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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Advanced Malignancies

Intervention / Treatment
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* Drug: AZD7648
* Drug: PLD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable and willing to give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). Participant must be at least 18 years of age, at the time of signing the ICF. Participants must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment. Eastern cooperative oncology group performance status 0-1. Life expectancy greater than 12 weeks. Progressive cancer at the time of study entry. Pharmacodynamics expansion cohorts: Participants must have at least 1 tumour suitable for biopsy and consent to having biopsies collected. Negative pregnancy test (urine or serum) prior to start of dosing for women of childbearing potential. 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. 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: Any unresolved toxicities from prior therapy common terminology criteria for adverse event (CTCAE) Grade ≥2 (with the exception of alopecia). Spinal cord compression or brain metastases unless definitively treated, asymptomatic, stable and not requiring steroids for at least 4 weeks. 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Core Module: AZD7648 Monotherapy<br>AZD7648 will be administered orally on an empty stomach | Drug: AZD7648<br>* Core: AZD7648 will be administered orally<br>|
| Experimental: Combination Module 1: AZD7648 + PLD<br>AZD7648 will be administered in combination with Pegylated liposomal doxorubicin (PLD) | Drug: AZD7648<br>* Core: AZD7648 will be administered orally<br>Drug: PLD<br>* The starting dose of PLD is 40 mg/m^2, administered by intravenous infusion once every 4 weeks, for a maximum of 6 cycles<br>* Other names: DOXIL, Caelyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events/serious adverse events | Safety and Tolerability | From Screening (Day -28) till study drug discontinuation (up to 3.5 years) | 
| Number of participants with dose limiting toxicities | Safety and Tolerability | From first dose of study treatment until the end of Cycle 1. The duration of each cycle is 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) | 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. | 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) | 
| Maximum plasma concentration at steady state (Cmax,ss) | 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. | 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) | 
| Minimum plasma concentration at steady state (Cmin,ss) | 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. | 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) | 
| Area under the plasma concentration versus time curve (AUC) | 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. | 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) | 
| AUC from zero to the time of the last measurable concentration after a single dose (AUC0-t) | 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. | 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) | 
| AUC from zero to the time of the last measurable concentration after multiple doses (AUCtau) | 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. | 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) | 
| Time to reach maximum plasma concentration (tmax) | 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. | 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) | 
| Half-life (t1/2) | 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. | 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) | 
| AUC0-t ratio for food effect (if conducted) | To characterise the effect of food on AZD7648 exposure | 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) | 
| Cmax ratio for food effect (if conducted) | To characterise the effect of food on AZD7648 exposure | 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) | 
| Accumulation ratio | 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. | 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) | 
| Dose proportionality | 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. | 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) | 
| Cytochrome P450 3A4 induction via 4-B hydroxy cholesterol levels | To assess post-dose to pre-dose 4-B-hydroxy cholesterol ratio. Duration of 1 cycle is 28 days. | Cycle 0 (Day 1), Cycle 1 (Day 8), and Cycle 2 (Day 1) in the AZD7648 monotherapy | 
| Objective response rate (ORR) | 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. | Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years | 
| Percentage best change in target lesion | 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. | Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years | 
| Duration of response | 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. | Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years | 
| Progression-free survival (PFS) | 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. | Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years | 
| Overall Survival (OS) (Part B, Combination module only) | Overall survival is defined as the time from first dose of any study treatment at Cycle 1 until death. | Screening, every 8 weeks (±1 week) from Cycle 1 (Day 1) until confirmed objective disease progression, up to 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety,, Pharmacokinetics,, Pegylated liposomal doxorubicin,, Dose finding