- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00701103
Dose Escalation Trial of Dalotuzumab (MK-0646) in Advanced Solid Tumors and Multiple Myeloma (MK-0646-001)
An Open-Label, Dose Escalation Phase I Trial of MK-0646 Given as a Once Weekly, Every Other Week, or Every Three Week Infusion in Patients With Advanced Solid Tumors and Multiple Myeloma
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.
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Dalotuzumab 1.25 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 1.25 mg/kg (10 mg/mL) intravenous (IV) infusion 1 time every 1 week (Q1W).
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IV infusion
Other Names:
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Experimental: Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 2.5 mg/kg (10 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 5 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 10 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 10 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 15 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 15 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 20 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 20 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W.
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IV infusion
Other Names:
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Experimental: Dalotuzumab 20 mg/kg Q2W (20 mg/mL)
Participants received dalotuzumab 20 mg/kg (20 mg/mL) IV infusion 1 time every 2 weeks (Q2W).
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IV infusion
Other Names:
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Experimental: Dalotuzumab 30 mg/kg Q3W (20 mg/mL)
Participants received dalotuzumab 30 mg/kg (20 mg/mL) IV infusion1 time every 3 weeks (Q3W).
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IV infusion
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs)
Time Frame: Up to 3 weeks
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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.
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Up to 3 weeks
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Mean Terminal Half-life (t1/2) of 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
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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.
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Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
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Area Under the Time-concentration Curve From 0 to Infinity Hours (AUC0-∞) of 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
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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.
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Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
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Mean Serum Clearance of 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
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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.
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Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion
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Mean Trough Serum Concentration (Ctrough) of Dalotuzumab
Time Frame: Pre-dose immediately prior to second infusion: 168 hours for Q1W, 336 hours for Q2W and 504 hours for Q3W dosing
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The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured.
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Pre-dose immediately prior to second infusion: 168 hours for Q1W, 336 hours for Q2W and 504 hours for Q3W dosing
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change From Baseline in Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Expression Level H-score in Skin Samples
Time Frame: Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
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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.
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Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
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Change From Baseline in IGF-1R Protein Expression Level H-score in Tumor Samples
Time Frame: Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
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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.
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Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4)
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Percentage of Participants Who Developed a Serum Human-anti-humanized-antibody (HAHA) Response to Dalotuzumab
Time Frame: Up to 2 years
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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).
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Up to 2 years
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Percentage of Participants Who Experienced a Complete Response (CR) or Partial Response (PR)
Time Frame: Up to 2 years
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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.
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Up to 2 years
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Collaborators and Investigators
Sponsor
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Immune System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Lymphoproliferative Disorders
- Immunoproliferative Disorders
- Hematologic Diseases
- Hemorrhagic Disorders
- Hemostatic Disorders
- Paraproteinemias
- Blood Protein Disorders
- Multiple Myeloma
- Neoplasms, Plasma Cell
Other Study ID Numbers
- 0646-001
- 2007_660 (Other Identifier: Merck Telerex Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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