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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

This study has been terminated.
(Principal investigator left the National Institutes of Health (NIH).)
Sponsor:
Information provided by (Responsible Party):
Arun Rajan, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01100944
First received: March 18, 2010
Last updated: November 14, 2016
Last verified: November 2016
  Purpose

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 Intervention Phase
Thymoma
Thymic Carcinoma
Drug: PXD101with cisplatin+doxorubicin+cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Belinostat [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat [ Time Frame: up to 122 months ] [ Designated as safety issue: Yes ]
    A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.

  • Objective Response Rate (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 [ Time Frame: 43 months ] [ Designated as safety issue: No ]
    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:
  • Number of Participants With Serious and Non-serious Adverse Events [ Time Frame: up to 122 months ] [ Designated as safety issue: Yes ]
    Here is the number of participants with serious and non-serious adverse events. For a detailed list of events, see the adverse event module.

  • Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient) [ Time Frame: up to 122 months ] [ Designated as safety issue: Yes ]
    Here are the number of treatment -related grade 3 and 4 adverse events (highest grade per event per patient).

  • Clinical Response [ Time Frame: 43 months ] [ Designated as safety issue: No ]
    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.

  • Disease Control Rate (DCR) [ Time Frame: 43 months ] [ Designated as safety issue: No ]
    DCR is defined as stable disease (SD) + partial response (PR) + complete response (CR) per the Response Criteria in Solid Tumors (RECIST).

  • Time to Response [ Time Frame: From the first day of treatment until the date of first documented response, assessed up to 43 months ] [ Designated as safety issue: No ]
    Time to response is the time between the first day of treatment until first date of response (complete response (CR) + partial response (PR)) (whichever is first recorded).

  • Duration of Response [ Time Frame: From the time of first response until date of progression, assessed up to 43 months ] [ Designated as safety issue: No ]
    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).

  • Progression Free Survival (PFS) [ Time Frame: Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months ] [ Designated as safety issue: No ]
    Duration of time from start of treatment to time of progression or death whichever occurs first.

  • Overall Survival (OS) [ Time Frame: Start of treatment to time of death, assessed up to 43 months ] [ Designated as safety issue: No ]
    Overall survival is defined as the on-study date until the date of death or progression as appropriate.

  • Time to Half Life (t1/2) of Belinostat [ 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. ] [ Designated as safety issue: No ]
    Half life is the duration of time for the drug to be reduced to half the original amount.

  • Total Clearance (CL) of Belinostat [ 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 ] [ Designated as safety issue: No ]
    Clearance is the amount of time for the drug to be eliminated from the body.

  • Maximum Observed Plasma Concentration (Cmax) of Belinostat [ 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 ] [ Designated as safety issue: No ]
    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.

  • Maximum Plasma Concentration (Cmax)/Dose [ 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 ] [ Designated as safety issue: No ]
    Plasma concentrations of Belinostat were measured using a newly designed and validated ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) assay, with a lower limit of quantification of 5ng/mL.

  • Time to Maximum Plasma Concentration (Tmax) [ 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 ] [ Designated as safety issue: No ]
    Time to reach peak concentration after drug administration.

  • Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)) [ 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 ] [ Designated as safety issue: No ]
    AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.

  • Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)/Dose [ 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 ] [ Designated as safety issue: No ]
    AUC is a measure of the serum concentration of Belinostat over time. It is used to characterize drug absorption.

  • Relative Change Observed in Total Protein Hyperacetylation of Cluster of Differentiation 3 (CD3)+T Cells With Belinostat [ Time Frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.

  • Relative Changes in the Number of Tregs With Treatment [ Time Frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.

  • Relative Changes in T Cell Immunoglobulin Domain and Mucin Domain-3 (TIM3)-Expressing Cluster of Differentiation 8 (CD8)+Tcells [ Time Frame: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Changes in marker levels from baseline. All pre values were set to 1 so that we could measure changes relative to the baseline.


Enrollment: 26
Study Start Date: March 2010
Estimated Study Completion Date: June 2017
Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.
  Eligibility

Ages Eligible for Study:   18 Years to 100 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

-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.

  7. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan.
  8. Patients must have recovered from toxicity related to prior therapy (surgery or radiation) to grade less than or equal to 1 and must be at least 28 days since any prior radiation or major surgery.

    Target lesions cannot be selected within previously irradiated areas, if not newly arising or clearly progressing after irradiation as proven by repeat scanning.

  9. Concurrent corticosteroids for myasthenia gravis, or other paraneoplastic syndromes, or other chronic conditions are allowed.

    Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of belinostat or cisplatin, doxorubicin or cyclophosphamide will be determined following review of their case by the Principal Investigator. Efforts should be made to switch patients with brain metastases who are taking enzyme-inducing anticonvulsant agents to other medications.

  10. 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.
  11. 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01100944

Locations
United States, Maryland
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)
  More Information

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Arun Rajan, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT01100944     History of Changes
Other Study ID Numbers: 100077  10-C-0077 
Study First Received: March 18, 2010
Results First Received: July 26, 2016
Last Updated: November 14, 2016
Health Authority: United States: Federal Government
United States: Food and Drug Administration
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by 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
Neoplasms, Complex and Mixed
Neoplasms by Histologic Type
Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lymphatic Diseases
Doxorubicin
Liposomal doxorubicin
Belinostat
Cyclophosphamide
Cisplatin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on December 02, 2016