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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00701103
First received: June 17, 2008
Last updated: April 5, 2017
Last verified: March 2017
  Purpose

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.


Condition Intervention Phase
Solid Tumor Multiple Myeloma Drug: Dalotuzumab Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Percentage of Participants Who Experienced One or More Dose-limiting Toxicities (DLTs) [ Time Frame: 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 [ 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 ]
    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 [ 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 ]
    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 [ 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 ]
    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.

  • 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 ]
    The lowest (trough) concentration of dalotuzumab prior to the next dose of dalotuzumab was measured.


Secondary Outcome Measures:
  • 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) ]
    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.

  • 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) ]
    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 [ Time Frame: 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) [ Time Frame: 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.


Enrollment: 80
Study Start Date: January 2006
Study Completion Date: December 2009
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 2.5 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 2.5 mg/kg (10 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 5 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 10 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 10 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 15 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 15 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 20 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
Experimental: Dalotuzumab 20 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W.
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
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).
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646
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).
Drug: Dalotuzumab
IV infusion
Other Name: MK-0646

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00701103

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT00701103     History of Changes
Obsolete Identifiers: NCT00282737
Other Study ID Numbers: 0646-001
2007_660 ( Other Identifier: Merck Telerex Number )
Study First Received: June 17, 2008
Results First Received: January 31, 2017
Last Updated: April 5, 2017

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 18, 2017