RNR Inhibitor COH29 in Treating Patients With Solid Tumors That Are Refractory to Standard Therapy or For Which No Standard Therapy Exists
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|ClinicalTrials.gov Identifier: NCT02112565|
Recruitment Status : Active, not recruiting
First Posted : April 14, 2014
Last Update Posted : March 21, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Unspecified Adult Solid Tumor, Protocol Specific||Drug: RNR inhibitor COH29 Other: laboratory biomarker analysis Other: pharmacological study||Phase 1|
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.
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 (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||June 13, 2016|
|Actual Primary Completion Date :||November 23, 2018|
|Estimated Study Completion Date :||December 31, 2023|
Experimental: Treatment (RNR inhibitor COH29)
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
Other: laboratory biomarker analysis
Other: pharmacological study
Other Name: pharmacological studies
- 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 [ Time Frame: Baseline to up to 30 days after completion of study treatment ]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.
- Pharmacokinetics of RNR inhibitor COH29 [ 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 ]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.
- Toxicities according to the National Cancer Institute (NCI) CTCAE v 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]Toxicities will be tabulated by type and grade.
- Response rate [ Time Frame: Up to 30 days after completion of study treatment ]Response rate will be estimated in the overall population and 95% exact confidence intervals will be estimated.
- RR protein levels as assessed by automated quantitative analysis (AQUA) [ Time Frame: Baseline ]Will be summarized descriptively using means, median, standard deviation and range.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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)
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02112565
|United States, California|
|City of Hope Medical Center|
|Duarte, California, United States, 91010|
|Principal Investigator:||Vincent Chung||City of Hope Medical Center|
|Responsible Party:||City of Hope Medical Center|
|Other Study ID Numbers:||
NCI-2014-00708 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
14023 ( Other Identifier: City of Hope Medical Center )
|First Posted:||April 14, 2014 Key Record Dates|
|Last Update Posted:||March 21, 2023|
|Last Verified:||March 2023|