KZR-261 in Subjects With Advanced Solid Malignancies

Study Overview
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Brief Summary
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A first-in-human, open-label, multicenter, Phase 1 study of KZR-261 designed to assess the safety and tolerability, preliminary anti-tumor activity, and pharmacokinetics (PK) of KZR-261, as well as identify the recommended Phase 2 dose (RP2D). The study comprises a Part 1 (Dose Escalation) and a Part 2 (Dose Expansion) in solid organ tumors (melanoma/uveal melanoma, mesothelioma, colorectal cancer, prostate cancer, and All-Tumors).

Detailed Description
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The first-in-human, open-label, multicenter, Phase 1 study of KZR-261, Study KZR-261-101, will be conducted in two parts (dose escalation and dose expansion) to evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and evaluate the preliminary anti-tumor activity of KZR-261 in subjects with locally advanced or metastatic solid malignancies for whom no therapeutics are available that can confer a reasonable likelihood of clinical benefit. The 5 tumor cohorts in the dose expansion part include advanced malignant: melanoma/uveal melanoma mesothelioma colorectal cancer castrate-resistant prostate cancer All-Tumors Part 1 (Dose Escalation) and Part 2 (Dose Expansion) comprise a 4-week Screening Period, a Treatment Period lasting approximately 24 weeks, 4-6-week Safety Follow-up, and a 12-month Long-Term Follow-up Period (after last dose of study treatment), for a total study duration of approximately 20 months.

Official Title
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A Phase 1 Study of KZR-261, a Small Molecule Sec61 Inhibitor, in Subjects With Advanced Solid Malignancies

Conditions
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Advanced/Metastatic Solid Tumor

Intervention / Treatment
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* Drug: KZR-261


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic or cytologic evidence of malignant solid tumor with advanced disease (except primary central nervous system [CNS] neoplasms), defined as cancer that is either metastatic or locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered to result in reasonable clinical benefit). Disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy in the Investigator's judgement likely to result in clinical benefit, or if such therapy has been refused by the subject. Documentation of the reason must be provided for subjects who have not received a standard therapy likely to result in clinical benefit. Eastern Cooperative Oncology Group Performance Status score of 0 or 1. Adequate baseline hematologic and organ function. Willing to use contraception. Additional Inclusion for Part 2: Histologic or cytologic evidence of malignancy (melanoma/uveal melanoma, colorectal cancer, prostate cancer, mesothelioma). Exclusion Criteria: Subjects who have participated in Part 1 dose escalation are not eligible to enroll in Part 2 dose expansion. Persistent clinically significant toxicities from previous anticancer therapy (excluding alopecia). Treatment with cytotoxic, biologic, or targeted therapies for advanced cancer within 14 days before administration of the subject's first dose of KZR-261. Treatment with an investigational drug within 28 days before administration of the subject's first dose of KZR-261. Radiation therapy within 14 days of before administration of the subject's first dose of KZR-261. Major surgical procedure within 28 days before administration of the subject's first dose of KZR-261. History of risk factors for Torsades de pointes. Active, symptomatic CNS metastases or primary CNS malignancy. Any female who is breastfeeding or who plans to become pregnant during the study, or who are actively trying to conceive at the time of signing of the informed consent form (ICF). Uncontrolled, clinically significant pulmonary disease.

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: Single Group Assignment
Interventional Model Description: All subjects will receive 30 to 60-minute intravenous infusion of KZR-261 via a central line on Days 1, 8, and 15 of a 4-week (28-day) treatment cycle. Up to approximately 50 subjects will be enrolled and treated with KZR-261 in Part 1 (Dose Escalation). In Part 2 (Dose Expansion), up to 175 subjects (15-35 per tumor cohort [melanoma, uveal melanoma, colorectal cancer, prostate cancer, mesothelioma, and All-Tumor]) will be enrolled.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KZR-261 with standard therapy: open-label<br>Part 1 (Dose Escalation) The initial dose cohort of the Dose Escalation will receive 1.8 mg/m2 of KZR-261. Subjects will receive 3 doses in a 28-day cycle. ___________________________________________ Part 2 (Dose Expansion) Following safety review of all Dose Escalation cohorts and determination of the maximum tolerated dose (MTD) or maximum administered dose (MAD), KZR-261 will be evaluated for safety and preliminary efficacy in 4 tumor-specific cohorts and 1 all-tumor cohort to determine the recommended phase 2 dose (RP2D). The 4 tumor-specific cohorts will include: melanoma (including uveal melanoma) colorectal cancer prostate cancer mesothelioma | Drug: KZR-261<br>* KZR-261 for Injection is a lyophilized drug product supplied in single-use vials delivering 75 mg of KZR-261.<br>* Other names: KZR-261 for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and percentage of participants experiencing adverse events as assessed by CTCAE v5.0 (Part 1 & 2) | Incidence and percentage of adverse events and serious adverse events will be collected from start of enrollment | Approximately 20 months | 
| Number and percentage of participants experiencing dose-limiting toxicities as assessed by CTCAE v5.0 (Part 1) | Incidence and percentage of dose-limiting toxicities will be collected from start of enrollment | Approximately 20 months | 
| Maximum plasma concentration of KZR-261 (Part 1) | Summary of maximum plasma concentration (Cmax) will be assessed | Approximately 20 months | 
| The plasma concentration time curve of KZR-261 (Part 1) | Summary of the plasma concentration time curve (AUC) will be assessed | Approximately 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) of KZR-261 | Defined as the rate of partial responses (PRs) plus complete responses (CRs) according to RECIST v1.1 | Approximately 20 months | 
| Duration of response (DOR) of KZR-261 | Duration of overall response (partial response and complete response) | Approximately 20 months | 
| Progression-free Survival of Patients treated with KZR-261 | Time to disease progression | Approximately 20 months | 
| Overall Survival of Patients treated with KZR-261 | Time of overall survival | Approximately 20 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melanoma, uveal melanoma, colorectal cancer, prostate cancer, mesothelioma