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

July 12, 2018 updated by: Merck Sharp & Dohme LLC

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

Status

Completed

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Phase 1

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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).
IV infusion
Other Names:
  • 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.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 5 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 5 mg/kg (10 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 10 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 10 mg/kg (10 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 10 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 10 mg/kg (20 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 15 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 15 mg/kg (10 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 15 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 15 mg/kg (20 mg/ mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 20 mg/kg Q1W (10 mg/mL)
Participants received dalotuzumab 20 mg/kg (10 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • MK-0646
Experimental: Dalotuzumab 20 mg/kg Q1W (20 mg/mL)
Participants received dalotuzumab 20.0 mg/kg (20 mg/mL) IV infusion Q1W.
IV infusion
Other Names:
  • 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).
IV infusion
Other Names:
  • 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).
IV infusion
Other Names:
  • MK-0646

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
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
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
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).
Up to 2 years
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.
Up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 12, 2006

Primary Completion (Actual)

December 1, 2009

Study Completion (Actual)

December 1, 2009

Study Registration Dates

First Submitted

June 17, 2008

First Submitted That Met QC Criteria

June 18, 2008

First Posted (Estimate)

June 19, 2008

Study Record Updates

Last Update Posted (Actual)

August 8, 2018

Last Update Submitted That Met QC Criteria

July 12, 2018

Last Verified

July 1, 2018

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

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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