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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03348514
Recruitment Status : Recruiting
First Posted : November 21, 2017
Last Update Posted : November 26, 2019
Sponsor:
Collaborator:
Cmed Clinical Services
Information provided by (Responsible Party):
CicloMed LLC

Tracking Information
First Submitted Date  ICMJE November 15, 2017
First Posted Date  ICMJE November 21, 2017
Last Update Posted Date November 26, 2019
Actual Study Start Date  ICMJE January 15, 2018
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2017)
Evaluate the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD)of CPX-POM [ Time Frame: 21 days ]
The primary objective of this study is to evaluate the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD) 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 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. The MTD is defined as the dose BELOW that dose which causes DLTs in ≥33% of patients.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors
Official Title  ICMJE A Phase 1, First-in-Human, Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors. The First Part of the Study is Completed and the Expansion Study is Ongoing (Reference Inclusion/Exclusion Criteria).
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.
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group 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
Condition  ICMJE Advanced Solid Tumors
Intervention  ICMJE Drug: CPX-POM
CPX-POM
Study Arms  ICMJE
  • Experimental: Accelerated Escalation Design
    Intervention: Drug: CPX-POM
  • Experimental: "3+3" Dose Escalation Design
    Intervention: Drug: CPX-POM
Publications * Weir SJ, Wood R, Schorno K, Brinker AE, Ramamoorthy P, Heppert K, Rajewski L, Tanol M, Ham T, McKenna MJ, McCulloch W, Dalton M, Reed GA, Jensen RA, Baltezor MJ, Anant S, Taylor JA 3rd. Preclinical Pharmacokinetics of Fosciclopirox, a Novel Treatment of Urothelial Cancers, in Rats and Dogs. J Pharmacol Exp Ther. 2019 Aug;370(2):148-159. doi: 10.1124/jpet.119.257972. Epub 2019 May 21.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 17, 2017)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2020
Estimated Primary Completion Date May 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria Include:

  1. Dose escalation cohorts only: Patient has histologically- or cytologically- confirmed metastatic or advanced-stage solid malignant tumor that is refractory to standard therapy. Patients should only be included if no therapy exists or if they have already received all standard therapies that would be potentially curative or might provide significant benefit.
  2. Dose escalation cohorts only: Patient may have received up to 4 prior lines of cytotoxic chemotherapy or immunotherapy for their metastatic disease (e.g., docetaxel + doxorubicin ± cyclophosphamide), and also may have received additional prior endocrine therapy, as appropriate (e.g., for breast or prostate cancer), or non-myelosuppressive therapy (e.g., bevacizumab, trastuzumab).
  3. Dose escalation cohorts only: Patient has experienced progressive disease during or following or was intolerant of their most recent treatment regimen. Supporting information about prior progressive disease will be collected, if available.
  4. Patient is male or female aged ≥18 years.
  5. Patient provided signed and dated informed consent prior to initiation of any study procedures.
  6. 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).
  7. Patient has a predicted life expectancy of ≥3 months.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. Patient is willing and able to participate in the study and comply with all study requirements.
  14. Expansion cohort only: Patients must have histologically confirmed MIBC (≥T2, N0-N1, M0 per AJCC) pure or mixed histology urothelial carcinoma. Clinical node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined to the true pelvis and are within the planned surgical LN dissection template.
  15. Expansion cohort only: The initial TURBT that showed muscularis propria invasion should be within 8 weeks prior to beginning study therapy, when feasible. There must be adequate evaluable tumor burden in the tissue blocks (from initial or repeat TURBT with highest tumor content) to allow for analysis as determined by the local site pathologist.
  16. Expansion cohort only: Patients must be ineligible for cisplatin-based chemotherapy due to any of the following:

    1. Creatinine clearance(CrCl) <60 mL/min with Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
    2. Hearing impaired ≥ Grade 2 by CTCAE criteria
    3. Neuropathy ≥ Grade 2 by CTCAE criteria
    4. Heart failure New York Heart Association (NYHA) ≥ III

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.

Exclusion criteria for Expansion cohort:

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

  1. Baseline GFR <30 mL/min/1.73 m^2.
  2. Women must not be pregnant or breastfeeding since we do not know the effects of CPX-POM on the fetus or breastfeeding child.
  3. Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
  4. Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances:

    1. Not currently active and diagnosed at least 3 years prior to the date of registration.
    2. Non-invasive diseases such as low risk cervical cancer or any cancer in situ.
    3. Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated.( (e.g. low/intermediate risk prostate cancer, etc.).
  5. Patients may not have undergone major surgery with the exception of TURBT (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
  6. Patients must not have clinically significant cardiac disease.
  7. Patients may not have chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV).
  8. Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion.
  9. Patients may not have known diagnosis of any condition (e.g. post-hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
  10. Patients with any serious and/or uncontrolled concurrent medical conditions (e.g.., active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that could, in the investigator's opinion, cause unacceptable safety risks or potentially interfere with the completion of the treatment according to the protocol are not eligible.
  11. Patients may not have any live viral vaccine used for prevention of infectious diseases within 4 weeks prior to study drug(s).
  12. Patients unwilling or unable to comply with the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03348514
Other Study ID Numbers  ICMJE CPX-POM-01-001
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party CicloMed LLC
Study Sponsor  ICMJE CicloMed LLC
Collaborators  ICMJE Cmed Clinical Services
Investigators  ICMJE
Principal Investigator: John Taylor Kansas Univeristy Medical Center
PRS Account CicloMed LLC
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP