E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Patients with peripheral T-cell lymphoma (PTCL) where the disease has reoccurred after initial treatment with chemotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10034622 |
E.1.2 | Term | Peripheral T-cell lymphomas NEC |
E.1.2 | System Organ Class | 100000004851 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to determine the objective response rate in patients with peripheral T cell lymphoma who are treated with belinostat monotherapy. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of the study are to determine: safety of belinostat monotherapy time to response duration of response time to progression (TTP) progression-free survival (PFS) one-year progression-free rate one-year survival rate overall survival (OS) Additional objectives are to assess: population pharmacokinetics medical care utilization during treatment with belinostat monotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A histologically confirmed diagnosis of PTCL based on pathology review at the local institution, using the most recent edition of the WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues as guidance leading to the diagnosis of: � Anaplastic large cell lymphoma, ALK-positive � Anaplastic large cell lymphoma, ALK-negative � Angioimmunoblastic T-cell lymphoma � Enteropathy-associated T-cell lymphoma � Extranodal NK/T-cell lymphoma, nasal type � Hepatosplenic T-cell lymphoma � Peripheral T-cell lymphoma, not otherwise specified (NOS) � Subcutaneous panniculitis-like T-cell lymphoma Diagnosis of PTCL should be based on identification in biopsy specimens of a peripheral T-cell lymphoma disorder characterized by positivity in the malignant cell population of at least 3 of the following T-cell markers: �F1, CD2, CD3, CD4, CD5, CD7, CD8, and negativity of at least 2 of the following B-cell markers CD19, CD20, CD79alpha and Pax-5. Further, CD56 should be used for the diagnosis of the nasal type, while CD30, ALK-1 and Pax-5 (that should be negative) are required for the anaplastic type. CD10, CXCL13, PD-1 and CD 21 are warranted for the diagnosis of angioimmunoblastic T-cell lymphoma along with EBER in situ hybridization. Mandatory is the determination of Mib-1/Ki-67 in all instances. Finally, additional markers useful within the context of anaplastic large cell lymphoma, extranodal NK/T-cell lymphoma and subcutaneous panniculitis-like T-cell lymphoma are TIA-1, granzyme B and Perforin. Thus, it is acknowledged that no marker has absolute lineage specificity, and that immunophenotypic studies should be performed with panels of monoclonal antibodies. Further, the pathology sample must be considered to be adequate, meaning that there must be enough well-preserved, formalin-fixed biopsy material for the pathologist to be able to perform a morphological and immunohistochemical examination so as to in confidence be able to state an unequivocal diagnosis of PTCL. Final diagnoses containing caveats such as �suspicious of� or �presumably� are considered inadequate for a patient to be enrolled in the trial. 2. Pathology material must be available at the site for each patient before enrolment so that it can be sent to the Sponsor (or designee) for central pathology review. 3. Patients must have relapsed or refractory disease after at least one prior systemic anticancer regimen. Systemic anticancer therapy is defined as chemotherapy or immunotherapy administered systemically. 4. Patients must have at least one site of disease measurable in two dimensions by computed tomography (CT). 5. Age ? 18 years. 6. Laboratory status as follows: a. Absolute neutrophil count ? 1.0 x 109/L, platelets ? 50 x 109/L. b. Total bilirubin ?1.5 x upper normal limit, or ? 3 x upper normal limit if documented hepatic involvement with lymphoma, or ? 5 x upper normal limit if history of Gilbert�s Disease. c. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 x upper normal limit (? 5 x upper normal limit if documented hepatic involvement with lymphoma). d. Serum potassium within normal range. e. Calculated creatinine clearance ? 45 mL/min/1.73 m2 based on Cockcroft and Gault�s method (Cockcroft 1976). f. PT or INR, and APTT ? 1.5 x upper limit of normal unless patient is receiving anticoagulants. If patient is on anticoagulation therapy, levels should be within therapeutic range. 7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 8. Estimated life expectancy greater than 3 months. 9. Negative pregnancy test for women of childbearing potential. 10. Signed informed consent form approved by the local Ethics Committee or Institutional Review Board. |
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E.4 | Principal exclusion criteria |
1. Any use of anticancer therapies within 2 weeks prior to initiation of study treatment; in addition, patients should have recovered from prior treatment-related toxicities and meet laboratory and ECOG criteria for inclusion. 2. Any use of investigational therapies within 3 weeks prior to initiation of study treatment. 3. Major surgery within 2 weeks of study drug administration. 4. Relapse within 100 days of autologous or allogeneic bone marrow transplant. 5. Prior HDAC inhibitor therapy. 6. Patients with a diagnosis of: � Precursor T-cell lymphoma or leukemia � Adult T-cell lymphoma/leukemia (ATLL) � T-cell prolymphocytic leukemia � T-cell large granular lymphocytic leukemia � Primary cutaneous type anaplastic large cell lymphoma � Mycosis fungoides/Sezary syndrome 7. Co-existing active infection or any medical condition likely to interfere with trial procedures. 8. Significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of frequency adjusting medication for atrial fibrillation is allowed, if stable medication for at least last month prior to randomization and medication not listed as causing Torsade de Points, see Section 16.2, Appendix B), or evidence of acute ischemia on ECG. 9. Baseline prolongation of QT/QTc interval, i.e., demonstration of a QTc interval > 450 msec; Long QT Syndrome; the required use of concomitant medication that may cause Torsade de Pointes (see Section 16.2 Appendix B for list of such medications). 10. Clinically significant central nervous system disorders with altered mental status or psychiatric disorders precluding understanding of the informed consent process and/or completion of the necessary studies. 11. Active concurrent malignancy (except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, the patient must be disease free for greater than or equal to 2 years (except carcinoma in situ of breast, prostate cancer, or superficial bladder cancer). 12. Symptomatic or untreated central nervous system (CNS) metastases. Patients with previously treated CNS metastases which are asymptomatic at baseline are permitted. 13. Pregnant or breast-feeding women. 14. Women of childbearing age and potential who are not willing to use effective contraception during the study and until 30 days after last dose of study drug. Male patients or male patients who have female partners of childbearing age and potential who are not willing to use effective contraception during the study and until 30 days after last dose of study drug. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner. 15. Known infection with HIV, hepatitis B or hepatitis C. 16. Patients that are not affiliated with social security (study centers in France only). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint is objective reponse rate (ORR), defined as complete response (CR) or partial response (PR) based on independent radiology review. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
2 years after start of treatment of last patient. |
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E.5.2 | Secondary end point(s) |
time to response, duration of response, time to progression (TTP), progression free-survival (PFS), one-year progression-free rate, one-year survival rate, overall (OS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
2 years after start of treatment of last patient is the timepoint of evaluations for all end points |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 58 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Croatia |
Denmark |
France |
Germany |
Hungary |
Israel |
Italy |
Netherlands |
Poland |
Slovakia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Patients will be treated with Belinostat 1000 mg/m2 30 minute iv infusion on days 1-5 every 3 weeks until there is disease progression or unmanageable treatment-related toxicities or patient wishes to stop treatment. All patients to be followed until progressive disease and furthermore patients are followed up till 2 years for survival. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |