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

NCT02586987 | Completed Phase 1 FDA Drug

• 1 other identifier: D1345C00003
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 6

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.

Conditions

Lung Cancer; Melanoma; Head and Neck Carcinoma; Gastroesophageal Cancer; Breast Cancer; Pancreatic Adenocarcinoma; Colorectal Cancer; Biliary Tract Cancer

Keywords

Selumetinib; Tremelimumab; MEDI4736; Safety; Tolerability; Pharmacokinetics; Patients with advanced solid tumours; Disease progression

Outcome Measures

Primary Outcomes (13)

• 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 Outcomes (8)

• 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

Study Arms (4)

Dose escalation: Selumetinib+MEDI4736

EXPERIMENTAL

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.

Drug: Selumetinib; Drug: MEDI4736

Mandatory paired biopsy expansion cohort: Selumetinib+MEDI4736

EXPERIMENTAL

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.

Drug: Selumetinib; Drug: MEDI4736

Dose escalation: Selumetinib+MEDI4736+tremelimumab

EXPERIMENTAL

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.

Drug: Selumetinib; Drug: MEDI4736; Drug: Tremelimumab

Mandatory paired biopsy expansion cohort: triple combination

EXPERIMENTAL

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.

Drug: Selumetinib; Drug: MEDI4736; Drug: Tremelimumab

Interventions

Selumetinib DRUG

Selumetinib oral

Dose escalation: Selumetinib+MEDI4736; Dose escalation: Selumetinib+MEDI4736+tremelimumab; Mandatory paired biopsy expansion cohort: Selumetinib+MEDI4736; Mandatory paired biopsy expansion cohort: triple combination

MEDI4736 DRUG

MEDI4736 IV

Dose escalation: Selumetinib+MEDI4736; Dose escalation: Selumetinib+MEDI4736+tremelimumab; Mandatory paired biopsy expansion cohort: Selumetinib+MEDI4736; Mandatory paired biopsy expansion cohort: triple combination

Tremelimumab DRUG

Tremelimumab, IV

Dose escalation: Selumetinib+MEDI4736+tremelimumab; Mandatory paired biopsy expansion cohort: triple combination

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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
• 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

You may not qualify if:

• 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
• 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
• 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
• 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

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (6)

Research Site

Chicago, Illinois, 60637, United States

Location

Research Site

Boston, Massachusetts, 02215, United States

Location

Research Site

Las Vegas, Nevada, 89169-3321, United States

Location

Research Site

New Brunswick, New Jersey, 08901, United States

Location

Research Site

Charlotte, North Carolina, 28204, United States

Location

Research Site

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Lung Neoplasms; Melanoma; Breast Neoplasms; Colorectal Neoplasms; Biliary Tract Neoplasms; Disease Progression

Interventions

AZD 6244; durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Breast Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Biliary Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Pasi A. Jänne, MD, PhD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 21, 2015
• First Posted: October 27, 2015
• Study Start: December 28, 2015
• Primary Completion: July 25, 2018
• Study Completion: September 20, 2019
• Last Updated: November 18, 2019

Record last verified: 2019-11

Locations

US (6)