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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01100944
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arm: 1
• Actual Duration (Months): 67.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Thymoma; Thymic Carcinoma	Drug: PXD101with cisplatin+doxorubicin+cyclophosphamide	Phase 1/Phase 2

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 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Mar 4, 2010
• Actual Primary Completion Date: Oct 21, 2015
• Actual Study Completion Date: Oct 21, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Therapy in Thymic Malignancies 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.

Drug: PXD101with cisplatin+doxorubicin+cyclophosphamide; 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.

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Belinostat [2 years]

   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.

2. Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat [up to 122 months]

   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.

3. 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 [43 months]

   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.

Secondary Outcome Measures

1. Number of Participants With Serious and Non-serious Adverse Events [up to 122 months]

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

2. Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) [up to 122 months]

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

3. Clinical Response [43 months]

   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.

4. Disease Control Rate (DCR) [43 months]

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

5. Time to Response [From the first day of treatment until the date of first documented response, assessed up to 43 months]

   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).

6. Duration of Response [From the time of first response until date of progression, assessed up to 43 months]

   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).

7. Progression Free Survival (PFS) [Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months]

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

8. Overall Survival (OS) [Start of treatment to time of death, assessed up to 43 months]

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

9. Time to Half Life (t1/2) of Belinostat [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose.]

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

10. Total Clearance (CL) of Belinostat [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

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

11. Maximum Observed Plasma Concentration (Cmax) of Belinostat [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

    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.

12. Maximum Plasma Concentration (Cmax)/Dose [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

    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.

13. Time to Maximum Plasma Concentration (Tmax) [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

    Time to reach peak concentration after drug administration.

14. Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

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

15. Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose [on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose]

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

16. Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat [Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)]

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

17. Relative Changes in the Number of Tregs With Treatment [Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)]

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

18. Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells [Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

-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. Eastern Cooperative Oncology Group (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

• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(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.

1. 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 computed tomography (CT) scan.

2. 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.

1. 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.

1. The effects of belinostat on the developing human fetus are unknown. For this reason and because histone deacetylase inhibitors (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.

2. 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. Human immunodeficiency virus (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 Q wave, T wave (QT)/corrected QT interval (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

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Arun Rajan, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol. 2005 Mar;17(2):140-6. Review.
• Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P. Thymoma: a focus on current therapeutic management. J Thorac Oncol. 2009 Jan;4(1):119-26. doi: 10.1097/JTO.0b013e31818e105c. Review.
• Loehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, Blum R. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol. 1994 Jun;12(6):1164-8.

• Responsible Party: Arun Rajan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT01100944
• Other Study ID Numbers: 100077; 10-C-0077
• First Posted: Apr 9, 2010
• Last Update Posted: Aug 10, 2017
• Last Verified: Jul 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Arun Rajan, M.D., Principal Investigator, 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; Thymus Neoplasms; Cyclophosphamide; Doxorubicin; Belinostat

Study Results

Participant Flow

Arm/Group Title	Belinostat 250mg/m(2) and Chemotherapy	Belinostat 500mg/m(2) and Chemotherapy	Belinostat and Chemotherapy at the Maximum Tolerated Dose(MTD)
Arm/Group Description	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).	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).	Patients were treated with belinostat, doxorubicin, cisplatin and cyclophosphamide at the maximum tolerated dose derived from the phase I dose level.
Period Title: Dose Escalation Phase 1 Dose Level 1
STARTED	6	0	0
COMPLETED	2	0	0
NOT COMPLETED	4	0	0
Period Title: Dose Escalation Phase 1 Dose Level 1
STARTED	0	2	0
COMPLETED	0	0	0
NOT COMPLETED	0	2	0
Period Title: Dose Escalation Phase 1 Dose Level 1
STARTED	0	0	18
COMPLETED	0	0	18
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants who had at least one dose of Belinostat.
Overall Participants	26
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	20 76.9%
>=65 years	6 23.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.9 (13.3)
Sex: Female, Male (Count of Participants)
Female	13 50%
Male	13 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.8%
Not Hispanic or Latino	23 88.5%
Unknown or Not Reported	2 7.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 7.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 15.4%
White	20 76.9%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	26 100%
ECOG Performance Status (Count of Participants)
Grade 0	18 69.2%
Grade 1	8 30.8%
Tumor Type (Count of Participants)
Thymoma	12 46.2%
B1	2 7.7%
B2	7 26.9%
B3	3 11.5%
Thymic carcinoma	14 53.8%
Stage at Enrolment (Count of Participants)
IVA	12 46.2%
IVB	14 53.8%
Prior Surgery (Count of Participants)
Radical	11 42.3%
Debulking	2 7.7%
Prior Radiation (Count of Participants)
Count of Participants [Participants]	7 26.9%
Prior Neoadjuvant or Adjuvant Chemotherapy (Count of Participants)
Count of Participants [Participants]	4 15.4%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Belinostat
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 & Phase I Dose Level 2
Arm/Group Description	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).
Measure Participants	8
Number [mg/m(2)]	1000

2. Primary Outcome

Title	Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat
Description	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.
Time Frame	up to 122 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 2
Arm/Group Description	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).
Measure Participants	2
Grade 3 Nausea	2 7.7%
Grade 3 Diarrhea	2 7.7%
Grade 4 Neutropenia	2 7.7%
Grade 4 Thrombocytopenia	2 7.7%

3. Primary Outcome

Title	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
Description	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.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Thymic Participants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Number (95% Confidence Interval) [percentage of participants]	21 80.8%	64 NaN	40 NaN

4. Secondary Outcome

Title	Number of Participants With Serious and Non-serious Adverse Events
Description	Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module.
Time Frame	up to 122 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	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.
Measure Participants	26
Serious	20 76.9%
Non-serious	26 100%

5. Secondary Outcome

Title	Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient)
Description	Here are the number of patients with treatment -related grade 3 and 4 adverse events (highest grade per event per patient).
Time Frame	up to 122 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2	All Participants
Arm/Group Description	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).	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).	All participants who had at least one dose of belinostat.
Measure Participants	24	2	26
Hematologic: Lymphocyte count decreased	24 92.3%	2 NaN	26 NaN
Hematologic: White blood cell decreased	22 84.6%	2 NaN	24 NaN
Hematologic: Neutrophil count decreased	19 73.1%	2 NaN	21 NaN
Hematologic: Platelet count decreased	10 38.5%	2 NaN	12 NaN
Hematologic: Anemia	7 26.9%	2 NaN	9 NaN
Hepatic and Renal: Hypophosphatemia	4 15.4%	2 NaN	6 NaN
Hepatic and Renal: Aspartate aminotransferase incr	4 15.4%	2 NaN	6 NaN
Hepatic/Renal: Alanine aminotransferase increased	3 11.5%	1 NaN	4 NaN
Hepatic and Renal: Hypokalemia	3 11.5%	1 NaN	4 NaN
Hepatic and Renal: Hypermagnesemia	3 11.5%	0 NaN	3 NaN
Hepatic and Renal: Hypoalbuminemia	1 3.8%	1 NaN	2 NaN
Hepatic and Renal: Hypocalcemia	1 3.8%	1 NaN	2 NaN
Hepatic and Renal: Hypomagnesemia	1 3.8%	0 NaN	1 NaN
Hepatic and Renal: Hyponatremia	1 3.8%	0 NaN	1 NaN
Cardiovascular: Thromboembolic event	3 11.5%	0 NaN	3 NaN
Cardiovascular: Atrial fibrillation	0 0%	1 NaN	1 NaN
Cardiovascular: Ejection fraction decreased	1 3.8%	0 NaN	1 NaN
Cardiovascular: Electrocardiogram QTc prolonged	1 3.8%	0 NaN	1 NaN
Others: Nausea	1 3.8%	2 NaN	3 NaN
Other: Febrile neutropenia	3 11.5%	0 NaN	3 NaN
Others: Diarrhea	1 3.8%	1 NaN	2 NaN
Others: Lung infection	2 7.7%	0 NaN	2 NaN
Otehrs: Entercolitis infectious	1 3.8%	1 NaN	2 NaN
Others: Fatigue	2 7.7%	0 NaN	2 NaN
Others: Hearing impaired	1 3.8%	0 NaN	1 NaN
Others: Hypoxia	1 3.8%	0 NaN	1 NaN
Others: Non-cardiac chest pain	1 3.8%	0 NaN	1 NaN
Others: Pain in extremity	1 3.8%	0 NaN	1 NaN
Others: Syncope	1 3.8%	0 NaN	1 NaN
Others: Tumor lysis syndrome	0 0%	1 NaN	1 NaN
Others: Limb edema	0 0%	1 NaN	1 NaN
Others: Urinary tract infection	1 3.8%	0 NaN	1 NaN
Others: Vomiting	0 0%	1 NaN	1 NaN

6. Secondary Outcome

Title	Clinical Response
Description	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.
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Thymic Particpants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Complete Response (CR)	0 0%	1 NaN	1 NaN
Partial Response (PR)	3 11.5%	6 NaN	9 NaN
Stable Disease (SD)	10 38.5%	4 NaN	14 NaN
Progressive Disease (PD)	1 3.8%	0 NaN	1 NaN

7. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST).
Time Frame	43 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Thymic Participants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Number (95% Confidence Interval) [percentage of participants]	93 357.7%	100 NaN	96 NaN

8. Secondary Outcome

Title	Time to Response
Description	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).
Time Frame	From the first day of treatment until the date of first documented response, assessed up to 43 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase I Dose Level 1 & Phase I Dose Level 2
Arm/Group Description	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).
Measure Participants	25
Median (Full Range) [days]	44.5

9. Secondary Outcome

Title	Duration of Response
Description	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).
Time Frame	From the time of first response until date of progression, assessed up to 43 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Thymic Participants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Median (95% Confidence Interval) [months]	7.4	NA	7.4

10. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Duration of time from start of treatment to time of progression or death whichever occurs first.
Time Frame	Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Thymic Participants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Median (Full Range) [months]	7.2	NA	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Thymic and Thymoma Participants
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

11. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as the on-study date until the date of death or progression as appropriate.
Time Frame	Start of treatment to time of death, assessed up to 43 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Thymic Participants	Thymoma Participants	Thymic and Thymoma Participants
Arm/Group Description	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.	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.	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.
Measure Participants	14	11	25
Median (Full Range) [months]	21.4	NA	28.5

12. Secondary Outcome

Title	Time to Half Life (t1/2) of Belinostat
Description	Half life is the duration of time for the drug to be reduced to half the original amount.
Time Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Dose Level 1 + Phase 2	Phase 1 Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [Hour]	0.47 (0.19)	0.40 (NA)

13. Secondary Outcome

Title	Total Clearance (CL) of Belinostat
Description	Clearance is the amount of time for the drug to be eliminated from the body.
Time Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 Dose Level 1 + Phase 2	Phase 1 Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [L/hr]	133.5 (145.1)	132.1 (NA)

14. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Belinostat
Description	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 Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [ng/ml]	650.6 (288.1)	1202 (NA)

15. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax)/Dose
Description	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 Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [ng/ml/mg]	0.36 (0.21)	0.31 (NA)

16. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax)
Description	Time to reach peak concentration after drug administration.
Time Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [Hour]	25.28 (22.29)	50.0 (NA)

17. Secondary Outcome

Title	Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF))
Description	AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.
Time Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [hr*ng/ml]	19756 (7634)	29686 (NA)

18. Secondary Outcome

Title	Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose
Description	AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.
Time Frame	on day 1: pre-belinostat and 0, 0.5, 1 and 2 hours after belinostat infusion, on day 3: 0, 0.8, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-last belinostat dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I Dose Level 1 + Phase 2	Phase I Dose Level 2
Arm/Group Description	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).	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).
Measure Participants	24	1
Mean (Standard Deviation) [hr*ng/ml/mg]	10.78 (5.57)	7.57 (NA)

19. Secondary Outcome

Title	Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat
Description	Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time Frame	Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Participants
Arm/Group Description	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).
Measure Participants	23
C1D2	3.45
C1D3	2.49
C2D1	1.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments	Fold change at Cycle 2 Day 1 vs. pre was assessed. Only differences with p<0.005 could be potentially considered statistically significant while those with 0.005<p<0.05 would represent trends towards a difference.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Fold change at Cycle 1 Day 2 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Fold change at Cycle 1 Day 3 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

20. Secondary Outcome

Title	Relative Changes in the Number of Tregs With Treatment
Description	Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time Frame	Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Participants
Arm/Group Description	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).
Measure Participants	22
C1D2	0.58
C1D3	0.47
C2D1	1.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	Fold change at Cycle 2 Day 1 vs. pre was assessed.Only differences with p<0.005 could be potentially considered statistically significant while those with 0.005<p<0.05 would represent trends towards a difference.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments	Fold change at Cycle 1 Day 2 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Fold change at Cycle 1 Day 3 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

21. Secondary Outcome

Title	Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells
Description	Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.
Time Frame	Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	All Participants
Arm/Group Description	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).
Measure Participants	22
C1D2	0.81
C1D3	0.66
C2D1	1.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments	Fold change at Cycle 2 Day 1 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Fold change at Cycle 1 Day 2 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase I Dose Level 1 & Phase I Dose Level 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Fold change at Cycle 1 Day 3 vs. pre was assessed. p values calculated were done using a Wilcoxon signed rank test relative to a ratio of 1.
	Method	Wilcoxon signed rank test
	Comments

Adverse Events

Time Frame	up to 122 months
Arm/Group Title	All Participants
Arm/Group Description	All participants who had at least one dose of belinostat.
All Cause Mortality
	All Participants
	Affected / at Risk (%)	# Events
Total	13/26 (50%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	20/26 (76.9%)
Blood and lymphatic system disorders
Anemia	1/26 (3.8%)	1
Febrile neutropenia	1/26 (3.8%)	1
Cardiac disorders
Atrial fibrillation	1/26 (3.8%)	1
Gastrointestinal disorders
Diarrhea	1/26 (3.8%)	1
General disorders
Death NOS	11/26 (42.3%)	11
Infusion related reaction	1/26 (3.8%)	1
Localized edema	1/26 (3.8%)	1
Infections and infestations
Catheter related infection	2/26 (7.7%)	2
Infections and infestations - Other, Meningoencephylitis	1/26 (3.8%)	1
Infections and infestations - Other, West Nile virus	1/26 (3.8%)	1
Lung infection	1/26 (3.8%)	1
Investigations
Electrocardiogram QT corrected interval prolonged	1/26 (3.8%)	1
Neutrophil count decreased	1/26 (3.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other,Basal cell carcinoma	1/26 (3.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, Death	2/26 (7.7%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/26 (3.8%)	1
Vascular disorders
Thromboembolic event	5/26 (19.2%)	5
Other (Not Including Serious) Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Anemia	23/26 (88.5%)	124
Cardiac disorders
Atrial fibrillation	1/26 (3.8%)	1
Pericardial effusion	1/26 (3.8%)	1
Sinus bradycardia	3/26 (11.5%)	6
Sinus tachycardia	2/26 (7.7%)	4
Ear and labyrinth disorders
Hearing impaired	2/26 (7.7%)	3
Otitis media	1/26 (3.8%)	1
Tinnitus	2/26 (7.7%)	2
Eye disorders
Blurred vision	1/26 (3.8%)	1
Floaters	1/26 (3.8%)	1
Watering eyes	1/26 (3.8%)	1
Gastrointestinal disorders
Constipation	6/26 (23.1%)	10
Diarrhea	9/26 (34.6%)	18
Dry mouth	1/26 (3.8%)	1
Dyspepsia	2/26 (7.7%)	3
Dysphagia	2/26 (7.7%)	2
Enterocolitis infectious	3/26 (11.5%)	3
Gastritis	1/26 (3.8%)	1
Gastroesophageal reflux disease	1/26 (3.8%)	1
Mucositis oral	7/26 (26.9%)	8
Nausea	16/26 (61.5%)	21
Oral pain	1/26 (3.8%)	1
Vomiting	6/26 (23.1%)	10
General disorders
Chills	3/26 (11.5%)	3
Edema limbs	4/26 (15.4%)	5
Fatigue	15/26 (57.7%)	28
Fever	3/26 (11.5%)	3
Non-cardiac chest pain	1/26 (3.8%)	1
Pain	2/26 (7.7%)	4
Infections and infestations
Catheter related infection	1/26 (3.8%)	1
Infections and infestations - Other, folliculitis, axilla right	1/26 (3.8%)	1
Infections and infestations - Other, Pseudomonas bacteremia	1/26 (3.8%)	1
Laryngitis	1/26 (3.8%)	1
Lung infection	3/26 (11.5%)	3
Mucosal infection	1/26 (3.8%)	1
Paronychia	1/26 (3.8%)	1
Pharyngitis	3/26 (11.5%)	4
Sinusitis	3/26 (11.5%)	3
Upper respiratory infection	2/26 (7.7%)	3
Injury, poisoning and procedural complications
Bruising	1/26 (3.8%)	1
Fall	1/26 (3.8%)	1
Investigations
Activated partial thromboplastin time prolonged	3/26 (11.5%)	6
Alanine aminotransferase increased	10/26 (38.5%)	26
Alkaline phosphatase increased	1/26 (3.8%)	1
Aspartate aminotransferase increased	10/26 (38.5%)	25
Creatinine increased	4/26 (15.4%)	12
Ejection fraction decreased	2/26 (7.7%)	2
Electrocardiogram QT corrected interval prolonged	8/26 (30.8%)	27
Lymphocyte count decreased	26/26 (100%)	294
Neutrophil count decreased	24/26 (92.3%)	112
Platelet count decreased	17/26 (65.4%)	82
Weight loss	1/26 (3.8%)	1
White blood cell decreased	26/26 (100%)	161
Metabolism and nutrition disorders
Anorexia	15/26 (57.7%)	18
Dehydration	1/26 (3.8%)	1
Hypercalcemia	2/26 (7.7%)	2
Hyperglycemia	4/26 (15.4%)	4
Hyperkalemia	1/26 (3.8%)	1
Hypermagnesemia	3/26 (11.5%)	7
Hypoalbuminemia	19/26 (73.1%)	66
Hypocalcemia	19/26 (73.1%)	58
Hypokalemia	7/26 (26.9%)	13
Hypomagnesemia	5/26 (19.2%)	14
Hyponatremia	3/26 (11.5%)	8
Hypophosphatemia	12/26 (46.2%)	34
Tumor lysis syndrome	1/26 (3.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/26 (7.7%)	3
Muscle weakness left-sided	1/26 (3.8%)	1
Muscle weakness lower limb	2/26 (7.7%)	2
Myalgia	1/26 (3.8%)	1
Pain in extremity	4/26 (15.4%)	6
Nervous system disorders
Concentration impairment	2/26 (7.7%)	2
Dizziness	2/26 (7.7%)	3
Dysgeusia	7/26 (26.9%)	9
Headache	5/26 (19.2%)	7
Peripheral sensory neuropathy	7/26 (26.9%)	7
Presyncope	1/26 (3.8%)	1
Syncope	1/26 (3.8%)	2
Psychiatric disorders
Agitation	1/26 (3.8%)	1
Anxiety	1/26 (3.8%)	1
Depression	3/26 (11.5%)	3
Insomnia	4/26 (15.4%)	4
Renal and urinary disorders
Hematuria	1/26 (3.8%)	1
Urinary incontinence	1/26 (3.8%)	1
Urinary tract infection	3/26 (11.5%)	5
Urinary tract pain	1/26 (3.8%)	1
Respiratory, thoracic and mediastinal disorders
Cough	6/26 (23.1%)	10
Dyspnea	5/26 (19.2%)	6
Epistaxis	2/26 (7.7%)	2
Hiccups	2/26 (7.7%)	2
Hoarseness	1/26 (3.8%)	1
Hypoxia	2/26 (7.7%)	3
Nasal congestion	2/26 (7.7%)	3
Pneumonitis	1/26 (3.8%)	1
Postnasal drip	2/26 (7.7%)	3
Sore throat	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
Alopecia	7/26 (26.9%)	7
Erythema multiforme	1/26 (3.8%)	1
Hyperhidrosis	1/26 (3.8%)	1
Nail discoloration	2/26 (7.7%)	2
Palmar-plantar erythrodysesthesia syndrome	1/26 (3.8%)	1
Rash maculo-papular	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders - Other, Basal Cell Carcinoma per biopsy	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders - Other, Ecchymotic nod L arm	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders - Other, skin lesion	1/26 (3.8%)	1
Skin hyperpigmentation	2/26 (7.7%)	3
Skin hypopigmentation	1/26 (3.8%)	1
Skin ulceration	1/26 (3.8%)	1
Vascular disorders
Hypertension	3/26 (11.5%)	52
Hypotension	1/26 (3.8%)	1
Superficial thrombophlebitis	1/26 (3.8%)	1
Thromboembolic event	5/26 (19.2%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.