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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Thymoma, Thymic Carcinoma

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Trial Information

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


- 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

- Belinostat alterations in target protein levels due to gene expression changes may
allow increased sensitivity of cancer cells to conventional chemotherapy.


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

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)


- Patients with histologically confirmed advanced thymic malignancies who are
chemotherapy na ve.

- Measurable disease by RECIST criteria

- Adequate renal, hepatic and hematopoietic function


- 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

- 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.

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

2. Patients must be chemotherapy na ve for the treatment of advanced thymic

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


- 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


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

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

Inclusion of Women and Minorities

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


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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Arun Rajan, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

March 2010

Completion Date:

July 2013

Related Keywords:

  • Thymoma
  • Thymic Carcinoma
  • Thymic
  • Thymome
  • Chemotherapy
  • PXD101 (Bellinostat)
  • Thymic Cancer
  • Thymoma
  • Carcinoma
  • Thymoma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
Massachusetts General Hospital Boston, Massachusetts  02114-2617