A Phase 1, Multicenter, Open-label, Single-arm, Dose-escalation Study to Evaluate the Safety, Tolerability, and Antitumor Activity of MEDI-575, a Fully Human Monoclonal Antibody Directed Against Platelet-derived Growth Factor Receptor Alpha (PDGFRα), in Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No Standard Therapy Exists
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- MedImmune LLC
- Enrollment
- 49
- Locations
- 1
- Primary Endpoint
- Number of Participants With Serious Adverse Events
Study Overview
Brief Summary
Evaluate the safety, tolerability and the tolerated maximum dose of MEDI-575 in adult subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically confirmed advanced solid tumor for which no curative or standard therapies exist
- •Karnofsky performance status of ≥ 60
- •Life expectancy of >12 weeks
- •Adequate hematologic and organ function
- •Negative serum pregnancy test (women only)
- •Two methods of birth control for female participants of child-bearing potential or male participants with their female partners of child-bearing potential
Exclusion Criteria
- •Prior chemotherapy or investigational treatment within 4 weeks of study drug administration
- •Prior biological or immunological treatment within 6 weeks of study drug administration
- •Concurrent therapy for of cancer
- •Major surgery within four weeks or minor surgery within two weeks of study drug administration
- •History of diabetes or current treatment for diabetes
- •New York Heart Association ≥ Grade 2 congestive heart failure
- •History of myocardial infarction, unstable angina, transient ischemic attack or stroke within the previous 6 months prior to study entry
- •History of other invasive malignancy within 5 years (exceptions are cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that are surgically cured)
- •Significant active infection
- •Known brain metastases
- •Pregnancy or lactation or plans to become pregnant while on study
- •Clinically significant abnormality on ECG
Arms & Interventions
MEDI-575, 3.0 mg/kg QWk Escalation Phase (Cohort 1)
Single lead-in dose of MEDI-575 at 0.5 mg/kg as a 60-minute intravenous (IV) infusion administered 7 days prior to first dose at 3.0 mg/kg; MEDI-575 administered at 3.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (once every 7 days [QWk]) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 6.0 mg/kg QWk Escalation Phase (Cohort 2)
MEDI-575 administered at 6.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (QWk) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 9.0 mg/kg QWk Escalation Phase (Cohort 3)
MEDI-575 administered at 9.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (QWk) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 12 mg/kg QWk Escalation Phase (Cohort 4)
MEDI-575 administered at 12.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (QWk) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 15 mg/kg QWk Escalation Phase (Cohort 5)
MEDI-575 administered at 15.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (QWk) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 25 mg/kg Q3Wk Escalation Phase (Cohort 6)
MEDI-575 administered at 25.0 mg/kg as a 90-minute IV infusion on Study Day 1 of each 21-day treatment cycle (once every 21 days [Q3Wk]) until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 35 mg/kg Q3Wk Escalation Phase (Cohort 7)
MEDI-575 administered at 35.0 mg/kg as a 90-minute IV infusion on Study Day 1 of each 21-day treatment cycle (Q3Wk) until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 9.0 mg/kg QWk Expansion Phase
MEDI-575 administered at 9.0 mg/kg as a 60-minute IV infusion on Study Days 1, 8, and 15 (QWk) of each 21-day treatment cycle until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
MEDI-575, 25 mg/kg Q3Wk Expansion Phase
MEDI-575 administered at 25.0 mg/kg as a 90-minute IV infusion on Study Day 1 of each 21-day treatment cycle (Q3Wk) until unacceptable toxicity, documentation of disease progression, or other reasons for participant withdrawal occurred.
Intervention: MEDI-575 (Drug)
Outcomes
Primary Outcomes
Number of Participants With Serious Adverse Events
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
A serious AE (SAE) is any AE that results in 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 that emerged after start of study drug were reported. Participants were counted only once for each event and by the highest event severity, regardless of how many events the participant experienced. The SAEs were summarized using MedDRA version 14.1.
Treatment-emergent Adverse Events Related to Electrocardiogram Evaluations
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
All 12-lead electrocardiograms (ECGs) performed during the study were obtained in triplicate (ie, 3 ECGs were obtained within a 5-minute time interval) and analyzed. ECG parameters included heart rate (high and low), QT interval, QTcB (corrected QT interval per Bazett's formula), and QTcF (corrected QT interval per Fridericia's formula). Number of participants with TEAEs related to ECG after the start of study drug were reported.
Number of Participants With Adverse Events
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
An adverse event (AE) is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Treatment-emergent AEs (TEAEs) are 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 30 days after the last dose of study drug. Participants were counted only once for each event and by the highest event severity, regardless of how many events the participant experienced. The AEs were summarized using Medical Dictionary for Regulatory Activities (MedDRA) version 14.1.
Maximum Tolerated Dose (MTD)
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
For the dose escalation phase, a minimum of 21 evaluable participants (3 participants each in Dose Cohorts 1 through 7) were required for this study if Dose Limiting Toxicities (DLTs) do not occur. If a DLT does occur among the first 3 participants in a cohort, 3 additional participants were to be added to the cohort; 3 more participants were to be added to a cohort to determine the MTD if only 3 participants have been previously treated at that dose. The MTD is the maximum dose at which no more than 1 out of 6 participants experienced a DLT. A DLT is defined as any grade 3 or higher hematologic toxicity or any grade 3 or higher non-hematologic toxicity except grade 3 fever (in the absence of neutropenia) or grade 3 rigors/chills.
Treatment-emergent Adverse Events Related to Laboratory Parameters
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
Laboratory evaluations of blood and urine samples were performed, including hematology (complete blood count, differential, and platelet count); serum chemistry (SrChem) aspartate transaminase (AST), alanine transaminase, total bilirubin, creatinine, alkaline phosphatase, sodium, potassium, chloride, phosphorus, calcium, glucose, magnesium, albumin, and lactate dehydrogenase); and routine urinalysis. Number of participants with TEAEs related to laboratory evaluations were reported.
Treatment-emergent Adverse Events Related to Vital Sign Parameters
Time Frame: From the start of study drug administration through 30 days after last dose of MEDI-575, up to 112 weeks
Vital signs (temperature, blood pressure, pulse rate, and respiratory rate) were performed throughout the study. The TEAEs related to vital signs in participants were reported.
Secondary Outcomes
- PK of MEDI-575 After the First Dose: Time to Maximum Concentration (Tmax)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- Number of Participants Positive for Anti-drug Antibodies Formation for MEDI-575 at Any Visit(Preinfusion on Cycle 1 Day 1 and 30 days after the last dose, up to 112 weeks)
- Duration of Response
- Overall Survival(From the start of treatment with MEDI-575 until death or end of study, up to 33 months)
- Pharmacokinetics (PK) of MEDI-575 After the First Dose: Observed Maximum Serum Concentration (Cmax)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- Percentage of Participants With Objective Response(From study entry through the end of the study, up to 34 months)
- PK of MEDI-575 After the First Dose: Dose-normalized Maximum Serum Concentration (Cmax/Dose)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- PK of MEDI-575 After the First Dose: Trough Serum Concentration (Ctrough)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- PK of MEDI-575 After the First Dose: Area Under the Serum Concentration-time Curve Over the Dosing Interval (AUCτ)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- PK of MEDI-575 After the First Dose: Dose-normalized Area Under the Serum Concentration-time Curve (AUCτ/Dose)(For 0.5/3, 6, 9, 12, 15 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3 and 8 (pre-dose); For 25 and 35 mg/kg: Cycle 1: Day 1 (pre- and end of infusion, 2 and 6 hours post infusion), Days 2, 3, 8 and 15.)
- Time to Response
- Time to Progression(Start of treatment with MEDI-575 until the documentation of disease progression, up to 24 months)
- Progression-free Survival(Start of treatment with MEDI-575 until the documentation of disease progression or death due to any cause whichever occurs first, up to 24 months)