Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects with Advanced Solid Tumors

A Phase 1, First-in-Human Study of IK-930, an Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects with Advanced Solid Tumors

This is a Phase 1, first-in-human (FIH) clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of IK-930, an oral TEAD inhibitor, administered orally (PO) as monotherapy in subjects with advanced solid tumors with or without gene alterations in the Hippo pathway for whom there are no further treatment options known to confer clinical benefit. The study consists of two phases, an initial Dose Escalation phase followed by a Dose Expansion phase.

Study Overview

• Status: Terminated
• Conditions: Solid Tumor; Solid Tumors, Adult; Malignant Pleural Mesothelioma (MPM); Epithelioid Hemangioendothelioma (EHE); NF2 Deficient Mesothelioma; NF2 Deficiency; YAP1 or TAZ Gene Fusions; Other NF2 Deficient Solid Tumors and Solid Tumors with YAP1/TAZ Fusion Genes
• Intervention / Treatment: Drug: IK-930; Drug: Osimertinib

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Peninsula South Eastern Haematology and Oncology Group (PASO Medical)
• United Kingdom
  • England
    • Leicester, England, United Kingdom, LE1 5WW
      • University Hospitals of Leicester NHS Trust
    • London, England, United Kingdom, SW3 6JJ
      • The Royal Marsden Hospital
• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Massachusetts General Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • START Midwest
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Abramson Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female subjects ≥ 18 years of age.
3. If feasible, subjects must be willing to consent to the submission of formalin-fixed paraffin-embedded tissue blocks or slides of tumor tissue, preferably from pre-treatment, baseline fresh tumor biopsy at Screening. Alternatively, archival tumor FFPE blocks or, unstained slides of tumor tissue from available archival sources are acceptable.
4. In the dose escalation cohort: Subjects with histologically proven advanced, unresectable, locally recurrent, or metastatic malignancy that has progressed on or following standard-of-care therapies and for whom there is no available therapy known to confer clinical benefit, regardless of the presence or absence of NF2 deficiency or other genetic alterations of the Hippo pathway. Subjects with histological confirmation of MPM; subjects with NF2-deficient MPM determined by local test results for testing can also be enrolled as well as subjects with any other solid tumors with documented NF2 deficiency determined by local test results for testing, including, but not limited to, meningioma, cholangiocarcinoma, thymoma, mucoepidermoid NSCLC, HCC, and others. Subjects diagnosed with EHE with documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined by local tests and subjects with solid tumors who have YAP1/TAZ gene fusions as determined by local test results can also be enrolled in the dose escalation part of the study.

5. In the Dose expansion: Four groups of subjects will be enrolled:

   1. Cohort 1: Subjects with histological confirmed MPM and that have documented NF2 deficiency,
   2. Cohort 2: Subjects with other documented NF2-deficient solid tumors agnostic to tumor type including, but not limited to, meningioma, cholangiocarcinoma, thymoma, NSCLC, HCC, and others.
   3. Cohort 3: Subjects with histopathological diagnosis of epithelioid hemangioendothelioma (EHE) and documented TAZ-CAMTA1 or YAP1-TFE3 gene fusions, as determined by local test results. Subjects who have objective disease progression to prior therapy or have active disease and cancer-related pain requiring narcotics for management are eligible.
   4. Cohort 4: Subjects with any solid tumor with documented YAP1/TAZ gene fusions as determined by local test results.
6. In the Osimertinib Combination Cohort subjects must have a histologically proven, incurable, locally advanced or metastatic NSCLC expressing osimertinib-sensitive EGFR mutations; have evidence of radiological disease progression on prior receipt of Osimertinib and have progressed on additional anticancer therapy such as chemotherapy.
7. Subjects can have measurable or evaluable disease by RECIST 1.1 criteria as assessed by the Investigator/local radiologist.

Exclusion Criteria:

1. Subjects with untreated or symptomatic primary central nervous system (CNS) tumors or with intracranial metastases (excluding primary CNS tumors that may be eligible for enrollment as part of Cohort 2 e.g., NF-2 deficient meningioma)

   a. Subjects with leptomeningeal metastases are excluded

2. Uncontrolled or life-threatening symptomatic concomitant disease
3. Clinically significant cardiovascular disease as defined in the protocol
4. Women who are pregnant or breastfeeding
5. Subjects who are unable to swallow or retain oral medication
6. Prior treatment/exposure to YAP/TAZ/TEAD inhibitors
7. Other inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IK-930 Single Agent Dose Escalation	Drug: IK-930; tablets for oral administration
Experimental: IK-930 Single Agent Dose Expansion	Drug: IK-930; tablets for oral administration
Experimental: IK-930 and Osimertinib Combination Dose Escalation	Drug: IK-930; tablets for oral administration; Drug: Osimertinib; tablets for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of IK-930	The frequency and severity, incidence of treatment-emergent and treatment-related adverse events using NCI-CTCAE v5.0	Through study completion, an average of 36 months
Occurrence of Dose Limiting Toxicity during first treatment cycle		Approximately 1 year
RP2D and/or MTD of IK-930	Define the recommended phase 2 dose (RP2D) and/or MTD of IK-930	Approximately 1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Antitumor activity per RECIST 1.1: Disease control rate (DCR) of IK-930 as a single agent	Through study completion, average of 36 months
Antitumor activity per RECIST 1.1: Time to response (TTR) of IK-930 as a single agent	Through study completion, average of 36 months
Antitumor activity per RECIST 1.1: Duration of response (DOR) of IK-930 as a single agent	Through study completion, average of 36 months
Antitumor activity per RECIST 1.1: Objective response rate (ORR) of IK-930 as a single agent	Through study completion, average of 36 months
Antitumor activity: Median progression-free survival (PFS) of IK-930 as a single agent	Through study completion, average of 36 months
Antitumor activity: Median overall survival (OS) of IK-930 as a single agent	Through study completion, average of 36 months
Pharmacokinetics of IK-930: half-life (t1/2)	Approximately 1 year
Pharmacokinetics of IK-930: Area Under the Curve (AUC)	Approximately 1 year
Pharmacokinetics of IK-930: Maximum Plasma Concentration (Cmax)	Approximately 1 year
Pharmacokinetics of IK-930: Minimum Plasma Concentration (Cmin)	Approximately 1 year

Collaborators and Investigators

• Sponsor: Ikena Oncology
• Investigators: Study Director: Katherine Kim, MD, Ikena Oncology; Study Chair: Caroline Germa, MD, Ikena Oncology

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2022
• Primary Completion (Actual): August 27, 2024
• Study Completion (Actual): September 9, 2024

Study Registration Dates

• First Submitted: January 7, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (Actual): February 8, 2022

Study Record Updates

• Last Update Posted (Estimated): November 18, 2024
• Last Update Submitted That Met QC Criteria: November 14, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: NF2 mutated tumors; YAP/TAZ; IK-930; HIPPO Pathway; TEAD
• Additional Relevant MeSH Terms: Neoplasms by Site; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Neoplasms, Vascular Tissue; Hemangioma; Mesothelioma, Malignant; Neoplasms; Mesothelioma; Hemangioendothelioma; Hemangioendothelioma, Epithelioid; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Osimertinib
• Other Study ID Numbers: IK930-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No