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 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.
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
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
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
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.
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
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
(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.