Clinical Trials /

Endoxifen in Adults With Hormone Receptor Positive Solid Tumors

NCT01273168

Description:

Background: - Some types of cancer cells that have hormone receptors on their surfaces need the hormone estrogen to grow. The drug tamoxifen blocks estrogen from binding to the tumor cells, which helps to slow or stop the growth of cancer. Tamoxifen has been approved for treatment of certain types of estrogen-linked cancers, such as breast and ovarian cancer. - The experimental drug Z-Endoxifen HCl (endoxifen) is related to tamoxifen, and has been shown to work against similar estrogen-linked cancers. In many cancer patients, tamoxifen is turned into endoxifen by enzymes in the liver; however, not all people have the liver enzymes that can turn tamoxifen into endoxifen, which means that the drug cannot work properly. Taking certain other drugs at the same time as tamoxifen can also keep it from turning into endoxifen. Researchers are interested in determining whether endoxifen tablets are effective in slowing or stopping tumor growth in individuals whose hormone-linked tumors have not responded to standard treatment. Objectives: - To test the safety and effectiveness of daily endoxifen in individuals with hormone receptor positive solid tumors that have not responded to standard treatment. Eligibility: - Individuals at least 18 years of age who have been diagnosed with hormone receptor positive solid tumors (breast or other tumors), desmoid tumors, or gynecologic tumors that have not responded to standard treatment. Individuals with breast cancer must have had at least one prior chemotherapy regimen and one prior hormonal regimen for metastatic disease. Design: - Participants will be screened with a full medical history (including prior hormone use) and physical examination, as well as blood and urine tests, tumor imaging studies, and an eye examination. - Participants will take endoxifen tablets daily for 28-day cycles of treatment, and will be asked to keep a medication diary to record any side effects. - Participants will have regular clinic visits with blood and urine samples and imaging studies to evaluate the cancer's response to treatment. - Participants will continue to take endoxifen for as long as the cancer responds to the treatment.

Related Conditions:
  • Breast Carcinoma
  • Desmoid-Type Fibromatosis
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
  • Uterine Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Endoxifen in Adults With Hormone Receptor Positive Solid Tumors

Title

  • Brief Title: Endoxifen in Adults With Hormone Receptor Positive Solid Tumors
  • Official Title: Phase I Trial of Z-Endoxifen in Adults With Refractory Hormone Receptor-Positive Breast Cancer, Desmoid Tumors, Gynecologic Tumors, or Other Hormone Receptor-Positive Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT01273168

    ORG ID: 110061

    NCI ID: 11-C-0061

    Trial Conditions

    Hormone Receptor-Positive Breast

    Gynecologic

    Desmoid

    Hormone Receptor-Positive Neoplasms

    Trial Interventions

    Drug Synonyms Arms
    Z-Endoxifen 1

    Trial Purpose

    Background:

    - Some types of cancer cells that have hormone receptors on their surfaces need the
    hormone estrogen to grow. The drug tamoxifen blocks estrogen from binding to the tumor
    cells, which helps to slow or stop the growth of cancer. Tamoxifen has been approved
    for treatment of certain types of estrogen-linked cancers, such as breast and ovarian
    cancer.

    - The experimental drug Z-Endoxifen HCl (endoxifen) is related to tamoxifen, and has been
    shown to work against similar estrogen-linked cancers. In many cancer patients,
    tamoxifen is turned into endoxifen by enzymes in the liver; however, not all people
    have the liver enzymes that can turn tamoxifen into endoxifen, which means that the
    drug cannot work properly. Taking certain other drugs at the same time as tamoxifen can
    also keep it from turning into endoxifen. Researchers are interested in determining
    whether endoxifen tablets are effective in slowing or stopping tumor growth in
    individuals whose hormone-linked tumors have not responded to standard treatment.

    Objectives:

    - To test the safety and effectiveness of daily endoxifen in individuals with hormone
    receptor positive solid tumors that have not responded to standard treatment.

    Eligibility:

    - Individuals at least 18 years of age who have been diagnosed with hormone receptor
    positive solid tumors (breast or other tumors), desmoid tumors, or gynecologic tumors that
    have not responded to standard treatment.

    Individuals with breast cancer must have had at least one prior chemotherapy regimen and one
    prior hormonal regimen for metastatic disease.

    Design:

    - Participants will be screened with a full medical history (including prior hormone use)
    and physical examination, as well as blood and urine tests, tumor imaging studies, and
    an eye examination.

    - Participants will take endoxifen tablets daily for 28-day cycles of treatment, and will
    be asked to keep a medication diary to record any side effects.

    - Participants will have regular clinic visits with blood and urine samples and imaging
    studies to evaluate the cancer's response to treatment.

    - Participants will continue to take endoxifen for as long as the cancer responds to the
    treatment.

    Detailed Description

    BACKGROUND:

    - Genetic polymorphisms in CYP2D6 and concomitant medications alter tamoxifen metabolism,
    limiting exposure to the active metabolite endoxifen. These factors are associated with
    a higher rate of recurrence and shorter disease-free survival in breast cancer patients
    receiving tamoxifen.

    - Administration of endoxifen directly to patients is anticipated to bypass the effects
    of CYP2D6 polymorphisms and concomitant medications and provide adequate active drug
    levels in all treated patients, resulting in clinical benefit.

    - 16 alpha-[(18)F]-fluoro-17 beta estradiol (FES) is an investigational radiolabeled
    imaging agent used with positron emission tomography (PET) to investigate tumor
    estrogen receptor activity

    OBJECTIVES:

    - Establish the safety and tolerability of oral endoxifen (Z-Endoxifen HCl) administered
    on a daily schedule to patients with refractory hormone receptor positive solid
    tumors (breast or other tumors), desmoid tumors, or gynecologic tumors.

    - Establish the maximum tolerated dose (MTD) of oral Z-endoxifen administered on a daily
    schedule.

    - Determine the pharmacokinetics of oral Z-endoxifen.

    - Evaluate the change in [(18)F]FES uptake using PET/CT in hormone receptor-positive
    tumors before and after treatment with oral Z-endoxifen.

    ELIGIBILITY:

    - Adults with histologically documented hormone receptor positive solid tumors (breast
    or other tumors), desmoid tumors, or gynecologic tumors.

    - Patients with breast cancer must have had at least one prior chemotherapy regimen and
    one prior hormonal regimen for metastatic disease. All other patients must have disease
    that has progressed following at least one line of standard therapy.

    - No major surgery, radiation, hormonal, or chemotherapy within 4 weeks prior to study
    enrollment, and recovered from toxicities of prior therapies to at least eligibility
    levels.

    - Patients in the 6-patient expansion cohort at the MTD will be asked to undergo optional
    tumor biopsies for research purposes.

    STUDY DESIGN:

    - Z-endoxifen will be administered orally once a day in 28-day cycles.

    - Dose escalation will proceed until the MTD is established. Six additional patients will
    be entered at the MTD to assess pharmacodynamics.

    - When imaging agent is available, optional FES PET/CT scans will be performed at
    baseline and 1-3 hours after Z-endoxifen treatment once during week 1 of cycle 1.

    Trial Arms

    Name Type Description Interventions
    1 Experimental Z-endoxifen will be administered orally once a day in 28-day cycles Z-Endoxifen

    Eligibility Criteria

    - INCLUSION CRITERIA:

    Patients with the following types of histologically documented solid tumors:

    - ER +/PR+, ER+/PR-, or ER-/PR+ breast cancer

    - Gynecologic tumors (endometrial, ovarian, uterine, fallopian tube, peritoneal, etc.)

    - Desmoid tumors

    - Tumors that are ER+ or PR+ by immunohistochemistry (including low-level expression)
    such as non-small cell lung, colorectal, and prostate

    Patients with breast cancer must have had at least one prior chemotherapy regimen for
    metastatic disease. Additionally, patients with breast cancer must have received prior
    tamoxifen and/or aromatase inhibitor therapy (if postmenopausal) with at least one
    hormonal regimen in the metastatic setting. Patients with HER2+ breast cancer must have
    progressed after at least one prior HER2-directed regimen (trastuzumab, lapatinib) for
    metastatic disease.

    All other patients must have disease that has progressed following at least one line of
    standard therapy. Prior therapy with tamoxifen is allowed.

    Patients enrolled based on tumor ER/PR status must have ER/PR status confirmed by the
    Laboratory of Pathology, NIH. ER/PR status will be determined on a metastatic site, if
    possible; otherwise, the original site or available tissue will be acceptable.

    Patients must have recovered to at least eligibility levels following any display of
    adverse events and/or toxicity due to prior chemotherapy or biologic therapy. They must
    not have had hormonal therapy, chemotherapy or biologic therapy within 4 weeks prior to
    entering the study (6 weeks for nitrosoureas or mitomycin C, or UCN-01). Patients must be
    greater than or equal 2 weeks since any prior administration of study drug in a Phase 0
    study (also referred to as an "early Phase I study" or "pre-Phase I study" where a
    sub-therapeutic dose of drug is administered) at the PI's discretion. Patients must be
    greater than or equal to 4 weeks since any prior radiation or major surgery. However,
    patients receiving bisphosphonates or therapeutic anticoagulation are eligible for this
    trial.

    Age greater than or equal 18 years

    The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2

    Life expectancy > 3 months

    Patients must have normal or adequate organ and marrow function as defined below:

    Absolute neutrophil count greater than or equal to 1,500/microL

    Platelets greater than or equal to 100,000/micorL

    Total bilirubin within less than or equal to 1.5 times institutional upper limit of normal

    AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit of normal

    Creatinine < 1.5 times upper limit of normal

    OR

    Creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
    creatinine levels greater than or equal to 1.5 times upper limit of normal.

    The effects of Z-endoxifen on the developing human fetus are unknown. For this reason,
    women of childbearing potential and men must agree to use adequate nonhormonal
    contraception (barrier method of birth control or abstinence) prior to study entry, for
    the duration of study participation, and for 2 months after discontinuation from the
    study. Women of childbearing potential must have a negative pregnancy test in order to be
    eligible. Should a woman become pregnant or suspect she is pregnant while participating in
    this study, she should inform her treating physician immediately. Because there is an
    unknown but potential risk for adverse events in nursing infants secondary to treatment of
    the mother with Z-endoxifen, breastfeeding should be discontinued if the mother is treated
    with Z-endoxifen.

    Ability to understand and the willingness to sign a written informed consent document.

    EXCLUSION CRITERIA:

    Patients receiving any other investigational agents.

    Patients with known brain metastases are excluded from this clinical trial, with the
    exception of patients whose brain metastatic disease status has remained stable for
    greater than or equal to 3 months after treatment of the brain metastases, without
    steroids or anti-seizure medications. These patients may be enrolled at the discretion of
    the principal investigator.

    Patients with clinically significant illnesses which could compromise participation in the
    study, including, but not limited to, uncontrolled infection, uncontrolled diabetes,
    uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris,
    myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia,
    stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social
    situations that in the investigator s opinion would make it undesirable for the patient
    to participate in the trial, or which would jeopardize compliance with the protocol.

    Patients with untreated spinal cord metastases or metastases close to vital organs (as
    determined by the principal investigator) are excluded because of the risk of hormonal
    flare.

    Patients with a history of deep vein thrombosis must be on anti-coagulation therapy prior
    to enrollment. Patients requiring prophylactic anti-coagulation are eligible.

    Patients with hypertension not controlled by medical therapy (hypertension defined as
    systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal
    medical management).

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Establish safety and MTD of Z-endoxifen

    Secondary Outcome Measures

    Determine the pharmacokinetics of oral Z-endoxifen.

    Trial Keywords

    Pharmacokinetics

    Advanced Cancer

    Cytochrome P 450

    Selective Estrogen Receptor Modulator

    Tamoxifen Metabolite

    Gynecologic Cancer

    Breast Cancer

    Desmoid Tumor

    Endometrial Cancer

    Ovarian Cancer

    Uterine Cancer

    Fallopian Tube Cancer

    Peritoneal Cancer