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

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