Endoxifen in Adults With Hormone Receptor Positive Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01273168
First received: January 7, 2011
Last updated: July 11, 2014
Last verified: June 2014
  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.

Condition Intervention Phase
Hormone Receptor-Positive Breast
Gynecologic
Desmoid
Hormone Receptor-Positive Neoplasms
Drug: Z-Endoxifen
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Establish safety and MTD of Z-endoxifen [ Time Frame: 28 days (1 cycle) ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Determine the pharmacokinetics of oral Z-endoxifen. [ Time Frame: 28 days (1 cycle) ] [ Designated as safety issue: No ]

Estimated Enrollment: 72
Study Start Date: December 2010
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Z-Endoxifen
    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
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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01273168

Contacts
Contact: Jennifer H Zlott (301) 435-5664 zlottjh@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01273168     History of Changes
Other Study ID Numbers: 110061, 11-C-0061
Study First Received: January 7, 2011
Last Updated: July 11, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
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

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Fibromatosis, Aggressive
Neoplasms by Site
Breast Diseases
Skin Diseases
Fibroma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Hormones
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Hormone Antagonists

ClinicalTrials.gov processed this record on August 26, 2014