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

NCT01577745 | Completed Phase 1 Results

• 1 other identifier: CD-ON-MEDI0639-1078
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Solid Tumors

Keywords

Cancer

Outcome Measures

Primary Outcomes (7)

• Maximum Tolerated Dose (MTD) of MEDI0639

  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.

  From the first dose of MEDI0639 to 21 days after the first dose

• Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  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.

  From the first dose of MEDI0639 until 90 days after the last dose of MEDI0639. Maximum time frame across participants was 11 months.

• Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)

  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.

  From the first dose of MEDI0639 until the end of participation in the study. Maximum time frame across participants was 4 years.

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Laboratory Parameters

  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.

  From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and Physical Examination

  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.

  From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Electrocardiogram (ECG) Evaluations

  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.

  From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Echocardiogram Evaluations

  Echocardiogram parameters included left ventricular ejection fraction (LVEF) and pulmonary arterial pressure (PAP). The TEAEs related to echocardiogram evaluations in participants were reported.

  From the first dose of MEDI0639 until 90 days after last dose of MEDI0639. Maximum time frame across participants was 11 months.

Secondary Outcomes (12)

• Area Under the Concentration-Time Curve From Time 0 to Infinity (AUCinf) After Cycle 1 Treatment Administration of MEDI0639

  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

• Maximum Observed Concentration (Cmax) After Cycle 1 Treatment Administration of MEDI0639

  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

• Clearance (CL) After Cycle 1 Treatment Administration of MEDI0639

  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

• Half-life (t1/2) After Cycle 1 Treatment Administration of MEDI0639

  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

• Number of Participants Positive With Antidrug Antibodies (ADA) for MEDI0639

  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.

Study Arms (6)

MEDI0639 Cohort 1

EXPERIMENTAL

Participants received MEDI0639 dose level 1 as a 60-minute intravenous (IV) infusion on Day 1 of each 21-day cycle.

Biological: MEDI0639

MEDI0639 Cohort 2

EXPERIMENTAL

Participants received MEDI0639 dose level 2 as a 60-minute IV infusion on Day 1 of each 21-day cycle.

Biological: MEDI0639

MEDI0639 Cohort 3

EXPERIMENTAL

Participants received MEDI0639 dose level 3 as a 60-minute IV infusion on Day 1 of each 21-day cycle.

Biological: MEDI0639

MEDI0639 Cohort 4

EXPERIMENTAL

Participants received MEDI0639 dose level 4 as a 60-minute IV infusion on Day 1 of each 21-day cycle.

Biological: MEDI0639

MEDI0639 Cohort 5

EXPERIMENTAL

Participants received MEDI0639 dose level 5 as a 60-minute IV infusion on Day 1 of each 21-day cycle.

Biological: MEDI0639

MEDI0639 Cohort 6

EXPERIMENTAL

Participants received MEDI0639 dose level 6 as a 60-minute IV infusion on Day 1 of each 21 day cycle.

Biological: MEDI0639

Interventions

MEDI0639 BIOLOGICAL

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.

MEDI0639 Cohort 1; MEDI0639 Cohort 2; MEDI0639 Cohort 3; MEDI0639 Cohort 4; MEDI0639 Cohort 5; MEDI0639 Cohort 6

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• MedImmune LLC: lead

Study Sites (11)

Research Site

Los Angeles, California, 90404, United States

Location

Research Site

New Haven, Connecticut, 06513, United States

Location

Research Site

Boston, Massachusetts, United States

Location

Research Site

Ann Arbor, Michigan, 48103, United States

Location

Research Site

Minneapolis, Minnesota, United States

Location

Research Site

New York, New York, 10002, United States

Location

Research Site

Cincinnati, Ohio, 45201, United States

Location

Research Site

Cleveland, Ohio, 44105, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Seattle, Washington, 98112, United States

Location

Research Site

Tacoma, Washington, 98405, United States

Location

MeSH Terms

Conditions

Neoplasms

Limitations and Caveats

OMs relationship modulation of DLL4-Notch signaling pathway in tumor and clinical response analysis was not conducted due to low number of evaluable tumor samples and low response rate. Study was terminated early due to lack of clinical activity.

Results Point of Contact

• Title: Mohammed Dar
• Organization: MedImmune, LLC

information.center@astrazeneca.com

301-398-1008

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2012
• First Posted: April 16, 2012
• Study Start: April 1, 2012
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: May 2, 2017
• Results First Posted: May 2, 2017

Record last verified: 2017-03

Locations

US (11)