Clinical Trials /

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

NCT03101839

Description:

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 maximum tolerated dose (MTD). Once the maximum tolerated dose (MTD) is established, a dose expansion cohort may be included in Part A, with up to an additional 6 patients to further explore the PK, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 MTD for confirmation of the recommended phase 2 dose (RP2D). Part B: Expansion cohort at the selected dose in patients with non-small cell lung cancer (NSCLC) to evaluate PK parameters, safety, tolerability, and preliminary anti-tumour activity of the AZD4785 RP2D as monotherapy in patients with NSCLC. Approximately 20 patients with NSCLC (Two groups of approximately 10 patients each) with NSCLC will be enrolled to Part B. Group 1 patients will have an option to provide tumour biopsies and Group 2 will be required (mandatory) to provide paired tumour biopsies. Overall up to 12 patients in Group 2Part B patients will be required (mandatory) to may provide paired tumour biopsies. A third group of up to 20 patients with other tumour types and/or a potential different schedule may be added based on the results seen in Parts A and B and any other emerging data and may also provide biopsies.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Dose-Escalation Study of AZD4785 in Patients With Advanced Solid Tumours
  • Official Title: A Phase I, Open-Label, Multicentre Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD4785 in Patients With Advanced Solid Tumours Where KRAS May Be an Important Driver of Tumour Survival

Clinical Trial IDs

  • ORG STUDY ID: D8360C00001
  • NCT ID: NCT03101839

Conditions

  • Advanced Solid Tumours

Interventions

DrugSynonymsArms
AZD4785AZD4785

Purpose

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 patients with 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.
    

Trial Arms

NameTypeDescriptionInterventions
AZD4785ExperimentalThis is a single-arm study in which all patients will receive AZD4785 by IV infusion. Patients will continue to receive treatment with AZD4785 until disease progression, intolerable toxicity, or discontinuation criteria are met.
  • AZD4785

Eligibility Criteria

        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.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Minimum of 28 days for a patient
Safety Issue:
Description:Determined through the evaluation of dose-limiting toxicity (DLT), adverse events, clinical laboratory test results, clinical evaluation and patient reported symptoms

Secondary Outcome Measures

Measure:Peak plasma concentration (Cmax) of AZD4785
Time Frame:Samples for determination of AZD4785 plasma conc. will be collected at multiple times on Day 1 Cycle 1, pre-dose on Days 3, 5, and 8 of Cycle 1, Day 22 of Cycle 2, and Day 1 of Cycles 3 and 4. Time points may be adjusted based on emerging data.
Safety Issue:
Description:The concentration of AZD4785 in plasma, including peak concentration (Cmax), will be determined.
Measure:Area under the plasma concentration versus time curve (AUC) for AZD4785
Time Frame:Samples for determination of AZD4785 plasma conc. will be collected at multiple times on Day 1 Cycle 1, pre-dose on Days 3, 5, and 8 of Cycle 1, Day 22 of Cycle 2, and Day 1 of Cycles 3 and 4. Time points may be adjusted based on emerging data.
Safety Issue:
Description:The concentration of AZD4785 in plasma, including area under the plasma concentration versus time curve (AUC), will be determined.
Measure:Objective Clinical Response
Time Frame:Every 8 weeks up to 12 months.
Safety Issue:
Description:CT scan to measure tumour
Measure:KRAS messenger RNA (mRNA)
Time Frame:1-3 months
Safety Issue:
Description:Change from baseline in KRAS mRNA following treatment.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Last Updated

June 16, 2017