| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
_Evaluate, efficacy, safety and tolerability of IMP
_To investigate the safety and tolerability of AZD7648 when given orally to patients with advanced malignancies, as monotherapy and in combination with anticancer agents, and to define the doses and schedules for further clinical evaluation. |
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| E.2.2 | Secondary objectives of the trial |
_To characterize the pharmacokinetics 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. To characterize the effect of food on AZD7648 exposure(if conducted)
_To understand the cytochrome P450 3A4 induction potential of AZD7648.
_To obtain a preliminary assessment of anti-tumor activity of AZD7648 as monotherapy and in combination with anti-cancer agents. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) and in this protocol.
2 .Provision of signed and dated written genetic informed consent prior to collection of sample for exploratory genetic analysis (optional).
3. Patient must be at least 18 years of age, at the time of signing the ICF. Type of Patient and Disease Characteristics
4. Patients must have histological or cytological confirmation of advanced malignancy considered to be suitable for study treatment.
5. ECOG PS of 0 to 1.
6. Life expectancy greater than 12 weeks.
7 .Progressive cancer at the time of study entry.
8 .PD expansion cohorts (or PD expansion subgroup): Patients must have at least 1 tumour suitable for biopsy and consent to having biopsies collected.
Reproduction
9. Negative pregnancy test (urine or serum) prior to start of dosing for women of childbearing
potential (WOCBP). Women of child-bearing potential are defined as women
between menarche and menopause who have not been permanently or surgically sterilised
and are capable of procreation.
10. Female patients must be 1-year post-menopausal, surgically sterile, or using an acceptable
method of contraception (acceptable methods of contraception are defined in Section 5.3.3) 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.
11. For the duration of the study and for 12 weeks after the last dose of study treatment,
sexually active male patients must be willing to use contraception as is defined inSection 5.3.3.
Post-menopausal is defined as:
- Amenorrhoeic for 1 year of more following cessation of exogenous hormonal treatments.
- Luteinising hormone and follicle stimulating hormone levels in the post-menopausal
range for women under 50.
- 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 (bilateral oophorectomy or hysterectomy)
Module 1 and 2 specific criteria can be found in the relevant CSP modules. |
|
| E.4 | Principal exclusion criteria |
1. Any unresolved toxicities from prior therapy CTCAE Grade ≥2 (with the exception of alopecia).
2. Spinal cord compression or brain metastases unless definitively treated (minimum of 3. weeks between completion of radiotherapy and first dose of study treatment and recovery from acute toxicity Grade ≥2), asymptomatic, stable)and not requiring steroids for at least 4 weeks. Disease outside the central nervous system must be present.
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 patient known to have hepatitis B, hepatitis C and 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
(without bone marrow involvement) 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: 3 weeks or 5 half-lives (whichever is longest)
(c) Small molecule investigational products: 3 weeks or 5 half-lives (whichever is
longest)
(d) Biological investigational products: 42 days
(e) Radiation with a limited field for palliation: 1 week (3 months for radiation to the abdomen or pelvis)
(f) Radiation to >30% of the bone marrow or with a wide field: 4 weeks
(g) Lung radiation: 60 days
(h) 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 . The required washout period prior to starting study treatment is 3 weeks (5 weeks for enzalutamide or phenobarbital) until 28 days after the last dose of study treatment. Patients can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study if these were started at least 2 weeks prior to study treatment
9.Prior exposure to a DNA-PK 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 eg, clinically important abnormalities in conduction or morphology of resting ECG such as complete left bundle branch block or
third-degree heart block
11.Any of the following cardiac criteria:
(a) Known reduced left ventricular ejection fraction below the institutional lower limit of normal (LLN)
(b) Mean resting corrected QT interval (QTc) >470 milliseconds obtained from 3 ECGs
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 haematological or organ function as defined by:
(a) Haemoglobin <90 g/L with no blood transfusions or erythropoietin within 14 days of obtaining these values or before starting treatment
(b) Absolute neutrophil count (ANC) <1.5 x 109/L with no haematopoietic growth factors within 14 days of obtaining these values or before starting treatment
(c) Platelet count <100×109/L with no platelet transfusions within 14 days of obtaining
these values or before starting treatment
(d) International normalised ratio (INR) ≥1.5 or other evidence of impaired hepatic synthesis function
(e) Bilirubin >1.5×upper limit normal (ULN) (or likely to be in 3 weeks)
(f) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5×ULN (or likely to be in 3 weeks)
(g) Creatinine clearance <50 mL/minute, as assessed using Cockcroft-Gault, EDTA clearance or 24 hours urine collection
Module 1 and 2 specific criteria can be found in the relevant CSP modules. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
_Adverse events (AEs)/serious adverse events (SAEs)
_Dose-limiting toxicity (DLT)
_Physical examination
_Eastern Cooperative Oncology Group performance status (ECOG PS)
_Vital signs
_Electrocardiogram (ECG) and Echocardiogram (ECHO; combination module 1 only)
_Laboratory data |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| According to schedule of activities. |
|
| E.5.2 | Secondary end point(s) |
Area under the curve (AUC) and/or AUC0-t after a single dose and AUCtau after multiple doses.
Maximum plasma concentration (Cmax) after a single dose and Cmax,ss after multiple doses
Time to reach maximum plasma concentration (tmax)
Minimum plasma concentration at steady state (Cmin,ss)
Half-life (t1/2)
Accumulation ratio
Dose proportionality
AUC0-t and Cmax ratio for food effect
Post-dose to pre-dose 4-β-hydroxy cholesterol ratio
Radiological response evaluated using response evaluation criteria in solid tumours (RECIST) 1.1
- Percentage best change in target lesion (TL)
-Duration of response
- Objective response rate (ORR)
- Progression-free survival (PFS)
-Overall Survival (Part B only) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| According to schedule of activities. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Korea, Republic of |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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