A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + Ridaforolimus Combination Therapies in Participants With Advanced Cancer (MK-0646-027)

Phase I Parallel Arm Study of MK-0646 (Dalotuzumab) + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 (Ridaforolimus) Doublets (MK-MK Doublets) in Patients With Advanced Cancer

This is an open-label, two-part study to evaluate the safety and tolerability of combination treatment with dalotuzumab + MK-2206, dalotuzumab + MK-0752, or dalotuzumab + ridaforolimus (MK-8669). Part 1 of the study will determine the dose-limiting toxicities (DLTs) observed after administration of each of the combinations at various doses and define the maximum tolerated dose (MTD) of each combination. Part 2 of the study will assess preliminary anti-tumor activity of these combinations (at MTD) in two groups of participants with selected tumor biomarkers: one group with metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and one group with metastatic or recurrent colorectal cancer. The dalotuzumab + ridaforolimus and dalotuzumab + MK-2206 arms will be enriched with female platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer participants. The dalotuzumab + MK-0752 arm will be enriched with metastatic or recurrent wild-type kirsten rat sarcoma (KRAS) colorectal cancer participants.

The primary hypothesis is that the DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of each of the MK-MK doublets will be dose-dependent to allow for definition of a MTD within each MK-MK doublet.

Study Overview

• Status: Terminated
• Conditions: Neoplasms Malignant
• Intervention / Treatment: Drug: dalotuzumab; Drug: MK-0752; Drug: MK-2206; Drug: ridaforolimus

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Participation Criteria

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:

• Participants must not have any medical conditions that may impact compliance with the protocol, limit interpretation of study results, or pose an unacceptable medical risk.
• Participant must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (EGOG) Performance Scale.
• Participant is able to swallow capsules and has no condition that will preclude swallowing and absorbing oral medications on an ongoing basis.
• Participant has no history of a prior malignancy with the exception of cervical intraepithelial neoplasia; basal cell carcinoma of the skin; adequately treated localized prostate carcinoma with prostatic specific antigen (PSA) < 1.0; or has undergone potentially curative therapy with no evidence of that disease for five years, or is deemed at low risk for recurrence by his/her treating physician.
• Participant has at least one measurable metastatic or recurrent lesion according to Response Criteria in Solid Tumors (RECIST).

Part 1:

• Participant must have a histologically-confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. There is no limit on the number of prior treatment regimens.

Part 2:

• A female participant assigned to the dalotuzumab + MK-2206 or dalotuzumab + ridaforolimus treatment arms must have histologically-confirmed metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. Participants may have received any number of prior treatment regimens.
• A participant assigned to the dalotuzumab + MK-0752 treatment arms must have histologically-confirmed metastatic or recurrent wild-type KRAS colorectal cancer that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. Participants may have received any number of prior treatment regimens.
• Participant agrees to provide archival tumor tissue sample or undergo biopsy for analysis of gene expression levels.

Exclusion Criteria:

• Participant has had chemotherapy, radiotherapy, or biological therapy (including monoclonal antibodies) within 4 weeks prior to study Day 1 (6 weeks for nitrosoureas or mitomycin C) or who has not recovered from adverse events due to agents administered more than 4 weeks earlier, or major surgery <4 weeks earlier.
• Participant is currently participating or has participated in a study with an investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. Participants previously treated with a monoclonal antibody will be eligible to participate after a 28 day washout period.
• Participants with known central nervous system (CNS) metastases and/or carcinomatous meningitis are excluded.
• Participant has significant or uncontrolled cardiovascular disease, including New York Heart Association (NYHA) Class III-IV heart failure, unstable angina, or a myocardial infarction within the last 6 months.
• Participant is known to have diabetes that is poorly controlled.
• Participant is pregnant, breastfeeding, or expecting to conceive or father children during the study.
• Participant is known to be human immunodeficiency virus (HIV)-positive.
• Participant has active Hepatitis B or C infection.
• Participant has symptomatic ascites or pleural effusion.
• Participant requires treatment with immunosuppressive agents other than prescribed corticosteroids at stable doses for at least two weeks prior to the first dose of study drug.
• Participant requires treatment with medication(s) that strongly or moderately induce or inhibit cytochrome P450.
• Participant is using growth hormone or growth hormone inhibitors.
• Participant requires treatment with therapeutic warfarin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg; Participants in Part 1 of the study receive dalotuzumab 7.5 mg/kg intravenously (IV) weekly + MK-0752 1800 mg orally (PO) weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-0752; Administered orally (PO) weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab 10 mg/kg + MK-0752 1800 mg; Participants in Parts 1 and 2 of the study receive dalotuzumab 10 mg/kg IV weekly + MK-0752 1800 mg PO weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-0752; Administered orally (PO) weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab 10 mg/kg + MK-2206 90 mg; Participants in Part 1 of the study receive dalotuzumab 10 mg/kg IV weekly + MK-2206 90 mg PO weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-2206; Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab 10 mg/kg + MK-2206 135 mg; Participants in Part 1 of the study receive dalotuzumab 10 mg/kg IV weekly + MK- 2206 135 mg PO weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-2206; Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab 10 mg/kg + MK-2206 150 mg; Participants in Parts 1 and 2 of the study receive dalotuzumab 10 mg/kg IV weekly + MK- 2206 150 mg PO weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-2206; Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab 10 mg/kg + MK-2206 200 mg; Participants in Part 1 of the study receive dalotuzumab 10 mg/kg IV weekly + MK- 2206 200 mg PO weekly in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: MK-2206; Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy
Experimental: Dalotuzumab + Ridaforolimus; Participants in Part 2 of the study receive dalotuzumab 10 mg/kg IV weekly + ridaforolimus 20 mg PO daily for 5 consecutive days per week in 28-day cycles for a maximum of 6 months of study therapy.	Drug: dalotuzumab; Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-0646; Drug: ridaforolimus; Administered PO daily for 5 consecutive days per week in 28-day cycles for a maximum of 6 months of study therapy; Other Names: MK-8669

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicities (DLTs)	DLTs were defined as follows: 1) non-hematological toxicity ≥Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 except for Grade 3 nausea, vomiting, diarrhea, and/or dehydration; Grade 3 or 4 hyperglycemia; alopecia; inadequately treated hypersensitivity reactions; dalotuzumab infusion-related reactions; Grade 3 transaminases ≤1 week in duration; or clinically non-significant, treatable or reversible lab abnormalities; 2) Grade 4-5 hematologic toxicity, with the exception of Grade 4 neutropenia <6 days in duration; 3) Grade 3 or Grade 4 neutropenia with fever >38.5 degrees C; 4) Grade 4 thrombocytopenia ≤25.0 x 10^9/Liter; 5) drug-related adverse experience leading to a dose modification during Cycle 1; 6) unresolved drug-related toxicity that causes ≥3 week delay of the next scheduled dose of study medication; 7) persistent increases in QTc interval >60 milliseconds from baseline, or clinically significant bradycardia.	Cycle 1-28 Days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR)	Best response was determined for the maximum tolerated dose from the start of treatment until disease progression, recurrence, or completion of 6 months of treatment. Lesions were measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). Partial response (PR), defined as a tumor burden decrease of 30%, or complete response (CR) was determined using Response Criteria in Solid Tumors (RECIST) 1.1 for participants with at least one measurable target lesion at baseline.	Up to 7 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Brana I, Berger R, Golan T, Haluska P, Edenfield J, Fiorica J, Stephenson J, Martin LP, Westin S, Hanjani P, Jones MB, Almhanna K, Wenham RM, Sullivan DM, Dalton WS, Gunchenko A, Cheng JD, Siu LL, Gray JE. A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours. Br J Cancer. 2014 Nov 11;111(10):1932-44. doi: 10.1038/bjc.2014.497. Epub 2014 Oct 7.

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2010
• Primary Completion (Actual): December 4, 2012
• Study Completion (Actual): March 25, 2013

Study Registration Dates

• First Submitted: November 17, 2010
• First Submitted That Met QC Criteria: November 17, 2010
• First Posted (Estimate): November 19, 2010

Study Record Updates

• Last Update Posted (Actual): August 16, 2018
• Last Update Submitted That Met QC Criteria: July 18, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Colorectal cancer; Solid tumors; Ovarian cancer; Primary peritoneal cancer; Fallopian tube cancer
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 0646-027

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No