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

Phase 1

Completed

Conditions: Solid Tumors

Interventions: Biological: MEDI0639

Registration Number: NCT01577745

Lead Sponsor: MedImmune LLC

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 58

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
MEDI0639 Cohort 1	MEDI0639	Participants received MEDI0639 dose level 1 as a 60-minute intravenous (IV) infusion on Day 1 of each 21-day cycle.
MEDI0639 Cohort 5	MEDI0639	Participants received MEDI0639 dose level 5 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
MEDI0639 Cohort 2	MEDI0639	Participants received MEDI0639 dose level 2 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
MEDI0639 Cohort 4	MEDI0639	Participants received MEDI0639 dose level 4 as a 60-minute IV infusion on Day 1 of each 21-day cycle.
MEDI0639 Cohort 6	MEDI0639	Participants received MEDI0639 dose level 6 as a 60-minute IV infusion on Day 1 of each 21 day cycle.
MEDI0639 Cohort 3	MEDI0639	Participants received MEDI0639 dose level 3 as a 60-minute IV infusion on Day 1 of each 21-day cycle.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Echocardiogram Evaluations	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.
Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)	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 Vital Signs and Physical Examination	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.
Maximum Tolerated Dose (MTD) of MEDI0639	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)	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 Adverse Events (TEAEs) Related to Laboratory Parameters	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 Electrocardiogram (ECG) Evaluations	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	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).
Progression-free Survival (PFS)	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).
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	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	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.
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	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	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	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.
Percentage of Participants With Best Overall Response	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	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	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	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)	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).