Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03907969
Recruitment Status : Recruiting
First Posted : April 9, 2019
Last Update Posted : September 24, 2021
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Malignancies Drug: AZD7648 Drug: PLD Phase 1 Phase 2

Detailed Description:

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 2 modules each evaluating the safety and tolerability of AZD7648 monotherapy or with a specific combination partner.

Core module of the study is dose escalation (Part A) of AZD7648 monotherapy, administered orally, in participants with advanced solid tumours.

Combination module 1 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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 186 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Masking Description: This is an open-label study; there will be no blinding.
Primary Purpose: Treatment
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
Actual Study Start Date : October 9, 2019
Estimated Primary Completion Date : February 26, 2024
Estimated Study Completion Date : February 26, 2024

Arm Intervention/treatment
Experimental: Core Module: AZD7648 Monotherapy
AZD7648 will be administered orally on an empty stomach
Drug: AZD7648
Core: AZD7648 will be administered orally

Experimental: Combination Module 1: AZD7648 + PLD
AZD7648 will be administered in combination with Pegylated liposomal doxorubicin (PLD)
Drug: AZD7648
Core: AZD7648 will be administered orally

Drug: PLD
The starting dose of PLD is 40 mg/m^2, administered by intravenous infusion once every 4 weeks, for a maximum of 6 cycles
Other Name: DOXIL, Caelyx




Primary Outcome Measures :
  1. 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 and Tolerability

  2. Number of participants with dose limiting toxicities [ Time Frame: From first dose of study treatment until the end of Cycle 1. The duration of each cycle is 28 days ]
    Safety and Tolerability


Secondary Outcome Measures :
  1. 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  2. Maximum plasma concentration at steady state (Cmax,ss) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  3. Minimum plasma concentration at steady state (Cmin,ss) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  4. 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  5. AUC from zero to the time of the last measurable concentration after a single dose (AUC0-t) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  6. AUC from zero to the time of the last measurable concentration after multiple doses (AUCtau) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  7. Time to reach maximum plasma concentration (tmax) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  8. Half-life (t1/2) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  9. AUC0-t ratio for food effect (if conducted) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]
    To characterise the effect of food on AZD7648 exposure

  10. Cmax ratio for food effect (if conducted) [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]
    To characterise the effect of food on AZD7648 exposure

  11. Accumulation ratio [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  12. Dose proportionality [ 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), Cycle X+1 (Day 1), study drug discontinuation, up to 3.5 years. Urine sample: Cycle 0 (Day 1), Cycle 1 (Day 8) ]

    To characterise the pharmacokinetics of AZD7648 when given orally as monotherapy and in combination with anti-cancer agents.

    Duration of 1 cycle is 28 days. Cycle X and Cycle X+1 will done if a patient has a dose escalation to another dose.


  13. Cytochrome P450 3A4 induction via 4-B hydroxy cholesterol levels [ Time Frame: Cycle 0 (Day 1), Cycle 1 (Day 8), and Cycle 2 (Day 1) in the AZD7648 monotherapy ]
    To assess post-dose to pre-dose 4-B-hydroxy cholesterol ratio. Duration of 1 cycle is 28 days.

  14. 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 ]
    ORR is defined as the percentage of patients who have a confirmed visit response of complete response or partial response prior to any evidence of progression. Duration of 1 cycle is 28 days.

  15. Percentage best change in target lesion [ Time Frame: Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years ]
    To obtain a preliminary assessment of anti-tumour activity of AZD7648 as assessed by change in the size of tumour according to RECIST 1.1 guidelines. Duration of 1 cycle is 28 days.

  16. Duration of response [ Time Frame: Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years ]
    Duration of response is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. Duration of 1 cycle is 28 days.

  17. Progression-free survival (PFS) [ Time Frame: Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years ]
    PFS is defined as the time from first dose of any study treatment at Cycle 1 until the date of objective disease progression or death. Duration of 1 cycle is 28 days.

  18. Overall Survival (OS) (Part B, Combination module only) [ Time Frame: Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years ]
    Overall survival is defined as the time from first dose of any study treatment at Cycle 1 until death.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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:

  • No menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy). However in the absence of 12 months of amenorrhea, a FSH measurement is insufficient.
  • Radiation-induced oophorectomy with last menses greater than 12 months ago.
  • Chemotherapy-induced menopause with greater than 12 month 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: including small molecule investigational products: 3 weeks or 5 half-lives (whichever is longest), (c) Biological products including investigational immuno-oncology agents: 4 weeks, (d) Radiation with a limited field for palliation: 1 week (3 months for radiation to the abdomen or pelvis), (e) Radiation to >30% of the bone marrow or with a wide field: 4 weeks, (f) Lung radiation: 60 days, (g) 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. Ongoing low dose steroids for longer than 3 months (excluding inhalational, nasal, creams, lotions, and gels) are not allowed.

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. 17. For food effect cohort only: insulin dependent diabetes. 18. History and/or presence of coronavirus disease 2019.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03907969


Contacts
Layout table for location contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
Layout table for location information
United States, Connecticut
Research Site Recruiting
New Haven, Connecticut, United States, 06510
United States, Texas
Research Site Recruiting
Houston, Texas, United States, 77030
United Kingdom
Research Site Recruiting
London, United Kingdom, NW1 2PG
Research Site Not yet recruiting
London, United Kingdom, SE1 9RT
Research Site Recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
Layout table for investigator information
Principal Investigator: Dr Timothy Yap MD Anderson Cancer Center, 1400 Holcombe Blvd. Houston, Texas, 77030
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03907969    
Other Study ID Numbers: D9170C00001
First Posted: April 9, 2019    Key Record Dates
Last Update Posted: September 24, 2021
Last Verified: September 2021

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Safety,
Pharmacokinetics,
Pegylated liposomal doxorubicin,
Dose finding
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms
AZD7648
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action