To Evaluate Efficacy of Belinostat or Pralatrexate in Combination Against CHOP Alone in PTCL

Study Overview
=================
Brief Summary
-----------------
Part 1: This is a 5 Arm study primarily to determine the best dose out of the two dose levels of Belinostat and Pralatrexate combined with CHOP/COP in newly diagnosed PTCL patients based on Safety for part 2 study. Part 2 (Efficacy and Safety): This is a 3 Arm study. Patients with previously untreated PTCL will be randomized 1:1:1 into 1 of 3 treatment groups: 2 experimental treatment groups (Bel-CHOP or Fol-COP) or 1 active comparator treatment group (CHOP). Patients will be treated for up to 6 cycles. The primary objective is to compare the Progression Free Survival of patients with newly diagnosed PTCL treated for up to 6 cycles with Beleodaq (belinostat) in combination with CHOP (Bel-CHOP) or Folotyn (pralatrexate injection) in combination with COP (Fol-COP) to CHOP alone.

Detailed Description
-----------------
Study Design and Treatment Plan: Part 1: Dose Finding It is a randomized, open label, multicenter study in patients with PTCL who have not been previously treated and the control arm is CHOP, COP, is the CHOP regimen without Doxorubicin (H). Two investigational agents are separately added to C(H)OP, Belinostat for Bel-CHOP and Pralatrexate for FOL-COP. In this first part, each investigational arm will have two dose levels which will be compared with CHOP as reference. Treatment will be randomized in five arms: Group 1a (Bel-CHOP) Belinostat 600 mg/m2 Group 1b (Bel-CHOP) Belinostat 1000 mg/m2 Group 2a (Fol-COP) Pralatrexate 20 mg/m2 Group 2b (Fol-COP) Pralatrexate 30 mg/m2 Group 3 for CHOP alone. Analysis will be done when 75 patients have received their planned treatment cycles to evaluate treatment compliance. Approximately 20 patients will be enrolled into each group and receive at least one cycle of drug thus 15 patients are expected to be evaluated with their planned treatment of 6 cycles completed. The safety data will be evaluated to select the proper dose for Belinostat -CHOP and Pralatrexate-COP for the Part 2 study. Part 2: Efficacy and Safety It is a randomized, open-label, multicenter study in newly diagnosed PTCL patients. This is a three arm study and 143 patients will enroll in each arm. Patients will be randomized in a balance manner (1:1:1) into 1 of 3 treatment groups and treated for up to 6 cycles: Group 1: (Bel-CHOP): Belinostat at the dose determined from Part 1 (600 or 1000 mg/m2) to be administered on Day 1 by 30 min intravenous (IV) infusion once daily for 5 days; CHOP will also be administered starting on Day 1 within 15 min (±5 min) after the end of the belinostat infusion at the doses shown below for Group 3, with cycles repeated every 21 days for up to 6 cycles Group 2: (Fol-COP): Pralatrexate at the dose determined from part 1 (20 or 30 mg/m2) is to be administered on Day 1 and Day 8 as an IV push over 3 to 5 min; CHOP will also be administered starting on Day 1 within 15 min (±5 min) after the end of the pralatrexate administration at the doses shown below for Group 3, with cycles repeated every 21 days for up to 6 cycles. COP combination refers to CHOP without Doxorubicin (H). Group 3: (CHOP): Combination chemotherapy to be administered starting on Day 1 at the doses shown below, with cycles repeated every 21 days for up to 6 cycles Cyclophosphamide 750 mg/m2 IV, Day 1 Doxorubicin 50 mg/m2 IV, Day 1 (limit lifetime cumulative dose to <550 mg/m² to reduce risk of cardiotoxicity) Vincristine 1.4 mg/m2 (maximum 2 mg) IV, Day 1 Prednisone 100 mg orally (PO) daily, Day 1 (after the end of the belinostat or pralatrexate administration for Groups 1 and 2) to Day 5 Randomization will be stratified on: Histology (nodal, extra-nodal) Prognostic Index for T-Cell Lymphoma (Group 1 or 2 vs 3 or 4) Region (US, ex-US) The study duration will include up to a 28-day screening period, a 6-cycle treatment period (18 weeks), follow-up until progression, an End-of-Treatment Visit at least 30 days after the last dose of study treatment, and long-term survival follow-up for patients by phone every 6 months thereafter until a 5-year median follow-up of the population is reached. Patients discontinuing the study for other reasons than progression will have the same long-term follow-up for OS analysis. Tumor assessments will be performed every 3 cycles (i.e., 9 weeks) on Cycle 4 Day 1 and End-of-Treatment Visit during treatment, then every 3 months for 3 years for patients with complete response (CR), partial response (PR), or stable disease, and every 6 months thereafter until disease progression or death

Official Title
-----------------
A Phase 3, Randomized, Open-Label Study Comparing the Efficacy and Safety of the Combination of Beleodaq-CHOP or Folotyn-COP to the CHOP Regimen Alone in Newly Diagnosed Patients With Peripheral T-Cell Lymphoma

Conditions
-----------------
Peripheral T Cell Lymphoma

Intervention / Treatment
-----------------
* Drug: Belinostat Injection
* Drug: Pralatrexate Injection
* Drug: CHOP
* Drug: COP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient with newly diagnosed, untreated histology-proven PTCL based on local pathology review who is eligible for receiving, Belinostat, Pralatrexate, and CHOP. Pathology material must be available at the site for each patient before enrollment so it can be sent to the Sponsor (or designee) for confirmation. The following subtypes, as defined by the updated World Health Organization (WHO) classification, may be included. This information should be available for eligibility: Pathology subtype: Peripheral T-cell lymphoma, not otherwise specified Angioimmunoblastic T-cell lymphoma Anaplastic lymphoma kinase (ALK)- negative anaplastic large-cell lymphoma (ALCL) Follicular T cell lymphoma Others: Extra-nodal natural killer/T-cell lymphoma, nasal type; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; and subcutaneous panniculitis-like T-cell lymphoma CD30 expression TFH phenotype Patient has at least 1 site of measurable disease according to Response Evaluation Criteria in Lymphoma (RECIL) 2017 criteria as assessed by the local Investigator (Appendix 3) Patient has an Eastern Cooperative Oncology Group performance status ≤2 For Part 1 (Dose Finding) - Patient has adequate hematological, hepatic, and renal function as defined by: a. Absolute neutrophil count ≥1.5×109 L b. Platelet count ≥100×109 L c. Total bilirubin ≤1.5 mg/dL d. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤3×the upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma) e. Serum creatinine ≤2.0×ULN or calculated creatinine clearance of ≥60 mL/min Part 2 (Efficacy and Safety) - disease related hypoplasia, hepatological or renal dysfunction can be included if any of the treatment groups can be administered based on package insert recommendation with the following restrictions: Absolute neutrophil count ≥1.0×109/L or >= ≥1.5×109/L if bone marrow involvement Platelet count ≥100×109 L or ≥75×109 L if bone marrow involvement Total bilirubin ≤1.5 mg/dL Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤3×the upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma) Serum creatinine ≤2.0×ULN Calculated creatinine clearance of ≥60 mL/min UGT1A1 genotype has been characterized (see Belinostat dose modifications if abnormal). A decision whether to use prophylactic growth factor for cycle 1 or not has been made Patient must be willing and capable of giving written informed consent and must be able to adhere to dosing and visit schedules and meet all study requirements Patient (male/female) is at least 18 years of age at the time of informed consent Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from study entry until at least 30 days after the last dose of study treatment Females of childbearing potential must have a negative urine pregnancy test within 4 weeks prior to the first day of study treatment. Females who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or are surgically sterilized do not require this test Exclusion Criteria: Patients with a diagnosis of: Precursor T-cell lymphoma or leukemia Adult T-cell lymphoma/leukemia T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Primary cutaneous type ALCL Cutaneous T-cell lymphoma (mycosis fungoides/Sezary syndrome) ALCL except if Brentuximab Vendotin cannot be utilized Patients taking drugs which are potent UGT1A1 inhibitors must discontinue one week before randomization; drug can be resumed if the treatment doesn't include belinostat Patient with an active concurrent malignancy/life-threatening disease with the exception of non melanoma skin tumors and in situ cervical cancer if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease. If there is a history of prior malignancies/life-threatening diseases, the patient must be disease free for at least 5 years Prior histone deacetylase (HDAC) inhibitor or pralatrexate therapy Any known cardiac abnormalities such as baseline prolongation of QT/corrected QT (QTc) interval (ie,demonstration of a QTc interval >450 msec); long QT syndrome; myocardial infarction within 6 months prior to starting study; history of significant cardiovascular disease; the required use of a concomitant medication that may cause Torsades de Pointes Patient with uncontrolled hypertension Patients with a known HIV-positive diagnosis, hepatitis B virus or hepatitis C virus diagnosis with detectable viral load or immunological evidence of chronic active disease Patient with central nervous system metastasis Patient with an active uncontrolled infection, underlying medical condition, laboratory abnormality, or other serious illness that would impair the ability of the patient to receive protocol treatment Patient who has used any investigational drugs, biologics, or devices within 28 days prior to study treatment or plans to use any of these during the course of the study Patient with a known history of drug or alcohol abuse Pregnant or breastfeeding women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A Phase 3, Randomized, Open-Label Study Comparing the Efficacy and Safety of the Combination of Beleodaq-CHOP or Folotyn-COP to the CHOP Regimen Alone in Newly Diagnosed Patients with Peripheral T-Cell Lymphoma
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1a<br>Group 1a Belinostat 600 mg/m2 + CHOP | Drug: Belinostat Injection<br>* Belinostat 600 mg/m2 or 1000 mg/m2 along with CHOP is given in each cycle<br>* Other names: Beleodaq®;Drug: CHOP<br>* CHOP is the comparator arm<br>* Other names: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and Prednisone;|
| Active Comparator: Group 1b<br>Group 1b Belinostat 1000 mg/m2 + CHOP | Drug: Belinostat Injection<br>* Belinostat 600 mg/m2 or 1000 mg/m2 along with CHOP is given in each cycle<br>* Other names: Beleodaq®;Drug: CHOP<br>* CHOP is the comparator arm<br>* Other names: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and Prednisone;|
| Active Comparator: Group 2a<br>Group 2a Pralatrexate 20 mg/m2 + COP | Drug: Pralatrexate Injection<br>* Pralatrexate 20 mg/m2 or 30 mg/m2 along with COP is given in each cycle<br>* Other names: Folotyn®;Drug: COP<br>* COP is given in combination with Pralatrexate<br>* Other names: Cyclophosphamide, Oncovin (vincristine), and Prednisone;|
| Active Comparator: Group 2b<br>Group 2b Pralatrexate 30 mg/m2 + COP | Drug: Pralatrexate Injection<br>* Pralatrexate 20 mg/m2 or 30 mg/m2 along with COP is given in each cycle<br>* Other names: Folotyn®;Drug: COP<br>* COP is given in combination with Pralatrexate<br>* Other names: Cyclophosphamide, Oncovin (vincristine), and Prednisone;|
| Active Comparator: Group 3<br>CHOP | Drug: CHOP<br>* CHOP is the comparator arm<br>* Other names: Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), and Prednisone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-free survival is determined from randomization to the first documented Progression of Disease or death, whichever occurs first. | 4.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | It is the time from randomization to the death | 8 years |