Enhancing Effect on Tumour Apoptosis With the Use of Pentoxifylline in Patients With Hodgkin Lymphoma

NCT05490953 | Unknown Phase 4 DMC

• 1 other identifier: CI-03122
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Hodgkin's Lymphoma (HL) is a neoplasm that affects the lymph nodes and the lymphatic system. In Mexico, HL is the seventh most incident cancer and the ninth with the highest mortality. It is characterized by the presence of Reed-Sternberg (HRS) cells derived from B cells of the germinal center. They harbor mutations that activate the NF-κB pathway, favoring cell survival and their reprogramming. Currently, the available therapeutic options are chemotherapy and radiotherapy, achieving cure rates of 75% in patients in advanced stages, in which 70% of these are found at the time of diagnosis. The investigators proposed the use of pentoxifylline (PTX) as a therapeutic option to enhance the antitumor effect generated by the treatment since it can increase the efficacy of apoptosis, in vitro and in vivo, induced by doxorubicin, cisplatin, and adriamycin in human leukemic and cervical cancer cells, through inhibition of NF-κB by preventing phosphorylation of serine 32 of the inhibitor κB; it also decreases the expression of Bcl-2 and Bcl-XL, induces the releasement of cytochrome c and caspases 3, 9, and cleavage of caspase 8. The investigators evaluated the effects of PTX during the steroid window phase at induction to remission in pediatric patients with LLA of a recent diagnosis, where it was shown that the combined treatment of prednisone (PRD) with PTX achieves greater percentages of apoptosis compared to individual treatment. In addition, the effect of PTX on the expression of genes associated with apoptosis was evaluated; where it was shown that it activates the intrinsic and extrinsic pathways of apoptosis. Fortilin is a protein whose serum levels increase 2.4 times more after treatment with chemotherapy or radiotherapy in patients with malignancies, so it is considered a specific and sensitive biomarker of early apoptosis in vivo. The present protocol will evaluate the enhancing effect of PTX on tumor apoptosis in combination with chemotherapeutical agents in pediatric and AYA patients with HL. Apoptosis will be measured in vivo by quantifying serum levels of fortilin and cytochrome c in participants before and after treatment by ELISA; as well as an evaluation of the clinical response based on the results of the PET-Scan, overall and event-free survival according to the Kaplan-Meier curves, and the adverse effects associated with the use of PTX according to the common terminology criteria for adverse events and causality algorithms.

Conditions

Hodgkin Lymphoma

Keywords

Hodgkin Lymphoma; Pentoxifylline; Apoptosis; Pediatric and adolescent and young adult patients

Outcome Measures

Primary Outcomes (2)

• Peripheral apoptosis (Fortilin)

  3 samples of peripheral venous blood will be obtained from the patients from both study groups before the beginning of treatment (day 0), at the end of the first cycle of chemotherapy (day 30), and the end of the second cycle (day 60). Fortilin plasma levels will be determined using the translationally controlled human tumor protein ELISA kit (TPT1), according to the manufacturer's specifications. The optical density will be determined using a Biotek Synergy™ HT plate reader at a wavelength of 450nm. The results will be presented as the mean ± standard deviation in pg/mL. In the 3 blood samples that will be taken from the participants, the same marker will be evaluated. As it is the same variable, it will be measured with the same unit of measure (pg/mL) for the 3 blood samples. At the end of the study, it will be evaluated if there was any change in the plasma levels of fortilin (in pg/mL), either an increase or a decrease.

  At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)

• Peripheral apoptosis (Cytochrome c)

  3 samples of peripheral venous blood will be obtained from the patients from both study groups before the beginning of treatment (day 0), at the end of the first cycle of chemotherapy (day 30), and the end of the second cycle (day 60). Cytochrome c plasma levels will be determined using the human cytochrome c ELISA kit, according to the manufacturer's specifications. The optical density will be determined using a Biotek Synergy™ HT plate reader at a wavelength of 450nm. The results will be presented as the mean ± standard deviation in pg/mL. In the 3 blood samples that will be taken from the participants, the same marker will be evaluated. As it is the same variable, it will be measured with the same unit of measure (pg/mL) for the 3 blood samples. At the end of the study, it will be evaluated if there was any change in the plasma levels of fortilin (in pg/mL), either an increase or a decrease.

  At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)

Secondary Outcomes (6)

• Assessment of the clinical response by positron emission tomography (PET)

  At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)

• Assessment of the clinical response by Computerized Axial Tomography

  At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)

• Assessment of the clinical response

  At the end of the second cycle of chemotherapy (day 60 after starting chemotherapy, since each cycle of treatment is 30 days)

• Determination of event-free survival

  A 24-month follow-up will be given after completion of the corresponding treatment, at the time, survival will be evaluated.

• Assessment of the severity of adverse effects

  A 24-month follow-up will be given after finishing the corresponding treatment, at that time, the adverse effects will be studied.

Study Arms (2)

Group A with placebo

PLACEBO COMPARATOR

Patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus placebo, during the first two cycles of chemotherapy.

Drug: Placebo

Group B with pentoxifylline

EXPERIMENTAL

Patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus pentoxifylline, during the first two cycles of chemotherapy. Pentoxifylline dose of 20 mg/kg/day, maximum dose 1200 mg/day

Drug: Pentoxifylline

Interventions

Pentoxifylline DRUG

Patients will be treated pentoxifylline during the first two chemotherapy cycles of their respective treatment.

Also known as: Experimental Group

Group B with pentoxifylline

Placebo DRUG

Patients will be treated with placebo during the first two chemotherapy cycles of their respective treatment.

Also known as: Placebo Group

Group A with placebo

Eligibility Criteria

• Age: 6 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Pediatric and AYA (adolescents and young adults) patients (age up to 35 years of either sex) newly diagnosed with Hodgkin lymphoma regardless of clinical stage.
• Patients with the ability to swallow tablets.
• Patients who agree to enter the protocol by signing the informed consent personally or by the parent/guardian

You may not qualify if:

• Patients previously treated with chemotherapy, corticoids, and/or radiotherapy
• History of active acid peptic disease or gastrointestinal bleeding Intolerance to pentoxifylline and in general to xanthines
• Patients under treatment with anticoagulants, cimetidine, ciprofloxacin or theophylline
• Patients with severe bleeding, retinal hemorrhage or bleeding diathesis
• Serious cardiac arrhythmias (E.g. paroxysmal supraventricular tachycardia, congenital AV block, arrhythmias associated with congenital heart disease, digitalis poisoning, postoperative cardiac surgery, hypoxia, hypercapnia, electrolyte disturbances)
• Patients with hypotension
• Severe liver failure
• Moderate to severe renal insufficiency (with a glomerular filtration rate ≤ 30 mL/min)
• Patients admitted to the Intensive Care Unit at diagnosis
• Patients with treatment adherence of less than 80%
• Patients who wish to withdraw from the study or withdraw informed consent
• Patients who present grade III adverse events related to the drug under study
• Patients who become pregnant during the study

Sponsors & Collaborators

• University of Guadalajara: lead
• Hospital Civil de Guadalajara: collaborator

Study Sites (1)

Hospital Civil de Guadalajara Fray Antonio Alcalde

Guadalajara, Jalisco, 44280, Mexico

RECRUITING

Related Publications (18)

• Wang HW, Balakrishna JP, Pittaluga S, Jaffe ES. Diagnosis of Hodgkin lymphoma in the modern era. Br J Haematol. 2019 Jan;184(1):45-59. doi: 10.1111/bjh.15614. Epub 2018 Nov 8.

  PMID: 30407610 BACKGROUND

• Connors JM, Cozen W, Steidl C, Carbone A, Hoppe RT, Flechtner HH, Bartlett NL. Hodgkin lymphoma. Nat Rev Dis Primers. 2020 Jul 23;6(1):61. doi: 10.1038/s41572-020-0189-6.

  PMID: 32703953 BACKGROUND

• Weniger MA, Kuppers R. Molecular biology of Hodgkin lymphoma. Leukemia. 2021 Apr;35(4):968-981. doi: 10.1038/s41375-021-01204-6. Epub 2021 Mar 8.

  PMID: 33686198 BACKGROUND

• Mathas S, Hartmann S, Kuppers R. Hodgkin lymphoma: Pathology and biology. Semin Hematol. 2016 Jul;53(3):139-47. doi: 10.1053/j.seminhematol.2016.05.007. Epub 2016 May 13.

  PMID: 27496304 BACKGROUND

• Hernandez-Flores G, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy Adel C, de Celis-Carrillo R, del Toro-Arreola S, Castellanos-Esparza YC, Bravo-Cuellar A. Pentoxifylline sensitizes human cervical tumor cells to cisplatin-induced apoptosis by suppressing NF-kappa B and decreased cell senescence. BMC Cancer. 2011 Nov 10;11:483. doi: 10.1186/1471-2407-11-483.

  PMID: 22074157 BACKGROUND

• Bravo-Cuellar A, Ortiz-Lazareno PC, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, Aguilar-Lemarroy A, del Toro-Arreola S, de Celis-Carrillo R, Sahagun-Flores JE, de Alba-Garcia JE, Hernandez-Flores G. Sensitization of cervix cancer cells to Adriamycin by Pentoxifylline induces an increase in apoptosis and decrease senescence. Mol Cancer. 2010 May 19;9:114. doi: 10.1186/1476-4598-9-114.

  PMID: 20482878 BACKGROUND

• Lerma-Diaz JM, Hernandez-Flores G, Dominguez-Rodriguez JR, Ortiz-Lazareno PC, Gomez-Contreras P, Cervantes-Munguia R, Scott-Algara D, Aguilar-Lemarroy A, Jave-Suarez LF, Bravo-Cuellar A. In vivo and in vitro sensitization of leukemic cells to adriamycin-induced apoptosis by pentoxifylline. Involvement of caspase cascades and IkappaBalpha phosphorylation. Immunol Lett. 2006 Mar 15;103(2):149-58. doi: 10.1016/j.imlet.2005.10.019. Epub 2005 Nov 18.

  PMID: 16388856 BACKGROUND

• Bravo-Cuellar A, Hernandez-Flores G, Lerma-Diaz JM, Dominguez-Rodriguez JR, Jave-Suarez LF, De Celis-Carrillo R, Aguilar-Lemarroy A, Gomez-Lomeli P, Ortiz-Lazareno PC. Pentoxifylline and the proteasome inhibitor MG132 induce apoptosis in human leukemia U937 cells through a decrease in the expression of Bcl-2 and Bcl-XL and phosphorylation of p65. J Biomed Sci. 2013 Feb 28;20(1):13. doi: 10.1186/1423-0127-20-13.

  PMID: 23445492 BACKGROUND

• Gonzalez-Ramella O, Ortiz-Lazareno PC, Jimenez-Lopez X, Gallegos-Castorena S, Hernandez-Flores G, Medina-Barajas F, Meza-Arroyo J, Jave-Suarez LF, Lerma-Diaz JM, Sanchez-Zubieta F, Bravo-Cuellar A. Pentoxifylline during steroid window phase at induction to remission increases apoptosis in childhood with acute lymphoblastic leukemia. Clin Transl Oncol. 2016 Apr;18(4):369-74. doi: 10.1007/s12094-015-1376-x. Epub 2015 Sep 2.

  PMID: 26329293 BACKGROUND

• Meza-Arroyo J, Bravo-Cuellar A, Jave-Suarez LF, Hernandez-Flores G, Ortiz-Lazareno P, Aguilar-Lemarroy A, Padilla-Corona M, Sanchez-Zubieta F, Gonzalez-Ramella O. Pentoxifylline Added to Steroid Window Treatment Phase Modified Apoptotic Gene Expression in Pediatric Patients With Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2018 Jul;40(5):360-367. doi: 10.1097/MPH.0000000000001152.

  PMID: 29683943 BACKGROUND

• Sinthujaroen P, Wanachottrakul N, Pinkaew D, Petersen JR, Phongdara A, Sheffield-Moore M, Fujise K. Elevation of serum fortilin levels is specific for apoptosis and signifies cell death in vivo. BBA Clin. 2014 Dec 1;2:103-111. doi: 10.1016/j.bbacli.2014.10.002.

  PMID: 25558447 BACKGROUND

• Kuppers R. The biology of Hodgkin's lymphoma. Nat Rev Cancer. 2009 Jan;9(1):15-27. doi: 10.1038/nrc2542. Epub 2008 Dec 11.

  PMID: 19078975 BACKGROUND

• Weniger MA, Kuppers R. NF-kappaB deregulation in Hodgkin lymphoma. Semin Cancer Biol. 2016 Aug;39:32-9. doi: 10.1016/j.semcancer.2016.05.001. Epub 2016 May 21.

  PMID: 27221964 BACKGROUND

• Schwarzer R, Jundt F. Notch and NF-kappaB signaling pathways in the biology of classical Hodgkin lymphoma. Curr Mol Med. 2011 Apr;11(3):236-45. doi: 10.2174/156652411795243423.

  PMID: 21375490 BACKGROUND

• de Oliveira KA, Kaergel E, Heinig M, Fontaine JF, Patone G, Muro EM, Mathas S, Hummel M, Andrade-Navarro MA, Hubner N, Scheidereit C. A roadmap of constitutive NF-kappaB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses. Genome Med. 2016 Mar 17;8(1):28. doi: 10.1186/s13073-016-0280-5.

  PMID: 26988706 BACKGROUND

• Hinz M, Lemke P, Anagnostopoulos I, Hacker C, Krappmann D, Mathas S, Dorken B, Zenke M, Stein H, Scheidereit C. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med. 2002 Sep 2;196(5):605-17. doi: 10.1084/jem.20020062.

  PMID: 12208876 BACKGROUND

• Hernandez-Flores G, Bravo-Cuellar A, Aguilar-Luna JC, Lerma-Diaz JM, Barba-Barajas M, Orbach-Arbouys S. [In vitro induction of apoptosis in acute myelogenous and lymphoblastic leukemia cells by adriamycine is increased by pentoxifylline]. Presse Med. 2010 Dec;39(12):1330-1. doi: 10.1016/j.lpm.2010.07.013. No abstract available. French.

  PMID: 20888731 BACKGROUND

• Sirois I, Raymond MA, Brassard N, Cailhier JF, Fedjaev M, Hamelin K, Londono I, Bendayan M, Pshezhetsky AV, Hebert MJ. Caspase-3-dependent export of TCTP: a novel pathway for antiapoptotic intercellular communication. Cell Death Differ. 2011 Mar;18(3):549-62. doi: 10.1038/cdd.2010.126. Epub 2010 Oct 22.

  PMID: 20966960 BACKGROUND

MeSH Terms

Conditions

Hodgkin Disease

Interventions

Pentoxifylline

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Ramón O. González Ramella, PhD

  University of Guadalajara

  STUDY DIRECTOR

Central Study Contacts

Ramón O. González Ramella, PhD

CONTACT

3331719826; glezramella@hotmail.com

Jesús A. Gutiérrez Ortiz

CONTACT

3310048524; alejandro.gutierrez2329@alumnos.udg.mx

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Patients will be stratified at randomization based on their clinical stage at diagnosis, according to the Cotswold classification system, into limited-stage (stage I or II disease without B symptoms and absence of bulky or stage IB disease without bulky disease) and advanced stage (patients with stage II disease with B symptoms or bulky disease, or stage III or IV disease). In addition, a random permutation method with blocks of size 6 will be used, thus creating 5 blocks of size 6 patients each. Each patient will be classified into a specific study group (Group A: conventional treatment plus placebo; group B: conventional treatment plus pentoxifylline).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Titular Research Professor

Model Details: Patients who agree to participate in this study, by signing the consent and/or informed assent, will be randomly assigned to each of the two study groups: Group A: Patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus placebo, during the first two cycles of chemotherapy. Group B: patients with conventional treatment based on the OEPA/COPDAC, ABVD or BEACOPP scheme plus pentoxifylline, during the first two cycles of chemotherapy.

Study Record Dates

• First Submitted: June 29, 2022
• First Posted: August 8, 2022
• Study Start: July 11, 2022
• Primary Completion: December 31, 2023
• Study Completion: July 1, 2024
• Last Updated: April 18, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)