A Dose-escalation Study to Evaluate the Safety, Tolerability, and Antitumor Activity of MEDI-573 in Subjects With Advanced Solid Tumors

Cancer Clinical Trial

Official title:

A Phase 1, Multicenter, Open-label, Single-arm, Dose-escalation Study to Evaluate the Safety, Tolerability, and Antitumor Activity of MEDI-573, a Fully Human Monoclonal Antibody Directed Against Insulin-like Growth Factors I and II, in Subjects With Advanced Solid Tumors Refractory to Standard Therapy or for Which No Standard Therapy Exists

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00816361
• Other study ID #: MI-CP184
• Status: Completed
• Phase: Phase 1
• Start date: March 9, 2009
• Est. completion date: September 11, 2012

Study information

• Verified date: October 2018
• Source: MedImmune LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Evaluate the safety and tolerability of MEDI-573 in adult subjects with advanced solid tumors refractory to standard therapy or for which no standard therapy exists.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: September 11, 2012
• Est. primary completion date: September 11, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed advanced solid tumor for which no curative or standard therapies exist.

• Karnofsky Performance Status =60.

• Adequate hematological function.

• Adequate organ function.

• Women of non-child-bearing potential (defined as being >1 year post-menopausal) or using effective contraception, e.g., use of oral contraceptives with an additional barrier method (since the investigational product may impair the effectiveness of oral contraceptives), double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera, partner vasectomy, or total abstinence, from the time the informed consent is signed through 30 days after the last dose of MEDI-573. Male subjects with partners of child-bearing potential must be surgically sterile or use contraceptive method as described above from the time of the initiation of MEDI-573 through 30 days after the last dose of MEDI-573.

Exclusion Criteria:

• No prior treatment within 4 weeks of study drug administration.

• No concurrent therapy for treatment of cancer.

• No uncontrolled 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.

• Documented brain metastasis.

• Pregnancy or lactation or plans to become pregnant while on study.

• Clinically significant abnormality on ECG.

Related Conditions & MeSH terms

• Cancer

Intervention

Drug:
• MEDI-573
Administered at a dose determined by the subject's enrollment cohort as an IV infusion as part of a 21 day treatment cycle.

Locations

Country	Name	City	State
United States	Research Site	Boston	Massachusetts
United States	Research Site	Detroit	Michigan
United States	Research Site	Jacksonville	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Rochester	Minnesota
United States	Research Site	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
MedImmune LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs)	AEs were any unfavorable and unintended signs (including abnormal laboratory findings), symptoms, or diseases temporally associated with the use of MEDI-573, whether or not considered related to MEDI-573. A SAE was any AE that resulted in: death; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability or incapacity; was life-threatening; was a congenital anomaly/birth defect in the offspring of a study participant; or was an important medical event that may not have resulted in death, threatened life, or required hospitalization and that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes above. TEAEs were defined as AEs present at baseline that worsened in intensity after administration of MEDI-573, or events absent at baseline that emerged after administration of MEDI-573, up to 30 days after the last dose.	From the start of study treatment through 30 days after the last dose of MEDI-573, up to 3.5 years
Primary	Number of Participants With Clinical Laboratory Abnormalities Reported as TEAEs	An abnormal laboratory finding that was judged by the investigator to be medically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-573, or events absent at baseline that emerged after administration of MEDI-573, for the period extending to 30 days after the last dose.	From the start of study treatment through 30 days after the last dose of MEDI-573, up to 3.5 years
Primary	Number of Participants With Vital Signs and Physical Findings Abnormalities Reported as TEAEs	Vital signs and physical findings included parameters such as heart rate, blood pressure, temperature, and respiratory rate. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-573 or events absent at baseline that emerged after administration of MEDI-573, for the period extending to 30 days after the last dose.	From the start of study treatment through 30 days after the last dose of MEDI-573, up to 3.5 years
Primary	Maximum Tolerated Dose (MTD) of MEDI-573	The MTD was defined as the highest dose that can be safely administered to participants and was determined by the number of participants in each cohort with a dose-limiting toxicity (DLT). The number and proportion of participants in each dose cohort and the number of participants with a DLT was presented using the total number of participants in the MTD Evaluable Population as the denominator. 2 participants from Cohorts 0.5 and 5 mg/kg QWk (1 in each cohort) did not complete the DLT period and therefore not evaluable for MTD.	Cycle 1 Day 1 through Cycle 1 Day 21
Primary	Number of Participants With Dose-Limiting Toxicities (DLTs)	A DLT was defined as any grade greater than or equal to (>=) 3 treatment-related non-hematologic toxicity that occurred during the DLT assessment period with the following exceptions: Grade less than (<) 4 serum-high glucose (fasting) with duration of < 24 hours; Grade 3 fever (in the absence of neutropenia) defined as > 40.0 degree centigrade (°C) [greater than (>) 104.0°F] that resolved to normal or baseline within 24 hours of treatment and was not considered an SAE; or Grade 3 rigors/chills that responded to optimal therapy; any Grade >= 3 treatment-related hematologic toxicity that occurred during the DLT assessment period.	Cycle 1 Day 1 through Cycle 1 Day 21
Primary	Optimal Biologically Effective Dose (OBED) of MEDI-573	The OBED was defined as the dose at which all circulating insulin-like growth factor (IGF)-1 and IGF-2 ligand was sequestered by MEDI-573.	From the start of study treatment through 30 days after the last dose of MEDI-573, up to 3.5 years
Secondary	Maximum Observed Serum Concentration (Cmax) After the First Dose	The Cmax was the maximum observed serum concentration of MEDI-573.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Time to Reach Maximum Observed Concentration (Tmax) After the First Dose	The tmax was defined as actual sampling time to reach the maximum observed serum concentration of MEDI-573.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Trough Serum Concentration (Ctrough) After the First Dose	The Ctrough was the lowest serum concentration of MEDI-573 within a dosing interval.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Dose Normalized Cmax (Cmax/Dose) After the First Dose	The Cmax/dose was the dose-normalized maximum serum concentration of MEDI-573.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Area Under the Serum Concentration-time Curve Over the First Dosing Interval (AUCt)	Area under the serum concentration-time curve over the first dosing interval.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Dose-normalized Area Under the Serum Concentration Time Curve Over the First Dosing Interval (AUCt/Dose)	The AUCtau/dose was a measure of dose-normalized area under the serum concentration-time curve over the first dosing interval.	For weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); For 3 weekly dosing: Pre- and post-infusion (0, 2, 6, 24, and 48 hours post-infusion); and on Days 8 and 15
Secondary	Number of Participants With Positive Anti-Drug Antibodies (ADA) to MEDI-573	Two methods were used to assess the immunogenicity data: an ECL-based method and measurement of neutralizing ADA. The titer was calculated by multiplying the minimum assay dilution factor by the reciprocal of the highest dilution factor which yielded an ECL multiple equal to or greater than the screening assay cut-point factor.	Pre-infusion on Day 1 of each cycle, end of treatment, and 90 days after last dose MEDI-573 (up to 3.5 years)
Secondary	Objective Response Rate (ORR)	The ORR was defined as the proportion of participants with confirmed complete response (CR) or partial response (PR) according to the RECIST criteria The CR was defined as disappearance of all target and nontarget lesions and no new lesions; and PR was definded as >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline [screening]) and no new lesions.	From study entry through the end of the study, up to 3.5 years
Secondary	Progression-free Survival (PFS)	Progression-free survival (PFS) was defined as the duration from the start of treatment with MEDI-573 until the documentation of disease progression or death due to any cause, whichever occurred first.	From study entry through the end of the study, up to 3.5 years
Secondary	Time to Progression	Time to disease progression (TTP) was defined as the duration from the start of treatment with MEDI-573 until the documentation of disease progression.	From study entry through the end of the study, up to 3.5 years
Secondary	Overall Survival	Overall survival (OS) was defined as the time from the start of treatment with MEDI-573 until death.	From study entry through the end of the study, up to 3.5 years
Secondary	Time to Response (TTR)	Time to response was defined as the duration from the start of treatment with MEDI-573 to the first documentation of objective response (confirmed CR or PR) and was only assessed in participants who had achieved objective response.	From study entry through the end of the study, up to 3.5 years
Secondary	Duration of Response	Duration of response was defined as the duration from the first documentation of objective response (confirmed CR or PR) to the first documented disease progression.	From study entry through the end of the study, up to 3.5 years
Secondary	Suppression Profiles of IGF-I and IGF-II Post-Administration of MEDI-573	The suppression profiles of both IGF-1 and IGF-2 post administration of MEDI-573 in relation to time course of antibody concentrations in serum were evaluated during treatment.	From the start of study treatment through 30 days after the last dose of MEDI-573, up to 3.5 years

External Links

•   Click here and search for drug information provided by the FDA.
•   Click here and search for information on any recalls, market or product safety alerts by the FDA which might have occurred with this product.
•   MEDI-573_CP-184_Protocol_Redacted_16Jul14