Clinical trial NCT05228015: Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects with Advanced Solid Tumors
Official title: A Phase 1, First-in-Human Study of IK-930, an Oral TEAD Inhibitor Targeting the Hippo Pathway in Subjects with Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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
Keywords: IK-930
HIPPO Pathway
TEAD
YAP/TAZ
NF2 mutated tumors
Lead sponsor: Ikena Oncology
Sponsor class: INDUSTRY
First posted: 2022-02-08
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 dose escalation: BOIN design; Part 2 dose expansion: 4 parallel cohorts, Simon 2-stage
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Safety and tolerability of IK-930
timeFrame: Through study completion, an average of 36 months
measure: Occurrence of Dose Limiting Toxicity during first treatment cycle
timeFrame: Approximately 1 year
measure: RP2D and/or MTD of IK-930
timeFrame: Approximately 1 year
Secondary outcomes:
measure: Antitumor activity per RECIST 1.1: Disease control rate (DCR) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Antitumor activity per RECIST 1.1: Time to response (TTR) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Antitumor activity per RECIST 1.1: Duration of response (DOR) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Antitumor activity per RECIST 1.1: Objective response rate (ORR) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Antitumor activity: Median progression-free survival (PFS) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Antitumor activity: Median overall survival (OS) of IK-930 as a single agent
timeFrame: Through study completion, average of 36 months
measure: Pharmacokinetics of IK-930: half-life (t1/2)
timeFrame: Approximately 1 year
measure: Pharmacokinetics of IK-930: Area Under the Curve (AUC)
timeFrame: Approximately 1 year
measure: Pharmacokinetics of IK-930: Maximum Plasma Concentration (Cmax)
timeFrame: Approximately 1 year
measure: Pharmacokinetics of IK-930: Minimum Plasma Concentration (Cmin)
timeFrame: Approximately 1 year
Other outcomes:
Locations:
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Grand Rapids
country: United States
facility: Start Midwest
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania Abramson Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center at Thomas Jefferson University Hospital
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Next Oncology
state: Texas
city: Frankston
country: Australia
facility: Peninsula South Eastern Haematology and Oncology Group (PASO Medical)
state: Victoria
city: Leicester
country: United Kingdom
facility: University Hospitals of Leicester NHS Trust
state: England
city: London
country: United Kingdom
facility: The Royal Marsden Hospital
state: England
Study officials:
affiliation: Ikena Oncology
name: Katherine Kim, MD
role: STUDY_DIRECTOR
affiliation: Ikena Oncology
name: Caroline Germa, MD
role: STUDY_CHAIR
References: