Dose Escalation Trial of Dalotuzumab (MK-0646) in Advanced Solid Tumors and Multiple Myeloma (MK-0646-001)

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Solid Tumor, Multiple Myeloma

Intervention / Treatment
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* Drug: Dalotuzumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention 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)<br>Participants received dalotuzumab 1.25 mg/kg (10 mg/mL) intravenous (IV) infusion 1 time every 1 week (Q1W). | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL)<br>Participants received dalotuzumab 2.5 mg/kg (10 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 5 mg/kg Q1W (10 mg/mL)<br>Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 10 mg/kg Q1W (10 mg/mL)<br>Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 10 mg/kg Q1W (20 mg/mL)<br>Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 15 mg/kg Q1W (10 mg/mL)<br>Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 15 mg/kg Q1W (20 mg/mL)<br>Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 20 mg/kg Q1W (10 mg/mL)<br>Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 20 mg/kg Q1W (20 mg/mL)<br>Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W. | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 20 mg/kg Q2W (20 mg/mL)<br>Participants received dalotuzumab 20 mg/kg (20 mg/mL) IV infusion 1 time every 2 weeks (Q2W). | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|
| Experimental: Dalotuzumab 30 mg/kg Q3W (20 mg/mL)<br>Participants received dalotuzumab 30 mg/kg (20 mg/mL) IV infusion1 time every 3 weeks (Q3W). | Drug: Dalotuzumab<br>* IV infusion<br>* Other names: MK-0646;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 3 weeks | 
| 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. | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | 
| 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. | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | 
| 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. | Predose; pre-end infusion; 0.5, 5, 10, 24, 30 (Q1W only), 48, 96, 168 (Q2W/Q3W only), 336 (Q3W only) hours post-infusion | 
| Mean Trough Serum Concentration (Ctrough) of Dalotuzumab | The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured. | Pre-dose immediately prior to second infusion: 168 hours for Q1W, 336 hours for Q2W and 504 hours for Q3W dosing | 

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 | 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. | Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4) | 
| 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. | Predose in Cycle 1 (Baseline) and predose in Cycle 3 (Week 4) | 
| 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). | Up to 2 years | 
| 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. | Up to 2 years |