To Evaluate Efficacy of Belinostat or Pralatrexate in Combination Against CHOP Alone in PTCL
- Conditions
- Peripheral T Cell Lymphoma
- Interventions
- Registration Number
- NCT06072131
- Lead Sponsor
- Acrotech Biopharma Inc.
- 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:
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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 504
-
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:
-
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
-
CD30 expression and T-cell Follicular Helper (TFH) phenotype status must be available for documentation.
-
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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)
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Patient has an Eastern Cooperative Oncology Group performance (ECOG) status ≤2
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For Part 1 (Dose Finding) - Patient has adequate hematological, hepatic, and renal function as defined by:
- Absolute neutrophil count ≥ 1.5 × 10⁹/L or ≥ 1.0 × 10⁹/L if evidence of bone marrow involvement
- Platelet count ≥100×10⁹/L or ≥ 75×10⁹/L if evidence of 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×upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma)
- 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 ≥ 1.5 × 10⁹/L or ≥ 1.0 × 10⁹/L if evidence of bone marrow involvement
- Platelet count ≥100×10⁹/L or ≥ 75×10⁹/L if evidence of 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 x the upper limit of normal (ULN; AST/ALT ≤5×ULN if documented hepatic involvement with lymphoma)
- Calculated creatinine clearance of ≥ 60 mL/min
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UGT1A1 genotype has been characterized (see Belinostat dose modifications if abnormal) and must be available for documentation.
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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
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Patient (male or female) is at least 18 years of age at the time of informed consent
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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.
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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.
A patient will not be eligible for inclusion if ANY of the criteria listed below apply:
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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 if they can be treated with Brentuximab Vedotin (BV)
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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
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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
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Prior histone deacetylase (HDAC) inhibitor or pralatrexate therapy
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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
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Patient with uncontrolled hypertension
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Patients status on the following:
- Has a known HIV-positive diagnosis with uncontrolled and detectable viral load
- Has Hepatitis B or Hepatitis C virus diagnosis with uncontrolled and detectable viral load or immunological evidence of chronic active disease
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Patient with central nervous system metastasis
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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
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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
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Patient with a known history of drug or alcohol abuse
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Pregnant or breastfeeding women
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 2b Pralatrexate Injection Group 2b Pralatrexate 30 mg/m2 + COP Group 1b CHOP Group 1b Belinostat 1000 mg/m2 + CHOP Group 1a Belinostat Injection Group 1a Belinostat 600 mg/m2 + CHOP Group 2a COP Group 2a Pralatrexate 20 mg/m2 + COP Group 1a CHOP Group 1a Belinostat 600 mg/m2 + CHOP Group 3 CHOP CHOP Group 1b Belinostat Injection Group 1b Belinostat 1000 mg/m2 + CHOP Group 2a Pralatrexate Injection Group 2a Pralatrexate 20 mg/m2 + COP Group 2b COP Group 2b Pralatrexate 30 mg/m2 + COP
- Primary Outcome Measures
Name Time Method PFS 4.5 years Progression-free survival is determined from randomization to the first documented Progression of Disease or death, whichever occurs first.
- Secondary Outcome Measures
Name Time Method Overall survival 8 years It is the time from randomization to the death
Trial Locations
- Locations (52)
University of California, San Francisco Fresno
🇺🇸Clovis, California, United States
University of California, Los Angeles Hem/ Onc Clinical Research Unit, Suite 600
🇺🇸Santa Monica, California, United States
Moffitt Malignant Hematology & Cellular Therapy at Memorial Healthcare System Memorial Cancer Institute
🇺🇸Pembroke Pines, Florida, United States
Norton Cancer Institute
🇺🇸Louisville, Kentucky, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
University of Texas, MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Baylor Scott & White Medical Center - Temple
🇺🇸Temple, Texas, United States
The Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Universitaetsklinikum Halle (Saale)
🇩🇪Halle, Germany
University of Debrecen Clinical Center
🇭🇺Debrecen, Nagyerdei krt. 98, Hungary
Andras Josa University Teaching Hospital
🇭🇺Nyíregyháza, Szent Istvan Utca, Hungary
Semmelweis Egyetem
🇭🇺Budapest, Hungary
National Institute of Oncology
🇭🇺Budapest, Hungary
Markhot Ferenc Oktato Korhaz
🇭🇺Eger, Hungary
Belgyogyaszati Klinika es Kardiologiai Kozpont
🇭🇺Szeged, Hungary
University of Milano Bicocca
🇮🇹Milano, Bicocca, Italy
Azienda Ospedaliera Cardinale Giovanni Panico
🇮🇹Tricase, Puglia, Italy
Policlinico GB Rossi Borgo Roma
🇮🇹Borgo Roma, Verona, Italy
Ospedale Policlinico San Martino, IRCCS
🇮🇹Genova, Italy
Azienda Ospedaliera Universitaria di Parma
🇮🇹Parma, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Azienda USL di Ravenna
🇮🇹Ravenna, Italy
Inje University Busan Paik Hospital
🇰🇷Busan, Busanjin District, Korea, Republic of
Ulsan University Hospital
🇰🇷Ulsan, Dong-gu, Korea, Republic of
Ajou University Hospital
🇰🇷Suwon-si, Gyenoggi-do, Korea, Republic of
The Catholic University of Korea - St. Vincents Hospital
🇰🇷Suwon-si, Gyeonggi-do, Korea, Republic of
Gyeongsang National University Hospital
🇰🇷Jinju-si, Gyeongsangnam-do, Korea, Republic of
Jeonbuk National University Hospital
🇰🇷Jeonju, Jeollabuk-do, Korea, Republic of
Yeungnam University Medical Center
🇰🇷Daegu, Nam-gu, Korea, Republic of
Asan Medical Center
🇰🇷Songpa-dong, Seoul, Korea, Republic of
Daegu Catholic University Medical Center
🇰🇷Daegu, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Pratia MCM Krakow
🇵🇱Krakow, Poland
Hospital Universitario Basurto
🇪🇸Bilbao, Bizkaia, Spain
Hospital Universitario Fundación Jiménez Díaz
🇪🇸Moncloa-Aravaca, Madrid, Spain
Hospital Universitario de Navarra
🇪🇸Pamplona, Navarra, Spain
Hospital del Mar Medical Research Institute
🇪🇸Barcelona, Spain
Clinica Universidad de Navarra - Madrid
🇪🇸Madrid, Spain
Clinica Universidad de Navarra
🇪🇸Pamplona, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario y Politecnico La Fe
🇪🇸Valencia, Spain
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
Changhua Christian Hospital CCH
🇨🇳Changhua City, Changhua County, Taiwan
Hualien Tzu Chi Medical Center
🇨🇳Hualien City, Hualien, Taiwan
National Cheng Kung University Hospital NCKUH
🇨🇳Tainan City, Southern Taiwan, Taiwan
Chang Bing Show Chwan Memorial Hospital
🇨🇳Changhua, Taiwan
Hematology Oncology Taipei Medical University - Shuang-Ho Hospital
🇨🇳New Taipei City, Taiwan
Chang Gung Memorial Hospital Linkou Branch
🇨🇳Taoyuan, Taiwan
Gazi University Faculty of Medicine
🇹🇷Yenimahalle, Ankara, Turkey
VKV AMERICAN HOSPITAL, Medical Oncology Outpatient Clinic
🇹🇷Şişli, Istanbul, Turkey