2025-06-10
• Last Update Posted: 2025-06-13
• Primary Completion: 2028-08
• Study Completion: 2030-08

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 380

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1, combination (Parts 1B)	Fulvestrant	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
Phase 1, combination (Parts 1B)	AVZO-023	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
Phase 1, combination (Parts 1C)	AVZO-021	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
Phase 1, combination (Parts 1C)	Letrozole	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
Phase 1, combination (Parts 1C)	AVZO-023	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
Phase 2, combination (Cohorts 2A, 2B, 2C, and 2D)	AVZO-021	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
Phase 2, combination (Cohorts 2A, 2B, 2C, and 2D)	Fulvestrant	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
Phase 2, combination (Cohorts 2A, 2B, 2C, and 2D)	Letrozole	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
Phase 2, combination (Cohorts 2A, 2B, 2C, and 2D)	AVZO-023	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
Phase 1, monotherapy (Part 1A) and food effect	Fulvestrant	Escalating doses of twice daily, oral AVZO-023 in 28-day cycles, with addition of fulvestrant for patients with HR+/HER2- mBC
Phase 1, monotherapy (Part 1A) and food effect	AVZO-023	Escalating doses of twice daily, oral AVZO-023 in 28-day cycles, with addition of fulvestrant for patients with HR+/HER2- mBC
Phase 1, combination (Parts 1B)	AVZO-021	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

Primary Outcome Measures

Name	Time	Method
Determine the Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) (Phase 1)	Approximately 16 months
Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1)	Cycle 1 (28 Days)	Number of participants with DLTs assessed for severity using CTCAE v5.0 criteria will be summarized by dose level.
Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 1)	From baseline until end of study treatment or study completion (approximately 2 years)
Objective Response Rate (ORR) (Phase 2)	From baseline through disease progression or study completion (approximately 2 years)	Defined as the proportion of patients with a confirmed Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1.

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) (Phase 1)	From baseline through disease progression or study completion (approximately 2 years)
Duration of response (DOR) (Phase 1 and Phase 2)	From baseline through time to event on study or study completion (approximately 2 years)	Defined as the time from the first confirmed response to radiologic/objective progression.
Progression Free Survival (PFS) (Phase 1 and Phase 2)	From baseline through time to event on study or study completion (approximately 2 years)	Defined as the time from study drug treatment to death or disease progression, as determined by the investigator by radiographic disease assessment according to RECIST v1.1.
Overall Survival (OS) (Phase 1 and Phase 2)	Approximately 76 months	Defined as the time from study drug treatment initiation to death from any cause.
Disease control rate (DCR) (Phase 1 and Phase 2)	From baseline through disease progression or study completion (approximately 2 years)	Defined as the proportion of patients who achieve tumor relief (CR or PR) and stable disease (SD) after treatment; calculated as the sum of CR, PR, and SD.
Clinical benefit rate (CBR) (Phase 1 and Phase 2)	From baseline through disease progression or study completion (approximately 2 years)	Defined as the percentage of advanced cancer patients who achieve CR, PR, or at least six months of SD after treatment.
PK Parameters: Maximum plasma concentration (Cmax) (Phase 1)	Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
PK Parameters: Time to maximum plasma concentration (Tmax) (Phase 1)	Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
PK Parameters: Elimination half-life (t1/2) (Phase 1)	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)	Day 1 and Day 15 of Cycle 1 (each cycle is 28 days)
Determination of RP2D (Phase 2)	Approximately 16 months
Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 2)	From baseline until end of study treatment or study completion (approximately 2 years)

Trial Locations

Locations (1)

Avenzo Therapeutics Recruiting Site; 🇺🇸 Fairfax, Virginia, United States