Clinical trial NCT01693562: A Phase 1/2 Study to Evaluate MEDI4736
Official title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI4736 in Subjects With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Keywords: Advanced solid tumors
Lead sponsor: MedImmune LLC
Sponsor class: INDUSTRY
First posted: 2012-09-26
Enrollment: 1022
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multicenter, open-label, first-time-in-human study with a standard 3+3 dose-escalation phase in participants with advanced solid tumors followed by an expansion phase in participants with advanced solid tumors. An exploration cohort has been added to determine the safety using every 4 weeks (Q4W) dosing.

Detailed description: A dose-escalation and dose-expansion study of MEDI4736 (a monoclonal antibody that targets programmed cell death ligand-1 (PD-L1)) will evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (IM), and antitumor activity of MEDI4736 in adult participants with solid tumors. A dose exploration cohort will look at the safety profile of Q4W dosing of MEDI4736.

Eligibility criteria: Inclusion Criteria:

* Age 18 or older.
* In the dose-escalation phase: histologically- or cytologically- confirmed advanced solid tumor that is refractory to standard therapy and for which no standard therapy exists.
* In the dose-expansion phase: histologically- or cytologically- confirmed advanced solid tumor where if an approved first-line therapy is available, participants must have failed, be intolerant to, be ineligible for, or have refused
* Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
* Adequate organ and marrow function.
* Participants must have at least 1 measurable lesion.
* Available archived tumor tissue sample.
* Willingness to provide consent for biopsy sample (dose-expansion only)

Exclusion Criteria:

* Any prior Grade ≥ 3 immune-mediated adverse event (imAE) while receiving immunotherapy
* Prior exposure to any anti-PD-1 or anti-PD-L1 antibody
* Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment.
* Prior treatment with immunotherapy agents including, but not limited to, tumor necrosis factor receptor superfamily agonists or checkpoint inhibitors or natural killer (NK) cell inhibitors.
* Active or prior documented autoimmune disease within the past 2 years
* History of primary immunodeficiency
* History of organ transplant that requires use of immunosuppressives
* Symptomatic or untreated central nervous system (CNS) metastases requiring concurrent treatment
* Other invasive malignancy within 2 years
* Women who are pregnant or lactating
* Uncontrolled intercurrent illness
* Known history of tuberculosis
* Known to be human immunodeficiency virus (HIV) positive
* Known to be Hepatitis B or C positive (except HCC participants)

Primary outcomes:
measure: Number of Participants With Dose-limiting Toxicities in the Dose-escalation Phase
timeFrame: For MEDI4736 0.1 to MEDI4736 10 mg/kg arms: from Day 1 to Day 28 of first dose; for MEDI4736 15 mg/kg arm: from Day 1 to Day 42 of first dose
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) in the Dose-escalation, Dose-exploration, and Dose-expansion Phase
timeFrame: From Day 1 through 90 days after the last dose of study drug (approximately 5.25 years)
measure: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs in the Dose-escalation, Dose-exploration, and Dose-expansion Phase
timeFrame: From Day 1 through 90 days after the last dose of study drug (approximately 5.25 years)
measure: Number of Participants With Abnormal Vital Signs Reported as TEAEs in the Dose-escalation, Dose-exploration, and Dose-expansion Phase
timeFrame: From Day 1 through 90 days after the last dose of study drug (approximately 5.25 years)
measure: Number of Participants With Change From Baseline in QT/QTc Interval in Local Electrocardiogram in the Dose-escalation, Dose-exploration, and Dose-expansion Phase
timeFrame: From Baseline (Day 1) through 90 days after the last dose of study drug (approximately 5.25 years)
measure: Objective Response Rate (ORR) Assessed by Blinded Independent Central Review (BICR) in Participants With Non-squamous NSCLC Who Had Received 2 or More Prior Lines of Therapy in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: ORR Assessed by BICR in Participants With Squamous NSCLC Who Had Received 1 and 2 or More Prior Lines of Therapy in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: ORR Assessed by BICR in Participants With UC Post-platinum (Programmed Cell Death Ligand [PD-L1] Status High) Who Had Received at Least 1 Line of Prior Therapy (2L+) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
Secondary outcomes:
measure: Area Under the Serum Concentration-time Curve up to the Last Measurable Concentration (AUClast) of MEDI4736 After the First Dose in the Dose-escalation and Dose-exploration Phase
timeFrame: After the first dose between Day 0 and Day 15 (Day 1 [pre and post dose] and predose of Dose 2 for all cohorts; Days 3, 5, 10 for Cohorts 0.1mg/kg to 10 mg/kg; Days 3, 5, 10, 15 for Cohort 15 mg/kg; Day 15 for Cohort 20 mg/kg)
measure: Maximum Serum Concentration (Cmax) of MEDI4736 After the First Dose in the Dose-escalation and Dose-exploration Phase
timeFrame: After the first dose between Day 0 and Day 15 (Day 1 [pre and post dose] and predose of Dose 2 for all cohorts; Days 3, 5, 10 for Cohorts 0.1mg/kg to 10 mg/kg; Days 3, 5, 10, 15 for Cohort 15 mg/kg; Day 15 for Cohort 20 mg/kg)
measure: Number of Participants With Positive Anti-drug Antibodies (ADA) to MEDI4736 in the Dose-escalation, Dose-exploration Phase, and Dose-expansion Phase.
timeFrame: Escalation: Day1 of Dose(D)1 & D3, even numbered doses after D4; Exploration: Day1 of D1 & D2, even numbered doses after D2; Expansion: Day1 of D1, every 12 weeks since D3; all phases: till EOT, 30 days and 3 and 6 months post last dose (~5.25 years)
measure: Number of Participants With Best Overall Response (BOR) Assessed by BICR in NSCLC and SCCHN Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Number of Participants With BOR Assessed by Investigator in the Dose-escalation, Dose-exploration, and Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Duration of Response (DoR) Assessed by BICR in NSCLC and SCCHN Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DoR Assessed by Investigator in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Disease Control Rate (DCR) Assessed by BICR in NSCLC and SCCHN Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DCR Assessed by Investigator in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Progression-free Survival (PFS) Assessed by BICR in NSCLC Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: PFS Assessed by BICR in SCCHN Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: PFS Assessed by Investigator in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: OS in the Dose-Expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: ORR Assessed by BICR in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: ORR Assessed by Investigator in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DoR Assessed by BICR in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DoR Assessed by Investigator in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DCR Assessed by BICR in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: DCR Assessed by Investigator in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: PFS Assessed by BICR in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: PFS Assessed by Investigator in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: OS in UC Cohort (PD-L1 Low/Negative, Total, and PD-L1 High) in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Adjusted Comparison of PFS by PD-L1 Status in UC Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
measure: Adjusted Comparison of OS by PD-L1 Status in UC Cohort in the Dose-expansion Phase
timeFrame: From Day 1 through disease progression, study withdrawal, or initiation of another anticancer therapy, whichever occurred first (approximately 5.25 years)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Research Site
state: Arizona
city: Burbank
country: United States
facility: Research Site
state: California
city: Gilroy
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Orange
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state: California
city: Palo Alto
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facility: Research Site
state: California
city: San Francisco
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facility: Research Site
state: California
city: Whittier
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facility: Research Site
state: California
city: New Haven
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facility: Research Site
state: Connecticut
city: Washington
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facility: Research Site
state: District of Columbia
city: Jacksonville
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state: Florida
city: Miami Beach
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state: Florida
city: Tampa
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state: Florida
city: Athens
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facility: Research Site
state: Georgia
city: Augusta
country: United States
facility: Research Site
state: Georgia
city: Chicago
country: United States
facility: Research Site
state: Illinois
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Ann Arbor
country: United States
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state: Michigan
city: Detroit
country: United States
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state: Michigan
city: Minneapolis
country: United States
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state: Minnesota
city: Saint Louis Park
country: United States
facility: Research Site
state: Minnesota
city: Billings
country: United States
facility: Research Site
state: Montana
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: Hackensack
country: United States
facility: Research Site
state: New Jersey
city: Paterson
country: United States
facility: Research Site
state: New Jersey
city: Bronx
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Chapel Hill
country: United States
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state: North Carolina
city: Huntersville
country: United States
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state: North Carolina
city: Cleveland
country: United States
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state: Ohio
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Dallas
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
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state: Texas
city: Salt Lake City
country: United States
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state: Utah
city: Blacksburg
country: United States
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state: Virginia
city: Fairfax
country: United States
facility: Research Site
state: Virginia
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liege
country: Belgium
facility: Research Site
city: Namur
country: Belgium
facility: Research Site
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Paris Cedex 10
country: France
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Gauting
country: Germany
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Jena
country: Germany
facility: Research Site
city: Minden
country: Germany
facility: Research Site
city: Lecce
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Siena
country: Italy
facility: Research Site
city: Gwangju
country: Korea, Republic of
facility: Research Site
city: Seo-Gu
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: MedImmune LLC
name: MedImmune, LLC
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