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.
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. Three dosing schedules will be executed
(Schedule 1, 2, or 3).
Screening evaluations will be completed following signing of informed consent and within
either 21 days or 28 days of Cycle 1 Day 1. Evaluations performed as part of the standard of
care within 21/28 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.
Key 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: Subject must have a locally confirmed diagnosis of either
of the following tumor types:
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 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.
4. Subject has at least one measurable lesion per RECIST v1.1.
5. 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.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Serum albumin ≥ 2.8 g/dL
8. 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.
9. 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.
10. Acceptable hematologic status:
1. Absolute neutrophil count (ANC) ≥ 1500 cells/μL
2. Platelet count ≥ 100,000/μL
3. Hemoglobin ≥ 9.0 g/dL
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. 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
5. Allergy or hypersensitivity to components of the KO-947 formulation, e.g. dextrose,
hydroxypropyl beta cyclodextrin, acetic acid, sodium acetate and water for injection.
6. 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).
7. Grade >1 gastrointestinal toxicity that cannot be managed with supportive care
measures.
8. 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.
9. 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.
10. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1,
without complete recovery.
11. 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.
