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

Phase 1

Terminated

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

• Registration Number: NCT05228015
• Lead Sponsor: Ikena Oncology

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2022-01-07
• Study First Submitted: 2022-01-07
• Study First Submitted QC: 2022-01-27
• Study First Posted: 2022-02-08
• Primary Completion: 2024-08-27
• Study Completion: 2024-09-09
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-14
• Last Update Posted: 2024-11-18

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 67

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
IK-930 and Osimertinib Combination Dose Escalation	Osimertinib	-
IK-930 Single Agent Dose Expansion	IK-930	-
IK-930 Single Agent Dose Escalation	IK-930	-
IK-930 and Osimertinib Combination Dose Escalation	IK-930	-

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Antitumor activity: Median progression-free survival (PFS) 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: Disease control rate (DCR) 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
Pharmacokinetics of IK-930: half-life (t1/2)	Approximately 1 year
Pharmacokinetics of IK-930: Area Under the Curve (AUC)	Approximately 1 year
Antitumor activity: Median overall survival (OS) of IK-930 as a single agent	Through study completion, average of 36 months
Pharmacokinetics of IK-930: Maximum Plasma Concentration (Cmax)	Approximately 1 year
Pharmacokinetics of IK-930: Minimum Plasma Concentration (Cmin)	Approximately 1 year

Trial Locations

Locations (12)

Peninsula South Eastern Haematology and Oncology Group (PASO Medical); 🇦🇺 Frankston, Victoria, Australia

The University of Chicago; 🇺🇸 Chicago, Illinois, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Start Midwest; 🇺🇸 Grand Rapids, Michigan, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

University of Pennsylvania Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

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

Sarah Cannon Research Institute; 🇺🇸 Nashville, Tennessee, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Next Oncology; 🇺🇸 San Antonio, Texas, United States

University Hospitals of Leicester NHS Trust; 🇬🇧 Leicester, England, United Kingdom

The Royal Marsden Hospital; 🇬🇧 London, England, United Kingdom