ThymomaPhase 1/2NCT01100944
A Phase 1/2 Study of PXD101 (Belinostat) in Combination With Cisplatin, Doxorubicin and Cyclophosphamide in the First Line Treatment of Advanced or Recurrent Thymic, Malignancies
A Phase 1/2 study testing PXD101with cisplatin+doxorubicin+cyclophosphamide in people with Thymoma and Thymic Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
Background: Tumors of the thymus are rare and can be treated with surgery, but it is often difficult to determine whether a thymic tumor is malignant based on biopsy alone and the long-term survival rate is less than 50 percent. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Thymoma, Thymic Carcinoma
- What is being tested?
- PXD101with cisplatin+doxorubicin+cyclophosphamide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 26 participants
- Where
- 1 siteUnited States
- Study dates
- 4 Mar 2010to 21 Oct 2015
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Both men and women of all races and ethnic groups are eligible for this trial
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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
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.
Read more
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....
Read the 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.
- Conditions
- Thymoma, Thymic Carcinoma
- Being tested
- PXD101with cisplatin+doxorubicin+cyclophosphamide
- Keywords
- Gene Expression, HDAC Class I and II enzymes, Thymoma, Chemotherapy, Hydroxamic Acid Deacetylase Inhibitor, Thymic Cancer
- Medical subject headings
- Thymoma, Thymus Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PXD101with cisplatin+doxorubicin+cyclophosphamideDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Therapy in Thymic Malignancies | Experimental | 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. Receives: Drug: PXD101with cisplatin+doxorubicin+cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 43 months
Secondary outcomes (18)
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.
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline Cycle 1 Day 1 (C1D1), Cycle 1 Day 2 (C1D2), Cycle 1 Day 3 (C1D3), and Cycle 2 Day 1 (C2D1)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2010 (estimated)
- Study start4 Mar 2010
- Primary completion21 Oct 2015
- Study completion21 Oct 2015
Why it stopped: Principal investigator left the National Institutes of Health (NIH).
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for ThymomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 26 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Arun Rajan, M.D., National Institutes of Health Clinical Center (CC)
- Investigators
- Arun Rajan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01100944
- Sponsor's protocol ID
- 100077
- Other IDs
- 10-C-0077
- Status last verified
- Jul 2017
- First submitted
- 18 Mar 2010
- Last updated
- 10 Aug 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P. Thymoma: a focus on current therapeutic management. J Thorac Oncol. 2009 Jan;4(1):119-26. doi: 10.1097/JTO.0b013e31818e105c.
PubMed 19096319Loehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, Blum R. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol. 1994 Jun;12(6):1164-8. doi: 10.1200/JCO.1994.12.6.1164.
PubMed 8201378Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol. 2005 Mar;17(2):140-6. doi: 10.1097/01.cco.0000152628.43867.8e.
PubMed 15725919Thomas A, Rajan A, Szabo E, Tomita Y, Carter CA, Scepura B, Lopez-Chavez A, Lee MJ, Redon CE, Frosch A, Peer CJ, Chen Y, Piekarz R, Steinberg SM, Trepel JB, Figg WD, Schrump DS, Giaccone G. A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clin Cancer Res. 2014 Nov 1;20(21):5392-402. doi: 10.1158/1078-0432.CCR-14-0968. Epub 2014 Sep 4.
PubMed 25189481Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ Sr. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol. 2011 May 20;29(15):2052-9. doi: 10.1200/JCO.2010.32.4467. Epub 2011 Apr 18.
PubMed 21502553
Study at a glance
From the registry record, last updated by the sponsor on 10 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01100944
- Acronym / sponsor ID
- 100077
- Conditions
- Thymoma, Thymic Carcinoma
- Keywords
- Gene Expression, HDAC Class I and II enzymes, Thymoma, Chemotherapy, Hydroxamic Acid Deacetylase Inhibitor, Thymic Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Principal investigator left the National Institutes of Health (NIH).
- Enrolment
- 26 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 4 Mar 2010 (actual)
- Primary completion
- 21 Oct 2015 (actual)
- Study completion
- 21 Oct 2015 (actual)
- First posted
- 9 Apr 2010 (estimated)
- Results
- Posted 15 Nov 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Background:
- New options for the treatment of patients with advanced thymoma and thymic carcinoma are needed.
- Belinostat, N-hydroxy-3-(phenylsulphamoylphenyl) acrylamide, is a hydroxamic acid deacetylase inhibitor that is able to inhibit both histone deacetylase inhibitors (HDAC) Class I and II enzymes.
- An ongoing phase II study of belinostat in recurrent or metastatic thymic malignancies has shown activity which warrants further consideration of belinostat in the first line.
- Belinostat alterations in target protein levels due to gene expression changes may allow increased sensitivity of cancer cells to conventional chemotherapy.
Objectives:
Primary Objectives
- In the Phase I portion the primary objective will be to determine a safe and tolerable phase 2 dose, dose limiting toxicities (DLTs) and preliminary activity for the combination of belinostat by continuous intravenous (IV) infusion (CIVI) with cisplatin, doxorubicin and cyclophosphamide in patients with advanced thymic malignancies.
- In the Phase II portion the primary objective will be to determine the clinical response rate (partial response (PR)+complete response (CR)) of belinostat in combination with cisplatin, doxorubicin and cyclophosphamide in the first line treatment of patients with advanced thymic malignancies.
Secondary Objectives
- To determine time to response, duration of response, progression free survival (PFS) and overall survival (OS).
- To determine the toxicity profile and safety of this combination.
- To assess exploratory correlative markers in relation to response to treatment (immunohistochemistry and array Comparative Genomic Hybridization (CGH))
Eligibility:
- Patients with histologically confirmed advanced thymic malignancies who are chemotherapy na(SqrRoot) ve.
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
- Adequate renal, hepatic and hematopoietic function
Design:
- The Phase I portion of the study will consist of four dose levels and dose escalations will follow according to traditional 3 patient cohorts.
- Once the maximum tolerated doe is determined, the phase II portion of the study will begin.
- Belinostat will be given as a 48h CIVI starting on day 1, doxorubicin as a slow intravenous (IV) injection on days 2 and 3, cisplatin will be infused over 1 hour on day 2 and cyclophosphamide as a slow IV infusion on Day 3.
- Treatment will be given every 21 days for no more than 6 cycles or until disease progression. Treatment with belinostat alone may continue until disease progression.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Therapy in Thymic Malignancies | Experimental | Drug: PXD101with cisplatin+doxorubicin+cyclophosphamidePXD101 (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. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Both men and women of all races and ethnic groups are eligible for this trial
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PXD101with cisplatin+doxorubicin+cyclophosphamidePXD101 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. | Drug | Therapy in Thymic Malignancies |
Primary outcome
Maximum Tolerated Dose (MTD) of Belinostat
Time frame: 2 years
The MTD is defined as the highest dose at which less than 2 out of 6 patients experienced a dose limiting toxicity (DLT). A DLT is defined as grade 4 neutropenia lasting more than 7 days despite prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia defined as absolute neutrophil count (ANC) less than 1000/mm(3) and temperature more than 38.5 degrees Celsius or 100.4 degrees Fahrenheit or life threatening sepsis, grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding during the first cycle of therapy. Any grade 3 or 4 non-hematologic toxicity was considered dose limiting with the following exceptions: grade 3 diarrhea lasting less than 48 hours, grade 3 nausea and/or vomiting lasting less than 48 hours, grade 3 electrolyte abnormalities lasting less than 48 hours, grade 3 creatinine elevation lasting less than 48 hours.
Number of Participants With Grade 3 and 4 Dose Limiting Toxicity (DLT) at 2000mg/m(2) Belinostat
Time frame: 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.
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
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.
18 secondary outcomes
Number of Participants With Serious and Non-serious Adverse Events
Time frame: up to 122 months
Treatment-related Grade 3 and 4 Adverse Events (Highest Grade Per Event Per Patient)
Time frame: up to 122 months
Clinical Response
Time frame: 43 months
Disease Control Rate (DCR)
Time frame: 43 months
Time to Response
Time frame: From the first day of treatment until the date of first documented response, assessed up to 43 months
Duration of Response
Time frame: From the time of first response until date of progression, assessed up to 43 months
Progression Free Survival (PFS)
Time frame: Start of treatment to time of disease progression or death whichever occurs first, assessed up to 43 months
Overall Survival (OS)
Time frame: Start of treatment to time of death, assessed up to 43 months
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.
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
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
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
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
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
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
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)
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)
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Aug 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19096319Girard N, Mornex F, Van Houtte P, Cordier JF, van Schil P. Thymoma: a focus on current therapeutic management. J Thorac Oncol. 2009 Jan;4(1):119-26. doi: 10.1097/JTO.0b013e31818e105c.
- Background: PubMed 8201378Loehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, Blum R. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol. 1994 Jun;12(6):1164-8. doi: 10.1200/JCO.1994.12.6.1164.
- Background: PubMed 15725919Giaccone G. Treatment of malignant thymoma. Curr Opin Oncol. 2005 Mar;17(2):140-6. doi: 10.1097/01.cco.0000152628.43867.8e.
- Results publication: PubMed 25189481Thomas A, Rajan A, Szabo E, Tomita Y, Carter CA, Scepura B, Lopez-Chavez A, Lee MJ, Redon CE, Frosch A, Peer CJ, Chen Y, Piekarz R, Steinberg SM, Trepel JB, Figg WD, Schrump DS, Giaccone G. A phase I/II trial of belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in thymic epithelial tumors: a clinical and translational study. Clin Cancer Res. 2014 Nov 1;20(21):5392-402. doi: 10.1158/1078-0432.CCR-14-0968. Epub 2014 Sep 4.
- Derived from this study: PubMed 21502553Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ Sr. Phase II study of belinostat in patients with recurrent or refractory advanced thymic epithelial tumors. J Clin Oncol. 2011 May 20;29(15):2052-9. doi: 10.1200/JCO.2010.32.4467. Epub 2011 Apr 18.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arun Rajan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing PXD101with cisplatin+doxorubicin+cyclophosphamide in people with Thymoma and Thymic Carcinoma, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 10 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Nov 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose (MTD) of Belinostat (time frame: 2 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01100944, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Aug 2017.