Neoplasms, Solid Tumors, Bone Cancer, Kidney Tumor, Neuroblastoma
Conditions
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.
Interventions
DRUGTemozolomide
DRUGVincristine
DRUGIfosfamide
DRUGIrinotecan
BIOLOGICALRobatumumab
DRUGDoxorubicin
DRUGCyclophosphamide
DRUGEtoposide
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities | 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
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of Robatumumab | 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). |
| Plasma Level of Insulin-like Growth Factor-I (IGF-I) | 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). |
| Number of Participants Who Developed Anti-robatumumab Antibodies | 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. |
| Time to Maximum Observed Concentration (Tmax) of Robatumumab | 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). |
| Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 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. |
| Area Under the Curve During a Dosing Interval τ (AUCτ) for Robatumumab | 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). |
| Plasma Level of Insulin-like Growth Factor-2 (IGF-II) | 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). |
| Plasma Level of Insulin-like Growth Factor Binding Protein-2 (IGFBP-2) | 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). |
| Plasma Level of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) | 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). |
| Area Under the Curve at the Time of Final Quantifiable Sample (AUCtf) for Robatumumab | 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). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temozolomide+Irinotecan+Robatumumab Participants receive temozolomide 100 mg/m\^2/day 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. | 1 |
| 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. | 0 |
| 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. | 3 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Progression of Disease | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Temozolomide+Irinotecan+Robatumumab | Ifosfamide+Etoposide+Robatumumab | Total |
|---|---|---|---|
| Age, Continuous | 23.0 Years STANDARD_DEVIATION 0 | 8.3 Years STANDARD_DEVIATION 4.5 | 12.0 Years STANDARD_DEVIATION 8.2 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 0 / 0 | 3 / 3 |
| serious Total, serious adverse events | 0 / 1 | 0 / 0 | 3 / 3 |
Outcome results
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.
Time frame: Up to ~30 days after last dose of study drug (Up to ~10.3 months)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide+Irinotecan+Robatumumab | Number of Participants With Dose Limiting Toxicities | 1 Participants |
| Ifosfamide+Etoposide+Robatumumab | Number of Participants With Dose Limiting Toxicities | 3 Participants |
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).
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
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for AUCtf were not produced.
Secondary
Area Under the Curve During a Dosing Interval τ (AUCτ) for Robatumumab
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).
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
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for AUCτ were not produced.
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.
Time frame: Screening, every 6 weeks and at ~30 days after last dose of study drug (Up to ~10.3 months)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Temozolomide+Irinotecan+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 0 Participants |
| Temozolomide+Irinotecan+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 1 Participants |
| Temozolomide+Irinotecan+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 0 Participants |
| Temozolomide+Irinotecan+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 0 Participants |
| Ifosfamide+Etoposide+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 1 Participants |
| Ifosfamide+Etoposide+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 0 Participants |
| Ifosfamide+Etoposide+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 0 Participants |
| Ifosfamide+Etoposide+Robatumumab | Best Overall Response Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 2 Participants |
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).
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
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for Cmax were not produced.
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.
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)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy and had a negative pre-treatment sample and a post-treatment sample.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temozolomide+Irinotecan+Robatumumab | Number of Participants Who Developed Anti-robatumumab Antibodies | 0 Participants |
| Ifosfamide+Etoposide+Robatumumab | Number of Participants Who Developed Anti-robatumumab Antibodies | 0 Participants |
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).
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)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for IGF-II were not produced.
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).
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)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for IGFBP-2 were not produced.
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).
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)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for IGFBP-3 were not produced.
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).
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)
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for IGF-I were not produced.
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).
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
Population: All Treated Set was defined as all participants who received ≥1 dose of robatumumab or chemotherapy. Individual data were collected, but, due to study termination and small numbers of participants, summary data for Tmax were not produced.