This phase I trial studies the side effects and best dose of RNR Inhibitor City of Hope 29 (COH29) in treating patients with solid tumors that are refractory to standard therapy or for which no standard therapy exists. COH29 may inhibit an enzyme called ribonucleotide reductase and may interfere with the ability of tumor cells to grow.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of COH29 (ribonucleotide reductase \[RNR\] inhibitor COH29) and recommended dose for further phase II testing. II. To determine the pharmacokinetics of COH29. SECONDARY OBJECTIVES: I. To characterize the safety and tolerability of COH29 by assessing toxicities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. II. To characterize any clinical activity of COH29 via objective tumor response. III. To assess pharmacodynamic response of COH29 on ribonucleotide reductase (RR) and poly-adenosine diphosphate-ribose polymerase (PARP) activity in peripheral blood mononuclear cells (PBMCs). IV. To explore baseline RRM2 tumor protein expression as a potential correlative marker for COH29 response. V. To explore measurement of plasma cytokeratin 18 (CK18) as a surrogate pharmacodynamic marker of COH29 antitumor activity. OUTLINE: This is a dose escalation study. Patients receive RNR inhibitor COH29 orally (PO) twice daily (BID) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Given PO
Correlative studies
Correlative studies
City of Hope Medical Center
Duarte, California, United States
Maximum tolerated dose of RNR inhibitor COH29, defined as the dose level with no more than 1 dose limiting toxicity (DLT) in the first 6 patients at a dose level below a dose level with DLT in 2 of 6 patients, graded according to CTCAE version 4.0
Time frame: Day 28
Changes in plasma biomarker expression levels
Descriptive statistics and graphical displays will be used to summarize levels of plasma CK18, dNTP pools, gamma-H2AX, and PAR expression at each time point and evaluate changes between pre- and post-treatment measurements. A paired t-test will be used to determine if there is a statistically significant change.
Time frame: Baseline to up to 30 days after completion of study treatment
Pharmacokinetics of RNR inhibitor COH29
COH29 levels in plasma will be quantitated using a validated High Performance Liquid Chromatography (HPLC) tandem mass spectrometry (LC-MS/MS) method. Summary statistics of the pharmacokinetic parameters for the population will be derived from the parameters obtained in individual patients.
Time frame: Pre-dose and 15 minutes, 30 minutes, 1, 2 , 3, 4, 6, 8, 24, and 168 hours post the day 1, course 1 dose
Toxicities according to the National Cancer Institute (NCI) CTCAE v 4.0
Toxicities will be tabulated by type and grade.
Time frame: Up to 30 days after completion of study treatment
Response rate
Response rate will be estimated in the overall population and 95% exact confidence intervals will be estimated.
Time frame: Up to 30 days after completion of study treatment
RR protein levels as assessed by automated quantitative analysis (AQUA)
Will be summarized descriptively using means, median, standard deviation and range.
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Time frame: Baseline