A Study of MK-8033 in Patients With Advanced Solid Tumors (MK-8033-001)

A Phase I Dose Escalation Study of MK-8033 in Patients With Advanced Solid Tumors

This is a first-in-human trial to establish the safety, tolerability, Recommended Phase II Dose (RP2D), pharmacodynamic, and clinical activity of MK-8033.

Parts A and B of the study will determine the maximum tolerated dose (MTD) and RP2D. Part C of the study will be a single panel crossover study to determine the effect of omeprazole, a gastric pH modifier, on the pharmacokinetics of MK-8033.

Study Overview

• Status: Completed
• Conditions: Advanced Cancer
• Intervention / Treatment: Drug: Comparator: MK-8033; Drug: Comparator: MK-8033 +/- omeprazole

• 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:

• Patient must be at least 18 years of age, with adequate organ function, and an Eastern Cooperative Oncology Group (ECOG) performance of <2
• Patient must be willing to undergo pre-study and post-dose tumor biopsy and have tumor accessible for biopsy (Waived during Parts A and C)

Exclusion Criteria:

• Patient is currently using bisphosphonate therapy or has received this therapy in past 6 months
• Patient has had chemotherapy, radiotherapy, or biological therapy within 4 weeks of study participation
• Patient has history of cardiac disease
• Patient with a primary central nervous system tumor
• Patient has a known psychiatric or substance abuse disorder
• Patient is pregnant or breastfeeding, or expecting to conceive during the study
• Patient is known to be Human Immunodeficiency Virus (HIV) positive and the HIV infection is not well controlled
• Patient has received therapy with a Proton-Pump Inhibitor, Histamine2-Receptor antagonist or antacid within one week of study participation (Part B only)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Parts A and B: MK-8033; Dose Escalation Study	Drug: Comparator: MK-8033; MK-8033 will be administered as an oral formulation in sequentially rising dose levels starting at 50 mg and continuing at 100% dose increments until dose level 4 (800 mg total daily dose). Dose levels 5 to 11 will be escalated at ~40% dose increments until 3000mg (total daily dose). The daily dose of MK-8033 will be divided into two equal doses. MK-8033 will be administered in a first cycle of 14 days (continuous drug administration from Day 1 through Day 14), followed by a 1 week drug holiday (Cycle 1, Day 15 through Day 21). Subsequent cycles of MK-8033 will be administered for 14 days (Cycles 2 to 4) and 28 days (Cycle 5 and beyond). Enrollment in Parts A and B has been completed.
Experimental: Part C: MK-8033 +/- omeprazole; Crossover Study	Drug: Comparator: MK-8033 +/- omeprazole; Part C will occur at only one of the investigational sites. In Cycle 1, patients will be randomized to one of two treatment sequences, A/B or B/A, over two treatment periods. Treatment A: 770 mg MK-8033 twice daily with co-administration of 20 mg omeprazole once daily. Treatment B: 770 mg MK-8033 twice daily. After Cycle 1 is complete, patients may continue to receive MK-8033 until disease progression or unacceptable toxicity. Enrollment for Part C has been suspended.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety and tolerability of MK-8033 based on drug-related dose limiting toxicity.	for the entire duration of study (27 months)
Recommended Phase II Dose (RP2D) based on safety, tumor pharmacodynamics, and pharmacokinetics	for the entire duration of study (27 months)
Plasma area under the curve (AUC) for F2 formulation alone or in combination with omeprazole	Day 1-21
Safety and tolerability of MK-8033 F2 formulation alone or in combination with omeprazole based on incidence of adverse experiences	Day 1-21
Tumor Pharmacodynamics (PD): phospho-c-Met (MET or MNNG HOS Transforming gene) Levels (Parts A & B)	Cycle 1 pre-dose & Day 12
Tumor PD: phospho-Akt (Protein Kinase B) Levels (Parts A & B)	Cycle 1 pre-dose & Day 12
Tumor PD: phospho-MAPK (mitogen-activated protein kinase) Levels (Parts A & B)	Cycle 1 pre-dose & Day 12
Bone PD: Cross-Linked N-telopeptides of Type I collagen (NTx) Levels (Parts A & B)	Baseline, Cycle 1 Day 8, & Cycle 3 Day 1

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Keedy VL, Lenz HJ, Saltz L, Whisenant JG, Berlin JD, Camacho LH. First-in-human phase I dose escalation study of MK-8033 in patients with advanced solid tumors. Invest New Drugs. 2018 Oct;36(5):860-868. doi: 10.1007/s10637-018-0567-z. Epub 2018 Jan 29.

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2007
• Primary Completion (Actual): June 10, 2010
• Study Completion (Actual): July 9, 2010

Study Registration Dates

• First Submitted: November 14, 2007
• First Submitted That Met QC Criteria: November 14, 2007
• First Posted (Estimate): November 16, 2007

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 22, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole
• Other Study ID Numbers: 8033-001; 2007_590