A Phase 1/2 Study of PXD101 (Belinostat) in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Advanced or Recurrent Thymic, Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01100944
First received: March 18, 2010
Last updated: August 15, 2014
Last verified: August 2014
  Purpose

Background:

  • Tumors of the thymus are rare and can be treated with surgery, but it is often difficult to determine whether a thymic tumor is malignant based on biopsy alone and the long-term survival rate is less than 50 percent. Because thymic tumors are so rare, most treatment knowledge comes from a relatively small series of cases, and the choice of treatment usually depends on the hospital or clinic staff's experience and familiarity with a given chemotherapy and surgery regimen.
  • Belinostat is an investigational anticancer drug that has not yet been approved by the Food and Drug Administration for use in any cancer. Researchers are interested in determining whether belinostat can be combined with conventional chemotherapy to safely and effectively treat advanced thymic cancer.

Objectives:

  • To determine a safe and tolerable dose of belinostat that can be given in combination with cisplatin, doxorubicin, and cyclophosphamide.
  • To determine if belinostat (combined with the abovementioned standard chemotherapy regimen) is effective against thymic cancer cells.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with advanced or recurrent thymic malignancy that is not considered to be curable with surgery or radiation therapy, and who have not received previous chemotherapy treatment.

Design:

  • Participants will be screened with a physical exam, blood tests, and imaging studies as directed by the study researchers.
  • Participants will receive six 21-day cycles (18 weeks) of treatment with belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide. The treatment will require continuous infusion over 3 days, and participants will remain in the treatment center during this time. Participants will have regular blood tests, clinic visits, and imaging studies during the treatment period.
  • Participants who complete the six treatment cycles with no severe side effects may be offered the option to continue treatment with belinostat alone.
  • After the 18-week study period, participants will return for regular follow-up exams for at least 4 weeks, and will be asked to remain in contact with the study researchers once a year to continue to study long-term effects....

Condition Intervention Phase
Thymoma
Thymic Carcinoma
Drug: PXD101 cisplatin+doxorbicin+cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Ph I portion - to determine a safe and tolerable phase 2 dose, DLTs and preliminary activity for the combo of belinostat by continuous IV infusion (CIVI) w/cisplatin, doxorubicin and cyclophosphamide in patients w/advanced thymic malignancies. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • n the Phase II portion the primary objective will be to determine theclinical response rate (PR+CR) of belinostat in combination with cisplatin, doxorubicin and cyclophosphamide in the first line treatment of patients with advanced thymic mal... [ Time Frame: every 6 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine time to response, duration of response, progression free survival (PFS) and overall survival (OS). To determine the toxicity profile and safety of this combination. [ Time Frame: 2/1/2013 ] [ Designated as safety issue: Yes ]

Enrollment: 26
Study Start Date: March 2010
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
PXD101 will be given as a 48h CIVI starting on day 1, doxorubicin as a slow IV injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3. Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatmentwith PXD101 alone may continue until disease progression.
Drug: PXD101 cisplatin+doxorbicin+cyclophosphamide
PXD101 will be given as a 48h CIVI starting on day 1, doxorubicin as a slow IV injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3. Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatment with PXD101 alone may continue until disease progression.

Detailed Description:

Background:

  • New options for the treatment of patients with advanced thymoma and thymic carcinoma are needed.
  • Belinostat, N-hydroxy-3-(phenylsulphamoylphenyl) acrylamide, is a hydroxamic acid deacetylase inhibitor that is able to inhibit both HDAC Class I and II enzymes.
  • An ongoing phase II study of belinostat in recurrent or metastatic thymic malignancies has shown activity which warrants further consideration of belinostat in the first line.
  • Belinostat alterations in target protein levels due to gene expression changes may allow increased sensitivity of cancer cells to conventional chemotherapy.

Objectives:

Primary Objectives

  • In the Phase I portion the primary objective will be to determine a safe and tolerable phase 2 dose, DLTs and preliminary activity for the combination of belinostat by continuous IV infusion (CIVI) with cisplatin, doxorubicin and cyclophosphamide in patients with advanced thymic malignancies.
  • In the Phase II portion the primary objective will be to determine the clinical response rate (PR+CR) of belinostat in combination with cisplatin, doxorubicin and cyclophosphamide in the first line treatment of patients with advanced thymic malignancies.

Secondary Objectives

  • To determine time to response, duration of response, progression free survival (PFS) and overall survival (OS).
  • To determine the toxicity profile and safety of this combination.
  • To assess exploratory correlative markers in relation to response to treatment (immunohistochemistry and array CGH)

Eligibility:

  • Patients with histologically confirmed advanced thymic malignancies who are chemotherapy na(SqrRoot) ve.
  • Measurable disease by RECIST criteria
  • Adequate renal, hepatic and hematopoietic function

Design:

  • The Phase I portion of the study will consist of four dose levels and dose escalations will follow according to traditional 3 patient cohorts.
  • Once the maximum tolerated doe is determined, the phase II portion of the study will begin.
  • Belinostat will be given as a 48h CIVI starting on day 1, doxorubicin as a slow IV injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3.
  • Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatment with belinostat alone may continue until disease progression.
  Eligibility

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

-INCLUSION CRITERIA:

  1. Both the phase I and phase II portions of the protocol will be only open to patients with histologically confirmed advanced stage (Masaoka stage III or IV) thymic malignancies.
  2. Patients must be chemotherapy na(SqrRoot) ve for the treatment of advanced thymic malignancies.
  3. Age > 18 years.
  4. ECOG performance status < 2 (Karnofsky > 60%).
  5. Life expectancy of greater than 3 months.
  6. Patients must have normal organ and marrow function as defined below:

    • leukocytes > 3,000/mcL
    • absolute neutrophil count > 1,500/mcL
    • platelets > 100,000/mcL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) less than or equal to 5 times the institutional upper limit of normal with evidence of metastatic disease to the liver or less than or equal to 3 times the institutional upper limit of normal without evidence of metastatic disease to the liver
    • creatinine less than or equal to 1.5 times institutional upper limits of normal

    OR

    - creatinine clearance > 45 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.

  7. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan.
  8. Patients must have recovered from toxicity related to prior therapy (surgery or radiation) to grade less than or equal to 1 and must be at least 28 days since any prior radiation or major

    surgery.

    Target lesions cannot be selected within previously irradiated areas, if not newly arising or clearly progressing after irradiation as proven by repeat scanning.

  9. Concurrent corticosteroids for myasthenia gravis, or other paraneoplastic syndromes, or other chronic conditions are allowed.

    Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of belinostat or cisplatin, doxorubicin or cyclophosphamide will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications.

  10. The effects of belinostat on the developing human fetus are unknown. For this reason and because HDAC inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  11. Ability to understand and the willingness to sign a written informed consent document.

Inclusion of Women and Minorities

Both men and women of all races and ethnic groups are eligible for this trial

EXCLUSION CRITERIA:

  1. Patients who have had major surgery or radiotherapy within 3 weeks of enrollment.
  2. Patients may not be receiving any other investigational agents.
  3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 1 month without steroids may be enrolled at the discretion of the principal investigator.
  4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to belinostat or other agents used in study.
  5. Patients with prior treatment with drugs of the HDAC inhibitor class are excluded, except for valproic acid (VPA) where prior treatment is accepted as long as it is not within the last 2 weeks before enrolment.
  6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  7. Pregnant women are excluded from this study because belinostat is an HDAC inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with belinostat, breastfeeding should be discontinued if the mother is treated with belinostat. These potential risks may also apply to other agents used in this study.
  8. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with belinostat. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
  9. Marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval > 500 ms; Long QT Syndrome. Patients taking medications that may cause QTc prolongation will be eligible as long as they comply with the

    recommendations in appendix D.

  10. History of another invasive malignancy in the last five years. Adequately treated non-invasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed.
  11. Patients with tumor amenable to potentially curative therapy as assessed by the investigator.
  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: NCT01100944

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Investigators
Principal Investigator: Arun Rajan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01100944     History of Changes
Other Study ID Numbers: 100077, 10-C-0077
Study First Received: March 18, 2010
Last Updated: August 15, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Gene Expression
HDAC Class I and II enzymes
Thymoma
Chemotherapy
Hydroxamic Acid Deacetylase Inhibitor
Thymic Cancer

Additional relevant MeSH terms:
Thymoma
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Neoplasms
Thymus Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lymphatic Diseases
Belinostat
Cisplatin
Cyclophosphamide
Doxorubicin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014