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

• Sponsor: CicloMed LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03348514
• Collaborator: Cmed Clinical Services (Other)
• Enrollment: 19
• Locations: 5
• Arms: 8
• Actual Duration (Months): 28.5
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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.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: Jan 15, 2018
• Actual Primary Completion Date: May 31, 2020
• Actual Study Completion Date: May 31, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities (DLTs) of CPX-POM [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 [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. [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. [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. [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. [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. [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. [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. [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. [Days 5-6]

   Measure urine CPX concentration (uM)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

10. 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.

11. 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.

12. 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

6. If female, patient is pregnant or breast-feeding.

7. Patient has evidence of a serious active infection (e.g., infection requiring treatment with intravenous antibiotics).

8. Patient has active Hepatitis A infection.

9. 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.

10. 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.

11. Patient is taking warfarin.

12. 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.

13. Patient has known allergy or hypersensitivity to components of CPX-POM.

14. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarah Cannon Research Institute	Denver	Colorado	United States	80218
2	Florida Cancer Specialists & Research Institute	Sarasota	Florida	United States	34232
3	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
4	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
5	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• CicloMed LLC
• Cmed Clinical Services

Investigators

• Principal Investigator: John A Taylor III, MD, MSc, University of Kansas Medical Center

Study Documents (Full-Text)

• Study Protocol - Aug 6, 2018
• Statistical Analysis Plan - Feb 2, 2018

More Information

Publications

None provided.

• Responsible Party: CicloMed LLC
• ClinicalTrials.gov Identifier: NCT03348514
• Other Study ID Numbers: CPX-POM-01-001
• First Posted: Nov 21, 2017
• Last Update Posted: Dec 3, 2021
• Last Verified: Dec 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neoplasms

Study Results

Participant Flow

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Period Title: Overall Study
STARTED	1	1	1	1	3	4	6	2
COMPLETED	1	1	1	1	3	4	6	2
NOT COMPLETED	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2	Total
Arm/Group Description	Period1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2	Total of all reporting groups
Overall Participants	1	1	1	1	3	4	6	2	19
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	46	62	76	61	54	63	60	82.5	63
Sex: Female, Male (Count of Participants)
Female	0 0%	1 100%	1 100%	1 100%	2 66.7%	4 100%	4 66.7%	0 0%	13 68.4%
Male	1 100%	0 0%	0 0%	0 0%	1 33.3%	0 0%	2 33.3%	2 100%	6 31.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	1 5.3%
White	1 100%	1 100%	1 100%	1 100%	3 100%	4 100%	5 83.3%	2 100%	18 94.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Cancer type (Count of Participants)
Colon	0 0%	1 100%	0 0%	0 0%	0 0%	2 50%	2 33.3%	0 0%	5 26.3%
Bladder	0 0%	0 0%	1 100%	0 0%	1 33.3%	0 0%	0 0%	0 0%	2 10.5%
Breast	0 0%	0 0%	0 0%	0 0%	0 0%	1 25%	1 16.7%	0 0%	2 10.5%
Gastric	1 100%	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	2 10.5%
Head and Neck	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	1 5.3%
Liver	0 0%	0 0%	0 0%	1 100%	0 0%	0 0%	0 0%	0 0%	1 5.3%
Ovarian	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	1 5.3%
Prostate	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 50%	1 5.3%
Other	0 0%	0 0%	0 0%	0 0%	1 33.3%	1 25%	1 16.7%	1 50%	4 21.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs) of CPX-POM
Description	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.
Time Frame	Up to 22 days for each cohort

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	2
Grade 3	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 50%
Grade 1	0 0%	0 0%	0 0%	0 0%	0 0%	2 50%	2 33.3%	0 0%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least one dose of CPX-POM either at 30 mg/m^2, 60 mg/m^2, 120 mg/m^2, 240 mg/m^2, 360 mg/m^2, 600 mg/m^2, 900 mg/m^2 and 1200 mg/m^2 via IV.
Measure Participants	19
Number [mg/m^2]	900

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Cohort Dose - 120 mg/m^2	Period 4, Cohort Dose - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Mean (Standard Deviation) [ng/mL]	371	1935	3491	6792	5297 (1182)	9457 (512)	17277 (1913)	15970

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Mean (Standard Deviation) [hours]	2.34	0.54	5.56	3.34	3.12 (1.34)	4.61 (1.46)	8.30 (2.63)	7.43

5. Secondary Outcome

Title	Assess Plasma PK: AUCss (ng/mL/hr) of the Active Metabolite, Ciclopirox (CPX), Following Five Consecutive Days of Once Daily Dosing.
Description	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.
Time Frame	Days 5-6

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Single Dose AUCs	589	1262	3736	4622	4731 (1310)	11914 (1852)	24148 (6067)	34470
Steady State AUCss	515	1328	5143	6000	4856 (910)	12484 (1182)	23414 (1913)	28048

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Single Dose Cls	614	581	361	515	1065 (435)	507 (95)	432 (142)	375
Steady State Cls	702	552	262	397	963 (271)	471 (113)	421 (184)	456

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Vd	2370	429	2100	1966	4522 (2715)	3090 (1015)	5340 (3935)	4887
Vss	2053	473	1633	736	1986 (802)	1346 (349)	2261 (1249)	2518

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic data not obtained in one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	4	6	1
Mean (Standard Deviation) [ratio]	0.86	1.05	1.59	1.30	1.08 (0.14)	1.09 (0.17)	1.03 (0.29)	0.81

9. Secondary Outcome

Title	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.
Description	Measure Percent Dose (%)
Time Frame	Days 5-6

Outcome Measure Data

Analysis Population Description

Urine pharmacokinetic data not obtained in one patient receiving 600 mg/m^2 and one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	3	6	1
% CPX-POM Dose Excreted as CPX-POM over 24 hours	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
% CPX-POM Dose Excreted as ciclopirox over 24 hours	0.81	0.82	1.74	1.25	0.80 (0.21)	1.21 (0.11)	4.42 (4.68)	2.89
% CPX-POM Dose Excreted as ciclopirox glucuronide over 24 hours	59.74	69.73	70.21	73.86	75.99 (10.40)	50.70 (29.28)	69.62 (15.16)	68.19

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Urine pharmacokinetic data not obtained in one patient receiving 600 mg/m^2 and one patient receiving 1200 mg/m^2

Arm/Group Title	CPX-POM - 30 mg/m^2	CPX-POM - 60 mg/m^2	CPX-POM - 120 mg/m^2	CPX-POM - 240 mg/m^2	CPX-POM - 360 mg/m^2	CPX-POM - 600 mg/m^2	CPX-POM - 900 mg/m^2	CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2	Period 2, Dose Cohort - 60 mg/m^2	Period 3, Dose Cohort - 120 mg/m^2	Period 4, Dose Cohort - 240 mg/m^2	Period 5, Dose Cohort - 360 mg/m^2	Period 6, Dose Cohort - 600 mg/m^2	Period 7, Dose Cohort - 900 mg/m^2	Period 8, Dose Cohort - 1200 mg/m^2
Measure Participants	1	1	1	1	3	3	6	1
Mean (Standard Deviation) [uM]	0.65	0.84	10.77	3.93	5.10 (0.86)	22.91 (12.83)	138.17 (157.97)	208.65

Adverse Events

Time Frame	28 days
Arm/Group Title	CPX-POM - 30 mg/m^2		CPX-POM - 60 mg/m^2		CPX-POM - 120 mg/m^2		CPX-POM - 240 mg/m^2		CPX-POM - 360 mg/m^2		CPX-POM - 600 mg/m^2		CPX-POM - 900 mg/m^2		CPX-POM - 1200 mg/m^2
Arm/Group Description	Period 1, Dose Cohort - 30 mg/m^2		Period 2, Dose Cohort - 60 mg/m^2		Period 3, Dose Cohort - 120 mg/m^2		Period 4, Dose Cohort - 240 mg/m^2		Period 5, Dose Cohort - 360 mg/m^2		Period 6, Dose Cohort - 600 mg/m^2		Period 7 Dose Cohort - 900 mg/m^2		Period 8, Dose Cohort - 1200 mg/m^2
All Cause Mortality
	CPX-POM - 30 mg/m^2		CPX-POM - 60 mg/m^2		CPX-POM - 120 mg/m^2		CPX-POM - 240 mg/m^2		CPX-POM - 360 mg/m^2		CPX-POM - 600 mg/m^2		CPX-POM - 900 mg/m^2		CPX-POM - 1200 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/1 (0%)		0/1 (0%)		0/1 (0%)		0/3 (0%)		0/4 (0%)		0/6 (0%)		0/2 (0%)
Serious Adverse Events
	CPX-POM - 30 mg/m^2		CPX-POM - 60 mg/m^2		CPX-POM - 120 mg/m^2		CPX-POM - 240 mg/m^2		CPX-POM - 360 mg/m^2		CPX-POM - 600 mg/m^2		CPX-POM - 900 mg/m^2		CPX-POM - 1200 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/1 (0%)		0/1 (0%)		0/1 (0%)		1/3 (33.3%)		3/4 (75%)		1/6 (16.7%)		1/2 (50%)
Cardiac disorders
Bradycardia	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Gastrointestinal disorders
Abdominal Pain	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Infections and infestations
Pneumonia	1/1 (100%)	1	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/2 (0%)	0
Meningitis bacterial	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Pneumococcal sepsis	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Sepsis	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Investigations
Hyperbilirubinaemia	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Psychiatric disorders
Confusional State	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	1/2 (50%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Haemoptysis	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/6 (0%)	0	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	CPX-POM - 30 mg/m^2		CPX-POM - 60 mg/m^2		CPX-POM - 120 mg/m^2		CPX-POM - 240 mg/m^2		CPX-POM - 360 mg/m^2		CPX-POM - 600 mg/m^2		CPX-POM - 900 mg/m^2		CPX-POM - 1200 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)		1/1 (100%)		1/1 (100%)		1/3 (33.3%)		3/4 (75%)		6/6 (100%)		1/2 (50%)
Eye disorders
Vision blurred	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Gastrointestinal disorders
Vomiting	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	4/6 (66.7%)	4	1/2 (50%)	1
Nausea	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	1/1 (100%)	1	1/3 (33.3%)	1	2/4 (50%)	2	1/6 (16.7%)	1	0/2 (0%)	0
Constipation	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/2 (0%)	0
Dry mouth	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Glossodynia	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Stomatitis	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Toothache	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
General disorders
Fatigue	0/1 (0%)	0	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Chills	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Feeling hot	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Non cardiac chest pain	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Injury, poisoning and procedural complications
Infusion related reaction	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	1/2 (50%)	1
Procedural dizziness	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/6 (0%)	0	0/2 (0%)	0
Hyperglycaemia	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Musculoskeletal and connective tissue disorders
Muscle twitching	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Muscular weakness	0/1 (0%)	0	0/1 (0%)	0	1/1 (100%)	1	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	0/2 (0%)	0
Musculoskeletal pain	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Neck pain	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Nervous system disorders
Amnesia	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	1/2 (50%)	1
Dizziness	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	1/2 (50%)	1
Somnolence	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/6 (16.7%)	1	0/2 (0%)	0
Dysarthria	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/6 (0%)	0	1/2 (50%)	1
Headache	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Taste Disorder	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Psychiatric disorders
Confusional state	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	2/6 (33.3%)	2	1/2 (50%)	1
Disorientation	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/6 (0%)	0	0/2 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	0/2 (0%)	0
Vascular disorders
Flushing	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/1 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/6 (16.7%)	1	1/2 (50%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.