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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. 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 : January 10, 2020
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: Pegylated liposomal doxorubicin (PLD) Drug: Olaparib Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 234 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 : January 16, 2024
Estimated Study Completion Date : January 16, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Olaparib

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 PLD
Drug: AZD7648
Core: AZD7648 will be administered orally

Drug: Pegylated liposomal doxorubicin (PLD)
The starting dose of PLD is 40 mg/m2, administered by intravenous infusion once every 4 weeks, for a maximum of 6 cycles
Other Name: DOXIL, Caelyx

Experimental: Combination Module 2: AZ7648 + Olaparib
AZD7648 will be administered in combination with olaparib
Drug: AZD7648
Core: AZD7648 will be administered orally

Drug: Olaparib
The starting dose of olaparib is 300 mg twice daily, administered orally on a continuous schedule in a 4-week cycle
Other Name: Lynparza




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) ]

    The concentration of AZD7648 in plasma will be determined (Cmax will be derived). 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. 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) ]

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


  3. 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 ]
    Post-dose to pre-dose 4-B-hydroxy cholesterol ratio. Duration of 1 cycle is 28 days.

  4. 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 ]
    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.



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.


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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 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: 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.

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.


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
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, Connecticut
Research Site Not yet recruiting
New Haven, Connecticut, United States, 06520
United States, Texas
Research Site Recruiting
Houston, Texas, United States, 77030
United Kingdom
Research Site Not yet recruiting
London, United Kingdom, NW1 2PG
Research Site Not yet recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Sponsors and Collaborators
AstraZeneca
Parexel
Investigators
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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):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03907969    
Other Study ID Numbers: D9170C00001
First Posted: April 9, 2019    Key Record Dates
Last Update Posted: January 10, 2020
Last Verified: January 2020

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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,
Olaparib,
Dose finding
Additional relevant MeSH terms:
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Neoplasms
Doxorubicin
Liposomal doxorubicin
Olaparib
Antineoplastic Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Poly(ADP-ribose) Polymerase Inhibitors