Multiple Myeloma, Solid Tumor
Conditions
Brief summary
This study will look for the highest tolerated dose of dalotuzumab (MK-0646) given as weekly, every other week. or a every three week infusion. The hypothesis of this study is that administration of dalotuzumab as a one- to two-hour weekly, every other week, or every three week infusion in participants with advanced cancer will be generally safe and tolerated at a dose which achieves a trough concentration ≥3 μg/mL.
Detailed description
Trial Duration of Treatment: Participants can be treated for up to two years if their disease has not progressed and they are not having unmanageable side effects.
Interventions
DRUGDalotuzumab
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has metastatic or locally advanced solid tumor or multiple myeloma * Tumor specimen has IGF-1R expression * Participant agrees to use birth control throughout study
Exclusion criteria
* Participant must not be recovering from antineoplastic therapy in the last 4 weeks * Participant has participated in a clinical trial in the last 4 weeks * Participant has a history of heart problems such as congestive heart failure, angina, heart attack or stroke in the last 3 months * Participant is taking growth hormone or growth hormone inhibitors * If female, participant is pregnant or breastfeeding * Participant is human immunodeficiency virus (HIV) positive * Participant has a history of hepatitis B or C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | Pre-dose immediately prior to second infusion: 168 hours for Q1W, 336 hours for Q2W and 504 hours for Q3W dosing | The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured. |
| Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | Up to 3 weeks | Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE 3.0). A DLT was defined as any Grade 3 or 4 toxicity. A Grade 3 toxicity was defined as severe or medically significant but not immediately life-threatening OR hospitalization or prolongation of hospitalization indicated OR disabling OR limiting self care activities of daily living. A Grade 4 toxicity was defined as: life-threatening consequences OR urgent intervention indicated. Participants were monitored for the occurrence of DLTs during the first 3 weeks of dosing with dalotuzumab. |
| Mean Terminal Half-life (t1/2) of Dalotuzumab | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | Terminal half-life is defined as the time it takes for the blood plasma concentration of a substance to halve (plasma half-life). Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion. Data presented are for the harmonic mean t1/2 for dalotuzumab. |
| Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | AUC0-∞ represents the total drug exposure over time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion. |
| Mean Serum Clearance of Dalotuzumab | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | Clearance is defined as the volume of serum from which study drug was completely removed per unit of time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4) | IGF-1R expression was measured in pre- and post-dose tumor biopsy samples using an IHC assay as a function of time and dose. Results were expressed as an IGF-1R membrane H-score which could range from 0 to 300; with a score of 0 representing the absence of IGF-1R expression and an H-score of 300 representing maximum IGF-1R expression. Changes in IGF-1R expression levels from Baseline are summarized for all participants for whom these paired data were available. A post-dose decrease in IGF-1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement. |
| Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | Up to 2 years | It is thought that the formation of HAHAs may block efficacy by prematurely clearing dalotuzumab and limit the possibility of future dalotuzumab therapy. Blood samples for the measurement of serum levels of HAHAs were obtained prior to treatment with dalotuzumab, and pre-dose Week 2 (Q1W), pre-dose Week 3 (Q2W), pre-dose Week 4 (QW3), pre-dose Week 5 (Q1W/Q2W), pre-dose Week 7 (Q2W/Q3W), pre-dose Week 9 (Q2W), pre-dose Week 10 (QW3) and pre-dose every 4 subsequent weeks and end of treatment (post-study: 4 weeks after last dose of study drug). |
| Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | Up to 2 years | Tumor responses were measured by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria in participants with solid tumors and using European Group for Blood and Marrow Transplantation (EBMT) criteria in participants with multiple myeloma. RECIST criteria for CR: Disappearance of all target lesions. RECIST criteria for PR: ≥30% decrease in the sum of diameters of target lesions. EBMT criteria for CR: Disappearance of the original mAb protein from the blood and urine AND \<5% plasma cells in the bone marrow AND no increase in the size or number of lytic bone lesions AND disappearance of soft tissue plasmacytomas AND normal serum calcium levels. EMBT criteria for PR: ≥50% reduction in the serum mAb protein level AND if a urine M-component is present, a reduction in 24-hour urinary light chain excretion by either ≥90% or to \<200 mg AND ≥50% reduction in the size of soft tissue plasmacytomas AND no increase in size or number of lytic bone lesions. |
| Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4) | IGF-1R expression was measured in pre- and post-dose skin biopsy samples using an immunohistochemistry (IHC) assay as a function of time and dose. Results were expressed as an IGF-1R membrane H-score which could range from 0 to 300; with a score of 0 representing the absence of IGF-1R expression and an H-score of 300 representing maximum IGF-1R expression. Changes in IGF-1R expression levels from Baseline are summarized for all participants for whom these paired data were available. A post-dose decrease in IGF-1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement. |
Participant flow
Recruitment details
Participants who were ≥18 years old, had metastatic or locally advanced solid tumors (including multiple myeloma) and failed to respond to standard therapy, or had progressed despite standard therapy, or for whom standard therapy did not exist were recruited for this study.
Participants by arm
| Arm | Count |
|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 1.25 mg/kg (10 mg/mL) IV infusion Q1W. | 5 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 2.5 mg/kg (10 mg/mL) IV infusion Q1W. | 3 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W. | 8 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W. | 6 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W. | 6 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W. | 6 |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W. | 8 |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W. | 7 |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W. | 9 |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) Participants received dalotuzumab 20 mg/kg (20 mg/mL) IV infusion Q2W. | 11 |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) Participants received dalotuzumab 30 mg/kg (20 mg/mL) IV infusion Q3W. | 11 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 | 0 | 1 | 1 | 0 | 0 | 2 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Progressive Disease | 5 | 2 | 6 | 5 | 6 | 5 | 7 | 7 | 8 | 8 | 11 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69 Years STANDARD_DEVIATION 9 | 60 Years STANDARD_DEVIATION 9 | 68 Years STANDARD_DEVIATION 9 | 56 Years STANDARD_DEVIATION 10 | 53 Years STANDARD_DEVIATION 17 | 49 Years STANDARD_DEVIATION 22 | 54 Years STANDARD_DEVIATION 18 | 46 Years STANDARD_DEVIATION 13 | 52 Years STANDARD_DEVIATION 18 | 55 Years STANDARD_DEVIATION 17 | 52 Years STANDARD_DEVIATION 15 | 55 Years STANDARD_DEVIATION 16 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 4 Participants | 6 Participants | 3 Participants | 3 Participants | 4 Participants | 2 Participants | 5 Participants | 5 Participants | 6 Participants | 40 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 0 Participants | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 6 Participants | 5 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 6 / 8 | 5 / 6 | 4 / 6 | 5 / 6 | 8 / 8 | 6 / 7 | 8 / 9 | 9 / 11 | 11 / 11 |
| serious Total, serious adverse events | 0 / 5 | 0 / 3 | 2 / 8 | 2 / 6 | 2 / 6 | 3 / 6 | 3 / 8 | 0 / 7 | 2 / 9 | 3 / 11 | 1 / 11 |
Outcome results
Primary
Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab
AUC0-∞ represents the total drug exposure over time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion.
Time frame: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had AUC0-last pharmacokinetic measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 1.6 mg*hr/mL | Standard Deviation 0.4 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 3.7 mg*hr/mL | Standard Deviation 1.1 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 12.9 mg*hr/mL | Standard Deviation 4.4 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 28.9 mg*hr/mL | Standard Deviation 10.4 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 18.4 mg*hr/mL | Standard Deviation 4.1 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 39.4 mg*hr/mL | Standard Deviation 14.5 |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 28.8 mg*hr/mL | Standard Deviation 8.8 |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 52.7 mg*hr/mL | Standard Deviation 19.2 |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 44.3 mg*hr/mL | Standard Deviation 20 |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 45.9 mg*hr/mL | Standard Deviation 14.4 |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of Dalotuzumab | 92.6 mg*hr/mL | Standard Deviation 29.8 |
Primary
Mean Serum Clearance of Dalotuzumab
Clearance is defined as the volume of serum from which study drug was completely removed per unit of time. Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion.
Time frame: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had mean serum clearance pharmacokinetic measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.013 mL/min/kg | Standard Deviation 0.004 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.012 mL/min/kg | Standard Deviation 0.003 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.007 mL/min/kg | Standard Deviation 0.003 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.006 mL/min/kg | Standard Deviation 0.002 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.009 mL/min/kg | Standard Deviation 0.002 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.007 mL/min/kg | Standard Deviation 0.004 |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.010 mL/min/kg | Standard Deviation 0.004 |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.007 mL/min/kg | Standard Deviation 0.003 |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.009 mL/min/kg | Standard Deviation 0.004 |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.008 mL/min/kg | Standard Deviation 0.003 |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Mean Serum Clearance of Dalotuzumab | 0.006 mL/min/kg | Standard Deviation 0.003 |
Primary
Mean Terminal Half-life (t1/2) of Dalotuzumab
Terminal half-life is defined as the time it takes for the blood plasma concentration of a substance to halve (plasma half-life). Blood samples for measurement of serum levels of dalotuzumab were obtained at: pre-dose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post infusion. For infusions \>1 hour in duration, an additional sample was obtained at the mid-point of the infusion. Data presented are for the harmonic mean t1/2 for dalotuzumab.
Time frame: Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had t1/2 pharmacokinetic measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 67 Hours |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 79 Hours |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 83 Hours |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 169 Hours |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 100 Hours |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 95 Hours |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 110 Hours |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 129 Hours |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 120 Hours |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 106 Hours |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Mean Terminal Half-life (t1/2) of Dalotuzumab | 142 Hours |
Primary
Mean Trough Serum Concentration (Ctrough) of Dalotuzumab
The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured.
Time frame: Pre-dose immediately prior to second infusion: 168 hours for Q1W, 336 hours for Q2W and 504 hours for Q3W dosing
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had mean trough serum concentration pharmacokinetic measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 2.4 ug/mL | Standard Deviation 2.2 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 7.2 ug/mL | Standard Deviation 3 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 21.2 ug/mL | Standard Deviation 8.3 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 54.8 ug/mL | Standard Deviation 13.3 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 45.2 ug/mL | Standard Deviation 17.4 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 81.2 ug/mL | Standard Deviation 38.6 |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 59.6 ug/mL | Standard Deviation 17.3 |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 110.5 ug/mL | Standard Deviation 46 |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 87.3 ug/mL | Standard Deviation 41.5 |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 57.0 ug/mL | Standard Deviation 22.7 |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | 70.4 ug/mL | Standard Deviation 34.1 |
Primary
Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs)
Toxicity was graded and recorded according to National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE 3.0). A DLT was defined as any Grade 3 or 4 toxicity. A Grade 3 toxicity was defined as severe or medically significant but not immediately life-threatening OR hospitalization or prolongation of hospitalization indicated OR disabling OR limiting self care activities of daily living. A Grade 4 toxicity was defined as: life-threatening consequences OR urgent intervention indicated. Participants were monitored for the occurrence of DLTs during the first 3 weeks of dosing with dalotuzumab.
Time frame: Up to 3 weeks
Population: The population consisted of all participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 13 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) | 0 Percentage of Participants |
Secondary
Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples
IGF-1R expression was measured in pre- and post-dose tumor biopsy samples using an IHC assay as a function of time and dose. Results were expressed as an IGF-1R membrane H-score which could range from 0 to 300; with a score of 0 representing the absence of IGF-1R expression and an H-score of 300 representing maximum IGF-1R expression. Changes in IGF-1R expression levels from Baseline are summarized for all participants for whom these paired data were available. A post-dose decrease in IGF-1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement.
Time frame: Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had IGF-1R tumor pharmacodynamics measurements at Baseline and at least once during treatment. No data were available for the Dalotuzumab 2.5 mg/kg Q1W and Dalotuzumab 30 mg/kg Q3W treatment groups.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Change from Baseline | -80.0 H-score | Standard Deviation 28.3 |
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Baseline | 145.0 H-score | Standard Deviation 91.9 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Baseline | 84.0 H-score | Standard Deviation 59 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Change from Baseline | -16.0 H-score | Standard Deviation 27 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Change from Baseline | 10.0 H-score | Standard Deviation 76.2 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Baseline | 110.0 H-score | Standard Deviation 46.9 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Baseline | 134.3 H-score | Standard Deviation 77 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Change from Baseline | -30.0 H-score | Standard Deviation 40 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Change from Baseline | -40.8 H-score | Standard Deviation 108.1 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples | Baseline | 152.5 H-score | Standard Deviation 72.4 |
Secondary
Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples
IGF-1R expression was measured in pre- and post-dose skin biopsy samples using an immunohistochemistry (IHC) assay as a function of time and dose. Results were expressed as an IGF-1R membrane H-score which could range from 0 to 300; with a score of 0 representing the absence of IGF-1R expression and an H-score of 300 representing maximum IGF-1R expression. Changes in IGF-1R expression levels from Baseline are summarized for all participants for whom these paired data were available. A post-dose decrease in IGF-1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement.
Time frame: Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had skin IGF-1R pharmacodynamics measurements at Baseline and at least once during treatment. No data were available for the Dalotuzumab 30 mg/kg Q3W treatment group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 186.7 H-score | Standard Deviation 35.1 |
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -1.7 H-score | Standard Deviation 42.5 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 203.3 H-score | Standard Deviation 55.1 |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -11.7 H-score | Standard Deviation 48.6 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 218.6 H-score | Standard Deviation 57.9 |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -20.0 H-score | Standard Deviation 68.6 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 171.8 H-score | Standard Deviation 40.2 |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -2.7 H-score | Standard Deviation 42.2 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 182.0 H-score | Standard Deviation 33.9 |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -39.0 H-score | Standard Deviation 36.3 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Baseline | 146.3 H-score | Standard Deviation 76.9 |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples | Change from Baseline | -27.0 H-score | Standard Deviation 54.1 |
Secondary
Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab
It is thought that the formation of HAHAs may block efficacy by prematurely clearing dalotuzumab and limit the possibility of future dalotuzumab therapy. Blood samples for the measurement of serum levels of HAHAs were obtained prior to treatment with dalotuzumab, and pre-dose Week 2 (Q1W), pre-dose Week 3 (Q2W), pre-dose Week 4 (QW3), pre-dose Week 5 (Q1W/Q2W), pre-dose Week 7 (Q2W/Q3W), pre-dose Week 9 (Q2W), pre-dose Week 10 (QW3) and pre-dose every 4 subsequent weeks and end of treatment (post-study: 4 weeks after last dose of study drug).
Time frame: Up to 2 years
Population: The population consisted of all participants who received \>90% of intended drug volume and had measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 40 Percentage of Participants |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 14 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab | 0 Percentage of Participants |
Secondary
Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR)
Tumor responses were measured by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria in participants with solid tumors and using European Group for Blood and Marrow Transplantation (EBMT) criteria in participants with multiple myeloma. RECIST criteria for CR: Disappearance of all target lesions. RECIST criteria for PR: ≥30% decrease in the sum of diameters of target lesions. EBMT criteria for CR: Disappearance of the original mAb protein from the blood and urine AND \<5% plasma cells in the bone marrow AND no increase in the size or number of lytic bone lesions AND disappearance of soft tissue plasmacytomas AND normal serum calcium levels. EMBT criteria for PR: ≥50% reduction in the serum mAb protein level AND if a urine M-component is present, a reduction in 24-hour urinary light chain excretion by either ≥90% or to \<200 mg AND ≥50% reduction in the size of soft tissue plasmacytomas AND no increase in size or number of lytic bone lesions.
Time frame: Up to 2 years
Population: The population consisted of all evaluable participants who received \>90% of intended drug volume and had efficacy measurements at Baseline and at least once during treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 5 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 10 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 15 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (10 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q1W (20 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 20 mg/kg Q2W (20 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |
| Dalotuzumab 30 mg/kg Q3W (20 mg/mL) | Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) | 0 Percentage of Participants |