A First-in-Human (FiH) Study of IK-595, an Oral Dual MEK/RAF Inhibitor, in Patients With RAS-or RAF-altered Advanced Solid Tumors

Study Identifier:
IK595-001
CT.gov Identifier:
NCT06270082
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
N/A
Study Contact Information:
(210) 593-5651 or [email protected]
Terminated/Withdrawn

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Study Summary

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.

To assess IK-595 in patients with RAS-mutated cancers potentially including CRAF dependent, NRAS mutant, and KRAS mutant tumors

To evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Bladder
  • Breast Cancers
  • Bowel (Colorectal)
  • Non-Small Cell Lung Cancer
  • Ovarian
  • Pancreas
  • Melanoma
  • Renal
  • Glioblastoma
  • Gastric
  • Solid Tumor
  • Thyroid
  • CNS
  • Astrocytoma
  • Oligodendroglioma
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
  • Drug: Experimental: IK-595
    • Read More
  • Drug: Intervention/treatment
  • Drug: 2024 ASCO:
    • Study Status
    Indicates the current recruitment status or the expanded access status
    Terminated/Withdrawn

    Requirements information
    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 drug if the possibility of conception
    • exists.
    • 9. Patient or their legally acceptable representative must be able and willing to:
    • 1. Provide Institutional Review Board-or Institutional Ethics Committee-approved
    • written informed consent in accordance with regulatory and institutional
    • guidelines. This must be obtained before the performance of any protocol-related
    • procedures that are not part of normal patient care.
    • 2. Comply with the study protocol and with the planned biopsy procedures.
    • Inclusion Criteria for Dose Escalation Patients
    • 10. Patients must have histologically or cytologically confirmed solid tumor malignancies
    • that are advanced and unresectable, or metastatic with no available therapy known to
    • confer clinical benefit, as evaluated by the treating physician. There is no upper
    • limit on the number of prior lines of anticancer therapy received. Tumors must have
    • confirmed RAS/RAF gene alterations as determined by next-generation sequencing or
    • fluorescence in situ hybridization, as documented by local testing:
    • 1. NRASmut solid tumors, including but not limited to melanoma, CRC, and others
    • 2. KRASmut solid tumors, including but not limited to NSCLC, pancreatic carcinoma,
    • and CRC
    • 3. BRAFmut Class I/II/ III or BRAF fusions solid tumors, including but not limited
    • to melanoma, NSCLC, thyroid carcinoma
    • 4. CRAF-altered solid tumors (mutations and gene fusions)
    • 5. NF1mut solid tumors, including but not limited to nerve sheath tumors, gliomas,
    • malignant melanoma, breast cancer, and others
    • 11. Patients who have measurable or evaluable disease by RECIST 1.1 criteria, as assessed
    • by the Investigator/local radiologist.
    • Inclusion Criteria for Dose Expansion Patients
    • 12. All patients must have a histological diagnosis of an advanced, unresectable, locally
    • recurrent, or metastatic disease with no available therapy known to confer clinical
    • benefit, as evaluated by the treating physician. There is no upper limit on the number
    • of prior lines of anticancer therapy received.
    • 13. Patients must be enrolled in 1 of the following 4 dose expansion cohorts:
    • 1. Cohort 1: Molecularly confirmed NRASmut CRC as determined by local test results
    • 2. Cohort 2: Molecularly confirmed NRASmut malignant melanoma as determined by local
    • test results
    • 3. Cohort 3 Molecularly confirmed KRASmut NSCLC as determined by local test results
    • 4. Cohort 4: Any solid tumors with molecularly confirmed pathogenic BRAF non-V600X
    • mutations or fusions, or pathogenic CRAF mutations or fusions as determined by
    • local test results
    • 14. Patients must have ≥ 1 measurable lesion per RECIST 1.1 criteria as assessed by the
    • Investigator/local radiologist. Lesions situated in a previously irradiated area are
    • considered measurable if progression has been demonstrated in such lesions.
    • Exceptionally, patients with tumors that are evaluable but non-measurable per RECIST
    • 1.1 criteria can be enrolled following approval by the Sponsor.
    Exclusion criteria
    • 1. Patients with any active central nervous system (CNS) lesion either symptomatic or
    • radiologically unstable and/or leptomeningeal metastasis. However, patients previously
    • treated for these conditions that have had stable CNS disease (verified with
    • consecutive imaging studies) for > 3 months, are asymptomatic and are not currently
    • taking corticosteroids, or are on stable dose or decreasing of corticosteroids for ≥ 7
    • days prior to enrollment are eligible.
    • 2. Patients who have not recovered to ≤ Grade 1 or baseline from all AEs due to prior
    • anticancer therapies. Exceptionally, patients with ≤ Grade 2 neuropathy or other TRAEs
    • may be eligible after discussion with the Sponsor.
    • 3. Any other concurrent antineoplastic treatment or investigational agent except for
    • localized radiation therapy for symptom palliation (to be considered nontarget lesions
    • after treatment) and/or hormonal therapy for ductal DCIS/LCIS/Stage 1 breast cancer
    • that has been stable on therapy for ≥ 3 years.
    • 4. Uncontrolled or life-threatening symptomatic concomitant disease (including known
    • symptomatic HIV-positive with an active AIDS-defining opportunistic infection or a
    • current CD4 count < 350 cells/μL; symptomatic active hepatitis B or C checked at
    • screening; or active tuberculosis). Patients with HIV are eligible if:
    • 1. They have received antiretroviral therapy (ART) as clinically indicated for ≥ 4
    • weeks prior to entering the Treatment Period of the study;
    • 2. They continue on ART as clinically indicated while on study;
    • 3. CD4 counts and viral loads are monitored per standard of care by a local health
    • care provider.
    • 5. Has received prior radiotherapy for palliation ≤ 2 weeks prior to the first dose of
    • study treatment. Patients must have recovered from all radiation-related toxicities.
    • 6. History of a second malignancy requiring systemic treatment ≤ 3 years prior to
    • enrollment. Patients who have remained cancer-free ≤ 3 years of enrollment are
    • eligible. Patients with history of prior early stage basal/squamous cell skin cancer
    • or noninvasive or in situ cancers that have undergone definitive treatment at any
    • prior time are eligible.
    • 7. Clinically significant cardiovascular disease:
    • 1. Cerebral vascular accident/stroke (< 6 months prior to enrollment)
    • 2. Myocardial infarction (< 6 months prior to enrollment)
    • 3. Unstable angina (< 6 months prior to enrollment)
    • 4. Congestive heart failure (New York Heart Association Classification Class III or
    • IV)
    • 5. The presence of any condition that can increase proarrhythmic risk (e.g.,
    • hypokalemia, bradycardia, heart block), including any new, unstable, or serious
    • cardiac arrhythmia requiring medication, or other baseline arrhythmias that might
    • interfere with interpretation of ECGs on study (e.g., bundle branch block).
    • 6. Patients with QT interval corrected by Fridericia's formula (QTcF) > 470 msec for
    • both men and women on screening ECG are excluded. Patients with a bundle branch
    • block must have QT interval corrected for bundle branch block.
    • 7. Patients who are on stable doses of concomitant medication with known
    • prolongation of QTcF if QTcF is > 470 msec.
    • 8. Known previous or current serious ophthalmic disorders, including history of glaucoma,
    • history of retinal vein occlusion (RVO) or current risk factors for RVO, history of
    • retinal pathology or evidence of retinal pathology.
    • 9. Active skin disorder requiring systemic treatment ≤3 months prior to start of study
    • treatment.
    • 10. History of rhabdomyolysis ≤3 months prior to start of study treatment.
    • 11. Patients taking any medication on the prohibited medication list are excluded from the
    • study unless they can be transferred to other medications.
    • 12. Has an active infection requiring systemic therapy.
    • 13. A woman of childbearing potential who has a positive pregnancy test prior to
    • initiating study treatment.
    • 14. Breastfeeding or expecting to conceive or father children within the projected
    • duration of the study, starting with the Screening visit through 5 months after the
    • last dose of study treatment.
    • 15. Patients who are unable to swallow or retain oral medication.

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Midwest
    Grand Rapids, MI, United States, 49546
    Investigator
    Nehal Lakhani
    Status
    Recruitment Complete
    Condition(s) Treated at Site
    Bladder
    Breast Cancers
    Bowel (Colorectal)
    Non-Small Cell Lung Cancer
    Ovarian
    Pancreas
    Melanoma
    Renal
    Glioblastoma
    Gastric
    Solid Tumor
    Thyroid
    CNS
    Astrocytoma
    Oligodendroglioma