Clinical Study Evaluating the Anticancer Effect of Pentoxiphylline in Patients With Metastatic Colorectal Cancer (CRC - PTX)

November 1, 2023 updated by: Nada Abu Eleneen Darwiesh Ibrahim, Tanta University
The aim of this work is to assess the antitumor effect of Pentoxiphylline in patients with metastatic colorectal cancer receiving stomatal chemotherapy ± targeted therapy.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Colorectal cancer (CRC) ranks as the third most common cancer globally and second in terms of mortality. Although CRC incidence rates are higher in high-income compared with low-to-middle-income countries (LMICs), mortality is higher in LMICs. And although more than 90% of CRC cases are diagnosed in individuals over age 55, CRC incidence is rising in younger populations. For example, Egypt, Saudi Arabia, the Philippines, and Iran have CRC incidence rates in individuals under age 40 of 38%, 21%, 17%, and 15%-35%, respectively. This is compared with only 2%-8% of new cases in the U.S. and the European Union in individuals in this age bracket. Along with the high incidence rate of CRC in individuals under age 40 in Egypt, CRC is diagnosed at more advanced stages in these younger Egyptians. CRC survival is highly dependent upon the stage of disease at diagnosis and typically ranges from a 90% 5-year survival rate for cancers detected at the localized stage to 14% for individuals diagnosed with distant metastatic cancer.

Apoptosis may occur via two major interconnected pathways: the extrinsic or death receptor-mediated pathway, which is activated by the binding of specific ligands (such as FasL, TNF-α and TRAIL) to the receptors of cell surfaces; and the intrinsic or mitochondrial-mediated pathway, which is regulated through proteins of the Bcl-2 family and triggered either by the loss of growth factor signals or in response to genotoxic stress. Therefore the replication of cells with DNA damage is generally avoided because harmful genomic alterations typically induce the activation of apoptosis. It has been widely accepted that alterations in the physiologic response to DNA damage can facilitate the accumulation of oncogenic mutations; this accumulation may eventually lead to the development of neoplasia.

Angiogenesis is a complex process by which new blood vessels are formed from endothelial precursor. It is a critical step in cancer progression and is considered one of the hallmarks of cancer. This process is mediated through a group of ligands and receptors that work in tight regulation. A group of glycoproteins, including the VEGFs (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) and the placental growth factor (PIGF), act as effectors of angiogenesis. These factors interact with three VEGF receptors (VEGFR- 1, VEGFR-2, and VEGFR-3) and two neuropilin co-receptors (NRP1 and NRP2). The VEGF-A gene consists of eight exons with splice variants forming different isoforms, namely, VEGFA121, VEGFA165, VEGFA189, and VEGFA209; VEGFA165 is the most biologically active of these isoforms [14]. The VEGFRs are tyrosine kinase receptors that are primarily located in the vascular endothelial cells. The binding of VEGF-A to VEGFR-2 is believed to be the most important activator of angiogenesis.

Pentoxifylline (PTX) is a methylxanthine derivative that is commercially available in the name of Trental. It is currently used for management of peripheral vascular diseases. Its postulated mechanism of action is thought to be mediated through reducing blood viscosity and enhancing RBCs flexibility. However, it has been shown that PTX also may potentially be used in the anticancer therapy.

The studies demonstrated the potential effects of pentoxifylline on angiogenesis inhibition. It can affect the release and function of some predominantly proangiogenic vascular endothelial growth factors. Specifically, the release of the VEGF family of pro-angiogenesis factors (notably VEGF-A and VEGF-C) [16]. Furthermore, the mechanism by which pentoxifylline inhibits angiogenesis may be through the inhibition of activation of STAT3 which contributes to tumor cell survival by regulating the expression of metastatic genes, MMPs, serine protease uPA and potent angiogenic genes.

In addition, PTX has also the ability to induce apoptosis and potentiate the apoptotic effects of chemotherapy in several cancer types, one major mechanism is through activation of the caspase-dependent apoptosis that is accompanied by a decrease in kappa B-alpha- phosphorylation and up-regulation of the pro-apoptotic genes Bax, Bad, Bak, and caspases- 3,

-8, and -9.

Study Type

Interventional

Enrollment (Estimated)

44

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Nada Abu Eleneen, Bachelor of Clinical Pharmacy
  • Phone Number: +201118161137
  • Email: nada.enx1@gmail.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Patients with histologically and/or radiologically confirmed diagnosis of metastatic colorectal carcinoma.
  • Both genders.
  • Age ≥ 18 years old, and ≤ 75 years old.
  • Performance status 0-1 according to the Eastern Cooperative Oncology Group (ECOG).

  • Patients with adequate hematologic parameters (white blood cell count

    ≥3000/mm3, granulocytes ≥1500/mm3, platelets ≥100,000/mm3, hemoglobin ≥ 8 gm/l).

  • Patients with adequate renal functions (serum creatinine ≤1.5 mg/dL).
  • Patients with adequate hepatic functions (bilirubin ≤1.5 mg/dL or albumin ≥3 g/dL).

Exclusion Criteria:

  • Patients with active liver diseases (chronic viral hepatitis, autoimmune hepatitis, alcoholic hepatitis, Wilson's disease, hemochromatosis, or cirrhosis).
  • Patients with brain metastasis.
  • Patients with active infection.
  • Patients on chronic use of corticosteroids.
  • Patients receiving blood thinning agents(aspirin, clopidogrel, warfarin)
  • Patients with other malignancy (synchronous, or metachronous)
  • Prior exposure to neurotoxic drugs (oxaliplatin, cisplatin, vincristine, paclitaxel, or docetaxel, INH) for at least 6 months prior the study treatment.
  • Evidence of pre-existing peripheral neuropathy resulting from another reason (diabetes, brain tumor, brain trauma, HCV, thyroid disorder).
  • Patients with diabetes and other conditions that predispose to neuropathy as hypothyroidism, autoimmune diseases, hepatitis C.
  • History of known allergy to oxaliplatin or other platinum agents.
  • Patients with moderate and severe renal impairment (CrCl <50 ml/min) or serum creatinine >1.5 mg/dl.
  • Pregnant and breastfeeding women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: People not recieving the drug
(Control group; n=22) which will receive FOLFOX (leucovorin, fluorouracil, oxaliplatin) or XELOX (oxaliplatin + capecitabine) ± target therapy (Bevacizumab).
Radiation: FOLFOX
(leucovorin, fluorouracil, oxaliplatin)
Radiation: XELOX
(oxaliplatin + capecitabine)
Drug: Monoclonal antibodies (target therapy)
target therapy (Bevacizumab).
Active Comparator: People recieving the drug
(Pentoxiphylline group; n=22) which will receive the same FOLFOX (leucovorin, fluorouracil, oxaliplatin) or XELOX regimen (oxaliplatin + capecitabine) ± target therapy (Bevacizumab) in addition to Pentoxiphylline 400 mg twice daily.
Radiation: FOLFOX
(leucovorin, fluorouracil, oxaliplatin)
Radiation: XELOX
(oxaliplatin + capecitabine)
Drug: Monoclonal antibodies (target therapy)
target therapy (Bevacizumab).
Drug: Pentoxifylline

Pentoxifylline (PTX) is a methylxanthine derivative that is commercially available in the name of Trental. It is currently used for management of peripheral vascular diseases. Its postulated mechanism of action is thought to be mediated through reducing blood viscosity and enhancing RBCs flexibility. However, it has been shown that PTX also may potentially be used in the anticancer therapy [15].

The studies demonstrated the potential effects of pentoxifylline on angiogenesis inhibition. It can affect the release and function of some predominantly proangiogenic vascular endothelial growth factors. Specifically, the release of the VEGF family of pro-angiogenesis factors (notably VEGF-A and VEGF-C) [16]. Furthermore, the mechanism by which pentoxifylline inhibits angiogenesis may be through the inhibition of activation of STAT3 which contributes to tumor cell survival by regulating the expression of metastatic genes, MMPs, serine protease uPA and potent angiogenic genes [17].

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison of RECIST between the two groups.
Time Frame: one year
Difference in response rate (RECIST) between the control and drug groups.
one year
Change in the serum concentration of the measured biological markers.
Time Frame: one year
one year
Difference in progression free survival 'PFS' between the two groups
Time Frame: One year.
One year.
Difference in overall survival 'OS' between the two groups.
Time Frame: One year.
One year.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tanta University

Investigators

  • Study Chair: Tarek Mohammed, Professor, Faculty of pharmacy - Tanta university
  • Study Chair: Dalia Refaat, Assistant Professor, Faculty of pharmacy - Tanta university
  • Study Chair: Sherif Refaat, Lecturer, Oncology Centre - Faculty of Medicine - Mansoura University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

November 1, 2023

Primary Completion (Estimated)

November 1, 2024

Study Completion (Estimated)

December 1, 2024

Study Registration Dates

First Submitted

October 13, 2023

First Submitted That Met QC Criteria

November 1, 2023

First Posted (Actual)

November 2, 2023

Study Record Updates

Last Update Posted (Actual)

November 2, 2023

Last Update Submitted That Met QC Criteria

November 1, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pentoxiphylline in CRC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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