Biliary Tract Cancer, Breast Cancer, Colorectal Cancer, Gastroesophageal Cancer, Head and Neck Carcinoma, Lung Cancer, Melanoma, Pancreatic Adenocarcinoma
Conditions
Keywords
Selumetinib, Tremelimumab, MEDI4736, Safety, Tolerability, Pharmacokinetics, Patients with advanced solid tumours, Disease progression
Brief summary
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.
Detailed description
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.
Interventions
DRUGSelumetinib
Selumetinib oral
DRUGMEDI4736
MEDI4736 IV
DRUGTremelimumab
Tremelimumab, IV
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Adverse Events | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of safety laboratory tests | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of blood pressure (BP) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Electrocardiogram (ECG) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of physical examinations | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Echocardiogram (ECHO) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of pulse | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of body temperature | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of respiratory rate | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Multigated Acquisition (MUGA) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Ophthalmic examination (best corrected visual acuity) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Ophthalmic examination (Intraocular pressure) | From screening until approximately 30 days after last dose of study drug at disease progression |
| Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Ophthalmic examination (slit lamp fundoscopy) | From screening until approximately 30 days after last dose of study drug at disease progression |
Secondary
| Measure | Time frame |
|---|---|
| Long-term tolerated dose and exposure predicted to result in biological activity (including but not limited to Response Evaluation Criteria in Solid Tumours (RECIST) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Objective response rate (ORR) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Change in tumour size | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Best Objective Response (BoR) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Duration of Response (DoR) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Progression-free survival (PFS) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| Overall survival (OS) | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
| MEDI4736 and/or tremelimumab anti-drug antibody (ADA) level in Plasma | From screening until 30 days after last dose of study drug at disease progression, approximately 6 months however there is no maximum duration of treatment |
Countries
United States
Outcome results
None listed