We updated the design of this site on September 25th. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI0639 in Advanced Solid Tumors

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01577745
First Posted: April 16, 2012
Last Update Posted: May 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
MedImmune LLC
  Purpose
This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK and immunogenicity of MEDI0639.

Condition Intervention Phase
Solid Tumors Biological: MEDI0639 Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI0639 in Adult Subjects With Advanced Solid Tumors

Further study details as provided by MedImmune LLC:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of MEDI0639 [ Time Frame: From the first dose of MEDI0639 to 21 days after the first dose ]
    The MTD evaluation was based on the dose-limiting toxicity (DLT) evaluable population. DLT is defined as any Grade 3 or higher treatment-related toxicity that occurred during the DLT evaluation period (defined as the time from the first dose of MEDI0639 to 21 days after the first dose), except for National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 hypertension that could be controlled within 96 hours; Grade 3 symptomatic hypertension of greater than (>) 180 millimetre of mercury (mm Hg) systolic or >120 mm Hg diastolic or asymptomatic hypertension of >200 mm Hg systolic or >120 mm Hg diastolic was considered a DLT.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From the first dose of MEDI0639 until 90 days after the last dose of MEDI0639. Maximum time frame across participants was 11 months. ]
    An adverse event (AE) is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. Treatment-emergent AEs (TEAEs) were events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug, for the period extending to 90 days after the last dose of study drug. The AEs were summarized using Medical Dictionary for Regulatory Activities (MedDRA) version 18.1.

  • Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From the first dose of MEDI0639 until the end of participation in the study. Maximum time frame across participants was 4 years. ]
    A serious AE (SAE) is any AE that results in death (refers to an event, which risk of death at the time of the event; it does not refer to an event that may have led to death), is immediately life threatening, require (or prolong) inpatient hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly or birth defect, or is an important medical event that may jeopardize the participant or may require medical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs defined as SAEs present at baseline that worsened in intensity after administration of study drug or SAEs absent at baseline that emerged after administration of study drug. The SAEs were summarized using MedDRA version 18.1.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Laboratory Parameters [ Time Frame: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months. ]
    Laboratory evaluations of blood and urine samples were performed, including hematology (white blood cell [WBC] count with differential, red blood cell [RBC] count, hematocrit, hemoglobin, platelet count, mean corpuscular volume [MCV], and mean corpuscular hemoglobin concentration [MCHC]); serum chemistry (calcium, chloride, magnesium, potassium, sodium, bicarbonate, aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase, total bilirubin, liver function test, gamma glutamyl transferase [GGT], lactate dehydrogenase, uric acid, creatinine, blood urea nitrogen [BUN], glucose, albumin, total protein, triglycerides, cholesterol, and troponin); and routine urinalysis. The TEAEs related to laboratory evaluations in participants were reported.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and Physical Examination [ Time Frame: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months. ]
    Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) were performed at baseline and throughout the study. The TEAEs related to vital signs in participants were reported.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Electrocardiogram (ECG) Evaluations [ Time Frame: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months. ]
    ECG parameters included QT interval and corrected QT (QTc) interval. Electrocardiogram (ECG) parameters were assessed at baseline as well as throughout the study. All 12-lead ECGs performed during the study were obtained in triplicate. The TEAEs related to ECG evaluations in participants were reported.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Echocardiogram Evaluations [ Time Frame: From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months. ]
    Echocardiogram parameters included left ventricular ejection fraction (LVEF) and pulmonary arterial pressure (PAP). The TEAEs related to echocardiogram evaluations in participants were reported.


Secondary Outcome Measures:
  • Area Under the Concentration‑Time Curve From Time 0 to Infinity (AUCinf) After Cycle 1 Treatment Administration of MEDI0639 [ Time Frame: Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1 ]
    The pharmacokinetics (PK) parameter was estimated using the noncompartmental analysis methods, based on the individual serum concentration-time data. The concentration-time curve is the result of blood sampling at specified time points and its measured concentration of MEDI0639.

  • Maximum Observed Concentration (Cmax) After Cycle 1 Treatment Administration of MEDI0639 [ Time Frame: Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1 ]
    The pharmacokinetics (PK) parameter was estimated using the noncompartmental analysis methods, based on the individual serum concentration-time data. The concentration-time curve is the result of blood sampling at specified time points and its measured concentration of MEDI0639.

  • Clearance (CL) After Cycle 1 Treatment Administration of MEDI0639 [ Time Frame: Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1 ]
    The pharmacokinetics (PK) parameter was estimated using the noncompartmental analysis methods, based on the individual serum concentration-time data. The concentration-time curve is the result of blood sampling at specified time points and its measured concentration of MEDI0639. Clearance was estimated as dose divided by the area under serum concentration-time curve from time zero to infinity.

  • Half-life (t1/2) After Cycle 1 Treatment Administration of MEDI0639 [ Time Frame: Days 1 (prior to start of infusion and 30 mins, 2, and 6 hours post end of infusion), 2, 5 , 8, and 15 of Cycle 1 ]
    The pharmacokinetics (PK) parameter was estimated using the noncompartmental analysis methods, based on the individual serum concentration-time data. The concentration-time curve is the result of blood sampling at specified time points and its measured concentration of MEDI0639.

  • Number of Participants Positive With Antidrug Antibodies (ADA) for MEDI0639 [ Time Frame: On Day 1 of Cycles 1, 2, 3, and every other cycle thereafter, end of treatment, 30 days, and 3 and 6 months after the last dose of MEDI0639. Maximum time frame across participants was 14 months. ]
    Blood samples were measured for the presence of ADA for MEDI0639 using a validated bridging immunoassay. Only the number of participants positive for anti-MEDI-575 antibodies at any visit were presented.

  • Percentage of Participants With Best Overall Response [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Percentage (%) of participants who were responders with BOR documented as confirmed CR, PR, stable disease (SD), progressive disease (PD) and non-evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<)10 mm. PR: At least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

  • Percentage of Participants With Objective Response [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Objective response rate (ORR) defined as the percentage of participants with a BOR of confirmed CR or confirmed PR.

  • Percentage of Participants With Disease Control [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Disease control rate (DCR) defined as the percentage of participants with a BOR of confirmed CR, confirmed PR or SD.

  • Time to Response [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Time to response (TTR) defined as the time from the first dose of MEDI0639 until the first documentation of a subsequently confirmed objective response. Only participants who have achieved objective response (confirmed CR or confirmed PR) was evaluated for TTR. TTR (months) = (Date of first disease response - Date of the first dose of MEDI0639 + 1) / (365.25/12).

  • Duration of Response (DR) [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    DR defined as time from start of first documented objective response [confirmed Complete Response (CR) or confirmed Partial Response (PR)] to first documented disease progression or death due to any cause, whichever occurs first. DR calculated as (months) = (Date of PD/death or censoring - Date of first disease response + 1)/ (365.25/12).

  • Progression-free Survival (PFS) [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Progression-free survival (PFS) is defined as the time from the first dose of MEDI0639 until the first documentation of disease progression or death due to any cause, whichever occurs first. PFS (months) = (Date of PD/death or censoring - Date of the first dose of MEDI0639 + 1) / (365.25/12).

  • Overall Survival [ Time Frame: From study entry through the end of the study. Maximum time frame across participants was 4 years. ]
    Overall survival defined as the time from the first dose of MEDI0639 until death due to any cause. OS (months) = (Date of death or censoring - Date of the first dose of MEDI0639 + 1) / (365.25/12).


Enrollment: 58
Study Start Date: April 2012
Study Completion Date: December 2015
Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MEDI0639 Cohort 1
Participants received MEDI0639 dose level 1 as a 60-minute intravenous (IV) infusion on Day 1 of each 21-day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.
Experimental: MEDI0639 Cohort 2
Participants received MEDI0639 dose level 2 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.
Experimental: MEDI0639 Cohort 3
Participants received MEDI0639 dose level 3 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.
Experimental: MEDI0639 Cohort 4
Participants received MEDI0639 dose level 4 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.
Experimental: MEDI0639 Cohort 5
Participants received MEDI0639 dose level 5 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.
Experimental: MEDI0639 Cohort 6
Participants received MEDI0639 dose level 6 as a 60-minute IV infusion on Day 1 of each 21 day cycle.
Biological: MEDI0639
MEDI0639 is an immunoglobulin G1 lambda (IgG1λ) monoclonal antibody. MEDI0639 selectively binds to DLL4 and blocks its ability to bind to and activate signaling through the Notch receptors.

Detailed Description:
This is a first-time-in-human, Phase 1, multicenter, open-label, single-arm, dose-escalation (3+3) study to evaluate the safety, tolerability, antitumor activity, PK, and immunogenicity of MEDI0639 in adult subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy exist. Up to 63 subjects will be enrolled at approximately 3 to 5 study centers in North America.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed solid tumors that are refractory to standard therapy or for which no standard therapy exist
  • Age ≥ 18 years
  • ECOG Performance Status of 0 or 1
  • LVEF (measured by Echocardiogram) > 50%
  • No gastrointestinal bleeding within 1 year of study entry.
  • Adequate organ and marrow function:

    • Hemoglobin ≥ 10g/dL
    • Absolute Neutrophil Count ≥ 1500/mm3
    • Platelet Count ≥ 100,000/mm3
    • AST & ALT ≤ 2.5 x ULN
    • Bilirubin ≤ 1.5 x ULN
    • Cr Cl ≥ 50 mL/min (as determined by the Cockcroft-Gault equation or by 24-hour urine collection)
  • Prior therapy against VEGF or VEGFRs including, but not limited to bevacizumab, sunitinib, sorafenib, pazopanib, motesanib (AMG706), or cediranib (AZD2171), is permitted so long as the agent does not have any known activity against DLL4 and the last dose received s at least 6 weeks prior to first dose of MEDI0639.
  • Life expectancy ≥ 12 weeks
  • Females of childbearing potential must be surgically sterile, have a sterile male partner, be premenarchal or at least 2 years postmenopausal, practice abstinence or otherwise must use 2 effective methods of contraception from the time of initiation of investigational product.
  • Males, unless surgically sterile, must use 2 effective methods of contraception with a female partner and must agree to continue using such contraception for 90 days after the last dose of MEDI0639

Exclusion Criteria:

  • Concurrent enrollment in another investigational clinical study
  • Receipt of any investigational anticancer therapy within 4 weeks prior to the first dose of MEDI0639 or in the case of monoclonal antibodies, 6 weeks prior to the first dose of MEDI0639
  • Concurrent or previous treatment with inhibitors of DLL4
  • Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment
  • Known bleeding diathesis, esophageal varices, or angioplasty
  • Pulmonary hemorrhage or gross hemoptysis within 12 months
  • Known arterial or venous thrombosis or pulmonary embolism within 2 years
  • Concurrent use of systemic low molecular weight heparin or low dose warfarin
  • Presence of brain metastases
  • Cerebrovascular accident or transient ischemic attack within 2 years
  • Cardiovascular events, such as myocardial infarction, unstable/severe angina, coronary/peripheral artery bypass graft, unstable cardiac arrhythmia requiring medication, congestive heart failure (NYHA > class II), within 2 years
  • Tumors with squamous cell histology
  • Major surgical procedure within 90 days
  • Pregnancy or lactation
  • Known HIV positive or Hepatitis A, B, or C infection
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01577745


Locations
United States, California
Research Site
Los Angeles, California, United States, 90404
United States, Connecticut
Research Site
New Haven, Connecticut, United States, 06513
United States, Massachusetts
Research Site
Boston, Massachusetts, United States
United States, Michigan
Research Site
Ann Arbor, Michigan, United States, 48103
United States, Minnesota
Research Site
Minneapolis, Minnesota, United States
United States, New York
Research Site
New York, New York, United States, 10002
United States, Ohio
Research Site
Cincinnati, Ohio, United States, 45201
Research Site
Cleveland, Ohio, United States, 44105
United States, Texas
Research Site
Houston, Texas, United States, 77030
United States, Washington
Research Site
Seattle, Washington, United States, 98112
Research Site
Tacoma, Washington, United States, 98405
Sponsors and Collaborators
MedImmune LLC
  More Information

Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT01577745     History of Changes
Other Study ID Numbers: CD-ON-MEDI0639-1078
First Submitted: April 5, 2012
First Posted: April 16, 2012
Results First Submitted: January 23, 2017
Results First Posted: May 2, 2017
Last Update Posted: May 2, 2017
Last Verified: March 2017

Keywords provided by MedImmune LLC:
Cancer