Trial Outcomes & Findings for 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 (NCT NCT01100944)

Last Updated: 2017-08-10

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

26 participants

Primary outcome timeframe

2 years

Results posted on

2017-08-10

Participant Flow

Participant milestones

Participant milestones
Measure	Belinostat 250mg/m(2) and Chemotherapy 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).	Belinostat 500mg/m(2) and Chemotherapy 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).	Belinostat and Chemotherapy at the 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.
Dose Escalation Phase 1 Dose Level 1 STARTED	6	0	0
Dose Escalation Phase 1 Dose Level 1 COMPLETED	2	0	0
Dose Escalation Phase 1 Dose Level 1 NOT COMPLETED	4	0	0
Dose Escalation Phase 1 Dose Level 2 STARTED	0	2	0
Dose Escalation Phase 1 Dose Level 2 COMPLETED	0	0	0
Dose Escalation Phase 1 Dose Level 2 NOT COMPLETED	0	2	0
Expansion Phase - Phase 2 STARTED	0	0	18
Expansion Phase - Phase 2 COMPLETED	0	0	18
Expansion Phase - Phase 2 NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Belinostat 250mg/m(2) and Chemotherapy 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).	Belinostat 500mg/m(2) and Chemotherapy 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).
Dose Escalation Phase 1 Dose Level 1 Adverse Event	2	0
Dose Escalation Phase 1 Dose Level 1 Discontinued due to treatment delay	1	0
Dose Escalation Phase 1 Dose Level 1 Progressive Disease	1	0
Dose Escalation Phase 1 Dose Level 2 Adverse Event	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=26 Participants All participants who had at least one dose of Belinostat.
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	20 Participants n=93 Participants
Age, Categorical >=65 years	6 Participants n=93 Participants
Age, Continuous	53.9 years STANDARD_DEVIATION 13.3 • n=93 Participants
Sex: Female, Male Female	13 Participants n=93 Participants
Sex: Female, Male Male	13 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	2 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	4 Participants n=93 Participants
Race (NIH/OMB) White	20 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Region of Enrollment United States	26 participants n=93 Participants
ECOG Performance Status Grade 0	18 Participants n=93 Participants
ECOG Performance Status Grade 1	8 Participants n=93 Participants
Tumor Type Thymoma	12 Participants n=93 Participants
Tumor Type B1	2 Participants n=93 Participants
Tumor Type B2	7 Participants n=93 Participants
Tumor Type B3	3 Participants n=93 Participants
Tumor Type Thymic carcinoma	14 Participants n=93 Participants
Stage at Enrolment IVA	12 Participants n=93 Participants
Stage at Enrolment IVB	14 Participants n=93 Participants
Prior Surgery Radical	11 Participants n=93 Participants
Prior Surgery Debulking	2 Participants n=93 Participants
Prior Radiation	7 Participants n=93 Participants
Prior Neoadjuvant or Adjuvant Chemotherapy	4 Participants n=93 Participants

PRIMARY outcome

Timeframe: 2 years

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=8 Participants 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).	Thymoma Participants 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 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.
Maximum Tolerated Dose (MTD) of Belinostat	1000 mg/m(2)	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=2 Participants 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).	Thymoma Participants 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 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.
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat Grade 3 Nausea	2 Participants	—	—
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat Grade 3 Diarrhea	2 Participants	—	—
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat Grade 4 Neutropenia	2 Participants	—	—
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat Grade 4 Thrombocytopenia	2 Participants	—	—

PRIMARY outcome

Timeframe: 43 months

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

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.

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
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	21 percentage of participants Interval 4.7 to 50.8	64 percentage of participants Interval 30.8 to 89.1	40 percentage of participants Interval 21.1 to 61.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=26 Participants 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).	Thymoma Participants 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 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.
Number of Participants With Serious and Non-serious Adverse Events Serious	20 Participants	—	—
Number of Participants With Serious and Non-serious Adverse Events Non-serious	26 Participants	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=24 Participants 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).	Thymoma Participants n=2 Participants 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 n=26 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.
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hematologic: Neutrophil count decreased	19 Participants	2 Participants	21 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hematologic: Platelet count decreased	10 Participants	2 Participants	12 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hematologic: Anemia	7 Participants	2 Participants	9 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypophosphatemia	4 Participants	2 Participants	6 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Aspartate aminotransferase incr	4 Participants	2 Participants	6 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic/Renal: Alanine aminotransferase increased	3 Participants	1 Participants	4 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypokalemia	3 Participants	1 Participants	4 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypermagnesemia	3 Participants	0 Participants	3 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypoalbuminemia	1 Participants	1 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypocalcemia	1 Participants	1 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hypomagnesemia	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Otehrs: Entercolitis infectious	1 Participants	1 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Fatigue	2 Participants	0 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Limb edema	0 Participants	1 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Urinary tract infection	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hematologic: Lymphocyte count decreased	24 Participants	2 Participants	26 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hematologic: White blood cell decreased	22 Participants	2 Participants	24 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Hepatic and Renal: Hyponatremia	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Cardiovascular: Thromboembolic event	3 Participants	0 Participants	3 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Cardiovascular: Atrial fibrillation	0 Participants	1 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Cardiovascular: Ejection fraction decreased	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Cardiovascular: Electrocardiogram QTc prolonged	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Nausea	1 Participants	2 Participants	3 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Other: Febrile neutropenia	3 Participants	0 Participants	3 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Diarrhea	1 Participants	1 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Lung infection	2 Participants	0 Participants	2 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Hearing impaired	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Hypoxia	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Non-cardiac chest pain	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Pain in extremity	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Syncope	1 Participants	0 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Tumor lysis syndrome	0 Participants	1 Participants	1 Participants
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) Others: Vomiting	0 Participants	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 43 months

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

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.

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
Clinical Response Complete Response (CR)	0 Participants	1 Participants	1 Participants
Clinical Response Stable Disease (SD)	10 Participants	4 Participants	14 Participants
Clinical Response Progressive Disease (PD)	1 Participants	0 Participants	1 Participants
Clinical Response Partial Response (PR)	3 Participants	6 Participants	9 Participants

SECONDARY outcome

Timeframe: 43 months

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

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

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
Disease Control Rate (DCR)	93 percentage of participants Interval 66.1 to 99.8	100 percentage of participants Interval 71.5 to 100.0	96 percentage of participants Interval 79.7 to 99.9

SECONDARY outcome

Timeframe: From the first day of treatment until the date of first documented response, assessed up to 43 months

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

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).

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=25 Participants 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).	Thymoma Participants 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 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.
Time to Response	44.5 days Interval 39.0 to 110.0	—	—

SECONDARY outcome

Timeframe: From the time of first response until date of progression, assessed up to 43 months

Population: 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 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).

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
Duration of Response	7.4 months Interval 4.2 to 8.5	NA months Median duration of response was not reached for thymoma participants.	7.4 months Interval 5.2 to 5.2 months to undefined upper limit.

SECONDARY outcome

Timeframe: Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months

Population: 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.

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

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
Progression Free Survival (PFS)	7.2 months Interval 2.0 to 9.0	NA months Interval 5.0 to 32.0 Median PFS was not reached for thymoma participants.	9 months Interval 2.0 to 32.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Phase I Dose Level 1 & Phase I Dose Level 2 n=14 Participants 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).	Thymoma Participants n=11 Participants 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 n=25 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.
Overall Survival (OS)	21.4 months Interval 3.0 to 37.0	NA months Interval 4.0 to 43.0 Median OS was not reached for thymoma participants. Thymoma patients with maximum and minimum OS values were alive at the time of data cutoff.	28.5 months Interval 3.0 to 43.0

SECONDARY outcome

Timeframe: 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.