Study of AVZO-021 in Patients With Advanced Solid Tumors

Advanced Solid Tumor Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05867251
• Other study ID #: AVZO-021-1001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 30, 2023
• Est. completion date: January 31, 2030

Study information

• Verified date: February 2024
• Source: Avenzo Therapeutics, Inc.
• Contact: Medical Information
• Phone: (858) 239-2944
• Email: ClinicalTrials[@]avenzotx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study, the first clinical trial of AVZO-021, aims to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and anti-tumor effects of AVZO-021 in patients with advanced solid tumors. AVZO-021 is an oral medication that inhibits cyclin-dependent kinase 2 (CDK 2).

Description:

AVZO-021 is a compound being developed for the treatment of patients with advanced solid tumors, specifically, HR+/HER2- breast cancer and cyclin E1 (CCNE1) altered malignancies. AVZO-021 is a selective and potent cyclin-dependent kinase 2 (CDK2) inhibitor, which plays an important role in cell cycle regulation. This is a Phase 1/2 first-in-human, open-label, nonrandomized, multicenter study of AVZO-021. Phase 1 is a dose-escalation phase aimed at assessing the safety and tolerability of AVZO-021 and determining the recommended phase 2 dose (RP2D) as monotherapy and combination therapy. Phase 2 is a dose-expansion phase that will be conducted to assess the antitumor activity of AVZO-021 as monotherapy and combination therapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 430
• Est. completion date: January 31, 2030
• Est. primary completion date: January 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

1. Male or female aged =18 years old at screening with Eastern Cooperative Oncology Group (ECOG) 0-1.

2. Disease-related inclusion criteria by study phase and part:

i) Phase 1a Monotherapy Dose Escalation: Locally advanced or metastatic solid tumor associated with dependency on CDK2 (eg, HR+/HER2- breast cancer, CCNE1 amplified solid tumors, FBXW7 loss of function mutation/deletion and retinoblastoma protein (Rb)1 loss of function mutation/deletion), for which standard therapies are no longer effective, appropriate, or safe in the opinion of the investigator (Cohort 1A).

ii) Phase 1b Combination Dose Escalation: Histologically or cytologically confirmed diagnosis of locally advanced or metastatic HR+/HER2- (HER2-low may be allowed if failed standard of care therapy) breast cancer in patients who have been previously treated with inhibitor of CDK4/6 and endocrine therapy (Cohorts 1B1, 1B2, 1B3, and 1B4); or Histologically or cytologically confirmed diagnosis of CCNE1 amplified locally advanced or metastatic EOC in patients who are platinum-refractory or platinum-resistant (Cohort 1C).

iii) Phase 2a Monotherapy dose expansion: Histologically or cytologically confirmed diagnosis of locally advanced or metastatic CCNE1 amplified solid tumors Cohort 2A

iv) Phase 2b Combination dose expansion: Histologically or cytologically confirmed diagnosis of locally advanced or metastatic HR+/HER2- (HER2-low may be allowed if failed standard of care therapy) breast cancer who have been previously treated with no more than 1 prior CDK4/6 inhibitor and endocrine therapy (Cohorts 2B1, 2B2, 2B3, and 2B4); or Histologically or cytologically confirmed diagnosis of CCNE1 amplified locally advanced or metastatic EOC in patients who are platinum-refractory or platinum-resistant (Cohort 2C).

3. No more than 2 prior cytotoxic chemotherapy regimens for locally advanced/metastatic disease (prior chemotherapy in the adjuvant or neoadjuvant setting allowed if >12 months prior to starting AVZO-021 treatment and is not considered a prior line).

4. Measurable disease as determined by RECIST version 1.1.

5. Adequate bone marrow and organ function.

6. Ability to swallow capsules or tablets.

Key Exclusion Criteria:

1. Received an investigational agent or anticancer therapy within 2 weeks, or 5 half-lives of the drug, whichever is shorter, prior to planned start of AVZO-021.

2. Received any CDK2 inhibitor, protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) inhibitor, or WEE1 inhibitor anticancer therapy.

3. Undergone major surgery within 4 weeks prior to planned start of AVZO-021.

4. Received radiotherapy for palliation within 7 days of the first dose of study treatment, unless specified otherwise in the protocol.

5. Active CNS metastases or confirmed leptomeningeal disease are not eligible.

6. Unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade >1 at the time of starting study treatment.

7. Clinically unstable cardiac function as described in the protocol.

8. Any active or chronic infection/disease that compromises the immune system.

9. Current treatment with strong or moderate cytochrome P450 (CYP)3A4 inhibitors or inducers.

10. Active second malignancy unless in remission with life expectancy > 2 years and with documented sponsor approval.

11. Pregnancy, lactation, or plans to breastfeed during the study or within 6 months of the last dose of study intervention.

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Neoplasms

Intervention

Drug:
• AVZO-021
AVZO-021 is a selective and potent oral inhibitor of CDK2 being developed for the treatment of patients with advanced solid tumors with CDK2 dependency (1A), CCNE1 amplified solid tumors (2A), HR+/HER2- BC (B1-B4) and CCNE1 amplified EOC (C)
• Palbociclib
Antineoplastic agent, cyclin-dependent kinase 4/6 inhibitor
• Fulvestrant
Antineoplastic agent, estrogen receptor antagonist
• Letrozole
Antineoplastic agent, aromatase inhibitor
• Ribociclib
Antineoplastic CDK4/6 inhibitor
• Abemaciclib
Antineoplastic CDK4/6 inhibitor
• Carboplatin
Alkylating agent

Locations

Country	Name	City	State
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	NEXT Virginia	Fairfax	Virginia
United States	Yale Cancer Center	New Haven	Connecticut
United States	Oklahoma University	Oklahoma City	Oklahoma
United States	Sidney Kimmel Cancer Center (SKCC) at Jefferson Health	Philadelphia	Pennsylvania
United States	Florida Cancer Specialists	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Avenzo Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1)	Number of participants with DLTs assessed for severity using CTCAE v5.0 criteria will be summarized by dose level.	28 Days
Primary	Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 1)	To evaluate the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events and any laboratory abnormalities summarized by dose level.	Approximately 22 months
Primary	Determination of Recommended Phase 2 Dose (RP2D) (Phase 1)	RP2D for AVZO-021 is less than or the same as the maximum tolerated dose (MTD) as defined by the occurrence of DLTs and TEAEs calculated using isotonic regression.	Approximately 16 months
Primary	Objective Response Rate (ORR) (Phase 2)	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.	Approximately 52 months
Primary	Progression Free Survival (PFS) (Phase 2)	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.	Approximately 52 months
Primary	Overall Survival (OS) (Phase 2)	Defined as the time from study drug treatment initiation to death from any cause.	Approximately 76 months
Primary	Duration of response (DOR) (Phase 2)	Defined as the time from the first confirmed response to radiologic/objective progression.	Approximately 52 months
Secondary	PK Parameters: Maximum plasma concentration (Cmax) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Time to maximum plasma concentration (Tmax) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-last) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-tau) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Minimum observed plasma concentration at steady state (Cmin, ss) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Accumulation ration (Rac) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Elimination half-life (t1/2) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Apparent clearance (CL/F) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	PK Parameters: Apparent volume of distribution during terminal phase (Vz/F) (monotherapy and combination)		Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)
Secondary	Evaluate the effect of a high-fat meal on the PK of AVZO-021 (Phase 1)		5 days