Clinical trial NCT06072131: To Evaluate Efficacy of Belinostat or Pralatrexate in Combination Against CHOP Alone in PTCL
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Peripheral T Cell Lymphoma
Lead sponsor: Acrotech Biopharma Inc.
Sponsor class: INDUSTRY
First posted: 2023-10-10
Enrollment: 504
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: PFS
timeFrame: 4.5 years
Secondary outcomes:
measure: Overall survival
timeFrame: 8 years
Other outcomes:
Locations:
city: Clovis
country: United States
facility: University of California, San Francisco Fresno
state: California
city: Santa Monica
country: United States
facility: University of California, Los Angeles Hem/ Onc Clinical Research Unit, Suite 600
state: California
city: Pembroke Pines
country: United States
facility: Moffitt Malignant Hematology &amp; Cellular Therapy at Memorial Healthcare System Memorial Cancer Institute
state: Florida
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Houston
country: United States
facility: University of Texas, MD Anderson Cancer Center
state: Texas
city: Temple
country: United States
facility: Baylor Scott & White Medical Center - Temple
state: Texas
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Halle
country: Germany
facility: Universitaetsklinikum Halle (Saale)
city: Debrecen
country: Hungary
facility: University of Debrecen Clinical Center
state: Nagyerdei Krt. 98
city: Nyíregyháza
country: Hungary
facility: Andras Josa University Teaching Hospital
state: Szent Istvan Utca
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Eger
country: Hungary
facility: Markhot Ferenc Oktato Korhaz
city: Szeged
country: Hungary
facility: Belgyogyaszati Klinika es Kardiologiai Kozpont
city: Milano
country: Italy
facility: University of Milano Bicocca
state: Bicocca
city: Meldola
country: Italy
facility: Servizio Sanitario Regionale Emilia-Romagna-Istituto Scientifico Romagnolo per lo Studio dei Tumori "Dino Amadori" Srl (IRST)
state: Province Of Forlì-Cesena
city: Tricase
country: Italy
facility: Azienda Ospedaliera Cardinale Giovanni Panico
state: Puglia
city: Borgo Roma
country: Italy
facility: Policlinico GB Rossi Borgo Roma
state: Verona
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino, IRCCS
city: Parma
country: Italy
facility: Azienda Ospedaliera Universitaria di Parma
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Ravenna
country: Italy
facility: Azienda USL di Ravenna
city: Busan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
state: Busanjin District
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
state: Dong-gu
city: Suwon-si
country: Korea, Republic of
facility: Ajou University Hospital
state: Gyenoggi-do
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea - St. Vincents Hospital
state: Gyeonggi-do
city: Jinju-si
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Gyeongsangnam-do
city: Jeonju
country: Korea, Republic of
facility: Jeonbuk National University Hospital
state: Jeollabuk-do
city: Daegu
country: Korea, Republic of
facility: Yeungnam University Medical Center
state: Nam-gu
city: Songpa-dong
country: Korea, Republic of
facility: Asan Medical Center
state: Seoul
city: Daegu
country: Korea, Republic of
facility: Daegu Catholic University Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Krakow
country: Poland
facility: Pratia MCM Krakow
city: Bilbao
country: Spain
facility: Hospital Universitario Basurto
state: Bizkaia
city: Moncloa-Aravaca
country: Spain
facility: Hospital Universitario Fundación Jiménez Díaz
state: Madrid
city: Pamplona
country: Spain
facility: Hospital Universitario de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital del Mar Medical Research Institute
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra - Madrid
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Changhua City
country: Taiwan
facility: Changhua Christian Hospital CCH
state: Changhua County
city: Hualien City
country: Taiwan
facility: Hualien Tzu Chi Medical Center
state: Hualien
city: Tainan City
country: Taiwan
facility: National Cheng Kung University Hospital NCKUH
state: Southern Taiwan
city: Changhua
country: Taiwan
facility: Chang Bing Show Chwan Memorial Hospital
city: New Taipei City
country: Taiwan
facility: Hematology Oncology Taipei Medical University - Shuang-Ho Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital Linkou Branch
city: Yenimahalle
country: Turkey
facility: Gazi University Faculty of Medicine
state: Ankara
city: Şişli
country: Turkey
facility: VKV AMERICAN HOSPITAL, Medical Oncology Outpatient Clinic
state: Istanbul
city: Adana
country: Turkey
facility: Adana City Education and Research Hospital
Study officials:
affiliation: Acrotech Biopharma Inc.
name: Uma Srinivas Atmuri, MPharm, MS
role: STUDY_DIRECTOR
References: