A Study to Assess the Safety, Tolerability and Anti-tumour Activity of Ascending Doses of Selumetinib in Combination With MEDI4736 and Selumetinib in Combination With MEDI4736 and Tremelimumab in Patients With Advanced Solid Tumours

This is a Phase I, open-label, multi-centre, drug combination study of double and triple
combination oral selumetinib (AZD6244 Hyd-sulfate) plus intravenous (IV) MEDI4736 and oral
selumetinib plus IV MEDI4736 and IV tremelimumab in patients with advanced solid tumours
refractory to standard therapy or for which no standard therapy exists. The safety,
tolerability, and preliminary anti-tumour activity of ascending doses of Selumetinib (AZD6244
Hyd-sulfate) in Combination with MEDI4736 and Selumetinib in Combination with MEDI4736 and
Tremelimumab will be investigated. Once safety and tolerability have been established for the
relevant dose, expansion cohorts will commence in order to further evaluate safety,
tolerability, and provide a preliminary evaluation of the mechanism of action and anti-tumour
activity of the drug combination. Mandatory paired biopsy expansion cohorts will be
tumour-type specific. Expansion cohorts will open independently for double and triple
combination treatments.

Inclusion Criteria:

1. Written informed consent and any locally-required authorization (eg, Health Insurance
Portability and Accountability Act in the US, EU Data Privacy Directive in the EU)
obtained from the patient prior to performing any protocol-related procedures,
including pre-screening and screening evaluations

2. Age ≥18 years at time of study entry

3. Histological or cytological confirmation of locally advanced (stage IIIB) or
metastatic (stage IV) solid tumours refractory to standard therapy or for which no
standard therapy exists

4. World Health Organisation Eastern Cooperative Oncology Group (ECOG) performance status
0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12
weeks

5. At least 1 lesion, not previously irradiated, that can be accurately measured at
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short
axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and
which is suitable for accurate repeated assessment as per Response Evaluation Criteria
in Solid Tumours (RECIST criteria v1.1)

6. Female patients and males with partners of childbearing potential should be using
highly effective contraceptive measures. Females should not be breastfeeding and must
have a negative pregnancy test prior to start of dosing if of childbearing potential
or must have evidence of non-childbearing potential by fulfilling 1 of the criteria
below at screening.

- Postmenopausal defined as aged more than 50 years and amenorrhoeic for at least
12 months following cessation of all exogenous hormonal treatments

- Women <50 years old would be considered postmenopausal if they have been
amenorrheic for the past 12 months or more following cessation of exogenous
hormonal treatments. The levels of luteinising hormone (LH) and follicle
stimulating hormone (FSH) must also be in the postmenopausal range (as per the
institution)

- Documentation of irreversible surgical sterilisation by hysterectomy and / or
bilateral oophorectomy and/or bilateral salpingectomy but not tubal ligation

7. Male patients should be willing to use barrier contraception ie, condoms plus
spermicide

8. Mandatory provision of tumour tissue sample available at study entry for exploratory
biomarker research. Cytology samples for this exploratory biomarker research will not
be acceptable

9. Patients must have mCRC and, if MSI status is known, non-high MSI status. MSI status
will be evaluated based on previous results of local MSI testing, if available.
Patients with known MSI-high status will be excluded; patients with MSS, MSI-low, or
unknown MSI status may be enrolled

Exclusion Criteria:

Patients must not enter the study if any of the following exclusion criteria are fulfilled

1. Previous enrolment in the present study

2. Treatment with any of the following:

- Cytotoxic chemotherapy or other anticancer drugs within 28 days of the 1st dose
of study treatment or any investigational agents within 5 half-lives of the
product

- MEDI4736 or selumetinib in the present study (ie, dosing with MEDI4736 or
selumetinib previously initiated in this study)

- Major surgical procedure, (excluding placement of vascular access) or significant
traumatic injury within 4 weeks of the 1st dose of study treatment, or have an
anticipated need for major surgery during the study

- Palliative radiotherapy with a wide field of radiation within 4 weeks or
radiotherapy with a limited field of radiation for palliation within 2 weeks of
the 1st dose of study treatment

- Prior exposure to immune-mediated therapy, including, but not limited to, other
anti-CTLA- 4 (Cytotoxic T-lymphocyte antigen-4), anti-PD-1 (Programmed cell death
1), anti-PD-L1 (Programmed cell death ligand 1), or anti-PD-L2 (Programmed cell
death ligand 2) antibodies, including therapeutic anticancer vaccines

- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP

- Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study

3. Any unresolved toxicity NCI CTCAE (National Cancer Institute Common Terminology
Criteria for Adverse Events) Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria

- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and
may be included after consultation with the medical monitor

- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with selumetinib, MEDI4736 or tremelimumab may be included after
consultation with the medical monitor

4. History of leptomeningeal carcinomatosis and brain metastases or spinal cord
compression. Patients with suspected brain metastases at screening should have a CT /
MRI of the brain prior to study entry

5. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], celiac disease, irritable bowel disease, or other
serious GI (Gastrointestinal) chronic conditions associated with diarrhoea, systemic
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis
with polyangiitis, Graves' disease; rheumatoid arthritis, hypophysitis, uveitis])
within the past 3 years prior to the start of treatment. The following are exceptions
to this criterion:

- Patients with vitiligo or alopecia

- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement or psoriasis not requiring systemic treatment

6. History of active primary immunodeficiency

7. Current or prior use of immunosuppressive medication within 14 days before the 1st
dose of MEDI4736. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection)

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent

- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)

8. As judged by the investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension, renal transplant, active bleeding
diatheses, which in the investigator's opinion makes it undesirable for the patient to
participate in the study or which would jeopardise compliance with the protocol or
active infection including hepatitis B surface antigen (HBsAg), hepatitis C virus
(HCV) antibody or human immunodeficiency virus (HIV) or known history of clinical
diagnosis of tuberculosis

9. Screening for chronic conditions is not required

10. Any of the following cardiac criteria:

- Any factors that increase the risk of QT(ECG interval measured from the onset of
the QRS complex to the end of the T wave) interval corrected for heart rate (QTc)
prolongation or risk of arrhythmic events (eg, heart failure, hypokalaemia,
congenital long QT syndrome, family history of long QT syndrome or unexplained
sudden death under 40 years of age) or mean QTc >470 msec

- Uncontrolled hypertension (eg, BP ≥150/95 mmHg despite medical therapy)

- Acute coronary syndrome within 6 months prior to starting treatment

- Angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy)

- Symptomatic heart failure (New York Heart Association II-IV)

- Prior or current cardiomyopathy

- Baseline LVEF (Left ventricular ejection fraction) <55% measured by
echocardiography or MUGA. Appropriate correction to be used if a MUGA is
performed.

- Atrial fibrillation with a ventricular rate >100 beats per minute at rest

- Severe valvular heart disease

11. Any of the following ophthalmic criteria:

- Current or past history of central serous retinopathy, detachment of retinal
pigmented epithelium, or retinal vein occlusion

- Intraocular pressure (IOP) >21 mmHg

- Uncontrolled glaucoma (irrespective of IOP)

12. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:

- Absolute neutrophil count <1.5 x 109/L

- Platelet count <100 x 109/L

- Haemoglobin <90 g/L

- Alanine aminotransferase >2.5 x ULN (upper limit of normal) if no demonstrable
liver metastases or >5 times ULN in the presence of liver metastases

- Aspartate aminotransferase >2.5 x ULN if no demonstrable liver metastases or >5
times ULN in the presence of liver metastases

- Serum bilirubin ≤1.5 x ULN. This will not apply to patients with confirmed
Gilbert's syndrome (persistent or recurrent hyperbilirubinaemia [predominantly
unconjugated bilirubin] in the absence of evidence of haemolysis or hepatic
pathology), who will be allowed in consultation with their physician

- Creatinine clearance <50 mL/min (calculated by Cockcroft and Gault equation).
Confirmation of creatinine clearance is only required when creatinine is >1.5
times ULN

13. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the
formulated product or previous significant bowel resection that would preclude
adequate absorption of selumetinib

14. History of hypersensitivity to active or inactive excipients of MEDI4736 or
selumetinib or drugs with a similar chemical structure or class to MEDI4736 or
selumetinib

15. Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions, and
requirements

16. Involvement in the planning and conduct of the study (applies to both AZ staff or
staff at the study site)

17. Previous allogeneic bone marrow transplant

18. Body weight <30 kg