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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)

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ClinicalTrials.gov Identifier: NCT00960063
Recruitment Status : Terminated (Study was terminated for business reasons.)
First Posted : August 17, 2009
Results First Posted : February 10, 2016
Last Update Posted : June 14, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief 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.


Condition or disease Intervention/treatment Phase
Neoplasms Solid Tumors Bone Cancer Kidney Tumor Neuroblastoma Drug: Temozolomide Drug: Vincristine Drug: Ifosfamide Drug: Irinotecan Biological: Robatumumab Drug: Doxorubicin Drug: Cyclophosphamide Drug: Etoposide Phase 1

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : November 11, 2009
Primary Completion Date : December 22, 2010
Study Completion Date : December 22, 2010


Arms and Interventions

Arm Intervention/treatment
Experimental: Temozolomide+Irinotecan+Robatumumab
Participants receive temozolomide 100 mg/m^2/day intravenously (IV) on Days 1-5 PLUS irinotecan 10 mg/m^2/day IV on Days 1-5 and Days 8-12 PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 3-week cycle.
Drug: Temozolomide Drug: Irinotecan Biological: Robatumumab
Experimental: Vincristine+Doxorubicin+Cyclophosphamide+Robatumumab
Participants receive vincristine 2 mg/m^2 (maximum 2 mg) IV on Day 1 PLUS cyclophosphamide 1200 mg/m^2 IV on Day 1 PLUS doxorubicin hydrochloride 75 mg/m^2 IV continuously over 48 hours PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 3-week cycle.
Drug: Vincristine Biological: Robatumumab Drug: Doxorubicin Drug: Cyclophosphamide
Experimental: Ifosfamide+Etoposide+Robatumumab
Participants receive ifosfamide 1800 mg/m^2 per day IV PLUS etoposide 100 mg/m^2 per day IV on Days 1-5 PLUS robatumumab 10 mg/kg or 20 mg/kg IV on Day 1 of each 3-week cycle.
Drug: Ifosfamide Biological: Robatumumab Drug: Etoposide


Outcome Measures

Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities [ Time Frame: Up to ~30 days after last dose of study drug (Up to ~10.3 months) ]
    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.


Secondary Outcome Measures :
  1. Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Screening, every 6 weeks and at ~30 days after last dose of study drug (Up to ~10.3 months) ]
    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.

  2. Maximum Observed Concentration (Cmax) of Robatumumab [ Time Frame: 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 ]
    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).

  3. Plasma Level of Insulin-like Growth Factor-I (IGF-I) [ Time Frame: On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months) ]
    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).

  4. Number of Participants Who Developed Anti-robatumumab Antibodies [ Time Frame: 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) ]
    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.

  5. Time to Maximum Observed Concentration (Tmax) of Robatumumab [ Time Frame: 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 ]
    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).

  6. Area Under the Curve at the Time of Final Quantifiable Sample (AUCtf) for Robatumumab [ Time Frame: 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 ]
    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).

  7. Area Under the Curve During a Dosing Interval τ (AUCτ) for Robatumumab [ Time Frame: 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 ]
    AUCτ was defined as the area under the plasma concentration-time curve during a dosage interval (τ). 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).

  8. Plasma Level of Insulin-like Growth Factor-2 (IGF-II) [ Time Frame: On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months) ]
    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).

  9. Plasma Level of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2) [ Time Frame: On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months) ]
    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).

  10. Plasma Level of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) [ Time Frame: On Day 1 of Cycles 1, 2, 3 and 5, and ~30 days after last dose of study drug (Up to~10.3 months) ]
    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).


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00960063


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
More Information

Study Data/Documents: CSR Synopsis  This link exits the ClinicalTrials.gov site

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00960063     History of Changes
Other Study ID Numbers: P05883
MK-7454-006 ( Other Identifier: Merck Protocol Number )
First Posted: August 17, 2009    Key Record Dates
Results First Posted: February 10, 2016
Last Update Posted: June 14, 2017
Last Verified: May 2017

Additional relevant MeSH terms:
Neoplasms
Neuroblastoma
Kidney Neoplasms
Bone Neoplasms
Osteosarcoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Bone Diseases
Musculoskeletal Diseases
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Cyclophosphamide
Temozolomide
Ifosfamide
Isophosphamide mustard
Liposomal doxorubicin
Irinotecan