Clinical Trials /

A Clinical Trial to Evaluate AZD7648 Alone and in Combination With Other Anti-cancer Agents in Patients With Advanced Cancers

NCT03907969

Description:

This is a modular Phase I/IIa, open-label, multi-centre, study of AZD7648 administered orally, either as a monotherapy, or in combination with either cytotoxic chemotherapies or novel anti-cancer agents in participants with advanced malignancies.

Related Conditions:
  • Cancer
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Clinical Trial to Evaluate AZD7648 Alone and in Combination With Other Anti-cancer Agents in Patients With Advanced Cancers
  • Official Title: A Phase I/IIa, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Ascending Doses of AZD7648 Monotherapy or in Combination With Either Cytotoxic Chemotherapies or Novel Anti-Cancer Agents in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: D9170C00001
  • NCT ID: NCT03907969

Conditions

  • Advanced Malignancies

Interventions

DrugSynonymsArms
AZD7648Core Module: AZD7648 Monotherapy
Pegylated liposomal doxorubicin (PLD)DOXIL, CaelyxCombination Module 1: AZD7648 + PLD
OlaparibLynparzaCombination Module 2: AZ7648 + Olaparib

Purpose

This is a modular Phase I/IIa, open-label, multi-centre, study of AZD7648 administered orally, either as a monotherapy, or in combination with either cytotoxic chemotherapies or novel anti-cancer agents in participants with advanced malignancies.

Detailed Description

      This is a modular Phase I/IIa, open-label, multi-centre, study of AZD7648 administered
      orally, either as a monotherapy, or in combination with either cytotoxic chemotherapies or
      novel anti-cancer agents in participants with advanced malignancies. The modular design
      allows for an escalation of the dose of AZD7648 alone or in combination with either cytotoxic
      chemotherapies or novel anti-cancer agents, with intensive safety monitoring to ensure the
      safety of the participants.

      The study consists of 3 modules each evaluating the safety and tolerability of AZD7648
      monotherapy or with a specific combination partner. Core module of the study is study dose
      escalation (Part A) of AZD7648 monotherapy, administered orally, in participants with
      advanced solid tumours. The study may have up to 5 additional combination modules. Each
      combination module has 2 study parts: Part A consisting of dose escalation cohorts and Part
      B, a safety and proof of concept Phase IIa expansion. A Safety Review Committee will review
      evaluable participants at each cohort and assess if the study should progress to Part B.
    

Trial Arms

NameTypeDescriptionInterventions
Core Module: AZD7648 MonotherapyExperimentalAZD7648 will be administered orally on an empty stomach
  • AZD7648
Combination Module 1: AZD7648 + PLDExperimentalAZD7648 will be administered in combination with PLD
  • AZD7648
  • Pegylated liposomal doxorubicin (PLD)
Combination Module 2: AZ7648 + OlaparibExperimentalAZD7648 will be administered in combination with olaparib
  • AZD7648
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          1. Capable and willing to give signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF).

          2. Participant must be at least 18 years of age, at the time of signing the ICF.

          3. Participants must have histological or cytological confirmation of advanced malignancy
             considered to be suitable for study treatment.

          4. Eastern cooperative oncology group performance status 0-1.

          5. Life expectancy greater than 12 weeks.

          6. Progressive cancer at the time of study entry.

          7. Pharmacodynamics expansion cohorts: Participants must have at least 1 tumour suitable
             for biopsy and consent to having biopsies collected.

          8. Negative pregnancy test (urine or serum) prior to start of dosing for women of
             childbearing potential.

          9. Female participants must be 1-year post-menopausal, surgically sterile, or using an
             acceptable method of contraception for the duration of the study (from the time they
             sign consent) and for 12 weeks after the last dose of study treatment to prevent
             pregnancy.

         10. For the duration of the study (from the time they sign consent) and for 12 weeks after
             the last dose of study treatment, sexually active male participants must be willing to
             use contraception.

        Post-menopausal is defined as:

          -  Amenorrhoeic for 1 year of more following cessation of exogenous hormonal treatments,
             without an alternative medical cause.

          -  A single follicle stimulating hormone (FSH) measurement may be used to confirm a
             postmenopausal state only after a participant has been amenorrhoeic for greater than
             12 months.

          -  Radiation-induced oophorectomy with last menses greater than 1 year ago.

          -  Chemotherapy-induced menopause with greater than 1-year interval since last menses

          -  Surgical sterilisation

        Exclusion Criteria:

          1. Any unresolved toxicities from prior therapy common terminology criteria for adverse
             event (CTCAE) Grade ≥2 (with the exception of alopecia).

          2. Spinal cord compression or brain metastases unless definitively treated, asymptomatic,
             stable and not requiring steroids for at least 4 weeks.

          3. As judged by the Investigator, any evidence of severe or uncontrolled medical
             conditions including but not limited to:

             • Uncontrolled diabetes mellitus, uncontrolled seizures, active infection requiring
             systemic antibiotics, antifungal or antiviral drugs, severe chronic obstructive
             pulmonary disease, severe Parkinson's disease, active inflammatory bowel disease,
             psychiatric condition, active bleeding diatheses, renal transplant, or active
             infection including any participant with active hepatitis B, hepatitis C or human
             immunodeficiency virus.

          4. Any other malignancy which has been active or treated within the past 3 years, with
             the exception of in situ cancer of the cervix, non-melanoma skin cancer, ductal
             carcinoma in situ, Stage 1 Grade 1 endometrial carcinoma, or other solid tumours
             including lymphomas curatively treated with no evidence of disease for ≥5 years.

          5. Refractory nausea and vomiting or unable to swallow and retain oral medication,
             chronic gastrointestinal diseases or previous bowel resection with clinically
             significant sequelae that would preclude adequate absorption of AZD7648,
             gastrointestinal symptoms CTCAE Grade >1, history of gastrointestinal ulceration and
             gastrointestinal haemorrhage within 6 months of first study drug administration.

        6 Receiving or having received anti-cancer treatment within the following periods prior to
        the first dose of investigational product:

        (a) Cytotoxic treatment: 3 weeks, (b) Non-cytotoxic drugs: 3 weeks or 5 half-lives, (c)
        Small molecule investigational products: 3 weeks or 5 half-lives, (d) Biological
        investigational products: 42 days, (e) Radiation with a limited field for palliation: 1
        week (3 months for radiation to the abdomen or pelvis), (f) Radiation to >30% of the bone
        marrow or with a wide field: 4 weeks, (g) Lung radiation: 60 days, (h) Major surgery: 4
        weeks; minor surgery or biopsy: 1 week 7. During the 4 weeks prior to the first dose,
        receiving corticosteroids at a dose of >10 mg prednisone/day or equivalent for any reason.

        8. Receiving or having received concomitant medications, herbal supplements and/or foods
        known to significantly modulate CYP3A4 activity.

        9. Prior exposure to a deoxyribonucleic acid-pharmacokinetics inhibitor or hypersensitivity
        to any excipient of the product.

        10. Cardiac dysfunction as defined by any of the following within 6 months of study entry:

        (a) Acute myocardial infarction, (b) New York Heart Association Class II/III/IV heart
        failure, (c) Unstable angina, (d) Unstable cardiac arrhythmias 11. Any of the following
        cardiac criteria:

        (a) Known reduced left ventricular ejection fraction below the institutional lower limit of
        normal, (b) Mean resting corrected QT interval (QTc) >470 milliseconds obtained from 3
        electrocardiograms in 24 hours using the Fridericia formula, (c) Any factors that increase
        the risk of QTc prolongation or arrhythmic events such as hypokalaemia, congenital long QT
        syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40
        years of age 12. Inadequate hematological or organ function 13. Involvement in the planning
        and/or conduct of the study. 14. Judgement by the Investigator that the participant should
        not participate in the study if the participant is unlikely to comply with study
        procedures, restrictions and requirements.

        15. Previous enrolment in the present study. 16. For female participant only: currently
        pregnant or breast-feeding.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with adverse events/serious adverse events
Time Frame:From Screening (Day -28) till study drug discontinuation (up to 3.5 years)
Safety Issue:
Description:Safety and Tolerability

Secondary Outcome Measures

Measure:Peak plasma concentration (Cmax)
Time Frame:Blood sample: Cycle 0, Cycle 1 (Day 1, 8 or Visit Y for intermittent visit), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle X (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8 or Visit Y for intermittent visit)
Safety Issue:
Description:The concentration of AZD7648 in plasma will be determined (Cmax will be derived). Duration of 1 cycle is 28 days.
Measure:Area under the plasma concentration versus time curve (AUC)
Time Frame:Blood sample: Cycle 0, Cycle 1 (Day 1, 8 or Visit Y for intermittent visit), Cycle 2 (Day 1), Cycle 3 (Day 1), Cycle X (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8 or Visit Y for intermittent visit)
Safety Issue:
Description:The concentration of AZD7648 in plasma will be determined. Area under the curve is the integral of the concentration-time curve. The AUC reflects the actual body exposure to drug after administration. The AUC is dependent on the rate of elimination of the drug from the body and the dose administered. Duration of 1 cycle is 28 days.
Measure:Cytochrome P450 3A4 induction via 4-B hydroxy cholesterol levels
Time Frame:Cycle 0 (Day 1), Cycle 1 (Day 8 or Visit Y for intermittent visit), and Cycle 2 (Day 1) in the AZD7648 monotherapy
Safety Issue:
Description:The concentration of 4-B hydroxy cholesterol in plasma will be determined. The ratio of Cycle 2 Day 1 vs Cycle 1 Day 8 will be measured as an exploratory marker on cytochrome P450 3A4 induction. Duration of 1 cycle is 28 days.
Measure:Objective response rate (ORR)
Time Frame:Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years
Safety Issue:
Description:To obtain a preliminary assessment of anti-tumour activity of AZD7648 as assessed by ORR according to RECIST 1.1 guidelines. Duration of 1 cycle is 28 days.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Safety,
  • Pharmacokinetics,
  • Pegylated liposomal doxorubicin,
  • Olaparib,
  • Dose finding

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