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NCT06072131PHASE3Recruiting

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

Acrotech Biopharma Inc.

Start Date

10/4/2023

Completion Date

11/1/2030

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: 1. Group 1a (Bel-CHOP) Belinostat 600 mg/m2 2. Group 1b (Bel-CHOP) Belinostat 1000 mg/m2 3. Group 2a (Fol-COP) Pralatrexate 20 mg/m2 4. Group 2b (Fol-COP) Pralatrexate 30 mg/m2 5. 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

Eligibility Criteria

Age Range: 18 years to No maximum

Inclusion Criteria: 1. 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 that it can be sent to the Sponsor (or designee) for later confirmation. The following subtypes, as defined by the updated World Health Organization (WHO) classification, may be included. This information should be available for eligibility: 1. Pathology subtype: * Peripheral T-cell lymphoma, not otherwise specified * Angioimmunoblastic T-cell lymphoma * Anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) patients are eligible only if Brentuximab Vedotin (BV) is not commercially approved for use, not available in the country or patient is contraindicated to receive BV. * 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 2. CD30 expression and T-cell Follicular Helper (TFH) phenotype status must be available for documentation. 2. 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) 3. Patient has an Eastern Cooperative Oncology Group performance (ECOG) status ≤2 4. For Part 1 (Dose Finding) - Patient has adequate hematological, hepatic, and renal function as defined by: 1. Absolute neutrophil count ≥ 1.5 × 10⁹/L or ≥ 1.0 × 10⁹/L if evidence of bone marrow involvement 2. Platelet count ≥100×10⁹/L or ≥ 75×10⁹/L if evidence of bone marrow involvement 3. Total bilirubin ≤1.5 mg/dL 4. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤ 3×upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma) 5. Calculated creatinine clearance of ≥ 60 mL/min 5. 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: 1. Absolute neutrophil count ≥ 1.5 × 10⁹/L or ≥ 1.0 × 10⁹/L if evidence of bone marrow involvement 2. Platelet count ≥100×10⁹/L or ≥ 75×10⁹/L if evidence of bone marrow involvement 3. Total bilirubin ≤1.5 mg/dL 4. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤ 3 x the upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma) 5. Calculated creatinine clearance of ≥ 60 mL/min 6. UGT1A1 genotype has been characterized (see Belinostat dose modifications if abnormal) and must be available for documentation. 7. 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 8. Patient (male or female) is at least 18 years of age at the time of informed consent 9. Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from study entry until at least 6 months after the last dose of study treatment. 10. 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: A patient will not be eligible for inclusion if ANY of the criteria listed below apply: 1. Patients with a diagnosis of: 1. Precursor T-cell lymphoma or leukemia 2. Adult T-cell lymphoma/leukemia 3. T-cell prolymphocytic leukemia 4. T-cell large granular lymphocytic leukemia 5. Primary cutaneous type ALCL 6. Cutaneous T-cell lymphoma (mycosis fungoides/Sezary syndrome) 7. ALCL if they can be treated with Brentuximab Vedotin (BV) 2. 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 3. 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 4. Prior histone deacetylase (HDAC) inhibitor or pralatrexate therapy 5. Any known cardiac abnormalities such as baseline prolongation of QT/corrected QT (QTc) interval (i.e. 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 6. Patient with uncontrolled hypertension 7. Patients status on the following: 1. Has a known HIV-positive diagnosis with uncontrolled and detectable viral load 2. Has Hepatitis B or Hepatitis C virus diagnosis with uncontrolled and detectable viral load or immunological evidence of chronic active disease 8. Patient with central nervous system metastasis 9. 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 10. 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 11. Patient with a known history of drug or alcohol abuse 12. Pregnant or breastfeeding women

Interventions

DRUG

Belinostat Injection

DRUG

Pralatrexate Injection

DRUG

CHOP

DRUG

COP

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Conditions

Peripheral T Cell Lymphoma

Locations

University of California, San Francisco Fresno

Clovis, California 93611

United States

University of California, Los Angeles Hem/ Onc Clinical Research Unit, Suite 600

Santa Monica, California 90404

United States

University of Colorado School of Medicine

Aurora, Colorado 80045

United States

Moffitt Malignant Hematology &amp; Cellular Therapy at Memorial Healthcare System Memorial Cancer Institute

Pembroke Pines, Florida 33026

United States

Norton Cancer Institute

Louisville, Kentucky 40207

United States

Henry Ford Health System

Detroit, Michigan 48202

United States

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey 08901

United States

Valley Cancer Associates

Harlingen, Texas 78550

United States

Houston Methodist Hospital

Houston, Texas 77030

United States

University of Texas, MD Anderson Cancer Center

Houston, Texas 77030

United States

Baylor Scott & White Medical Center - Temple

Temple, Texas 76508

United States

The Ottawa Hospital

Ottawa, Ontario K1H 8L6

Canada

Princess Margaret Hospital

Toronto, Ontario M5G 2C4

Canada

Universitatsmedizin Gottingen

Göttingen, 37075

Germany

Universitaetsklinikum Halle (Saale)

Halle, 06120

Germany

University of Debrecen Clinical Center

Debrecen, Nagyerdei Krt. 98 4032

Hungary

Andras Josa University Teaching Hospital

Nyíregyháza, Szent Istvan Utca 68

Hungary

Semmelweis Egyetem

Budapest, 1088

Hungary

National Institute of Oncology

Budapest, 1122

Hungary

Markhot Ferenc Oktato Korhaz

Eger, 3300

Hungary

Belgyogyaszati Klinika es Kardiologiai Kozpont

Szeged, 6725

Hungary

Azienda Ospedaliera Cardinale Giovanni Panico

Tricase, Apulia 73039

Italy

University of Milano Bicocca

Milan, Bicocca 20126

Italy

Servizio Sanitario Regionale Emilia-Romagna-Istituto Scientifico Romagnolo per lo Studio dei Tumori "Dino Amadori" Srl (IRST)

Meldola, Province Of Forlì-Cesena 47014

Italy

Policlinico GB Rossi Borgo Roma

Borgo Roma, Verona 37134

Italy

Azienda Ospedaliera SS. Antonio e Biagio e C. Arrigo

Alessandria,

Italy

Ospedale Policlinico San Martino, IRCCS

Genova, 16132

Italy

Azienda Ospedaliera Universitaria di Parma

Parma, 43126

Italy

Fondazione IRCCS Policlinico San Matteo

Pavia, 27100

Italy

Azienda USL di Ravenna

Ravenna, 41800

Italy

University Hospital in Wroclaw

Wroclaw, Wroclaw 50-367

Poland

Pratia MCM Krakow

Krakow, 30-727

Poland

Narodowy Instytut Onkologii im Marii Sklodowskiej-Curie Panstwowy Instytut Badawczy

Warsaw,

Poland

Wojewodzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi

Lodz, Łódź Voivodeship 93-513

Poland

Inje University Busan Paik Hospital

Busan, Busanjin District

South Korea

Ulsan University Hospital

Ulsan, Dong-gu

South Korea

Ajou University Hospital

Suwon, Gyenoggi-do 16499

South Korea

The Catholic University of Korea - St. Vincents Hospital

Suwon, Gyeonggi-do

South Korea

Gyeongsang National University Hospital

Jinju, Gyeongsangnam-do

South Korea

Jeonbuk National University Hospital

Jeonju, Jeollabuk-do

South Korea

Yeungnam University Medical Center

Daegu, Nam-gu

South Korea

Severance hospital, Yonsei University

Sinchon-dong, Seoul

South Korea

Asan Medical Center

Songpa-dong, Seoul 05505

South Korea

Daegu Catholic University Medical Center

Daegu, 42472

South Korea

Gachon University Gil Medical Center

Incheon, 21565

South Korea

Samsung Medical Center

Seoul, 6351

South Korea

Seoul National University Hospital

Seoul,

South Korea

Hospital Universitario Basurto

Bilbao, Bizkaia 48013

Spain

Hospital Universitario Fundación Jiménez Díaz

Moncloa-Aravaca, Madrid 28040

Spain

Hospital Universitario de Navarra

Pamplona, Navarre 31008

Spain

Hospital del Mar Medical Research Institute

Barcelona, 08003

Spain

ICO - Hospital Duran i Reynals

Barcelona, 08908

Spain

Clinica Universidad de Navarra - Madrid

Madrid, 28027

Spain

Clinica Universidad de Navarra

Pamplona, 31008

Spain

Hospital Universitario de Salamanca

Salamanca, 37007

Spain

Hospital Universitario y Politecnico La Fe

Valencia, 46026

Spain

Hospital Universitario Miguel Servet

Zaragoza, 50009

Spain

Changhua Christian Hospital CCH

Changhua, Changhua County

Taiwan

Hualien Tzu Chi Medical Center

Hualien City, Hualien 970

Taiwan

National Cheng Kung University Hospital NCKUH

Tainan, Southern Taiwan 704

Taiwan

Chang Bing Show Chwan Memorial Hospital

Changhua, 505

Taiwan

Hematology Oncology Taipei Medical University - Shuang-Ho Hospital

New Taipei City,

Taiwan

Chang Gung Memorial Hospital Linkou Branch

Taoyuan, 333

Taiwan

Ankara University Medical Faculty Hospital

Altındağ, Ankara 06230

Turkey (Türkiye)

Bilkent University

Çankaya, Ankara 06800

Turkey (Türkiye)

Gazi University Faculty of Medicine

Yenimahalle, Ankara 06560

Turkey (Türkiye)

VKV AMERICAN HOSPITAL, Medical Oncology Outpatient Clinic

Şişli, Istanbul 34365

Turkey (Türkiye)

Adana City Education and Research Hospital

Adana, 4522

Turkey (Türkiye)

Ege Univ. Hospital

Bornova, 35100

Turkey (Türkiye)