Study of IK-595 in RAS- or RAF-altered Advanced Tumors

Brief summary public domain (ClinicalTrials.gov)

This is a Phase 1, FIH, Dose Escalation and Dose Expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) effects, and preliminary antitumor activity of IK-595, a MEK/RAF molecular glue, administered orally as monotherapy in patients with advanced solid tumors with gene alterations in the RAS- MAPK pathway for whom there are no further treatment options known to confer clinical benefit.

Detailed description public domain (ClinicalTrials.gov)

This is a Phase 1, FiH clinical study to evaluate the safety, tolerability, PK and pharmacodynamic effects, and preliminary anti-tumor activity of IK-595, a dual mitogen-activated protein kinase kinase (MEK)/ RAF kinase inhibitor, administered orally (PO) as monotherapy in patients with advanced solid tumors with gene alterations in the RAS- MAPK pathway for whom there are no further treatment options known to confer clinical benefit. The study consists of an initial Dose Escalation phase using a Bayesian Optimal Interval (BOIN) design, followed by a Dose Expansion phase in 4 genetically/molecularly defined cohorts using 2-stage adaptive design. During the Dose Escalation phase, backfilling may occur, where ≥ 3 additional patients can be enrolled at a given dose level once that dose level is deemed safe and tolerable by the Safety Review Committee. Backfilling includes, but is not limited to, patients with the following diagnoses: neuroblastoma RAS viral oncogene homolog-mutant (NRASmut) colorectal carcinoma (CRC), NRASmut malignant melanoma , Kirsten rat sarcoma viral oncogene homolog-mutant (KRASmut) CRC, KRASmut pancreatic cancer, KRASmut non-small cell lung cancer(NSCLC), B-Raf proto-oncogene, serine/threonine kinase-mutant (BRAFmut) Class II/III or BRAF fusion positive solid tumors, and Raf-1 proto-oncogene, serine/threonine kinase-mutant (CRAFmut) or fusion positive solid tumors. Various dose levels and schedules will be explored.

Intervention public domain (ClinicalTrials.gov)

Drug: IK-595. Oral tablet administered in 28-day or 30-day cycles until treatment discontinuation criteria are met.

Arm public domain (ClinicalTrials.gov)

IK-595 (experimental): Dose Escalation and Dose Expansion

Primary outcome public domain (ClinicalTrials.gov)

Treatment-emergent adverse events, including treatment-related adverse events, and serious adverse events. • Frequency and severity of treatment-emergent adverse events, including treatment-related adverse events, and serious adverse events Time frame: From treatment initiation through study completion, average of 36 months.

Primary outcome public domain (ClinicalTrials.gov)

Dose Limiting Toxicities. Number of patients with dose-limiting toxicities (Dose Escalation only) Time frame: The first 30 days of treatment for each patient during Dose Escalation.

Primary outcome public domain (ClinicalTrials.gov)

Treatment-Emergent Adverse Events. Number and percentage of patients with ≥ 1 treatment-emergent adverse events leading to dose modifications and treatment discontinuation Time frame: From treatment initiation through study completion, average of 36 months.

Primary outcome public domain (ClinicalTrials.gov)

Recommended Phase 2 Dose (RP2D) and/or maximum tolerated dose (MTD) of IK-595. Selection of dose level to take proceed with in Dose Expansion and/or Phase 2 Time frame: From treatment initiation through dose escalation, approximately 1 year.

Secondary outcome public domain (ClinicalTrials.gov)

Pharmacokinetics of IK-595: half-life (t1/2). Time frame: From treatment initiation through dose escalation, approximately 1 year.

Secondary outcome public domain (ClinicalTrials.gov)

Pharmacokinetics of IK-595: Area Under the Curve (AUC). Time frame: Approximately 1 year.

Secondary outcome public domain (ClinicalTrials.gov)

Pharmacokinetics of IK-595: Maximum Plasma Concentration (Cmax). Time frame: Approximately 1 year.

Secondary outcome public domain (ClinicalTrials.gov)

Pharmacokinetics of IK-595: Minimum Plasma Concentration (Cmin). Time frame: Approximately 1 year.

Secondary outcome public domain (ClinicalTrials.gov)

To evaluate pERK fold change from baseline in paired tumor biopsies. Time frame: Through study completion, average of 36 months.

Secondary outcome public domain (ClinicalTrials.gov)

Antitumor activity per RECIST 1.1: Disease control rate (DCR) of IK-595 as a single agent. Time frame: Through study completion, average of 36 months.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria: 1. Patients ≥ 18 years of age. 2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 3. Adequate organ function as follows (specimens must be collected during the Screening Period within 7 days prior to entering the Treatment Period): 1. ANC ≥ 1000/μL 2. Hemoglobin \> 9 g/dL 3. Platelet count \> 75,000/μL 4. Calculated creatinine clearance ≥ 60 mL/min (using the Cockcroft-Gault formula or using other formulae per institutional guidelines) 5. Serum total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 × ULN. Known Gilbert syndrome is allowed if total bilirubin is \<3 × ULN 6. AST and ALT ≤ 2.5 × ULN (or ≤ 5 × ULN if liver function abnormalities are due to underlying liver metastases) 7. Coagulation: ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy, as long as prothrombin time, international normalized ratio, or activated partial thromboplastin time is within therapeutic range of intended use of anticoagulants when applicable 4. Left ventricular ejection fraction ≥ 50% by echocardiogram or radionuclide test. 5. Patients must have recovered from the side effects of prior cancer-specific therapy to a minimum of ≥ Grade 1 by NCI-CTCAE version 5.0 criteria or return to baseline. Exceptionally, patients with ≤ Grade 2 neuropathy or other TRAEs may be eligible after discussion with the Sponsor. 6. Washout period since receipt of the last dose of prior anticancer therapy (including other investigational therapy): 1. Checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death ligand 1 (PD-L1) inhibitors: ≥ 4 weeks 2. For all other biologic agents (e.g., antiangiogenics): ≥ 3 weeks or a minimum of their dosing interval if shorter than 3 weeks (e.g., agents administered every 2 weeks would require a 2-week washout period) 3. All other investigational agents: ≥ 4 weeks or ≥ 5 × t1/2, whichever is shorter. 7. If feasible, patients must be willing to consent to the submission of formalin-fixed paraffin-embedded (FFPE) tissue blocks of tumor tissue, preferably from a pretreatment, fresh tumor biopsy. Alternatively, archival tumor FFPE blocks or, ≥ 20 unstained slides of tumor tissue from available archival sources that are \< 2 years old are acceptable. 8. Highly effective contraception for both male and female patients from Screening through 5 months after the last dose of study …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 75 participants (actual).

Why stopped public domain (ClinicalTrials.gov)

Limited resources and strategic priorities