First-in-Human Study of KO-947 in Non-Hematological Malignancies

Overview

NCT ID: NCT03051035
Sponsor Protocol Number: KO-ERK-001

About this study

This phase 1 first-in-human (FIH) dose escalation study will determine the maximum tolerated dose (MTD) of KO-947 in subjects with locally advanced unresectable or metastatic, relapsed and/or refractory, non-hematological malignancies. If an MTD cannot be identified, a recommended phase 2 dose (RP2D) will be determined. In addition, two tumor specific extension cohorts may be conducted to further characterize the safety and tolerability of KO-947 and provide preliminary evidence of anti-tumor activity.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Subject is at least 18 years of age.
  • Subject has a locally advanced unresectable or metastatic, relapsed and/or refractory, non-hematological malignancy for which treatment with an approved agent that is considered standard of care in the indication either does not exist or has proven ineffective.
  • To be enrolled in the dose escalation, Subject must have a locally confirmed diagnosis of either of the following tumor types:
    • Malignancy of non-squamous histology that carries a BRAF, KRAS, NRAS or HRAS mutation(s);
    • Malignancy of squamous histology. In cases of mixed histology, squamous must be the predominant histology.
  • Upon the identification of an MTD or RP2D, the Sponsor, in consultation with the study investigators, may open the enrolment of an MTD/RP2D expansion cohort and two nonrandomized tumor specific extension cohorts. Subject must have a locally confirmed diagnosis of either of the following tumor types:
    • RASMUT/BRAFMUT NSCLC: Subject must have a locally confirmed diagnosis of RAS (NRAS, KRAS, HRAS) or BRAF mutated non-small cell malignancies of the lung. Subject must have received at least 1 prior approved regimen for locally advanced or metastatic disease followed by documented progressive disease;
    • SCCHN and/or SCCE: Subject must have a locally confirmed diagnosis of SCCHN or SCCE with amplification of the 11q13 chromosome. Subject must have received at least 1 prior approved agent for advanced or metastatic disease followed by documented progressive disease. For subjects with 11q13 amplification, the tumor must have > 3 copies of the 11q13 chromosome as determined by a methodology approved by the Sponsor.
  • Subject has at least one measurable lesion per RECIST v1.1.
  • Subject has consented to provide at least 10 unstained tumor slides from an archival formalin-fixed, paraffin-embedded (FFPE) tumor block or the entire tissue block for retrospective testing of genetic abnormalities and gene expression profiles. If archival tissue is not available, subject must consent to tumor biopsy.
  • For the MTD/RP2D expansion cohort, subject must have an accessible tumor lesion(s) and consent to tumor biopsy of such a lesion(s) during screening and after starting KO-947 treatment for the analysis of ERK pathway signalling and biological effects.
  • At least 2 weeks since the last systemic therapy regimen prior to enrolment. Subjects must have recovered to NCI CTCAE v4.03 Grade 1 or less from all acute toxicities (excluding Grade 2 toxicities that are not considered a safety risk by the Sponsor and Investigator) or toxicity must be deemed irreversible by the Investigator. 
  • At least 2 weeks since last radiotherapy. If radiation was localized to the only site of measurable disease, there must be documentation of disease progression of the irradiated site. Subjects must have recovered from all acute toxicities from radiotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Serum albumin ≥ 2.8 g/dL.
  • Acceptable liver function:
    • Bilirubin ≤ 1.5 times upper limit of normal (x ULN); if liver metastases are present, then ≤ 2 x ULN is allowed. Criteria does not apply to subjects with Gilbert’s syndrome diagnosed as per institutional guidelines;
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN; if liver metastases are present, then ≤ 5 x ULN is allowed.
  • Acceptable renal function with serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance ≥50 mL/min using the Cockcroft-Gault or Modification of Diet in Renal Disease formulas.
  • Acceptable hematologic status:
    • Absolute neutrophil count (ANC) ≥ 1500 cells/μ;
    • Platelet count ≥ 100,000/μ;
    • Hemoglobin ≥ 9.0 g/dL.
  • Female subjects:
    • Of non-child-bearing potential (surgically sterilized or at least 2 years postmenopausal); or
    • If of child-bearing potential, subject must use a highly effective method of contraception, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence. Both females and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception for 2 weeks prior to screening, during, and at least 28 days after last dose of trial medication for females and 90 days for males. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication;
    • Not breast feeding at any time during the study.
  • Male subjects with female partners of childbearing potential must agree to use an adequate method of contraception for 2 weeks prior to screening, during, and at least 4 weeks after last dose of trial medication.
  • Written and voluntary informed consent understood, signed and dated.

Exclusion Criteria:

  • Ongoing treatment with an anticancer agent not contemplated in this protocol.
  • History of prior significant toxicity (Grade 2 or higher that required permanent treatment discontinuation) from a BRAF, MEK (MAPK [Mitogen-activated protein]/ERK kinase) or ERK inhibitor.
  • History of retinal vein occlusion, neurosensory retinal detachment, or neovascular macular degeneration. Evidence of visible retinal pathology as assessed by ophthalmologic examination that is considered a risk factor for retinal vein thrombosis or neurosensory retinal detachment.
  • Mean QTcF of > 470 ms on triplicate ECGs performed within 5 minutes of each other; subjects currently taking drugs known to be associated with prolonging the QT interval for which there are no adequate therapeutic substitutes; subjects with congenital long QT syndrome. As a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause torsades de pointes, https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.
  • Allergy or hypersensitivity to components of the KO-947 formulation, e.g. dextrose, hydroxypropyl beta cyclodextrin, acetic acid, sodium acetate and water for injection.
  • Participation in any interventional study within 4 weeks of Cycle 1 Day 1. or 5 half-lives of the investigational agent(s) used in the interventional study prior to Cycle 1 Day 1 (whichever is shorter).
  • Grade > 1 gastrointestinal toxicity that cannot be managed with supportive care measures.
  • Received treatment for unstable angina within the prior year, myocardial infarction within the prior year, cerebro-vascular attack within the prior year, history of New York Heart Association grade III or greater congestive heart failure, or current serious cardiac arrhythmia requiring medication except atrial fibrillation.
  • Known uncontrolled brain, leptomeningeal or epidural metastases (unless treated and well controlled for at least 4 weeks prior to Cycle 1 Day 1). Controlled brain metastases that require continuous high dose corticosteroid use within 4 weeks of Cycle 1 Day 1.
  • Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery.
  • Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. Known infection with human immunodeficiency virus, or an active infection with hepatitis B or hepatitis C.
  • Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the Subject in this study.
  • Subject has legal incapacity or limited legal capacity.
  • Significantly altered mental status that would limit the understanding or rendering of informed consent and compliance with the requirements of this protocol. Unwillingness or inability to comply with the study protocol for any reason.

 

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