Clinical Trials /

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

NCT03051035

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: First-in-Human Study of KO-947 in Non-Hematological Malignancies
  • Official Title: A Phase 1 First-in-Human Study of KO-947 in Locally Advanced Unresectable or Metastatic, Relapsed and/or Refractory Non-Hematological Malignancies

Clinical Trial IDs

  • ORG STUDY ID: KO-ERK-001
  • NCT ID: NCT03051035

Conditions

  • Advanced Malignant Neoplasm

Interventions

DrugSynonymsArms
KO-947KO-947

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
KO-947Experimental
  • KO-947

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the MTD of KO-947 monotherapy in a 28-day cycle.
Time Frame:Dose-limiting toxicities will be evaluated during the first 28 days of KO-947 monotherapy treatment.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Number of patients that experience Adverse Events (AEs)
Time Frame:Until 30 days after the end of study
Safety Issue:
Description:
Measure:Maximum plasma concentration (Cmax) of KO-947 on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Plasma concentration of KO-947 over 24 hours after dosing on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Time to maximum plasma concentration (tmax) of KO-947 on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Time to the last detectable plasma concentration (tlast) of KO-947 on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Terminal half-life (t½λz) of KO-947 on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve for KO-947 from zero to 24 hours [AUC(0-24)] on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve for KO-947 from zero to the last detectable plasma concentration [AUC(0-last)] on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:
Measure:Trough plasma concentration (Ctrough) of KO-947 on Cycle 1 Day 1 and Cycle 2 Day 1
Time Frame:Blood samples for determination of KO-947 concentration will be collected at 0, 1, end of infusion, 1.5 2, 2.5 3, 3.5, 4, 6, 8, 24 hours during dose escalation and dose expansion.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kura Oncology, Inc.

Trial Keywords

  • non-hematological malignancies
  • non-squamous
  • squamous
  • BRAF
  • KRAS
  • NRAS

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