A Study of Robatumumab (SCH 717454, MK-7454) in Combination With Different Treatment Regimens in Pediatric Participants With Advanced Solid Tumors (P05883, MK-7454-006)

Neoplasms Clinical Trial

Official title:

A Phase 1/1B Dose-Escalation Study to Determine the Safety and Tolerability of SCH 717454 Administered in Combination With Chemotherapy in Pediatric Subjects With Advanced Solid Tumors (Protocol No. 05883)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00960063
• Other study ID #: P05883
• Secondary ID: MK-7454-006
• Status: Terminated
• Phase: Phase 1
• Start date: November 11, 2009
• Est. completion date: December 22, 2010

Study information

• Verified date: July 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1/1B, non-randomized, open-label, dose-escalation study of robatumumab (SCH 717454, MK-7454) administered in combination with chemotherapy in pediatric participants with solid tumors, to be conducted in conformance with Good Clinical Practices. This study will evaluate the safety, tolerability and dose-finding of robatumumab when administered in combination with temozolomide and irinotecan (Arm A); or cyclophosphamide, doxorubicin, and vincristine (Arm B), or ifosfamide and etoposide (Arm C).

The primary study hypothesis is that robatumumab can be safely administered in combination with chemotherapy regimens in pediatric participants with solid tumors.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: December 22, 2010
• Est. primary completion date: December 22, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

Inclusion Criteria:

• Must be <= 21 years of age (older participants may be allowed on study on a case-by-case basis); may be of either sex, and of any race/ethnicity.

• Must have histologic confirmation of the advanced solid tumor, except for brainstem tumors.

• Must have Karnofsky performance score of >=50 (if participant is >16 years of age) or a Lansky score of >50 (if participant is <=16 years of age).

• Must have adequate organ function during Screening.

• Must be able to adhere to dose and visit schedules.

Exclusion Criteria:

• Must not have a history of another malignancy.

• Must not have uncontrolled diabetes mellitus.

• Must not have persistent, unresolved common terminology criteria for adverse events (CTCAE) Grade >=2 drug-related toxicity associated with previous treatment.

• Must not have known hypersensitivity to other antibodies, or any accompanying excipients associated with these medications.

• If female, must not be breast-feeding, pregnant, intending to become pregnant, or have a positive pregnancy test at Screening.

• Must not be known to have human immunodeficiency virus (HIV) infection or known HIV-related malignancy.

• Must not be known to have active Hepatitis B, or Hepatitis C.

• Must not have any serious or uncontrolled infection.

Related Conditions & MeSH terms

• Bone Cancer
• Bone Neoplasms
• Kidney Neoplasms
• Kidney Tumor
• Neoplasms
• Neuroblastoma
• Osteosarcoma
• Solid Tumors

Intervention

Drug:
• Temozolomide

• Vincristine

• Ifosfamide

• Irinotecan

Biological:
• Robatumumab

Drug:
• Doxorubicin

• Cyclophosphamide

• Etoposide

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicities	Dose-limiting toxicity was defined by the following adverse events (AEs) that were considered possibly or probably related to either robatumumab or to its interaction with the chemotherapy regimen assigned: neutropenia (Grade 4 for >1 week that did not resolve prior to Day 1 of the next cycle; Grade 3-4 neutropenia with Grade =2 fever lasting 3 days; neutropenic infection; failure to recover to study entry/eligibility criteria laboratory requirement levels that resulted in a delay of 14 days between treatment cycles), thrombocytopenia (Grade 4 for >1 week that did not resolve prior to Day 1 of the next cycle; Grade 3-4 requiring a platelet transfusion on 2 separate days within a cycle) or all other AEs (Grade =3 [any duration] not ameliorable by supportive or symptomatic measures). The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) was to be used to grade AEs.	Up to ~30 days after last dose of study drug (Up to ~10.3 months)
Secondary	Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST)	All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs were to be identified as target lesions. Data were to be collected at Screening, every 6 weeks and at 30 days after the final dose of robatumumab or the standard treatment assigned (whichever was last). The best overall response was to be the best response recorded from the start of the treatment until disease progression/recurrence. Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): >30% decrease in the sum of the longest diameter (LD) of target lesions; Progressive Disease (PD): >20% increase in the sum of the LD of target lesions or the appearance of one or more new lesions; or Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.	Screening, every 6 weeks and at ~30 days after last dose of study drug (Up to ~10.3 months)
Secondary	Maximum Observed Concentration (Cmax) of Robatumumab	Cmax was defined as the maximum observed serum concentration of robatumumab when administered in combination with other treatments. Blood samples for analysis of robatumumab pharmacokinetics (PK) were to be obtained at Cycles 1 and 2 at the following time points: predose, immediately post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post the start time of infusion. For all odd-numbered cycles (Cycle 3 and on) samples were to be obtained at each of the following two time points: predose and immediately postdose of robatumumab. Additionally, PK samples were to be obtained at the Post Study Visits 1 (30 days after last dose of robatumumab or standard treatment and 2 (approximately 4 months after last dose of robatumumab or standard treatment).	Cycles 1 & 2: pre- and post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post start of infusion; then pre-and post-dose in odd-numbered cycles, and Post Study Visits 1 and 2
Secondary	Plasma Level of Insulin-like Growth Factor-I (IGF-I)	IGF-I is produced largely by the liver in response to growth hormone from the hypothalamic-pituitary axis. The IGF ligands can promote neoplastic events (cancer growth) through a number of different mechanisms. Robatumumab inhibits IGF ligand binding, IGF-stimulated receptor phosphorylation and human tumor cell proliferation. Plasma levels of IGF-I were to be analyzed on Day 1 of Cycles 1, 2, 3, 5, and approximately 30 days after the final dose of robatumumab or the standard treatment assigned (whichever was last).	On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months)
Secondary	Number of Participants Who Developed Anti-robatumumab Antibodies	The incidence of anti-robatumumab antibodies was to be assessed. Only participants who had a negative pre-treatment sample and a post-treatment sample were considered to be evaluable. If a participant had a single sample considered positive in the anti-robatumumab antibody assay (with the exception of pre-treatment positive participants), then they would be counted as positive in the immunogenicity assessment.	Prior to 1st and 8th doses of robatumumab, ~30 days after last dose of study drug, and 4 months after last dose of study drug (Up to ~13.3 months)
Secondary	Time to Maximum Observed Concentration (Tmax) of Robatumumab	Tmax was defined as time of Cmax of robatumumab when administered in combination with other treatments. Blood samples for analysis of robatumumab PK were to be obtained at Cycles 1 and 2 at the following time points: predose, immediately post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post the start time of infusion. For all odd-numbered cycles (Cycle 3 and on) samples were to be obtained at each of the following two time points: predose and immediately postdose of robatumumab. Additionally, PK samples were to be obtained at the Post Study Visits 1 (30 days after last dose of robatumumab or standard treatment and 2 (approximately 4 months after last dose of robatumumab or standard treatment).	Cycles 1 & 2: pre- and post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post start of infusion; then pre-and post-dose in odd-numbered cycles, and Post Study Visits 1 and 2
Secondary	Area Under the Curve at the Time of Final Quantifiable Sample (AUCtf) for Robatumumab	AUCtf for robatumumab was defined as the area under the curve at the time of the final quantifiable sample of robatumumab. Blood samples for analysis of robatumumab PK were to be obtained at Cycles 1 and 2 at the following time points: predose, immediately post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post the start time of infusion. For all odd-numbered cycles (Cycle 3 and on) samples were to be obtained at each of the following two time points: predose and immediately postdose of robatumumab. Additionally, PK samples were to be obtained at the Post Study Visits 1 (30 days after last dose of robatumumab or standard treatment and 2 (approximately 4 months after last dose of robatumumab or standard treatment).	Cycles 1 & 2: pre- and post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post start of infusion; then pre-and post-dose in odd-numbered cycles, and Post Study Visits 1 and 2
Secondary	Area Under the Curve During a Dosing Interval t (AUCt) for Robatumumab	AUCt was defined as the area under the plasma concentration-time curve during a dosage interval (t). Blood samples for analysis of robatumumab PK were to be obtained at Cycles 1 and 2 at the following time points: predose, immediately post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post the start time of infusion. For all odd-numbered cycles (Cycle 3 and on) samples were to be obtained at each of the following two time points: predose and immediately postdose of robatumumab. Additionally, PK samples were to be obtained at the Post Study Visits 1 (30 days after last dose of robatumumab or standard treatment and 2 (approximately 4 months after last dose of robatumumab or standard treatment).	Cycles 1 & 2: pre- and post-infusion, and at 3, 6, 24, 48, 168, 336, and 504 hours post start of infusion; then pre-and post-dose in odd-numbered cycles, and Post Study Visits 1 and 2
Secondary	Plasma Level of Insulin-like Growth Factor-2 (IGF-II)	IGF-II is generally produced locally in response to growth hormone from the hypothalamic-pituitary axis. The IGF ligands can promote neoplastic events (cancer growth) through a number of different mechanisms. Robatumumab inhibits IGF ligand binding, IGF-stimulated receptor phosphorylation and human tumor cell proliferation. Plasma levels of IGF-II were to be analyzed on Day 1 of Cycles 1, 2, 3, 5, and approximately 30 days after the final dose of robatumumab or the standard treatment assigned (whichever was last).	On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months)
Secondary	Plasma Level of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2)	The IGFBP-2 protein is secreted into the bloodstream where it binds to IGF-I and IGF-II. High expression levels of this protein promote the growth of several types of tumors and may be predictive of the chances of recovery of the participant. Robatumumab inhibits expression of this protein. Plasma levels of IGFBP-2 were to be analyzed on Day 1 of Cycles 1, 2, 3, 5, and approximately 30 days after the final dose of robatumumab or the standard treatment assigned (whichever was last).	On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months)
Secondary	Plasma Level of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3)	The IGFBP-3 protein is secreted into the bloodstream where it binds to IGF-I and IGF-II. High expression levels of this protein promote the growth of several types of tumors and may be predictive of the chances of recovery of the participant. Robatumumab inhibits expression of this protein. Plasma levels of IGFBP-3 were to be analyzed on Day 1 of Cycles 1, 2, 3, 5, and approximately 30 days after the final dose of robatumumab or the standard treatment assigned (whichever was last).	On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months)