RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I, Dose-Escalation, Safety and Tolerability Study of COH29 in Patients With Solid Tumors Refractory to Standard Therapy or for Which No Standard Therapy Exists

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: RNR inhibitor COH29
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients must have the ability to understand and the willingness to sign a written informed consent Life expectancy of greater than 3 months by physician assessment Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Patients must have histologically or cytologically confirmed (at original diagnosis or subsequent recurrence or progression) solid tumor that is metastatic, unresectable, progressive, or recurrent, and for which standard curative or palliative measures do not exist or are no longer effective Patients must have measurable or evaluable disease Patients must not have received prior chemotherapy or radiation for < 4 weeks prior to start of study treatment Patients may be entered if they have received prior radiation therapy involving =< 30% of the bone marrow; any prior radiation therapy must have been administered >= 4 weeks prior to start of study treatment and the patient must be recovered from the acute toxic effects of the treatment prior to start of study treatment Patients may be enrolled with a history of treated brain metastases that are clinically stable for >= 4 weeks prior to start of study treatment Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; women of child-bearing age will undergo urine pregnancy testing prior to study enrollment; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Active breast-feeding is also not allowed on study enrollment Leukocytes >= 3,000 cells/µL Absolute neutrophil count >= 1,500 cells/µL Platelets >= 100, 000 cells/µL Total bilirubin =< 1.5 times the upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN; AST/ALT =< 5 x ULN if liver metastasis is present Serum creatinine =< 1.5 mg/dL or a measured creatinine clearance >= 50 mL/min Prothrombin time (PT)/international normalized ratio (INR)/ activated partial thromboplastin time (aPTT) =< 1.5 x ULN Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) Exclusion Criteria: Patients may not be receiving any other investigational agents; use of over-the-counter herbal medications will also be excluded Patients with uncontrolled undercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements Patients unable or unwilling to swallow pills Active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease or heart block, or uncontrolled congestive heart failure Patients with a history of noninfectious pneumonitis will be excluded during the dose-escalation phase of the trial Patients, who in the opinion of the investigator and another independent party, may not be able to adhere to the safety monitoring requirements of the study

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (RNR inhibitor COH29)<br>Patients receive RNR inhibitor COH29 PO BID on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: RNR inhibitor COH29<br>* Given PO<br>* Other names: ribonucleotide reductase holoenzyme inhibitor COH29;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | Baseline |