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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT3645 in Participants With Select Advanced or Metastatic Solid Tumors

Conditions
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Non-small Cell Lung Cancers, Sarcoma, Endometrial Cancer, Breast Cancer, Glioblastoma, Head and Neck Squamous Cell Carcinoma, Malignant Mesothelioma

Intervention / Treatment
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* Drug: PRT3645


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy that have either progress or ineligible for standard of care therapy: HR+ and HER2- or HR+ and HER2+ breast cancer Recurrent GBM (IDH wild type) or CDKN2A/B homozygous deleted IDH-mutant astrocytoma KRAS-mutant or SMARCA4 loss NSCLC 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 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT3645<br>PRT3645 capsules will be self-administered once daily, continuously, at the dose-level assigned | Drug: PRT3645<br>* PRT3645 capsules will be self-administered once daily, continuously, at the dose-level assigned<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) of PRT3645 | Dose limiting toxicity will be evaluated over the 28-day observation period | Baseline through Day 28 | 
| Safety and tolerability of PRT3645: AEs, CTCAE Assessments | 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. | Baseline through approximately 2 years | 
| Maximally tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT3645 | The MTD/RP2D will be established for further investigation in participants with advanced solid tumors | Baseline through approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of PRT3645: Tumor assessment and responses | 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. | Baseline through approximately 2 years | 
| Pharmacokinetic profile of PRT3645: Minimum and maximum observed plasma concentration | PRT3645 pharmacokinetics will be calculated including the minimum and maximum observed plasma concentration. | Baseline through approximately 2 years | 
| Pharmacodynamic effect of PRT3645: Target engagement | Pharmacodynamic effect of PRT3645 demonstrating target engagement by assessment of phosphorylation of Rb. | Baseline through approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Solid Tumors, Breast Cancer, CDK4/6, Cyclin-dependent Kinase 4, Cyclin-dependent Kinase 6, Glioblastoma, Head and Neck Squamous Cell Carcinoma, HNSCC, Malignant Mesothelioma, Metastatic Solid Tumors, Non-small Cell Lung Cancers, NSCLC, PRT3645, Sarcoma, Endometrial Cancer