Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Phase I Dose-Escalation Study of AZD4785 in Patients With Advanced Solid Tumours

Summary: A Phase I, open-label, multicentre, dose-escalation study to investigate the safety, pharmacokinetics and maximum tolerated dose (MTD) of AZD4785 in patients with advanced solid tumours where KRAS may be an important driver of tumour survival.
  Part A: Dose escalation in patients with solid tumours to evaluate safety, pharmacokinetics and dose
  Part B: Expansion cohort at the selected dose in patients with non small cell lung cancer to evaluate pharmacodynamics and clinical response

Detailed description: This is a First-Time-in-Human (FTIH), Phase 1 study to determine the MTD, recommended Phase 2 dose (RP2D), safety, tolerability, pharmacodynamics, and pharmacokinetics of AZD4785. The study will be conducted in two parts: a dose-escalation part (Part A) and an expansion part (Part B). Part B will include three patient groups. Patients must have KRAS mutations (KRASm+) identified in tumour tissue samples in order to enter the study.
  AZD4785 will be given as an IV infusion over 1 hour, initially in 3 loading doses during the first week and then weekly thereafter. The loading doses will be given on Days 1, 3, and 5 of the first week and weekly thereafter on Days 8, 15, and 22 of 28 Day cycles. In subsequent cycles AZD4785 will be administered on Days 1, 8, 15, and 22 until disease progression, intolerable toxicity, or discontinuation criteria have been met.

Eligibility: Inclusion Criteria
  Part A: Adult patients with solid tumours known to harbour KRAS mutations for whom no standard therapies are available.
  Part B: Adult patients with locally advanced or metastatic non-small cell lung cancer known to harbour KRAS mutations for whom no standard therapies are available.
  1. Signed written informed consent
  2. ≥ 18 years old
  3. Adequate organ system function as indicated by:
  1. Absolute neutrophil count (ANC) ≥ 1.5 x 10(exp9)/L
  2. Platelets ≥ 100 x 10(exp9)/L
  3. Haemoglobin ≥ 9g/dL
  4. Activated partial thromboplastin time (aPTT) ≤ 1.5 times the upper limit of normal (ULN)
  5. Total bilirubin ≤ 1.5 mg/dL
  6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 times the ULN if no liver involvement or ≤ 5 times the ULN with liver involvement.
  7. Creatinine ≤ 1.5 times the ULN or creatinine clearance ≥ 60 mL/min as calculated by the Cockcroft-Gault method, or 24 hour measured urine creatinine clearance ≥ 60 mL/min.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  5. Life expectancy ≥ 12 weeks
  6. Willing to use appropriate methods of contraception
  Exclusion Criteria:
  1. Patients who have received chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs within 21 days or 5 half lives (whichever is shorter) from enrolment.
  2. With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of enrolment.
  3. Unresolved immunotherapy-related hepatotoxicity from previous therapy.
  4. Major surgery (excluding placement of vascular access) ≤ 21 days from beginning of the enrolment or minor surgical procedures ≤ 7 days. No waiting is required following implantable port and catheter placement.
  5. Patients receiving full-dose anti-coagulation therapies.
  6. Has active or prior documented autoimmune disease within the past 2 years with the exception of vitiligo, Grave's disease, and/or psoriasis not requiring systemic treatment.
  7. Has a history of atypical Haemolytic Uremic Syndrome.
  8. Patients with leptomeningeal metastases.
  9. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 3 weeks prior to enrolment and there is no evidence of central nervous system disease progression or mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.
  10. Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
  11. Any of the following cardiac criteria:
  1. Congestive heart failure (CHF) per New York Heart Association (NYHA) classification > Class II.
  2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  3. Unstable angina or new-onset angina.
  4. QT interval (QTcF) >470 ms on screening electrocardiogram (ECG) by Fridericia's formula.
  12. History of hypersensitivity to active or inactive excipients of AZD4785 or drugs with a similar chemical structure or class to AZD4785.
  13. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
  14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.

Relevance to patient case: not relevant