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

Study Overview
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Brief Summary
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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....

Detailed Description
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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.

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

Conditions
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Thymoma, Thymic Carcinoma

Intervention / Treatment
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* Drug: PXD101with cisplatin+doxorubicin+cyclophosphamide


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: 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. Patients must be chemotherapy na(SqrRoot) ve for the treatment of advanced thymic malignancies. Age > 18 years. Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 60%). Life expectancy of greater than 3 months. 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. 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. 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. 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. 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. 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: Patients who have had major surgery or radiotherapy within 3 weeks of enrollment. Patients may not be receiving any other investigational agents. 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. History of allergic reactions attributed to compounds of similar chemical or biologic composition to belinostat or other agents used in study. 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. 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. 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. 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. 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. 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. Patients with tumor amenable to potentially curative therapy as assessed by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapy in Thymic Malignancies<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Belinostat | 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 years | 
| Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat | 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. | up to 122 months | 
| 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 | 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. | 43 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events | Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module. | up to 122 months | 
| Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) | Here are the number of patients with treatment -related grade 3 and 4 adverse events (highest grade per event per patient). | up to 122 months | 
| Clinical 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. | 43 months | 
| Disease Control Rate (DCR) | DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST). | 43 months | 
| Time to 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). | From the first day of treatment until the date of first documented response, assessed up to 43 months | 
| 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). | From the time of first response until date of progression, assessed up to 43 months | 
| Progression Free Survival (PFS) | Duration of time from start of treatment to time of progression or death whichever occurs first. | Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months | 
| Overall Survival (OS) | Overall survival is defined as the on-study date until the date of death or progression as appropriate. | Start of treatment to time of death, assessed up to 43 months | 
| Time to Half Life (t1/2) of Belinostat | Half life is the duration of time for the drug to be reduced to half the original amount. | 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. | 
| Total Clearance (CL) of Belinostat | Clearance is the amount of time for the drug to be eliminated from the body. | 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 | 
| Maximum Observed Plasma Concentration (Cmax) of Belinostat | 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. | 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 | 
| Maximum Plasma Concentration (Cmax)/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. | 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 Maximum Plasma Concentration (Tmax) | Time to reach peak concentration after drug administration. | 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 | 
| Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) | AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption. | 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 | 
| Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose | AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption. | 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 | 
| Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | 
| Relative Changes in the Number of Tregs With Treatment | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | 
| Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells | Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline. | Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene Expression, HDAC Class I and II enzymes, Thymoma, Chemotherapy, Hydroxamic Acid Deacetylase Inhibitor, Thymic Cancer