Study of AVZO-021 in Patients With 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-021 as a Single Agent and in Combination Therapy in Patients With Advanced Solid Tumors

Overview

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).

Detailed 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.

Interventions

• 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 (1B1-1B5, 2B1-2B5) and CCNE1 amplified EOC (1C, 2C)
• Drug Palbociclib
  Antineoplastic agent, cyclin-dependent kinase 4/6 inhibitor
• Drug Fulvestrant
  Antineoplastic agent, estrogen receptor antagonist
• Drug Letrozole
  Antineoplastic agent, aromatase inhibitor
• Drug Ribociclib
  Antineoplastic CDK4/6 inhibitor
• Drug Abemaciclib
  Antineoplastic CDK4/6 inhibitor
• Drug Carboplatin
  Alkylating agent
• Drug Sacituzumab Govitecan-hziy
  Trop-2 antibody and topoisomerase inhibitor

Primary outcome measures

• Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1) [Time frame: 28 Days]
• Number of Participants with Treatment Emergent Adverse Events (TEAEs) and lab abnormalities (Phase 1) [Time frame: Approximately 22 months]
• Determination of Recommended Phase 2 Dose (RP2D) (Phase 1) [Time frame: Approximately 16 months]
• Objective Response Rate (ORR) (Phase 2) [Time frame: Approximately 52 months]
• Progression Free Survival (PFS) (Phase 2) [Time frame: Approximately 52 months]
• Overall Survival (OS) (Phase 2) [Time frame: Approximately 76 months]
• Duration of response (DOR) (Phase 2) [Time frame: Approximately 52 months]

Secondary outcome measures (10)

• PK Parameters: Maximum plasma concentration (Cmax) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Time to maximum plasma concentration (Tmax) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-last) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC 0-tau) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Minimum observed plasma concentration at steady state (Cmin, ss) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Accumulation ration (Rac) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Elimination half-life (t1/2) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Apparent clearance (CL/F) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• PK Parameters: Apparent volume of distribution during terminal phase (Vz/F) (monotherapy and combination) [Time frame: Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days)]
• Evaluate the effect of a high-fat meal on the PK of AVZO-021 (Phase 1) [Time frame: 5 days]

Eligibility criteria

Inclusion criteria

• Male or female aged ≥18 years old at screening with Eastern Cooperative Oncology Group (ECOG) 0-1.
• Disease-related inclusion criteria by study phase and part:

i) Phase 1a Monotherapy Dose Escalation: Patients with locally advanced or metastatic HR+/HER2- breast cancer, CCNE1-amplified tumors that are either epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer or TNBC, with no other oncogenic driver mutations that are treatable and standard therapies are no longer effective, appropriate, or safe in the opinion of the investigator and medical monitor. Patients with any additional tumor type with CCNE1 amplification can be enrolled only if clinical data is supportive and approved by medical monitor (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, who have been previously treated with inhibitor of CDK4/6 and endocrine therapy(Cohorts 1B1, 1B2, 1B3, 1B4, and 1B5); or histologically or cytologically confirmed diagnosis of CCNE1- amplified, locally advanced or metastatic, platinum-refractory or platinum-resistant EOC, primary peritoneal, or fallopian tube cancer (Cohort 1C).

iii) Phase 2a Monotherapy dose expansion: Histologically or cytologically confirmed diagnosis of locally advanced or metastatic CCNE1 amplified epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, endometrial cancer or TNBC, with no other oncogenic driver mutations that are treatable and standard therapies are no longer effective, appropriate, or safe in the opinion of the investigator and medical monitor (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, 2B4, and 2B5); or Histologically or cytologically confirmed diagnosis of locally advanced or metastatic, CCNE1-amplified, platinum-refractory or platinum-resistant EOC, primary peritoneal cancer, or fallopian tube cancer (Cohort 2C).

• No more than 2 prior cytotoxic chemotherapy regimens for locally advanced/metastatic disease (excepting patients treated with an antibody-drug conjugate, with ovarian cancer if there disease is platinum resistant or refractory, having progressed beyond all SOC care; and patients who have received prior chemotherapy in the adjuvant or neoadjuvant setting >12 months prior to starting AVZO-021 treatment).
• Measurable disease as determined by RECIST version 1.1.
• Adequate bone marrow and organ function.
• Ability to swallow capsules or tablets.

Exclusion criteria

• 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.
• Received any CDK2 inhibitor, protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) inhibitor, or WEE1 inhibitor anticancer therapy. For cohort B5, prior therapy with topoisomerase inhibitors is not permitted.
• Undergone major surgery within 4 weeks prior to planned start of AVZO-021.
• Received radiotherapy for palliation within 7 days of the first dose of study treatment, unless specified otherwise in the protocol.
• Active CNS metastases or confirmed leptomeningeal disease are not eligible.
• 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.
• Clinically unstable cardiac function as described in the protocol.
• Any active or chronic infection/disease that compromises the immune system.
• Current treatment with strong or moderate cytochrome P450 (CYP)3A4 inhibitors or inducers.
• Active second malignancy unless in remission with life expectancy > 2 years and with documented sponsor approval.
• Pregnancy, lactation, or plans to breastfeed during the study or within 6 months of the last dose of study intervention.

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 · 11 centers

• Yale Cancer Center — New Haven
• Florida Cancer Specialists — Sarasota
• Moffitt Cancer Center — Tampa
• Perlmutter Cancer Center at NYU Langone Hospital - Long Island — Mineola
• NYU Langone Medical Center (Tisch Hospital) — New York
• University Hospitals Cleveland Medical Center — Cleveland
• Oklahoma University — Oklahoma City
• Providence Cancer Institute — Portland
• … and 3 more centers

Australia · 2 centers

• Macquarie University Hospital — Macquarie University
• Cancer Care Wollongong — Wollongong

Identifiers

NCT: NCT05867251 · AVZO-021-1001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗