Patient case: 39-year-old female with melanoma; genetic feature: KIT (N822Y)

Clinical trial: A Safety, Tolerability and PK Study of DCC-2618 in Patients With Advanced Malignancies

Summary: This is a Phase 1, open-label, first-in-human (FIH) dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of DCC-2618, administered orally (PO), in adult patients with advanced malignancies. The study consists of 2 parts, a dose-escalation phase and an expansion phase.


Eligibility: Inclusion Criteria:
  Patients must meet all of the following criteria to be eligible to enroll in the study:
  1. Patients with solid tumor or hematologic malignancy must have a histologically confirmed, locally advanced malignancy refractory or intolerant to standard therapies and/or have no alternative effective therapy available, with the following exceptions:
  -  GIST patients must have progressed at least on imatinib.
  -  Systemic mastocytosis patients must have a confirmed diagnosis of aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL) according to 2008 World Health Organization (WHO) criteria for SM.
  2. Solid tumor or hematologic malignancy require an archival biopsy sample as long as no cancer therapy was administered since the sample was collected; otherwise, a fresh biopsy is required.
  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.
  4. The patient, or legally authorized representative, is capable of understanding and complying with the protocol and has signed the informed consent document.
  5. Adequate organ function and bone marrow reserve as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug:
  -  Bone Marrow Function: ANC ≥1500/µL; hemoglobin ≥9 g/dL; platelet count ≥75,000/µL.
  -  Hepatic Function: Total bilirubin ≤1.5 times the upper limit of normal (ULN); aspartate transaminase (AST)/alanine transaminase (ALT), ≤3 × ULN (≤5 × ULN in the presence of hepatic metastases).
  -  Renal Function: Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min based either on urine collection or Cockcroft Gault estimation.
  -  Coagulation Profile: Prothrombin time (PT) - international normalized ratio (INR)/partial thromboplastin time (PTT) ≤1.5 × ULN. Patients on a stable, maintenance regimen of anticoagulant therapy for at least 30 days prior to study drug administration may have PT/INR measurements >1.5 × ULN if, in the opinion of the Investigator, the patient is suitable for the study. An adequate rationale must be provided to the Sponsor prior to enrollment.
  SM patients with one or more inadequate organ function laboratory value may be eligible if both the Principal Investigator and Sponsor deem it to be disease related.
  Exclusion Criteria:
  Patients meeting any of the following criteria will be excluded from the study:
  1. Patients with leukemias, with the exception of MCL.
  2. Treatment with anticancer therapy, including investigational therapy, within 2 weeks prior to the administration of study drug. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days prior to the first administration of study drug.
  3. Unresolved toxicity NCI CTCAE Version 4.03 (i.e., >Grade 1 or baseline) from previous anticancer therapy, excluding alopecia.
  4. The patient has known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate.
  5. New York Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition.
  6. Arterial thrombotic or embolic events such as cerebrovascular accident (including ischemic attacks), pulmonary embolism, or hemoptysis within 6 months before start of study drug.
  7. Venous thrombotic events (e.g. deep vein thrombosis) within the 3 months before start of study drug.
  8. Baseline prolongation of the rate-corrected QT interval based on repeated demonstration of QTcF >450 ms in males or >470 ms in females or history of long QTc syndrome.
  9. Left ventricular ejection fraction <50% or below the lower limit of normal (whichever is higher).
  10. Concurrent treatment with proton-pump inhibitor.
  11. Major surgery within 4 weeks of the first dose of study drug.
  12. Any other clinically significant comorbidities, such as uncontrolled pulmonary disease, active infection, or any other condition, which in the judgment of the Investigator, could compromise compliance with the protocol, interfere with the interpretation of study results, or predispose the patient to safety risks.
  13. Malabsorption syndrome or other illness that could affect oral absorption.
  14. Known human immunodeficiency virus, active hepatitis B, or active hepatitis C infection.
  15. If female, the patient is pregnant or lactating.
  16. Known allergy or hypersensitivity to any component of the investigational drug product.

Relevance to patient case: not relevant