Part A: The starting doses for both intermittent schedules will be 300 mg bd of olaparib and
either AZD5363 given at 320 mg bd 4-days-on, 3-days-off, or 480 mg bd 2-days-on, 5-days-off.
These starting doses are based on available data from the first-in-human studies
[D0810C00002] (AstraZeneca) and [D3610C00001] (AstraZeneca) of both drugs, respectively.
A general schema for 3 potential dose levels to be pursued on the 4-days-on, 3-days-off
AZD5363 schedule (Schedule A) and 2-days-on, 5-days-off AZD5363 schedule (Schedule B) in
Part A of the study are listed below. The starting dose of olaparib will be fixed at 300mg
bd in both schedules. These schema only provide general guidance; it will be possible for
doses of one or both drugs to be escalated or de-escalated in a "seesaw" fashion contingent
on the toxicity and/or PK/PD data reported. This may create dose cohort combinations not
listed below. Both PK and PD data will be taken into consideration if available. With the
exception of dose level 1, actual dose escalation/de-escalation will be determined following
a discussion with the SRC during dose escalation teleconferences. Dose escalation will
continue until MTD(s) are reached. Patients will be dosed on a flat scale and not by body
weight or body surface area. Both schedules will be carried out in parallel.
Table 1: Schema for dose escalation in schedule A (4-days-on, 3-days-off AZD5363) Dose level
(DL) olaparib bd AZD5363 bd 4d-on, 3d-off
- 1 200mg* 240mg
1. 300mg 320mg
2. 300mg 400mg
3. 300mg 480mg
*An intermediate dose of 250mg bd of olaparib may be considered depending on
drug-related toxicities observed and patient tolerability
Table 2: Schema for dose escalation in schedule B (2-days-on, 5-days-off AZD5363)
Dose level (DL) olaparib bd AZD5363 bd 2d-on, 5d-off
- 1 200mg* 400mg
1. 300mg 480mg
2. 300mg 560mg
3. 300mg 640mg
- An intermediate dose of 250mg bd of olaparib may be considered depending on
drug-related toxicities observed and patient tolerability
After careful review of the clinical toxicity data, if the DLT is deemed to be caused by one
of the agents, the responsible drug may be dose decreased and if well tolerated, the other
agent maybe be increased in subsequent cohorts. If necessary, both drugs can also be dose
In Part A of the study, olaparib will be administered continuously with intermittent AZD5363
in 21-day cycles. Intrapatient dose escalation of AZD5363 will be utilised to evaluate
different dose levels. The optimal dose schedule selected based on toxicity, PK-PD and/or
efficacy data will be taken forward into two expansion cohorts in Part B of the study.
Cohort 1 will comprise patients with germline BRCA1/2 mutated tumours, while Cohort 2 will
comprise advanced sporadic cancers that may harbour HR defects (e.g. TNBC, CRPC and HGSOC)
or those with somatic mutations or other aberrations known to result in a hyperactivated
phosphatidylinositol-3-kinase (PI3K)-AKT pathway.
1. Part A: Patients with histologically or cytologically confirmed malignant advanced
solid tumours refractory to standard therapy or for which no suitable effective
standard therapy exists, including, but not limited to patients with: BRCA1/2 mutant
cancers, TNBC, CRPC and HGSOC, and those with somatic mutations or other aberrations
known to result in a hyperactivated PI3K-AKT pathway.
Part B: (1) BRCA1/2 mutation cohort: Patients with advanced germline BRCA1/2 mutant
solid tumours; (2) Sporadic cancers cohort: This cohort will include advanced
sporadic cancers that are not known to harbour germline BRCA1/2 mutations, but which
may harbour homologous recombination (HR) defects, e.g. advanced TNBC, CRPC and
HGSOC, and those with somatic mutations or other aberrations known to result in a
hyperactivated PI3K-AKT pathway.
2. Life expectancy of at least 12 weeks
3. WHO performance status of 0-1 with no significant deterioration over the previous 2
4. Evaluable or measurable disease as assessed by RECIST 1.1
5. Haematological and biochemical indices within the ranges shown below. These
measurements must be performed within one week.
- Hb 10.0 g/dL
- Absolute neutrophil count 1.5 x 109/L
- Platelet count 100 x 109/L
- Serum bilirubin 1.5 x upper limit of normal except for patient with documented
- ALT or AST 2.5 x (ULN) unless raised due to tumour in which case up to 5 times
ULN is permissible
If creatinine > 1.5 times ULN then: Either:
- Creatinine Clearance 50 mL/min (uncorrected value)
- Isotope clearance measurement 50 mL/min (corrected) 6.18 years or over 7. Signed
and dated informed consent and be capable of co-operating with treatment and
1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or
chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C)
and 4 weeks for investigational medicinal products before treatment, except for
hormonal therapy with luteinizing hormone-releasing hormone analogues for medical
castration in patients with CRPC, which are permitted.
2. Ongoing toxic manifestations of previous treatments. Exceptions to this are Grade 1
toxicities, which in the opinion of the Investigator should not exclude the patient.
3. Ability to become pregnant (or already pregnant or lactating). However, those female
patients who have a negative serum or urine pregnancy test before enrolment and agree
to use two highly effective forms of contraception (oral, injected or implanted
hormonal contraception and condom, have an intra-uterine device and condom, diaphragm
with spermicidal gel and condom) for four weeks before entering the trial, during the
trial and for six months afterwards are considered eligible.
4. Male patients with partners of child-bearing potential (unless they agree to take
measures not to father children by using one form of highly effective contraception
[condom plus spermicide] during the trial and for six months afterwards). Men with
pregnant or lactating partners should be advised to use barrier method contraception
(for example, condom plus spermicidal gel) to prevent exposure to the foetus or
5. Major surgery (excluding minor procedures, e.g. placement of vascular access) within
4 weeks of the first dose of study treatment.
6. At high medical risk because of severe or uncontrolled systemic disease including
active bleeding diathesis or active infection including hepatitis B, hepatitis C and
human immunodeficiency virus. Screening for chronic conditions is not required.
7. Clinically significant abnormalities of glucose metabolism as defined by any of the
- Diagnosis of diabetes mellitus type I or II (irrespective of management).
- HbA1C 8.0% at screening (64 mmol/mol) (conversion equation for HbA1C
[IFCC-HbA1C (mmol/mol)] = [DCCT-HbA1C (%) - 2.15] x 10.929)
- Fasting Plasma Glucose 8.9mmol/L at screening. Fasting is defined as no
caloric intake for at least 8 hours.
8. Proteinuria 3+ on dipstick analysis or >500mg/24 hours.
9. Previous treatment with a PARP inhibitor or PI3K/AKT inhibitor (Part B: sporadic
cancers arm of dose expansion cohort only).
10. Treatment with potent inhibitors or inducers or substrates of CYP3A4 or substrates of
CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's
11. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks prior to start of study treatment
12. Any of the following cardiac criteria:
- Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive
- Any clinically significant abnormalities in rhythm, conduction or morphology of
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events, such as heart failure, hypokalaemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age or
any concomitant medication known to prolong the QT interval
- Experience of any of the following procedures or conditions in the preceding 6
months: coronary artery bypass graft, angioplasty, vascular stent, myocardial
infarction, angina pectoris, congestive heart failure New York Heart Association
[NYHA0 Grade 2
- Uncontrolled hypotension - Systolic BP <90mmHg and/or diastolic BP <50mmHg
- LVEF below institutional lower limit of normal.
13. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of olaparib and AZD5363.
14. History of hypersensitivity to active or inactive excipients of AZD5363 or olaparib
or drugs with a similar chemical structure or class to AZD5363 and olaparib.
15. Is a participant or plans to participate in another interventional clinical trial,
whilst taking part in this Phase I study. Participation in an observational trial
would be acceptable.
16. Any other condition which in the Investigator's opinion would not make the patient a
good candidate for the clinical trial.
17. Patients with myelodysplastic syndrome or acute myeloid leukaemia
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both