A Clinical Trial to Evaluate AZD7648 Alone and in Combination With Other Anti-cancer Agents in Patients With Advanced Cancers.
Study Details
Study Description
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 |
|---|---|---|
| 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.
Study Design
Arms and Interventions
| 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 Names:
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Outcome Measures
Primary Outcome Measures
- Number of participants with adverse events/serious adverse events [From Screening (Day -28) till study drug discontinuation (up to 3.5 years)]
Safety and Tolerability
- Number of participants with dose limiting toxicities [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
- Peak plasma concentration (Cmax) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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 [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 [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 [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) [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 [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 [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) [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) [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.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Capable and willing to give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
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Participant must be at least 18 years of age, at the time of signing the ICF.
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Participants must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment.
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Eastern cooperative oncology group performance status 0-1.
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Life expectancy greater than 12 weeks.
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Progressive cancer at the time of study entry.
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Pharmacodynamics expansion cohorts: Participants must have at least 1 tumour suitable for biopsy and consent to having biopsies collected.
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Negative pregnancy test (urine or serum) prior to start of dosing for women of childbearing potential.
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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.
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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:
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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.
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Radiation-induced oophorectomy with last menses greater than 12 months ago.
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Chemotherapy-induced menopause with greater than 12 month interval since last menses.
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Surgical sterilisation.
Exclusion Criteria:
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Any unresolved toxicities from prior therapy common terminology criteria for adverse event (CTCAE) Grade ≥2 (with the exception of alopecia).
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Spinal cord compression or brain metastases unless definitively treated, asymptomatic, stable and not requiring steroids for at least 4 weeks.
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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.
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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.
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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.
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Receiving or having received concomitant medications, herbal supplements and/or foods known to significantly modulate CYP3A4 activity.
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Prior exposure to a deoxyribonucleic acid-pharmacokinetics inhibitor or hypersensitivity to any excipient of the product.
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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.
- 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.
- History and/or presence of coronavirus disease 2019.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | New Haven | Connecticut | United States | 06510 |
| 2 | Research Site | Houston | Texas | United States | 77030 |
| 3 | Research Site | London | United Kingdom | EC1A 7BE | |
| 4 | Research Site | London | United Kingdom | SE1 9RT | |
| 5 | Research Site | Newcastle upon Tyne | United Kingdom | NE7 7DN |
Sponsors and Collaborators
- AstraZeneca
- Parexel
Investigators
- Principal Investigator: Dr Timothy Yap, MD Anderson Cancer Center, 1400 Holcombe Blvd. Houston, Texas, 77030
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D9170C00001