Patient case: 57-year-old male with lung adenocarcinoma; genetic feature: KRAS (G12V), high tumor mutational burden

Clinical trial: First-in-Human Study of KO-947 in Non-Hematological Malignancies

Summary: 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.

Detailed description: 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. Screening evaluations will be completed following signing of informed consent and within 4 weeks (28 days) of Cycle 1 Day 1. Evaluations performed as part of the standard of care within 28 days of dosing but prior to consent do not need to be repeated. By signing the consent form, study subjects agree to the collection of standard of care health information.
  The study will consist of three parts: dose escalation, MTD expansion and tumor specific extension.

Eligibility: Inclusion Criteria:
  1. 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.
  2. To be enrolled in the dose escalation or in the MTD expansion, Subject must have a locally confirmed diagnosis of either of the following tumor types:
  1. Malignancy of non-squamous histology that carries a BRAF, KRAS, NRAS or HRAS mutation(s).
  2. Malignancy of squamous histology. In cases of mixed histology, squamous must be the predominant histology.
  3. Upon the identification of an MTD or RP2D, the Sponsor, in consultation with the study investigators, may open the enrollment of two of the following nonrandomized tumor specific extension cohorts:
  1. 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.
  2. SCCHN: Subject must have a locally confirmed diagnosis of SCCHN. Subject must have received at least 1 prior approved agent for advanced or metastatic disease followed by documented progressive disease.
  4. Subject has at least one measurable lesion per RECIST v1.1.
  5. Subject has consented to provide archival formalin-fixed, paraffin-embedded (FFPE) tumor block; if archival tissue is not available, Subject must consent to tumor biopsy.
  6. For the MTD 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.
  7. At least 2 weeks since the last systemic therapy regimen prior to enrollment. 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.
  8. 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.
  9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  10. Serum albumin ≥ 2.8 g/dL
  11. Acceptable liver function:
  1. 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.
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN; if liver metastases are present, then ≤ 5 x ULN is allowed.
  12. 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.
  13. Acceptable hematologic status:
  1. Absolute neutrophil count (ANC) ≥ 1500 cells/μL
  2. Platelet count ≥ 100,000/μL
  3. Hemoglobin ≥ 9.0 g/dL
  14. Female subjects:
  1. Of non-child-bearing potential (surgically sterilized or at least 2 years postmenopausal); or
  2. Of child-bearing potential, Subject must use an adequate method of contraception consisting of two-barrier method or one barrier method with a spermicide or intrauterine device from the time of signing the informed consent through at least 4 weeks after the last dose of study drug. Female subjects must have a negative serum or urine pregnancy test within 72 hours prior to start of trial medication.
  3. Not breast feeding at any time during the study.
  15. 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.
  16. Written and voluntary informed consent understood, signed and dated.
  Exclusion Criteria:
  1. Ongoing treatment with an anticancer agent.
  2. 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.
  3. 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.
  4. Allergy or hypersensitivity to components of the KO-947 formulation, e.g. dextrose, hydroxypropyl beta cyclodextrin, acetic acid, sodium acetate and water for injection.
  5. 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 longer).
  6. Grade >1 gastrointestinal toxicity that cannot be managed with supportive care measures.
  7. 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.
  8. 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.
  9. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery.
  10. 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.
  11. 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.
  12. Subject has legal incapacity or limited legal capacity.
  13. 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.

Relevance to patient case: possibly relevant