A Study of PRT3645 in Participants With Select Advanced or Metastatic Solid Tumors

Phase 1

Completed

• Conditions: Breast Cancer; Glioblastoma; Head and Neck Squamous Cell Carcinoma; Non-small Cell Lung Cancers; Malignant Mesothelioma; Sarcoma; Endometrial Cancer
• Interventions: Drug: PRT3645

• Registration Number: NCT05538572
• Lead Sponsor: Prelude Therapeutics

Brief Summary

This is a Phase 1 dose-escalation study of PRT3645, a Cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor, in patients with advanced or metastatic solid tumors. The purpose of this study is to investigate the safety, tolerability, dose limiting toxicity, and to determine maximally tolerated dose and recommended phase 2 dose to be used in subsequent development of PRT3645.

Detailed Description

This is an open-label, multicenter, dose-escalation Phase 1 study of PRT3645, a CDK4/6 inhibitor, evaluating patients with selected advanced or metastatic solid tumors including breast cancer (BC), glioblastoma (GBM), non-small cell lung cancer (NSCLC), sarcomas, head and neck squamous cell carcinoma (HNSCC), malignant mesothelioma, and endometrial cancer. The study plan expects to evaluate approximately eight dose levels however additional dose levels may be explored. Taking into account pharmacokinetic and pharmacodynamic data from the preceding dose levels, the dose may be escalated until a dose limiting toxicity is identified. Up to 15 patients may be enrolled at a dose shown to be tolerated for confirmation of the MTD and/or RP2D.

Study Timeline

• Study First Submitted: 2022-09-09
• Study First Submitted QC: 2022-09-09
• Study First Posted: 2022-09-14
• Study Start: 2022-12-27
• Status Verified: 2024-06
• Primary Completion: 2024-06-26
• Study Completion: 2024-06-26
• Last Update Submitted: 2024-06-27
• Last Update Posted: 2024-07-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

• Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy that have either progress or ineligible for standard of care therapy:

  1. HR+ and HER2- or HR+ and HER2+ breast cancer
  2. Recurrent GBM (IDH wild type) or CDKN2A/B homozygous deleted IDH-mutant astrocytoma
  3. KRAS-mutant or SMARCA4 loss NSCLC
  4. CDK pathway alternation in any of the following tumor types: malignant mesothelioma, HPV-negative HNSCC (including oral cavity, oropharynx, hypopharynx, and larynx), sarcoma, or NSCLC
  5. Estrogen receptor positive with TP53 wild type endometrial cancer

• Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures

• Must have measurable or non-measureable (but evaluable) disease

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 or Karnofsky Performance Status (KPS) ≥80% (KPS is for GBM only)

• Adequate organ function.

• Able to swallow and retain oral medication.

• Must provide either archival or fresh tumor tissue sample during screening.

Exclusion Criteria

• Participants with advanced, symptomatic, extensive visceral disease.
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, any upper gastrointestinal surgery including gastric resection, known malabsorption syndrome, or other condition that may impair absorption of PRT3645.
• Treatment with strong inhibitors of CYP3A4.
• History of another malignancy within 3 years except for adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancies, or malignancies previously treated with curative intent and not on active therapy or expected to require treatment or recurrence during the study.
• Clinically significant or uncontrolled cardiac disease, uncontrolled electrolyte disorders, uncontrolled or symptomatic CNS metastases or leptomeningeal disease except for GBM.
• Endometrial cancer patients who had received prior treatment with a CDK 4/6 inhibitor.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
PRT3645	PRT3645	PRT3645 capsules will be self-administered once daily, continuously, at the dose-level assigned

Primary Outcome Measures

Name	Time	Method
Safety and tolerability of PRT3645: AEs, CTCAE Assessments	Baseline through approximately 2 years	Safety and tolerability will be evaluated by incidence of DLTs, laboratory measurements, severity of adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.
Maximally tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT3645	Baseline through approximately 2 years	The MTD/RP2D will be established for further investigation in participants with advanced solid tumors
Dose limiting toxicity (DLT) of PRT3645	Baseline through Day 28	Dose limiting toxicity will be evaluated over the 28-day observation period

Secondary Outcome Measures

Name	Time	Method
Efficacy of PRT3645: Tumor assessment and responses	Baseline through approximately 2 years	Objective response rate (ORR), Progression-free survival (PFS), Disease control rate (DCR) and Duration of response (DOR) will use RECIST v1.1, mRECIST v1.1, and/or RANO as primary measure for tumor assessment and response.
Pharmacokinetic profile of PRT3645: Minimum and maximum observed plasma concentration	Baseline through approximately 2 years	PRT3645 pharmacokinetics will be calculated including the minimum and maximum observed plasma concentration.
Pharmacodynamic effect of PRT3645: Target engagement	Baseline through approximately 2 years	Pharmacodynamic effect of PRT3645 demonstrating target engagement by assessment of phosphorylation of Rb.

Trial Locations

Locations (13)

Florida Cancer Specialists; 🇺🇸 Sarasota, Florida, United States

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

NEXT Virginia; 🇺🇸 Fairfax, Virginia, United States

Tennessee Oncology, PLLC; 🇺🇸 Nashville, Tennessee, United States

South Texas Accelerated Research Therapeutics, LLC; 🇺🇸 San Antonio, Texas, United States

AdventHealth Medical Group Oncology Research at Celebration; 🇺🇸 Celebration, Florida, United States

Miami Cancer Institute; 🇺🇸 Miami, Florida, United States

Winship Cancer Institute, Emory University; 🇺🇸 Atlanta, Georgia, United States

Thomas Jefferson University, Sidney Kimmel Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

National Cancer Centre Singapore; 🇸🇬 Singapore, Singapore

Laura and Isaac Perlmutter Cancer Center/ NYU Langone Health; 🇺🇸 New York, New York, United States

Smilow Cancer Hospital Phase 1 Unit; 🇺🇸 New Haven, Connecticut, United States