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Thymoma

Thymus Neoplasms

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Cyclophosphamide

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Enzyme Inhibitors

Histone Deacetylase Inhibitors

PXD101 (Belinostat) will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (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. A conventional 3+3 dose escalation design was used with up to 3 additional patients added if one patient exhibited a dose limiting toxicity (DLT). Dose escalation was halted if at least 2 out of a maximum of 6 patients within a cohort exhibited a DLT.

PXD101 will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (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.

PXD101with cisplatin+doxorubicin+cyclophosphamide

Arun Rajan, M.D.

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....

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 histone deacetylase inhibitors (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, dose limiting toxicities (DLTs) and preliminary activity for the combination of belinostat by continuous intravenous (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 (partial response (PR)+complete response (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 Comparative Genomic Hybridization (CGH))

Eligibility:

* Patients with histologically confirmed advanced thymic malignancies who are chemotherapy na(SqrRoot) ve.
* Measurable disease by Response Evaluation Criteria in Solid Tumors (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 intravenous (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.

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

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

The MTD is defined as the highest dose at which less than 2 out of 6 patients experienced a dose limiting toxicity (DLT). A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.

A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.

Objective response rate is the number of participants with a best objective response of partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST) divided by the number of participants who had treatment.

Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module.

Here are the number of patients with treatment -related grade 3 and 4 adverse events (highest grade per event per patient).

Response is defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST).

Time to response is the time between the first day of treatment until first date of response (complete response (CR) + partial response (PR)) (whichever is first recorded).

Duration of response is measured from the time measurement criteria (e.g. Response Evaluation Criteria in Solid Tumors (RECIST)) are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Duration of time from start of treatment to time of progression or death whichever occurs first.

Overall survival is defined as the on-study date until the date of death or progression as appropriate.

Half life is the duration of time for the drug to be reduced to half the original amount.

Clearance is the amount of time for the drug to be eliminated from the body.

Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL.

Time to reach peak concentration after drug administration.

AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.

Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.

National Cancer Institute (NCI)

Principal Investigator

All participants who had at least one dose of belinostat.

All Participants

All participants who had at least one dose of Belinostat.

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Grade 0

Grade 1

Eastern Cooperative Oncology Group (ECOG).

Grade 0 is normal activity. Fully active, able to carry on all pre-disease performance without restriction.

Grade 1 is symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work).

ECOG Performance Status

Thymic carcinoma

The World Health Organization (WHO) classification of epithelial thymic malignancies shown under Thymoma are defined as type B1: histology - predominantly cortical thymoma, type B2: histology - cortical thymoma, and type B3: histology - well-differentiated thymoma.

Tumor Type

Masaoka Staging System:

Stage IVA is pleural or pericardial dissemination. Stage IVB is lymphogenous or hematogenous metastases.

Stage at Enrolment

Radical

Debulking

11 patients had radical surgery including 2 who underwent debulking subsequently.

Prior Surgery

Prior Radiation

Prior Neoadjuvant or Adjuvant Chemotherapy

Per protocol, two group results, as well as single arm results are reported throughout the results data.

Dr. Arun Rajan

Patients received 250mg/m(2) of belinostat via four consecutive 12 hour continuous intravenous infusion (CIVI) for 48 hours starting on day 1. At dose levels 1 and 2, patients received the same doses of doxorubicin (25mg/m(2) on days 2 and 3, intravenous push over 3-5 minutes), cisplatin (50 mg/m(2) over 60 minutes intravenous on day 2 after doxorubicin), and cyclophosphamide (500mg/m(2) over 60 minutes intravenous on day 3 after doxorubicin). Combination of chemotherapy and belinostat was repeated every 21 days for a total of 6 cycles unless there was evidence of disease progression or intolerance of the study treatment.

A conventional 3 + 3 dose escalation design was used to determine maximum tolerated dose (MTD).

Phase I Dose Level 1 & Phase I Dose Level 2

Maximum Tolerated Dose (MTD) of Belinostat

Grade 3 Nausea

Grade 3 Diarrhea

Grade 4 Neutropenia

Grade 4 Thrombocytopenia

Patients received 500mg/m(2) of belinostat via four consecutive 12 hour continuous intravenous infusion (CIVI) for 48 hours starting on day 1. At dose levels 1 and 2, patients received the same doses of doxorubicin (25mg/m(2) on days 2 and 3, intravenous push over 3-5 minutes), cisplatin (50 mg/m(2) over 60 minutes intravenous on day 2 after doxorubicin), and cyclophosphamide (500mg/m(2) over 60 minutes intravenous on day 3 after doxorubicin). Combination of chemotherapy and belinostat was repeated every 21 days for a total of 6 cycles unless there was evidence of disease progression or intolerance of the study treatment.

A conventional 3 + 3 dose escalation design was used to determine maximum tolerated dose (MTD).

Phase I Dose Level 2

Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat

The thymic tumors are rare tumors that arise from the thymus and are histologically composed of epithelial cells which are the putative source of malignancy, B and T lymphocytes, interdigitating reticulum cells, macrophages, and myeloid cells. The most common tumors of the thymus are thymomas (well-differentiated neoplasms), atypical thymomas (moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas.

Thymic Participants

Thymoma Participants

All participants who had at least one dose of belinostat. PXD101 (Belinostat) will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2, 3, cisplatin will be infused over 1 hr 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.

The thymic tumors are rare tumors that arise from the thymus and are histologically composed of epithelial cells which are the putative source of malignancy, B and T lymphocytes, interdigitating reticulum cells, macrophages, and myeloid cells. The most common tumors of the thymus are thymomas (well-differentiated neoplasms), atypical thymomas (moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas.

Thymic and Thymoma Participants

One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response.

Objective Response Rate (Partial Response (PR) + Complete Response (CR) of Belinostat in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Patients With Advanced Thymic Malignancies

Serious

Non-serious

Number of Participants With Serious and Non-serious Adverse Events

Hematologic: Lymphocyte count decreased

Hematologic: White blood cell decreased

Hematologic: Neutrophil count decreased

Hematologic: Platelet count decreased

Hematologic: Anemia

Hepatic and Renal: Hypophosphatemia

Hepatic and Renal: Aspartate aminotransferase incr

Hepatic/Renal: Alanine aminotransferase increased

Hepatic and Renal: Hypokalemia

Hepatic and Renal: Hypermagnesemia

Hepatic and Renal: Hypoalbuminemia

Hepatic and Renal: Hypocalcemia

Hepatic and Renal: Hypomagnesemia

Hepatic and Renal: Hyponatremia

Cardiovascular: Thromboembolic event

Cardiovascular: Atrial fibrillation

Cardiovascular: Ejection fraction decreased

Cardiovascular: Electrocardiogram QTc prolonged

Others: Nausea

Other: Febrile neutropenia

Others: Diarrhea

Others: Lung infection

Otehrs: Entercolitis infectious

Others: Fatigue

Others: Hearing impaired

Others: Hypoxia

Others: Non-cardiac chest pain

Others: Pain in extremity

Others: Syncope

Others: Tumor lysis syndrome

Others: Limb edema

Others: Urinary tract infection

Others: Vomiting

Patients received 250mg/m(2) of belinostat via four consecutive 12 hour continuous intravenous infusion (CIVI) for 48 hours starting on day 1. At dose levels 1 and 2, patients received the same doses of doxorubicin (25mg/m(2) on days 2 and 3, intravenous push over 3-5 minutes), cisplatin (50 mg/m(2) over 60 minutes intravenous on day 2 after doxorubicin), and cyclophosphamide (500mg/m(2) over 60 minutes intravenous on day 3 after doxorubicin). Combination of chemotherapy and belinostat was repeated every 21 days for a total of 6 cycles unless there was evidence of disease progression or intolerance of the study treatment.

A conventional 3 + 3 dose escalation design was used to determine maximum tolerated dose (MTD) and was utilized in the expansion phase (phase 2).

Phase I Dose Level 1 + Phase 2

Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient)

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

PXD101 (Belinostat) will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2, 3, cisplatin will be infused over 1 hr 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.

The thymic tumors are rare tumors that arise from the thymus and are histologically composed of epithelial cells which are the putative source of malignancy, B and T lymphocytes, interdigitating reticulum cells, macrophages, and myeloid cells. The most common tumors of the thymus are thymomas (well-differentiated neoplasms), atypical thymomas (moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas.

Thymic Particpants

All participants who had at least one dose of belinostat.

PXD101 (Belinostat) will be given as a 48h continuous intravenous infusion (CIVI) starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2, 3, cisplatin will be infused over 1 hr 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.

The thymic tumors are rare tumors that arise from the thymus and are histologically composed of epithelial cells which are the putative source of malignancy, B and T lymphocytes, interdigitating reticulum cells, macrophages, and myeloid cells. The most common tumors of the thymus are thymomas (well-differentiated neoplasms), atypical thymomas (moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas.

Clinical Response

Disease Control Rate (DCR)

Patients received 250mg/m(2) or 500mg/m(2) of belinostat via four consecutive 12 hour continuous intravenous infusion (CIVI) for 48 hours starting on day 1. At dose levels 1 and 2, patients received the same doses of doxorubicin (25mg/m(2) on days 2 and 3, intravenous push over 3-5 minutes), cisplatin (50 mg/m(2) over 60 minutes intravenous on day 2 after doxorubicin), and cyclophosphamide (500mg/m(2) over 60 minutes intravenous on day 3 after doxorubicin). Combination of chemotherapy and belinostat was repeated every 21 days for a total of 6 cycles unless there was evidence of disease progression or intolerance of the study treatment.

A conventional 3 + 3 dose escalation design was used to determine maximum tolerated dose (MTD).

Time to Response

One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable for response. The reason median was not reached is that patients with thymoma have a more indolent disease with a longer survival, therefore a longer duration of response

Duration of Response

One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. The reason median was not reached is that patients with thymoma have a more indolent disease with a longer survival, therefore a longer duration of response.

Progression Free Survival (PFS)

Overall Survival (OS)

Phase 1 Dose Level 1 + Phase 2

Phase 1 Dose Level 2

Time to Half Life (t1/2) of Belinostat

Total Clearance (CL) of Belinostat

One patient was excluded from pharmacokinetic analysis due to insufficient sampling in dose level 2. Dose normalized parameters are normalized to absolute total dose (over 48 hours continuous intravenous infusion (CIVI)) for that patient, not dose level.

Maximum Observed Plasma Concentration (Cmax) of Belinostat

Maximum Plasma Concentration (Cmax)/Dose

Time to Maximum Plasma Concentration (Tmax)

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF))

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose

C1D2

C1D3

C2D1

One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. Two samples could not be analyzed since they were of poor quality with too few cells for immune cell subset analysis or the samples could not be collected in time for pharmacodynamics analysis.

Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat

One patient hospitalized for viral meningoencephalitis during the first cycle was not evaluable. Three samples could not be analyzed since they were of poor quality with too few cells for immune cell subset analysis or the samples could not be collected in time for pharmacodynamics analysis.

Relative Changes in the Number of Tregs With Treatment

Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells

Belinostat 250mg/m(2) and Chemotherapy

Belinostat 500mg/m(2) and Chemotherapy

Patients were treated with belinostat, doxorubicin, cisplatin and cyclophosphamide at the maximum tolerated dose derived from the phase I dose level.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT01100944	Thymoma Thymic Carcinom...	PXD101with cisp...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
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	NCT01100944	Thymoma Thymic Carcinom...	PXD101with cisp...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

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