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

Study Overview
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Brief Summary
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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.

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

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: Comparator: MK-8033
* Drug: Comparator: MK-8033 +/- omeprazole


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Parts A and B: MK-8033<br>Dose Escalation Study | Drug: Comparator: MK-8033<br>* 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.<br>|
| Experimental: Part C: MK-8033 +/- omeprazole<br>Crossover Study | Drug: Comparator: MK-8033 +/- omeprazole<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 |