Study of 4-Demethyl-4-cholesteryloxycarbonylpenclome (DM-CHOC-PEN) in Patients With Brain Tumors
Condition: Primary Brain Tumors; Metastatic Malignant Neoplasm to Brain
MeSH terms: Brain Neoplasms; Neoplasms
Intervention: 4-Demethyl-4-cholestryloxycarbonylpenclomedine
Intervention description: This will be an open-label, uncontrolled two-arm, multi-center study in patients with CNS involvement from melanoma, breast, lung cancers or primary malignancies of the CNS. Patients can be previously treated with radiation and systemic therapies and are eligible if they also have other sites of cancer involvement.
Two Cohorts of patients will be treated every 21 days with a single infusion of DM-CHOC-PEN as an out-patient:
Cohort 1: Patients with liver involvement or history of disease will be treated at a dose of 85.8 mg/m2 and;
Cohort 2: Patients without liver involvement or history of liver disease, will be treated at a dose of 98.7 mg/m2.
Patients in both cohorts will discontinue dosing with DM-CHOC-PEN when there are any unacceptable toxicities, progression of cancer or patient compliance.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: DM-CHOC-PEN; CNS; brain; melanoma; lung cancer; breast cancer; glioblastoma multiforme; primary brain tumors

Summary:

      DM-CHOC-PEN is a polychlorinated pyridine cholesteryl carbonate that has demonstrated
      antineoplastic activities in patients with advanced cancers - melanoma, lung, breast and
      glioblastoma multiforme (GBM) involving the CNS during a Phase I study. These findings
      support the preclinical responses seen in mice bearing intracerebrally implanted human breast
      and GBM tumor xenografts. Toxicity was acceptable - hyperbilirubinemia (in patients with
      liver disease and/or liver metastasis). No hematological, renal, cardiovascular, behavioral
      or cognitive impairment/neurotoxicities were noted during the Phase I human trial or in
      previous pre-clinical studies.

      The drug is available for use as a soy bean oil/egg yolk lecithin/glycerin water emulsion;
      the latter continues to be chemically and biologically stable and safe.

      Patients with advanced lung, breast and melanoma cancers spread to the CNS and primary CNS
      malignancies will be eligible for enrollment and treatment, providing the required blood and
      other eligibility requirements are met. The trial will be 2-tiered - patients with liver
      involvement vs. non-liver involvement will be treated with different doses of the drug.

      The trial is open and patients are currently being enrolled and treated with the protocol.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients must have histological proof of a cancer - melanoma, breast, or lung cancer -
             which has spread to the CNS or glioblastoma (GBM) or other primary malignant neoplasm
             of the CNS which has been treated with standard treatments, which may include
             radiation, and must be measurable (RECIST).

          -  Patients must have life expectancy of at least 12 weeks and a Karnofsky performance
             score: > 60 % (or a Zubrod performance status of < 2).

          -  The age limit - 18 or older. Gender is not a criterion.

          -  All patients must be off previous chemo- and/or radiotherapy for at least three (3)
             weeks prior to entrance into the study and have recovered from any toxic effects
             induced by such treatment(s); no nitrosourea type drug or ipilumimab treatments are
             permitted within the last six (6) weeks prior to enrollment. No major surgery within
             14 days of enrollment. Patients may continue to receive anti-estrogen/steroid therapy
             that has been initiated at least eight weeks prior to enrollment in the study.

          -  Patients should have adequate bone marrow function defined as a peripheral WBC
             >3,000/mm3 with an ANC >1500/mm3 and a platelet count >100,000/mm3.

          -  Patients should have hepatic function (alkaline phosphatase, AST and ALT) < ULN and
             renal functions with serum creatinine - <1.5 x UNL. If a patient has liver metastasis
             and/or a history of liver disease - they will receive a lower dose of the drug per
             treatment protocol.

          -  Patients should not be allergic to eggs or soy beans. Patients must be medically,
             psychologically and neurologically stable and have triplicate baseline ECG's with a
             mean QTc interval <500 ms and >300 ms and neither a history of congenital prolonged or
             short QT syndrome. Patients with a history of cardiac disease must be stable.

          -  Patients must understand the nature of the study and be willing to sign an informed
             consent that complies with the investigator/DEKK-TEC policies and approved by the
             Human Investigation Review Committee. Patients must have CNS involvement - from a
             malignancy. Lung cancer may be either small cell or non-small cell.

        Exclusion Criteria:

          -  Patients with concurrent severe and/or uncontrolled medical co-morbidities - including
             active infections, unstable uncontrolled diabetes, cardiovascular and pulmonary,
             renal, psychiatric or social conditions that could compromise the safety or compliance
             of treatment are not eligible.

          -  Concomitant chemotherapy or radiotherapy is not permitted.

          -  Pregnant or lactating females are excluded. Women of childbearing age, and their
             sexual partners, must use an effective contraception program. Males who are having
             sexual relations with women capable of child bearing must use the barrier birth
             control while on the study and for 3- months after the last dose of the study drug.

          -  Patients taking CYP3A4 inducers or inhibitors are not eligible since it is not known
             whether the study drug is metabolized through this pathway. The following CYP3A4
             inhibitors/inducers are not permitted during the trial - the azole antifungal -
             fluconazole, erythromycin, phenobarbital, verapamil.

          -  Patients taking the following medications may experience QT/QTc interval prolongation
             and are not eligible for the trial - most anti-arrhythmia drugs (incl. amiodarone),
             erythromycin, quinolone antibiotics, ketoconazole, Zithromax, and phenothiazine and
             will be denied enrollment in the study. The possible interactions of these drugs and
             DM-CHOC-PEN have not been established. Patients receiving these drug will only be
             eligible if they discontinue the drugs and have an acceptable ECG.

          -  Coagulopathies - patients requiring full dose anticoagulation with warfarin are
             excluded, however, patients stable and on other anticoagulants can be included.