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

• ClinicalTrials.gov Identifier: NCT00635778
• Recruitment Status: Completed
• First Posted: March 14, 2008
• Results First Posted: October 9, 2018
• Last Update Posted: October 9, 2018
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumors	Drug: dalotuzumab	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 7, 2006
• Actual Primary Completion Date: November 5, 2008
• Actual Study Completion Date: November 5, 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: dalotuzumab 2.5/2.5 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 5.0/5.0 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 10.0/5.0 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 15.0/5.0mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 20.0/5.0 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 15.0/10.0 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646
Experimental: dalotuzumab 15.0/15.0 mg/kg; 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.	Drug: dalotuzumab; Administered as an IV infusion over one to two hours; Other Name: MK-0646

Outcome Measures

Primary Outcome Measures :

1. Steady-state Serum Concentration of Dalotuzumab at 336 Hours (C336) After the First Maintenance Dose [ Time Frame: 2 weeks post first maintenance dose of study drug (3 weeks post loading dose of study drug) ]
   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.
2. Number of Participants Who Experience One or More Dose- Limiting Toxicities (DLTs) [ Time Frame: The entire treatment period (Up to 18 months) ]
   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.

Secondary Outcome Measures :

1. Number of Participants Who Experienced a Complete Response (CR) or Partial Response (PR) [ Time Frame: Up to 18 months post first dose of study drug ]
   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.
2. Percent Change From Baseline in Serum Insulin-like Growth Factor Receptor Type 1 (IGF-1R) Protein Level at Week 1 [ Time Frame: Baseline and Week 1 ]
   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.
3. Number of Participants With a Positive Human-anti-humanized-antibody (HAHA) Titer [ Time Frame: Prior to second and subsequent doses of study drug (Up to 1 year post-first dose) ]
   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.
4. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 5 [ Time Frame: Baseline and Week 5 ]
   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.
5. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 9 [ Time Frame: Baseline and Week 9 ]
   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.
6. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 13 [ Time Frame: Baseline and Week 13 ]
   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.
7. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 17 [ Time Frame: Baseline and Week 17 ]
   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.
8. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 21 [ Time Frame: Baseline and Week 21 ]
   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.
9. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 25 [ Time Frame: Baseline and Week 25 ]
   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.
10. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 29 [ Time Frame: Baseline and Week 29 ]
    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.
11. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 33 [ Time Frame: Baseline and Week 33 ]
    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.
12. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 37 [ Time Frame: Baseline and Week 37 ]
    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.
13. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 41 [ Time Frame: Baseline and Week 41 ]
    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.
14. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 45 [ Time Frame: Baseline and Week 45 ]
    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.
15. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 49 [ Time Frame: Baseline and Week 49 ]
    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.
16. Percent Change From Baseline in Serum IGF-1R Protein Level at Week 53 [ Time Frame: Baseline and Week 53 ]
    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.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Males and females with advanced solid tumors who have failed to respond to standard therapy, ages 18 years and older, with adequate organ function

Exclusion Criteria:

• Participant is using growth hormones or growth hormone inhibitors
• Participant is known to be allergic to components of the drug or similar drugs (e.g. monoclonal antibodies such as rituximab or biological therapies such as immunoglobulin G
• Participant has had chemotherapy, radiotherapy, or biological therapy within 4-6 weeks of entering the study or has not recovered from previous therapy
• Participant is taking part in or has taken part in a study of an investigational compound or device within 30 days of their first dose of study drug
• Participant has an active Central Nervous System metastases and/or carcinomatous meningitis. However, a participant who has completed a course of therapy and is clinically stable may be able to participate
• Participant is pregnant or breastfeeding
• Participant is human immunodeficiency virus (HIV) positive
• Participant has a history of Hepatitis B or C
• Participant has symptomatic ascites or pleural effusion. However, if the participant has received treatment and is stable, they may be able to participate
• Female participant plans to become pregnant or a male participant who plans to impregnate their partner during the time the study is ongoing

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT00635778
• Other Study ID Numbers: 0646-002; MK-0646-002 ( Other Identifier: Merck Protocol Number )
• First Posted: March 14, 2008
• Results First Posted: October 9, 2018
• Last Update Posted: October 9, 2018
• Last Verified: February 2018