Advanced Cancer
Conditions
Brief summary
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.
Interventions
DRUGComparator: 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.
DRUGComparator: 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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| 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 |
Outcome results
None listed