KZR-261 in Subjects With Advanced Solid Malignancies

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

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 comprised a Part 1 (Dose Escalation) and a Part 2 (2A Dose Expansion and 2B Dose Optimization) in solid organ tumors (melanoma/uveal melanoma, mesothelioma, colorectal cancer, castration-resistant prostate cancer, and "All-Tumors").

Study Overview

• Status: Terminated
• Conditions: Advanced/Metastatic Solid Tumor
• Intervention / Treatment: Drug: KZR-261

Detailed Description

The first-in-human, open-label, multicenter, Phase 1 study of KZR-261, Study KZR-261-101, was 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 participants with locally advanced or metastatic solid malignancies for whom no therapeutics are available (or available therapeutics were refused) 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
• castration-resistant prostate cancer
• "All-Tumors" (other advanced solid malignancies)

Part 1 (Dose Escalation) and Part 2 (2A Dose Expansion and 2B Dose Optimization) comprised 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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals - Cleveland Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sara Cannon Research Institution (SCRI) - Tennessee Oncology Nashville
  • Texas
    • San Antonio, Texas, United States, 78229
      • START (South Texas Accelerated Research Therapeutics)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists (VCS)
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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, castration-resistant 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: KZR-261 with standard therapy: open-label; Part 1 (Dose Escalation): The initial dose cohort of the Dose Escalation received 1.8 mg/m2 of KZR-261. Participants received 3 doses in a 28-day cycle as an intravenous (IV) infusion for up to 6 cycles. _________________ Part 2A (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 was to 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; castration-resistant prostate cancer; mesothelioma Part 2B (Dose Optimization): Dose optimization in tumor-specific cohorts could have been initiated based on the totality of data after the MTD/MAD had been determined. Participants were to receive KZR-261 at the MTD/MAD or a lower clinically active dose of KZR-261.

Drug: KZR-261; KZR-261 for Injection is a lyophilized drug product supplied in single-use vials delivering 75 mg of KZR-261.; Other Names: KZR-261 for Injection

What is the study measuring?

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	20 months
Number and Percentage of Participants Experiencing Dose-limiting Toxicities	Number and percentage of participants experiencing dose-limiting toxicities (DLT) collected from start of enrollment through the first 28 days of Cycle 1 as assessed by CTCAE v5.0 (Part 1).	28 days
Maximum Plasma Concentration of KZR-261 (Part 1)	This is the maximum observed plasma concentration (Cmax) observed after administration of KZR-261 in Cycle 1 (Days 1 and 15) and Cycle 2 (Days 1 and 15). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose, 15 minutes post start of infusion, end of infusion, and 5, 15, 30 minutes, 1, 2, 4, 6, 24, 48, and 96 hours post infusion.	Cycle 1: Day 1, Cycle 1: Day 15, Cycle 2: Day 1, and Cycle 2: Day 15
The Plasma Concentration Time Curve of KZR-261 (Part 1)	This is the area under the curve (AUC) from predose through postdose observed after administration of KZR-261 in Cycle 1 (Days 1 and 15) and Cycle 2 (Days 1 and 15). The PK parameters were calculated using all timepoints at which the concentration was measured, ie. predose, 15 minutes post start of infusion, end of infusion, and 5, 15, 30 minutes, 1, 2, 4, 6, and 24 hours post infusion.	Cycle 1: Day 1, Cycle 1: Day 15, Cycle 2: Day 1, and Cycle 2: Day 15

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response (ORR) Following KZR-261	The objective response following KZR-261 defined as a best overall response of Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. A CR is defined as the disappearance of all target lesions and a PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of longest lesion diameters.	20 months
Participants With Clinical Benefit of Stable Disease Following KZR-261	The clinical benefit rate defined as the number of participants achieving a best response of complete response (CR)/partial response (PR) or stable disease over at least 2 consecutive response assessment time points. Stable disease is defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of longest diameters of target lesions while on study.	20 months
Progression-free Survival of Participants Treated With KZR-261	The number of participants with progression-free survival (PFS), defined as the date of initiation of study treatment to the date of documented PD or death from any cause, whichever occurs first, at 4 months and 6 months. PFS is based on the number of subjects in each group in the response evaluable population at the specific timepoints (4 or 6 months).	4 months and 6 months
Overall Survival of Participants Treated With KZR-261	Time of overall survival for participants treated with KZR-261.	20 months

Collaborators and Investigators

• Sponsor: Kezar Life Sciences, Inc.
• Investigators: Study Director: Kezar Study Director, Kezar Life Sciences, Inc.

Publications and helpful links

Helpful Links

• Kezar Life Sciences, Inc. corporate website

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Actual): January 17, 2025
• Study Completion (Actual): January 17, 2025

Study Registration Dates

• First Submitted: September 3, 2021
• First Submitted That Met QC Criteria: September 11, 2021
• First Posted (Actual): September 17, 2021

Study Record Updates

• Last Update Posted (Estimated): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: colorectal cancer; mesothelioma; melanoma; uveal melanoma; castration-resistant prostate cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Eye Diseases; Neoplasms, Glandular and Epithelial; Colonic Diseases; Neoplastic Processes; Adenoma; Neoplasms, Mesothelial; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Eye Neoplasms; Uveal Diseases; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Uveal Neoplasms; Colorectal Neoplasms; Mesothelioma; Neoplasm Metastasis; Melanoma; Uveal Melanoma; Therapeutics; Drug Administration Routes; Drug Therapy; Injections
• Other Study ID Numbers: KZR-261-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No