Safety, Tolerability and Pharmacokinetics of AZD1775 Plus MEDI4736 in Patients With Advanced Solid Tumours

This is a Phase I, multi-center, dose-escalation study to assess the safety, tolerability and
pharmacokinetics of oral therapy with AZD1775 when combined with a fixed-dose of MEDI4736.
Immunogenicity, pharmacodynamics, and preliminary anti-tumour activity in patients with
refractory solid tumours will also be investigated. In the initial design of this study a
novel combination of AZD1775 and MEDI4736 was tested. The starting dose of AZD1775 was 125 mg
BID, over 5 days with 9 days off in 14-day cycles. This was designated Schedule A. This dose
was not well tolerated. Two of six patients experienced dose limiting toxicity (DLT). The
protocol was amended to include three additional dosing schedules. designated Schedules B, C,
and D. In Schedule B patients will receive MEDI4736 on Day 1, AZD1775 on Days 15-17 and Days
22-24 of a 28-day cycle. In Schedule C, patients will receive MEDI4736 on Day 1, AZD1775 on
Days 8-10, Days 15-17 and Days 22-24 of 28-day cycles. In Schedule D, patients will receive
MEDI4736 on Day 1 and AZD1775 QD on Days 15-19 and Days 22-26 of a 28-day cycle. AZD1775 will
be dosed on a maximum of 6 days (Schedule B), 9 days (Schedule C), or 10 days (Schedule D) in
each 28-day cycle. In all schedules, dexamethasone will be administered as an anti-emetic on
the first day of each of the AZD1775 consecutive dosing day blocks including the lead-in
portion for Schedules B, C, and D. AZD1775 will be administered at least 1 week after
MEDI4736 administration. Three to six patients will be enrolled in dose level 1 of Schedule B
and evaluated for safety over a 28-day cycle prior to opening Schedule C dose level 1 for
enrolment. Following safety evaluation of three to six patients in Schedule C dose level 1, a
decision will be made by the Safety Review Team (SRT) to move forward with one or both
schedules for further dose escalation. Three to six patients will be enrolled in Schedule D
dose level 1 and evaluated for safety over a 28-day cycle. Patients in Schedule D will be
evaluated for escalation independently of those in Schedules A, B, and C. Dose escalation
will continue until identification of the Maximum Tolerated Dose (MTD). Once the MTD is
determined this cohort will be expanded to a total of 18 patients to collect further safety
data and for preliminary assessment of efficacy. Alternative dose levels/cohorts and/or
schedules may be explored if emerging data suggest these would be more appropriate. The first
day of Cycle 1 in Schedules B, C, and D will be preceded by a lead-in period of AZD1775
monotherapy to enable serial sampling for assessment of pharmacokinetic parameters.

Inclusion Criteria:

1. Capable of giving informed consent.

2. Males/females ≥18.

3. Weight ≥ 30 kg.

4. Histologic confirmation of a solid tumour, excluding lymphoma, refractory to standard
therapy or for which no standard of care exists.

5. Measurable or non-measureable disease according to RECIST v1.1.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

7. Baseline laboratory values:

- Absolute neutrophil count (ANC) ≥1500/μL

- Haemoglobin (HgB) ≥9 g/dL

- Platelets ≥100,000/μL

- Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 x Upper
Limit of Normal (ULN).

- Serum bilirubin within normal limits (WNL) or ≤ 1.5 x ULN in patients with liver
metastases; or total bilirubin ≤ 3.0 x ULN with direct bilirubin WNL in patients
with well documented Gilbert's Syndrome.

- Serum creatinine ≤ 1.5 x ULN, or creatinine clearance (CrCl) ≥ 40 mL/min as
calculated by Cockcroft-Gault method.

8. Fertile females of child-bearing potential who agree to use adequate contraceptive
measures, who are not breast feeding, and who have a negative serum pregnancy test
within 3 days prior to start of study treatment.

9. Male patients must agree to use at least one medically acceptable form of
contraception for the duration of the study and for 3 months after the last dose.

10. Predicted life expectancy ≥ 12 weeks.

11. Willingness to provide consent for collection of biological samples.

Exclusion Criteria:

1. Previous enrolment in this study.

2. Concurrent enrolment in another interventional clinical study.

3. Participation in another interventional clinical study or study with an
investigational product during the last 28 days or 5 half-lives whichever is shorter.

4. Major surgical procedures ≤ 28 days of study, or minor surgical procedures ≤ 7 days.

5. Palliative radiation therapy completed ≤ 7 days prior to start of study drugs.

6. No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal anti-cancer
radiotherapy [except for palliative local radiotherapy]), biological therapy or other
novel agent is permitted while the patient is receiving study medication. Patients on
luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months
are allowed entry into the study and can continue this treatment during the study.

7. Any unresolved NCI CTCAE Grade >1 toxicity from prior therapy (except alopecia or
anorexia). Patients with irreversible toxicity not reasonably expected to be
exacerbated by treatment with AZD1775 or MEDI4736 may be included after consultation
with the Medical Monitor.

8. Inability to swallow oral medication.

9. Brain metastases or spinal cord compression unless the patient is stable (no evidence
of new or emerging brain metastases) and off steroids for at least 14 days.

10. History of leptomeningeal carcinomatosis.

11. Ascites requiring intervention (e.g. need for paracentesis or Tenckhoff catheter).

12. History of primary immunodeficiency.

13. History of tuberculosis.

14. Organ transplant that requires the use of immunosuppressive treatment.

15. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis, systemic
lupus erythematous; sarcoidosis syndrome, or Wegner syndrome; Grave's disease;
rheumatoid arthritis, hypophysitis, uveitis, etc.). The following are exceptions to
this criterion: vitiligo or alopecia, hypothyroidism stable on hormone replacement,
chronic skin condition that does not require treatment, patients without active
disease in the last 5 years may be included after consultation with Medical Monitor,
patients with celiac disease controlled by diet alone.

16. Any of the following cardiac diseases currently or within the last 6 months: unstable
angina pectoris, congestive heart failure, acute myocardial infarction, heart failure
≥ 2 defined by NYHA, conduction abnormality not controlled with pacemaker or
medication, significant ventricular or supraventricular arrhythmias (patients with
chronic rate-controlled atrial fibrillation in the absence of other cardiac
abnormalities are eligible), history of Torsades de pointes unless all risk factors
that contributed to Tdp have been corrected.

17. Uncontrolled hypertension.

18. Interstitial lung disease.

19. Known active cancers.

20. Mean resting corrected QT interval (specifically QTc calculated using the Fridericia
formula [QTcF]) > 450 msec for males and > 470 msec for females from 3 ECGs performed
within 2-5 minutes apart at study entry or congenital long QT syndrome.

21. Known serious active infection at study entry.

22. Serious gastrointestinal chronic conditions associated with diarrhoea within the past
12 months.

23. Pregnant or lactating.

24. Previous allogeneic bone marrow transplant.

25. Psychiatric illness or social situations that would limit compliance with study
requirements, substantially increase risk of incurring AEs or compromise the ability
of the patient to give written informed consent.

26. Use of approved treatment (e.g. chemotherapy, targeted therapy, biologic therapy, or
monoclonal antibody [mAb]) ≤ 21 days prior to the first dose of study drug. If there
are questions relating to this criterion, a longer wash-out period may be required
after discussion with the Medical Monitor.

27. Current or prior use of WEE-1 inhibitor or any immunosuppressive medication (e.g.
anti-PDL1, anti-PD1, or previous cell-depleting therapies such as alemtuzumab,
anti-CD4, anti-CD5, anti-CD3, anti-CD20, etc.) ≤ 14 days prior to the first dose of
MEDI4736. The following are exceptions to this criterion: Intranasal, inhaled,
topical, or local steroid injections (e.g. intra-articular injection), systemic
corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
equivalent. Please note: This does not include use of corticosteroids as part of
antiemetic prophylaxis or treatment in relation to AZD1775 dosing or steroids as
premedication for hypersensitivity reactions (e.g. CT scan premedication).

28. Any known allergy, hypersensitivity or contraindication to the components of the study
drug AZD1775 or MEDI4736 or any of their excipients, or to corticosteroids.

29. Prior randomisation in a previous MEDI4736 clinical study regardless of treatment arm
assignment.

30. Receipt of live attenuated vaccine ≤ 30 days prior to the first dose of study drug.
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
30 days after the last dose of IP.

31. Prescription or non-prescription drugs or other products known to be sensitive to
CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be
moderate to strong inhibitors or inducers of CYP3A4 which cannot be discontinued 2
weeks prior to the first day of study drug dosing and withheld throughout the study
until 2 weeks after the last dose of study drug.

32. Herbal preparations must be stopped 7 days prior to first dose of study drug.

33. Any evidence of severe or uncontrolled systemic disease such as active bleeding
diatheses (as judged by the Investigator), or positive for immunodeficiency virus
(HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV).

34. Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample
collection.