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Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03348514
Recruitment Status : Completed
First Posted : November 21, 2017
Results First Posted : November 17, 2021
Last Update Posted : December 3, 2021
Sponsor:
Collaborator:
Cmed Clinical Services
Information provided by (Responsible Party):
CicloMed LLC

Brief Summary:
This is a first-in-human, Phase I, multicenter, open label, dose escalation study to evaluate the DLTs and MTD and to determine the recommended Phase 2 dose (RP2D) of CPX-POM administered IV in patients with any histologically- or cytologically-confirmed solid tumor type.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: CPX-POM - 30 mg/m^2 Drug: CPX-POM - 60 mg/m^2 Drug: CPX-POM - 120 mg/m^2 Drug: CPX-POM - 240 mg/m^2 Drug: CPX-POM - 360 mg/m^2 Drug: CPX-POM - 600 mg/m^2 Drug: CPX-POM - 900 mg/m^2 Drug: CPX-POM - 1200 mg/m^2 Phase 1

Detailed Description:

The study will initially employ an accelerated escalation design, with a single patient enrolled in each cohort (i.e., Single-Patient Cohorts). The initial patient will receive CPX-POM at a starting dose of 30 mg/m2. Doses will be escalated (doubling), until a ≥Grade 2 toxicity (with the exception of alopecia), is encountered. Subsequently that and all subsequent cohorts will follow a classical "3+3" dose escalation design.

Note: Fosciclopirox is the generic name for CPX-POM.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This is a Phase I, first-in-human, multicenter, open label, dose escalating study to evaluate the DLTs and MTD and to determine the recommended Phase 2 dose (RP2D) of CPX-POM administered IV in patients with any histologically- or cytologically-confirmed solid tumor type.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, First-in-Human, Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors.
Actual Study Start Date : January 15, 2018
Actual Primary Completion Date : May 31, 2020
Actual Study Completion Date : May 31, 2020

Arm Intervention/treatment
Experimental: CPX-POM - 30 mg/m^2 Drug: CPX-POM - 30 mg/m^2
CPX-POM

Experimental: CPX-POM - 60 mg/m^2 Drug: CPX-POM - 60 mg/m^2
CPX-POM

Experimental: CPX-POM - 120 mg/m^2 Drug: CPX-POM - 120 mg/m^2
CPX-POM

Experimental: CPX-POM - 240 mg/m^2 Drug: CPX-POM - 240 mg/m^2
CPX-POM

Experimental: CPX-POM - 360 mg/m^2 Drug: CPX-POM - 360 mg/m^2
CPX-POM

Experimental: CPX-POM - 600 mg/m^2 Drug: CPX-POM - 600 mg/m^2
CPX-POM

Experimental: CPX-POM - 900 mg/m^2 Drug: CPX-POM - 900 mg/m^2
CPX-POM

Experimental: CPX-POM - 1200 mg/m^2 Drug: CPX-POM - 1200 mg/m^2
CPX-POM




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLTs) of CPX-POM [ Time Frame: Up to 22 days for each cohort ]

    The primary objective of this study is to evaluate the dose limiting toxicities (DLTs) of ciclopirox phosphoryloxymethyl ester (CPX-POM) administered intravenously (IV) and establish the CPX POM dose recommended for further investigation.

    A DLT will include some Grade 3 or 4 AEs (as assessed by CTCAE version 4.03) if deemed related to study drug. In addition, any patient who is unable to receive 80% of the expected dose of CPX-POM (i.e., patients who are unable to receive at least 4 of the 5 scheduled doses) because of AEs will be considered to have a DLT.

    In order to identify any DLTs, safety assessments including AEs, physical examinations, vital signs, and clinical laboratory tests will be conducted during each study visit through Day 22.


  2. Determine the Maximum Tolerated Dose (MTD) of CPX-POM [ Time Frame: Days 1, 2, 3, 4, 5, 6, 10, 22 and 28 ]

    The primary objective of this study is to evaluate the maximum tolerated dose (MTD) of ciclopirox phosphoryloxymethyl ester (CPX-POM) administered intravenously (IV) and establish the CPX POM dose recommended for further investigation. MTD was determined by testing increasing doses up to 1200 mg/m^2 by IV.

    The MTD is defined as the dose BELOW that dose which causes DLTs in ≥33% of patients.



Secondary Outcome Measures :
  1. Assess Plasma PK: Cmax (ng/mL) of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure PK parameter Cmax (ng/mL)

  2. Assess Plasma PK: Terminal Half-life of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Determine Terminal Half-Life

  3. Assess Plasma PK: AUCss (ng/mL/hr) of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure PK parameter area-under-the-plasma-drug/metabolite-concentration-time curve (ng/mL/hr) following single dose (AUC) and at steady-state AUCss following single and repeat drug administration.

  4. Assess Plasma PK: Cls (mL/hr/kg) of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure PK parameter Cls (mL/hr/kg) - systemic clearance following single dose (Cls) following single and repeat drug administration.

  5. Assess Plasma PK: Vd and Vss (mL/kg) of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure PK parameters Vd (apparent volume of distribution) and Vss (steady state volume of distribution) (mL/kg)

  6. Characterize Plasma PK: AUCss/AUCi Accumulation Ratio of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Determine PK parameter AUC derived accumulation ratio (AUCss/AUCi ratio)

  7. Assess Urine PK: Percent (%) of the CPX-POM Dose Excreted in Urine as CPX-POM and Metabolites, Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure Percent Dose (%)

  8. Assess Urine PK: Average 24-hour Urine Concentration of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing. [ Time Frame: Days 5-6 ]
    Measure urine CPX concentration (uM)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria Include:

  1. Patient is male or female aged ≥18 years.
  2. Patient provided signed and dated informed consent prior to initiation of any study procedures.
  3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able to carry out all pre-disease activities without restriction) or 1 (unable to perform physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature).
  4. Patient has a predicted life expectancy of ≥3 months.
  5. Dose escalation cohorts only: Patient has adequate renal function (creatinine ≤1.5 × the upper limit of normal [ULN]) or a glomerular filtration rate (GFR) of ≥50 mL/min/1.73 m^2). Expansion cohort only: Patient has a GFR of ≥30 mL/min/1.73 m^2.
  6. Patient has adequate hepatic function, as evidenced by a total bilirubin ≤1.5 × ULN, aspartate transaminase (AST), and /or alanine transaminase (ALT) ≤3 × ULN or ≤5 ×ULN, if due to liver involvement by tumor.
  7. Patient has adequate bone marrow function, as evidenced by hemoglobin ≥9.0 g/dL in the absence of transfusion within the previous 72 hours, platelet count ≥100×10^9cells/L, and absolute neutrophil count (ANC) ≥1.5×10^9 cells/L.
  8. Patient has no significant ischemic heart disease or myocardial infarction (MI) within 6 months before the first dose of CPX-POM and currently has adequate cardiac function, as evidenced by a left ventricular ejection fraction of >50% as assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and corrected QT interval (QTc) <470 msec by Fridericia (QTcF). The eligibility of patients with ventricular pacemakers for whom the QT interval may not be accurately measurable will be determined on a case-by-case basis by the Sponsor in consultation with the Medical Monitor.
  9. Patient and his/her partner agree to use adequate contraception after providing written informed consent through 3 months after the last dose of CPX-POM, as follows:

    1. For women: Negative pregnancy test during Screening and at Day 1 of each treatment cycle and compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile or postmenopausal.
    2. For men: Compliant with a medically-approved contraceptive regimen during and for 3 months after the treatment period or documented to be surgically sterile. Men whose sexual partners are of child-bearing potential must agree to use 2 methods of contraception prior to study entry, during the study, and for 3 months after the treatment period.
  10. Patient is willing and able to participate in the study and comply with all study requirements.

Exclusion Criteria Include:

Patients who meet any of the following exclusion criteria are not to be enrolled in this study

  1. Patient has a history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or requires the use of concomitant medications that prolong the QT/QTc interval during study participation. Patients should not receive anti-emetic medications before and following Dose 1 of Cycle 1 for each treatment cohort. However, anti-emetics such as ondansetron or granisetron that have a mild QTc prolonging effect are allowed starting with Dose 2 of Cycle 1, if used with caution and attention to the approved labelling.
  2. Patient has an abnormal cardiac appearance/heart size, as evidenced by chest X-ray or computed tomography (CT) scan.
  3. Patient has an uncontrolled or severe intercurrent medical condition (including uncontrolled brain metastases). Patients with stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants, with no dose change within 4 weeks before the first dose of CPX-POM and no anticipated dose change, are allowed. The decision to exclude a patient from the study for an uncontrolled or severe intercurrent medical condition will be made by the Principal Investigator. Examples could include epilepsy, resistant infection, or any other neurological disease that would make clinical assessment difficult.
  4. Patient underwent major surgery within 4 weeks before the first dose of CPX-POM or received cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) or an drug or device within 4 weeks (6 weeks for mitomycin C and nitrosoureas) or 5 half-lives of that agent (whichever is shorter) before the first dose of CPX-POM. A minimum of 10 days between termination of the investigational drug and administration of CPX-POM is required. In addition, any drug-related toxicity, with the exception of alopecia, should have recovered to ≤Grade 1.
  5. If female, patient is pregnant or breast-feeding.
  6. Patient has evidence of a serious active infection (e.g., infection requiring treatment with intravenous antibiotics).
  7. Patient has active Hepatitis A infection.
  8. Patient known human immunodeficiency virus (HIV) or Hepatitis B or C infection, as such patients may be at increased risk for toxicity due to concomitant treatment and disease-related symptoms may preclude accurate assessment of the safety of CPX POM.
  9. Patient has an important medical illness or abnormal laboratory finding that, in the Investigator's opinion, would increase the risk of participating in this study.
  10. Patient is taking warfarin.
  11. Patient has a history of other malignancy treated with curative intent within the previous 5 years with the exception of adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix. Patients with previous invasive cancers are eligible if the treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.
  12. Patient has known allergy or hypersensitivity to components of CPX-POM.
  13. Patient is taking any iron replacement therapy administered IV, IM, or orally due to the potential for loss of anticancer activity due to drug and metabolites chelating iron.

Information from the National Library of Medicine

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): NCT03348514


Locations
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United States, Colorado
Sarah Cannon Research Institute
Denver, Colorado, United States, 80218
United States, Florida
Florida Cancer Specialists & Research Institute
Sarasota, Florida, United States, 34232
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Oklahoma
Stephenson Cancer Center
Oklahoma City, Oklahoma, United States, 73104
United States, Tennessee
Tennessee Oncology PLLC
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
CicloMed LLC
Cmed Clinical Services
Investigators
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Principal Investigator: John A Taylor III, MD, MSc University of Kansas Medical Center
  Study Documents (Full-Text)

Documents provided by CicloMed LLC:
Study Protocol  [PDF] August 6, 2018
Statistical Analysis Plan  [PDF] February 2, 2018

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: CicloMed LLC
ClinicalTrials.gov Identifier: NCT03348514    
Other Study ID Numbers: CPX-POM-01-001
First Posted: November 21, 2017    Key Record Dates
Results First Posted: November 17, 2021
Last Update Posted: December 3, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms