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
- Phase
- Phase 1/2
- Status
- Recruiting
- Sponsor
- Avenzo Therapeutics Inc.
- Enrollment
- 52
- Locations
- 13
- Primary Endpoint
- Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1)
Overview
Brief 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).
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 years to 65+ years (18-64 Years, 65+ Years)
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Phase 1, monotherapy (Part 1A)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles.
Intervention: AVZO-021 (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: AVZO-021 (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Palbociclib (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Fulvestrant (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Letrozole (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Ribociclib (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Abemaciclib (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Carboplatin (Drug)
Phase 1, combination (Parts 1B and 1C)
Escalating doses of once daily, oral AVZO-021 in 28-day cycles starting at least 1 DL below the monotherapy MTD/RP2D dose in combination with:
1B1) fulvestrant
1B2) palbociclib plus either fulvestrant or letrozole
1B3) ribociclib plus either fulvestrant or letrozole
1B4) abemaciclib plus either fulvestrant or letrozole
1B5) sacituzumab govitecan-hziy
1C) carboplatin
Intervention: Sacituzumab Govitecan-hziy (Drug)
Phase 2, monotherapy (Part 2A)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Part 1A.
Intervention: AVZO-021 (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: AVZO-021 (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Palbociclib (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Fulvestrant (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Letrozole (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Ribociclib (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Abemaciclib (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Carboplatin (Drug)
Phase 2, combination (Parts 2B and 2C)
Oral doses of AVZO-021 in 28-day cycles at the RP2D determined in Parts 1B/1C, in combination with:
2B1) fulvestrant
2B2) palbociclib plus either fulvestrant or letrozole
2B3) ribociclib plus either fulvestrant or letrozole
2B4) abemaciclib plus either fulvestrant or letrozole
2B5) sacituzumab govitecan-hziy
2C) carboplatin
Intervention: Sacituzumab Govitecan-hziy (Drug)
Outcomes
Primary Outcomes
Occurrence of Dose Limiting Toxicities (DLTs) during the first cycle (Phase 1)
Time Frame: 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)
Time Frame: Approximately 22 months
To evaluate the type, incidence, severity, timing, seriousness, and relationship to study treatment of adverse events and any laboratory abnormalities summarized by dose level.
Determination of Recommended Phase 2 Dose (RP2D) (Phase 1)
Time Frame: Approximately 16 months
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.
Objective Response Rate (ORR) (Phase 2)
Time Frame: Approximately 52 months
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.
Progression Free Survival (PFS) (Phase 2)
Time Frame: Approximately 52 months
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 2)
Time Frame: Approximately 76 months
Defined as the time from study drug treatment initiation to death from any cause.
Duration of response (DOR) (Phase 2)
Time Frame: Approximately 52 months
Defined as the time from the first confirmed response to radiologic/objective progression.
Secondary Outcomes
- PK Parameters: Maximum plasma concentration (Cmax) (monotherapy and combination)(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)(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)(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)(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)(Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days))
- PK Parameters: Elimination half-life (t1/2) (monotherapy and combination)(Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days))
- PK Parameters: Accumulation ration (Rac) (monotherapy and combination)(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)(5 days)
- PK Parameters: Apparent clearance (CL/F) (monotherapy and combination)(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)(Cycle 1 days 1, 2, 8, 14, and 15 (each cycle is 28 days))
Investigators
Naresh Nayyar
Scientific
Avenzo Therapeutics Inc.