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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Malignancies
• Intervention / Treatment: Drug: AZD7648; Drug: PLD

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: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • Newcastle upon Tyne, United Kingdom, NE7 7DN
    • Research Site
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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: DOXIL, Caelyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Adverse Events or Serious Adverse Events	Safety and tolerability of AZD7648 when given orally to patients with advanced malignancies, as monotherapy and in combination with anti-cancer agents was assessed.	From Screening (Day -28) till study drug discontinuation (3.2 years)
Number of Patients With Dose Limiting Toxicities (DLTs)	A DLT is defined as an AE that occurs from the first dose of study treatment up to and including Cycle 1, Day 28 (the DLT assessment period) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications.	From Screening (Day -28) till study drug discontinuation (3.2 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Plasma Concentration-time Curve From Zero to Infinity (AUCinf)	The AUCinf of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy and Combination therapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose [each cycle is 28 days]
Area Under the Plasma Concentration-curve From Zero to the Last Quantifiable Concentration (AUClast)	The AUClast of AZD7648, following a single dose, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy and Combination therapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose (each cycle is 28 days)
Area Under Plasma Concentration-time Curve in the Dosing Interval τ (AUCτ)	The AUCτ of AZD7648, at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy and Combination therapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose (each cycle is 28 days)
Maximum Observed Plasma (Peak) Drug Concentration After Single Dose and Multiple Doses (Cmax)	The Cmax of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose, Cycle 1 Day 8 Pre-dose to 12 hours post dose; Combination therapy: Cycle 0 Day 1 Pre-dose to 12 hours post dose and Cycle 1 Days 7, 8 Pre-dose to 8 hours post dose (each cycle is 28 days)
Time to Reach Maximum Plasma Concentration (Tmax)	The tmax of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose, Cycle 1 Day 8 Pre-dose to 12 hours post dose; Combination therapy: Cycle 0 Day 1 Pre-dose to 12 hours post dose and Cycle 1 Days 7, 8 Pre-dose to 8 hours post dose (each cycle is 28 days)
Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve (t½λz)	The t½λ of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents.	Monotherapy and Combination therapy: Cycle 0 Day 1 Pre-dose to 72 hours post-dose (each cycle is 28 days)
Accumulation Ratio for Area Under Curve (Rac AUC)	The Rac AUC of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents. Accumulation ratio for AUC, calculated by multiple dose AUCτ/single dose AUC(0-12) or AUC(0-24).	Monotherapy: Cycle 1 Day 8 Pre-dose to 12 hours post dose; Combination therapy: Cycle 1 Days 7 and 8 Pre-dose to 8 hours post dose (each cycle is 28 days)
Accumulation Ratio for Cmax (Rac Cmax)	The Rac Cmax of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents. Accumulation ratio for Cmax, calculated by multiple dose Cmax/single dose Cmax.	Monotherapy: Cycle 1 Day 8 Pre-dose to 12 hours post dose; Combination therapy: Cycle 1 Days 7 and 8 Pre-dose to 8 hours post dose (each cycle is 28 days)
Dose Proportionality (TCP)	The TCP of AZD7648, following a single dose and at steady state after multiple dosing, when given orally as monotherapy and in combination with anti-cancer agents. Temporal change parameter in systemic exposure, calculated as multiple dose AUCtau/single dose AUCinf.	Monotherapy: Cycle 1 Day 8 Pre-dose to 12 hours post dose; Combination therapy: Cycle 1 Days 7 and 8 Pre-dose to 8 hours post dose (each cycle is 28 days)
Objective Response Rate (ORR)	ORR is defined as the percentage of patients who have a confirmed visit response of complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by Response Evaluation Criteria in Solid Tumours 1.1). CR is defined when all target lesions (TLs) and non-target lesions (NTLs) present at baseline have disappeared (with the exception of lymph nodes which must be <10mm to be considered non pathological) and no new lesions have developed since baseline. PR is defined when the sum of diameters of the TLs has decreased by 30% or more compared to baseline (with no evidence of progression) and the NTLs are at least stable with no evidence of new lesions.	First dose of study treatment on Cycle 1 Day 1 (each cycle is 28 days) until progression or the last evaluable assessment in the absence of progression (3.2 years)
Progression Free Survival (PFS) for Monotherapy	PFS is defined as the time from first dose of Cycle 1 until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from study therapy or receives another anti-cancer therapy prior to progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as increased by > 20% or more compared to the smallest sum of diameters on study.	At 12 months
Progression Free Survival (PFS) for Combination Therapy	PFS is defined as the time from first dose of Cycle 1 until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from study therapy or receives another anti-cancer therapy prior to progression. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as increased by > 20% or more compared to the smallest sum of diameters on study.	At 18 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Dr Timothy Yap, MD Anderson Cancer Center, 1400 Holcombe Blvd. Houston, Texas, 77030

Publications and helpful links

General 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.

Helpful Links

• Protocol redacted
• SAP redacted
• CSR Synopsis redacted

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2019
• Primary Completion (Actual): December 7, 2022
• Study Completion (Actual): December 7, 2022

Study Registration Dates

• First Submitted: February 21, 2019
• First Submitted That Met QC Criteria: April 5, 2019
• First Posted (Actual): April 9, 2019

Study Record Updates

• Last Update Posted (Actual): February 6, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Dose finding; Safety,; Pharmacokinetics,; Pegylated liposomal doxorubicin,
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; AZD7648
• Other Study ID Numbers: D9170C00001; 2018-003688-73 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No