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

Study Overview
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Brief Summary
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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.

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

Conditions
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Solid Tumors, Adult, Solid Tumor, 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

Intervention / Treatment
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* Drug: IK-930


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study. Male or female subjects ≥ 18 years of age. If feasible, subjects must be willing to consent to the submission of formalin-fixed paraffin-embedded tissue blocks of tumor tissue, preferably from pre-treatment fresh tumor biopsy. Alternatively, archival tumor FFPE blocks or, preferably, 10 unstained slides of tumor tissue from available archival sources are acceptable. 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 RNA-seq, FISH or IHC and subjects with solid tumors who have YAP1/TAZ gene fusions as determined by RNA-seq, FISH or IHC, as documented by local test results can also be enrolled in the dose escalation part of the study. In the Dose expansion: Four groups of subjects will be enrolled: Cohort 1: Subjects with histological confirmed MPM and that have documented NF2 deficiency, 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. 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 for RNA-seq, FISH or IHC. Subjects who have objective disease progression to prior therapy or have active disease and cancer-related pain requiring narcotics for management are eligible. Cohort 4: Subjects with any solid tumor with documented YAP1/TAZ gene fusions as determined by local test results for RNA-seq, FISH or IHC. Subjects can have measurable or evaluable disease by RECIST 1.1 criteria as assessed by the Investigator/local radiologist. Comply with the study protocol and with the planned biopsy procedures. Exclusion Criteria: 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 Uncontrolled or life-threatening symptomatic concomitant disease Clinically significant cardiovascular disease as defined in the protocol Women who are pregnant or breastfeeding Subjects who are unable to swallow or retain oral medication Other inclusion/exclusion criteria may apply

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 dose escalation: BOIN design; Part 2 dose expansion: 4 parallel cohorts, Simon 2-stage
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: IK-930 Single Agent Dose Escalation<br> | Drug: IK-930<br>* tablets for oral administration<br>|
| Experimental: Experimental: IK-930 Single Agent Dose Expansion<br> | Drug: IK-930<br>* tablets for oral administration<br>|

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IK-930, HIPPO Pathway, TEAD, YAP/TAZ, NF2 mutated tumors