Trial Title:
Clinical Study Evaluating the Anticancer Effect of Pentoxiphylline in Patients With Metastatic Colorectal Cancer
NCT ID:
NCT06115174
Condition:
Metastatic Colorectal Carcinoma
Conditions: Official terms:
Colorectal Neoplasms
Pentoxifylline
Antibodies
Antibodies, Monoclonal
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
The design of this study is a randomized, controlled parallel clinical trial which will
be conducted on 44 patients with metastatic colorectal cancer. The duration of the study
will be one year to determine progression free survival (PFS) and the overall survival
(OS). Patients will be recruited from Medical Oncology Department, Oncology Centre,
Mansoura University, Mansoura, Egypt. The patients will be randomized using sealed
envelope method into the following two groups:
Group I (Control group; n=22) which will receive FOLFOX (leucovorin, fluorouracil,
oxaliplatin) or XELOX (oxaliplatin + capecitabine) ± target therapy (Bevacizumab).
Group II: (Pentoxiphylline group; n=22) which will receive the same FOLFOX or XELOX
regimen ± target therapy (Bevacizumab) in addition to Pentoxiphylline 400 mg twice daily.
Primary purpose:
Other
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Pentoxifylline
Description:
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].
Arm group label:
People recieving the drug
Intervention type:
Radiation
Intervention name:
FOLFOX
Description:
(leucovorin, fluorouracil, oxaliplatin)
Arm group label:
People not recieving the drug
Arm group label:
People recieving the drug
Intervention type:
Radiation
Intervention name:
XELOX
Description:
(oxaliplatin + capecitabine)
Arm group label:
People not recieving the drug
Arm group label:
People recieving the drug
Intervention type:
Drug
Intervention name:
Monoclonal antibodies (target therapy)
Description:
target therapy (Bevacizumab).
Arm group label:
People not recieving the drug
Arm group label:
People recieving the drug
Summary:
The aim of this work is to assess the antitumor effect of Pentoxiphylline in patients
with metastatic colorectal cancer receiving stomatal chemotherapy ± targeted therapy.
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.
Criteria for eligibility:
Criteria:
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.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
Accepts Healthy Volunteers
Start date:
November 1, 2023
Completion date:
December 1, 2024
Lead sponsor:
Agency:
Tanta University
Agency class:
Other
Source:
Tanta University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06115174
