Neoplasm
Conditions
Brief summary
This clinical study evaluates the safety, tolerability, pharmacokinetics, and immunogenicity of dalotuzumab (MK-0646) in participants with relapsed or refractory locally advanced or metastatic solid tumors using once weekly and once every other week dose infusion regimens. The primary study hypothesis is that administration of dalotuzumab as a once weekly and an every other week infusion will be generally safe and well tolerated
Interventions
BIOLOGICALDalotuzumab
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically- or cytologically-confirmed metastatic or locally advanced solid tumor(s) that has (have) failed to respond to standard therapy, or for which adequate standard therapy does not exist * Has tumor(s) associated with insulin-like growth factor 1 receptor (IGF-1R) expression in the literature (e.g. prostate, pancreatic, colon, lung and breast) * Has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 * Demonstrates adequate organ function
Exclusion criteria
* Has had chemotherapy, radiotherapy, or biological therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration * Is concurrently using growth hormone (GH), or growth hormone inhibitor * Has any active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has any primary CNS tumor - any symptomatic ascites or plural effusion * Has a history or current evidence of any clinically significant disease that might confound the results of the study, complicate the interpretation of the study results, interfere with the participant's participation, or pose an additional risk to the participant * Is pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | Cycle 1 (Up to 4 weeks) | Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. DLTs were defined as the occurrence of any of the following events when judged to be related to the study medication: Grade 4 neutropenia; Grade 3 neutropenia with fever \>38.5°C; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity, except alopecia and inadequately treated diarrhea, nausea and vomiting. The number of participants who experienced a DLT is presented. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to 30 days after last dose of study treatment (Up to 101 days) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to 71 days | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | Cmax was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | AUC0-∞ was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Time to Cmax (Tmax) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | Tmax was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Apparent Terminal Half-life (t1/2) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | t1/2 was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Clearance (CL) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | CL of dalotuzumab was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Steady State Volume of Distribution (Vss) of Dalotuzumab | Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose | Vss was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group. |
| Number of Participants Who Developed a Human Anti-Humanized Antibody (HAHA) Response to Dalotuzumab | Cycle 1: predose on Days 1, 8, 15, and 22; Cycles 2 and 3: predose on Day 1; 4 weeks after last dose of study drug | Formation of HAHAs may block efficacy by substantially increasing the clearance of dalotuzumab and limit the possibility of future dalotuzumab therapy. The occurrence of HAHAs in the sera of dalotuzumab treated participants at any of the serum collection times was assessed. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dalotuzumab 5 mg/kg Participants receive dalotuzumab 5 mg/kg by IV infusion once each week for up to 1 year or until participant withdraws consent, experiences an AE, progressive disease or major protocol violation, has moved or is lost to follow up. | 3 |
| Dalotuzumab 10 mg/kg Participants receive dalotuzumab 10 mg/kg by IV infusion once each week for up to 1 year or until participant withdraws consent, experiences an AE, progressive disease or major protocol violation, has moved or is lost to follow up. | 6 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg Participants receive an initial dose of dalotuzumab 15 mg/kg by IV infusion followed by a maintenance dose of dalotuzumab 7.5 mg/kg by IV infusion once every 2 weeks for up to 1 year or until participant withdraws consent, experiences an AE, progressive disease or major protocol violation, has moved or is lost to follow up. | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Progressive Disease | 2 | 6 | 6 |
Baseline characteristics
| Characteristic | Dalotuzumab 5 mg/kg | Dalotuzumab 10 mg/kg | Dalotuzumab 15 mg/kg/7.5 mg/kg | Total |
|---|---|---|---|---|
| Age, Continuous | 66.3 Years STANDARD_DEVIATION 1.5 | 63.5 Years STANDARD_DEVIATION 3.9 | 59.2 Years STANDARD_DEVIATION 14.2 | 62.3 Years STANDARD_DEVIATION 9.3 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 4 Participants | 11 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 | 3 / 3 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / 3 | 1 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Time frame: Up to 71 days
Population: The population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 5 mg/kg | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| Dalotuzumab 10 mg/kg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
Primary
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. DLTs were defined as the occurrence of any of the following events when judged to be related to the study medication: Grade 4 neutropenia; Grade 3 neutropenia with fever \>38.5°C; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity, except alopecia and inadequately treated diarrhea, nausea and vomiting. The number of participants who experienced a DLT is presented.
Time frame: Cycle 1 (Up to 4 weeks)
Population: The population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 5 mg/kg | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Dalotuzumab 10 mg/kg | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
Primary
Number of Participants Who Experienced an Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented.
Time frame: Up to 30 days after last dose of study treatment (Up to 101 days)
Population: The population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 5 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Dalotuzumab 10 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) | 6 Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Number of Participants Who Experienced an Adverse Event (AE) | 6 Participants |
Secondary
Apparent Terminal Half-life (t1/2) of Dalotuzumab
t1/2 was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had PK measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Apparent Terminal Half-life (t1/2) of Dalotuzumab | 129.85 h | Geometric Coefficient of Variation 12.44 |
| Dalotuzumab 10 mg/kg | Apparent Terminal Half-life (t1/2) of Dalotuzumab | 110.36 h | Geometric Coefficient of Variation 20.18 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Apparent Terminal Half-life (t1/2) of Dalotuzumab | 167.09 h | Geometric Coefficient of Variation 20.94 |
Secondary
Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) of Dalotuzumab
AUC0-∞ was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had PK measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) of Dalotuzumab | 11.72 mg*h/mL | Geometric Coefficient of Variation 10.06 |
| Dalotuzumab 10 mg/kg | Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) of Dalotuzumab | 21.71 mg*h/mL | Geometric Coefficient of Variation 37.64 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Area Under the Concentration-Time Curve From Zero to Infinity (AUC0-∞) of Dalotuzumab | 38.99 mg*h/mL | Geometric Coefficient of Variation 21.27 |
Secondary
Clearance (CL) of Dalotuzumab
CL of dalotuzumab was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had PK measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Clearance (CL) of Dalotuzumab | 0.0071 mL/min/kg | Geometric Coefficient of Variation 10.06 |
| Dalotuzumab 10 mg/kg | Clearance (CL) of Dalotuzumab | 0.0077 mL/min/kg | Geometric Coefficient of Variation 37.64 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Clearance (CL) of Dalotuzumab | 0.0064 mL/min/kg | Geometric Coefficient of Variation 21.27 |
Secondary
Maximum Plasma Concentration (Cmax) of Dalotuzumab
Cmax was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had pharmacokinetic (PK) measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Maximum Plasma Concentration (Cmax) of Dalotuzumab | 85.60 µg/mL | Geometric Coefficient of Variation 6.94 |
| Dalotuzumab 10 mg/kg | Maximum Plasma Concentration (Cmax) of Dalotuzumab | 161.78 µg/mL | Geometric Coefficient of Variation 23.02 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Maximum Plasma Concentration (Cmax) of Dalotuzumab | 244.05 µg/mL | Geometric Coefficient of Variation 11.57 |
Secondary
Number of Participants Who Developed a Human Anti-Humanized Antibody (HAHA) Response to Dalotuzumab
Formation of HAHAs may block efficacy by substantially increasing the clearance of dalotuzumab and limit the possibility of future dalotuzumab therapy. The occurrence of HAHAs in the sera of dalotuzumab treated participants at any of the serum collection times was assessed.
Time frame: Cycle 1: predose on Days 1, 8, 15, and 22; Cycles 2 and 3: predose on Day 1; 4 weeks after last dose of study drug
Population: The population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 5 mg/kg | Number of Participants Who Developed a Human Anti-Humanized Antibody (HAHA) Response to Dalotuzumab | 0 Participants |
| Dalotuzumab 10 mg/kg | Number of Participants Who Developed a Human Anti-Humanized Antibody (HAHA) Response to Dalotuzumab | 0 Participants |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Number of Participants Who Developed a Human Anti-Humanized Antibody (HAHA) Response to Dalotuzumab | 0 Participants |
Secondary
Steady State Volume of Distribution (Vss) of Dalotuzumab
Vss was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had PK measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Steady State Volume of Distribution (Vss) of Dalotuzumab | 0.0776 L/kg | Geometric Coefficient of Variation 17.46 |
| Dalotuzumab 10 mg/kg | Steady State Volume of Distribution (Vss) of Dalotuzumab | 0.0740 L/kg | Geometric Coefficient of Variation 24.1 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Steady State Volume of Distribution (Vss) of Dalotuzumab | 0.0924 L/kg | Geometric Coefficient of Variation 16.74 |
Secondary
Time to Cmax (Tmax) of Dalotuzumab
Tmax was assessed on Week 2 (Day 8) for the Dalotuzumab 5 mg/kg and Dalotuzumab 10 mg/kg treatment groups and on Week 3 (Day 15) for the Dalotuzumab 15 mg/kg/7.5 mg/kg treatment group.
Time frame: Pre-dose, 0.5 h after start of infusion, end of infusion, 5, 10, 24, 30, 48 and 96 and 168 h post-dose
Population: The population consisted of all participants who had PK measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 5 mg/kg | Time to Cmax (Tmax) of Dalotuzumab | 1.0 h | Full Range 1 |
| Dalotuzumab 10 mg/kg | Time to Cmax (Tmax) of Dalotuzumab | 3.0 h | Full Range 23.02 |
| Dalotuzumab 15 mg/kg/7.5 mg/kg | Time to Cmax (Tmax) of Dalotuzumab | 1.0 h | Full Range 11.57 |