A Phase I, Open-Label, Multi-Centre Study to Assess 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 in Patients With Advanced Solid Tumours
Overview
- Phase
- Phase 1
- Intervention
- Selumetinib
- Conditions
- Lung Cancer
- Sponsor
- AstraZeneca
- Enrollment
- 58
- Locations
- 1
- Primary Endpoint
- Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Adverse Events
- Status
- Completed
- Last Updated
- 6 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
- •Age ≥18 years at time of study entry
- •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
- •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
- •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)
- •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
- •Male patients should be willing to use barrier contraception ie, condoms plus spermicide
Exclusion Criteria
- •Patients must not enter the study if any of the following exclusion criteria are fulfilled
- •Previous enrolment in the present study
- •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
Arms & Interventions
Dose escalation: Selumetinib+MEDI4736
An oral formulation of selumetinib will be administered in combination with an IV dose of MEDI4736. 4 cohorts of double combination (Selumetinib+MEDI4736). The decision to escalate to the next dose level/cohort will be made by the Safety Review Committee (SRC) following the completion of the dose limiting toxicity (DLT) assessment period for at least 3 evaluable patients in each cohort.
Intervention: Selumetinib
Dose escalation: Selumetinib+MEDI4736
An oral formulation of selumetinib will be administered in combination with an IV dose of MEDI4736. 4 cohorts of double combination (Selumetinib+MEDI4736). The decision to escalate to the next dose level/cohort will be made by the Safety Review Committee (SRC) following the completion of the dose limiting toxicity (DLT) assessment period for at least 3 evaluable patients in each cohort.
Intervention: MEDI4736
Mandatory paired biopsy expansion cohort: Selumetinib+MEDI4736
One or more independent mandatory paired biopsy expansion cohorts for double combination treatment will start after safety and tolerability have been established for the relevant dose. It will be tumour-type specific for double combination, the tumor type will be determined from emerging data.
Intervention: Selumetinib
Mandatory paired biopsy expansion cohort: Selumetinib+MEDI4736
One or more independent mandatory paired biopsy expansion cohorts for double combination treatment will start after safety and tolerability have been established for the relevant dose. It will be tumour-type specific for double combination, the tumor type will be determined from emerging data.
Intervention: MEDI4736
Dose escalation: Selumetinib+MEDI4736+tremelimumab
An oral formulation of selumetinib will be administered in combination with an IV dose of MEDI4736 and an IV dose of tremelimumab. For triple combination treatment, the starting dose of selumetinib (DL1) will be determined by the SRC based on emerging data from dose escalation cohorts of double combination treatment.
Intervention: Selumetinib
Dose escalation: Selumetinib+MEDI4736+tremelimumab
An oral formulation of selumetinib will be administered in combination with an IV dose of MEDI4736 and an IV dose of tremelimumab. For triple combination treatment, the starting dose of selumetinib (DL1) will be determined by the SRC based on emerging data from dose escalation cohorts of double combination treatment.
Intervention: MEDI4736
Dose escalation: Selumetinib+MEDI4736+tremelimumab
An oral formulation of selumetinib will be administered in combination with an IV dose of MEDI4736 and an IV dose of tremelimumab. For triple combination treatment, the starting dose of selumetinib (DL1) will be determined by the SRC based on emerging data from dose escalation cohorts of double combination treatment.
Intervention: Tremelimumab
Mandatory paired biopsy expansion cohort: triple combination
One or more independent mandatory paired biopsy expansion cohorts for triple combination treatment will start after safety and tolerability have been established for the relevant dose. It will be tumour-type specific for triple combination, the tumor type will be determined from emerging data.
Intervention: Selumetinib
Mandatory paired biopsy expansion cohort: triple combination
One or more independent mandatory paired biopsy expansion cohorts for triple combination treatment will start after safety and tolerability have been established for the relevant dose. It will be tumour-type specific for triple combination, the tumor type will be determined from emerging data.
Intervention: MEDI4736
Mandatory paired biopsy expansion cohort: triple combination
One or more independent mandatory paired biopsy expansion cohorts for triple combination treatment will start after safety and tolerability have been established for the relevant dose. It will be tumour-type specific for triple combination, the tumor type will be determined from emerging data.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Safety and tolerability of Selumetinib in combination with MEDI4736, and in combination with MEDI4736+ tremelimumab by assessment of Adverse Events
Time Frame: 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
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: 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)
Time Frame: From screening until approximately 30 days after last dose of study drug at disease progression
Secondary Outcomes
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)