Clinical Trials /

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

NCT02112565

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 14023
  • SECONDARY ID: NCI-2014-00708
  • SECONDARY ID: 14023
  • NCT ID: NCT02112565

Conditions

  • Unspecified Adult Solid Tumor, Protocol Specific

Interventions

DrugSynonymsArms
RNR inhibitor COH29COH29, ribonucleotide reductase holoenzyme inhibitor COH29Treatment (RNR inhibitor COH29)

Purpose

This phase I trial studies the side effects and best dose of 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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (RNR inhibitor COH29)ExperimentalPatients receive RNR inhibitor COH29 PO BID on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • RNR inhibitor COH29

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Changes in plasma biomarker expression levels
Time Frame:Baseline to up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Toxicities according to the National Cancer Institute (NCI) CTCAE v 4.0
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Toxicities will be tabulated by type and grade.
Measure:Response rate
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:Response rate will be estimated in the overall population and 95% exact confidence intervals will be estimated.
Measure:RR protein levels as assessed by automated quantitative analysis (AQUA)
Time Frame:Baseline
Safety Issue:
Description:Will be summarized descriptively using means, median, standard deviation and range.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

March 10, 2017