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

NCT01243762 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 0646-027
• Study Type: interventional
• Target: 47
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Neoplasms Malignant

Keywords

Colorectal cancer; Solid tumors; Ovarian cancer; Fallopian tube cancer; Primary peritoneal cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR)

  Up to 7 months

Study Arms (7)

Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg

EXPERIMENTAL

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; Drug: MK-0752

Dalotuzumab 10 mg/kg + MK-0752 1800 mg

EXPERIMENTAL

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; Drug: MK-0752

Dalotuzumab 10 mg/kg + MK-2206 90 mg

EXPERIMENTAL

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; Drug: MK-2206

Dalotuzumab 10 mg/kg + MK-2206 135 mg

EXPERIMENTAL

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; Drug: MK-2206

Dalotuzumab 10 mg/kg + MK-2206 150 mg

EXPERIMENTAL

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; Drug: MK-2206

Dalotuzumab 10 mg/kg + MK-2206 200 mg

EXPERIMENTAL

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; Drug: MK-2206

Dalotuzumab + Ridaforolimus

EXPERIMENTAL

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; Drug: ridaforolimus

Interventions

dalotuzumab DRUG

Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy

Also known as: MK-0646

Dalotuzumab + Ridaforolimus; Dalotuzumab 10 mg/kg + MK-0752 1800 mg; Dalotuzumab 10 mg/kg + MK-2206 135 mg; Dalotuzumab 10 mg/kg + MK-2206 150 mg; Dalotuzumab 10 mg/kg + MK-2206 200 mg; Dalotuzumab 10 mg/kg + MK-2206 90 mg; Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg

MK-0752 DRUG

Administered orally (PO) weekly in 28-day cycles for a maximum of 6 months of study therapy

Dalotuzumab 10 mg/kg + MK-0752 1800 mg; Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg

ridaforolimus DRUG

Administered PO daily for 5 consecutive days per week in 28-day cycles for a maximum of 6 months of study therapy

Also known as: MK-8669

Dalotuzumab + Ridaforolimus

MK-2206 DRUG

Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy

Dalotuzumab 10 mg/kg + MK-2206 135 mg; Dalotuzumab 10 mg/kg + MK-2206 150 mg; Dalotuzumab 10 mg/kg + MK-2206 200 mg; Dalotuzumab 10 mg/kg + MK-2206 90 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• 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.

  PMID: 25290091 RESULT

MeSH Terms

Conditions

Neoplasms; Colorectal Neoplasms; Ovarian Neoplasms; Fallopian Tube Neoplasms

Interventions

dalotuzumab; 3-(4-((4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)propanoic acid; ridaforolimus; MK 2206

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Fallopian Tube Diseases

Limitations and Caveats

The study was terminated for business reasons and not due to any safety or efficacy concerns related to dalotuzumab.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 17, 2010
• First Posted: November 19, 2010
• Study Start: November 22, 2010
• Primary Completion: December 4, 2012
• Study Completion: March 25, 2013
• Last Updated: August 16, 2018
• Results First Posted: October 30, 2017

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share