Clinical Trials /

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

NCT03348514

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Safety, Dose Tolerance, Pharmacokinetics, and Pharmacodynamics Study of CPX-POM in Patients With Advanced Solid Tumors
  • Official Title: 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).

Clinical Trial IDs

  • ORG STUDY ID: CPX-POM-01-001
  • NCT ID: NCT03348514

Conditions

  • Advanced Solid Tumors

Interventions

DrugSynonymsArms
CPX-POM"3+3" Dose Escalation Design

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Accelerated Escalation DesignExperimental
  • CPX-POM
"3+3" Dose Escalation DesignExperimental
  • CPX-POM

Eligibility Criteria

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

Primary Outcome Measures

Measure:Evaluate the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD)of CPX-POM
Time Frame:21 days
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:CicloMed LLC

Last Updated

August 29, 2020