Neoplasms

Symptoms and General Pathology

All Conditions

Neoplasm Metastasis

Participants received a loading dose of dalotuzumab 2.5 mg/kg administered by intravenous (IV) infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 2.5 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 5.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 10.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 20.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 5.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 10.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Participants received a loading dose of dalotuzumab 15.0 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 15.0 mg/kg administered by IV infusion every two weeks for up to 18 months.

Administered as an IV infusion over one to two hours

dalotuzumab

Medical Director

The study determined the recommended Phase 2 loading and maintenance doses and dose schedules for administering dalotuzumab using dose-limiting toxicities (DLTs) observed during the entire treatment period (Up to 18 months). The primary hypothesis of the study was that administration of dalotuzumab as an every other week infusion in participants with relapsed or refractory locally advanced or metastatic cancers associated with a high frequency of insulin-like growth factor receptor type 1(IGF-1R) overexpression will be generally safe and well tolerated to permit further study and achieve a constant clearance and a minimum trough concentration of 3 µg/mL.

The study consisted of 3 parts. In Part 1 the loading dose was escalated while the maintenance dose was kept constant. In Part 2 the loading dose was kept constant while the maintenance dose was escalated. In Part 3 the recommended phase 2 loading and maintenance doses and schedule were administered to an expanded cohort to explore safety and efficacy of dalotuzumab.

A Dose-finding Study of Dalotuzumab in Subjects With Advanced Solid Tumors (MK-0646-002)

An Open-Label, Dose Escalation Phase I Trial of MK-0646 Given as a One to Two Hour Every Other Week Infusion in Patients With Relapsed or Refractory Locally Advanced or Metastatic Cancers

Blood samples were obtained for analysis of steady-state serum concentration of dalotuzumab at 336 hours (C336) after the first maintenance dose of dalotuzumab. The C336 of dalotuzumab after intravenous administration is presented.

Dose-limiting toxicities (DLT) were assessed and graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE). A DLT was defined as the occurrence of any of the following events, that were judged by the study investigator, to be related to the study medication: Grade 4 neutropenia; Grade 3 neutropenia with fever \>38.5 degrees Celsius; Grade 4 thrombocytopenia; Grade 3 or Grade 4 non-hematologic toxicity (except alopecia and inadequately treated diarrhea, nausea, and vomiting, and hyperglycemia lasting less than 5 days; and Grade 3 or greater hyperglycemia lasting for more than 5 days in spite of optimal medical management.

Complete Response (disappearance of all target lesions) or Partial Response (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) using Response Criteria in Solid Tumors (RECIST). Tumor response was assessed prior to first dose and every 8 weeks beginning pre-dose of Week 9 for up to 18 months. The best response out of all measurements for each participant was used for determining CR and PR.

IGF-1R expression was measured in pre- and post-dose biopsy samples using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) assays. Results were expressed as a percent change from baseline in IG1-FR expression for participants pooled across all dose arms in the study and calculated by study week. A post-dose decrease in IGF-1R expression was an indication of target engagement by dalotuzumab. A larger percent change correlated with a greater target engagement.

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 3, Week 5, pre-dose every 8 subsequent weeks, and end of treatment (post-study: 4 weeks after last dose of study drug). Positive HAHA status for a participant is defined as testing positive on both the screening and immunodepletion assays at one or more visits.

Merck Sharp & Dohme LLC

The safety population consisted of all participants who received at least one dose of study drug.

Participants received a loading dose of dalotuzumab 2.5 mg/kg administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab 2.5 mg/kg administered by IV infusion every two weeks for up to 18 months.

Dalotuzumab 2.5 mg/kg / Dalotuzumab 2.5 mg/kg

Dalotuzumab 5.0 mg/kg / Dalotuzumab 5.0 mg/kg

Dalotuzumab 10.0 mg/kg / Dalotuzumab 5.0 mg/kg

Dalotuzumab 15.0 mg/kg / Dalotuzumab 5.0 mg/kg

Dalotuzumab 20.0 mg/kg / Dalotuzumab 5.0 mg/kg

Dalotuzumab 15.0 mg/kg / Dalotuzumab 10.0 mg/kg

Dalotuzumab 15.0 mg/kg / Dalotuzumab 15.0 mg/kg

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Number of Prior Chemotherapy Regimens

Participants were assessed for ECOG PS: Grade 0: Fully active, able to carry on all pre-disease performance without restriction; Grade 1: Restricted in physically strenuous activity but ambulatory \& able to carry out work of a light or sedentary nature; Grade 2: Ambulatory \& capable of all self-care but unable to carry out any work activities, up \& about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Grade 4: Completely disabled, cannot carry on any self-care, totally confined to bed or chair or Grade 5: Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

Senior Vice President, Global Clinical Development

All participants who received dalotuzumab and had blood samples drawn for pharmacokinetic (PK) analyses.

Steady-state Serum Concentration of Dalotuzumab at 336 Hours (C336) After the First Maintenance Dose

All participants who received at least one dose of study drug.

Number of Participants Who Experience One or More Dose- Limiting Toxicities (DLTs)

All participants who received at least one dose of study therapy.

Number of Participants Who Experienced a Complete Response (CR) or Partial Response (PR)

Participants were pooled from all dose arms in the study. Participants received a loading dose of dalotuzumab administered by IV infusion. Two weeks following completion of the loading dose, participants received a maintenance dose of dalotuzumab administered by IV infusion every two weeks for up to 18 months.

Pooled Participants Who Received Dalotuzumab

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 1.

Percent Change From Baseline in Serum Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Level at Week 1

All participants who received one dose of study therapy.

Number of Participants With a Positive Human-anti-humanized-antibody (HAHA) Titer

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 5

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 5

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 9

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 9

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 13

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 13

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 17

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 17

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 21

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 21

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 25

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 25

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 29

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 29

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 33

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 33

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 37

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 37

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 41

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 41

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 45

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 45

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 49

Percent Change From Baseline in Serum IGF-1R Protein Level at Week 49

All participants who took at least one dose of study drug and had available IGF-1R protein data for Baseline and Week 53

Spots Global Cancer Trial Database for A Dose-finding Study of Dalotuzumab in Subjects With Advanced Solid Tumors (MK-0646-002)

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