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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03907969
Recruitment Status : Active, not recruiting
First Posted : April 9, 2019
Last Update Posted : November 10, 2022
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE February 21, 2019
First Posted Date  ICMJE April 9, 2019
Last Update Posted Date November 10, 2022
Actual Study Start Date  ICMJE October 9, 2019
Estimated Primary Completion Date December 26, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 5, 2019)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2021)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2019)
  • 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) ]
    The concentration of AZD7648 in plasma will be determined (Cmax will be derived). Duration of 1 cycle is 28 days.
  • 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) ]
    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.
  • 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 ]
    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.
  • Objective response rate (ORR) [ Time Frame: Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until objective disease progression, up to 3.5 years ]
    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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Trial to Evaluate AZD7648 Alone and in Combination With Other Anti-cancer Agents in Patients With Advanced Cancers.
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE 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
Condition  ICMJE Advanced Malignancies
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Core Module: AZD7648 Monotherapy
    AZD7648 will be administered orally on an empty stomach
    Intervention: Drug: AZD7648
  • Experimental: Combination Module 1: AZD7648 + PLD
    AZD7648 will be administered in combination with Pegylated liposomal doxorubicin (PLD)
    Interventions:
    • Drug: AZD7648
    • Drug: PLD
Publications * Goldberg FW, Finlay MRV, Ting AKT, Beattie D, Lamont GM, Fallan C, Wrigley GL, Schimpl M, Howard MR, Williamson B, Vazquez-Chantada M, Barratt DG, Davies BR, Cadogan EB, Ramos-Montoya A, Dean E. The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor. J Med Chem. 2020 Apr 9;63(7):3461-3471. doi: 10.1021/acs.jmedchem.9b01684. Epub 2020 Jan 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 10, 2022)
30
Original Estimated Enrollment  ICMJE
 (submitted: April 5, 2019)
230
Estimated Study Completion Date  ICMJE December 26, 2022
Estimated Primary Completion Date December 26, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03907969
Other Study ID Numbers  ICMJE D9170C00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Parexel
Investigators  ICMJE
Principal Investigator: Dr Timothy Yap MD Anderson Cancer Center, 1400 Holcombe Blvd. Houston, Texas, 77030
PRS Account AstraZeneca
Verification Date November 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP