Desmopressin (DDAVP) in Patients With Colorectal Cancer and Rectal Bleeding

Study Overview
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Brief Summary
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The objective of this study is to find the maximum tolerated dose and preliminary efficacy of desmopressin as an haemostatic agent, when is administered to patients with colorectal cancer and rectal bleeding, before specific oncologic treatment with surgery and/or chemotherapy and/or radiotherapy.

Detailed Description
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Colorectal cancer is the third cause of cancer in men and women, according to data recently published in the United Sates, and the third cause of death in the same population. Ninety percent (90%) of patients have symptoms at the time of diagnosis, being rectal bleeding the most frequent one (50% of cases). Bleeding, mainly mild or moderate, has no specific treatment, and during the staging of the disease, can not be controlled. Desmopressin, a synthetic analogue of vasopressin, is a selective agonist of the receptor V2 of vasopressin, inducing, among others, an haemostatic effect. Interestingly, the expression of this receptor has been described in human gastrointestinal tract, including colon and rectum and in colorectal tumors. Moreover, desmopressin has shown a significant antitumor activity in preclinical murine models of colorectal cancer. This is a dose finding study, to investigate a new indication of desmopressin as an haemostatic agent in patients with colorectal cancer with mild to moderate rectal bleeding.

Official Title
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Prospective, Open-labelled, Phase II Study, of the Administration of Desmopressin in Patients With Colorectal Cancer, With or Without Metastasis, With Rectal Bleeding, Before Treatment With Surgery and/or Chemotherapy and/or Radiotherapy.

Conditions
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Colorectal Cancer, Rectal Bleeding

Intervention / Treatment
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* Drug: Desmopressin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients > 18 to < 80 years of age who have signed the informed consent form Histological diagnosis of rectal adenocarcinoma localized, locally advanced or metastatic Treatment indication with chemotherapy and/or radiotherapy and/or surgery according to disease stage Rectal bleeding associated with the primary tumor within 48 hours prior to study entry Acceptable organ function to be able to participate in the study, performed within 14 days prior to admission; defined by the following parameters: Electrocardiogram (ECG) without significant clinical abnormalities Haemoglobin greater than or equal to 8 g/dL Total leukocyte count greater than or equal to 4.0 x 10^9/L Absolute neutrophil count greater than or equal to 1.5 x 10^9/L Total platelet count greater to 100.0 x 10^9/L Total bilirubin less than or equal to 1.5 times the upper limit of normality (ULN) Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) less than or equal to 1.5 times upper limit of normality (ULN) Creatinine clearance greater than 50 ml/min Performance status (Eastern Cooperative Oncology Group [ECOG]) less than or equal to 2 Patients with childbearing potential should use one of the following contraceptives methods: intrauterine devices, barrier methods and tubal ligation Exclusion Criteria: Colorectal cancer without bleeding evidences Pregnancy or lactation Use of hormonal contraceptives or treatments with sexual hormones in general Patients with other illnesses not adequately controlled such as congestive heart failure, arterial blood pressure, unstable angina, severe cardiac arrhythmia, thromboembolic disease, diabetes 1 or 2, any hidden coronary disease determined by previous assessments Psychiatric diseases implying patient incompetence Known hypersensitivity to desmopressin or vasopressin Severe von Willebrand disease (vWD)(defined by vWF<10% Ui/dl) or 2B vWD (defined by increased platelet agregation induced by ristocetin at low concentration) or hemophilia A or B carriers History of seizures Renal insufficiency (Creatinine clearance < 50 ml/min), hyponatremia (serum sodium lower than the lower limit of normality-UNL)or previous history of hyponatremia Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Positive serology for hepatitis B, C or known human immunodeficiency virus (HIV) infection Known liver disease (cirrhosis, liver enzymes greater than or equal to 1.5 times the upper limit of normality or total bilirubin greater than or equal to 1.5 times the upper limit of normality Active infections wich, according to the investigator judgement, coud interfere with patient safety Other malignancies, with the exception of basal cell carcinoma, in situ cervical carcinoma, or any other tumour adequately treated and with a disease-free period greater than or equal to 5 years Patients receiving or having received other investigational drugs 30 days prior to study entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Desmopressin<br>Four dose levels and two dosing schedules with 3 patients in each group. | Drug: Desmopressin<br>* Dose groups: Group 1: 0.25 µg/kg/day; Group 2: 0.25 µg/kg/12 hours; Group 3: 0.50 µg/kg/12 hours; Group 4: 1 µg/kg/day; Group 5: 1 µg/kg/12 hours; Group 6: 2 µg/kg/day. All groups will receive desmopressin intravenously, in a 15-20 minutes infusion, one or two times a day. The administration will be repeated 24 hours after the first infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence or absence of grade 3 or 4 adverse events related to the study drug, in a maximum of 2 out of 6 patients assessed in each dose level. | A total of 6 groups with 3 patients each, with different dose ranges and dosing schedules will be assessed. The number of patients in each group with grade 3 or 4 adverse events, including clinical or analytical findings, will be determined in order to stablish the maximum tolerated dose. | Up to one week after the administration of the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with grade 3 or 4 local adverse events | Once the maximum tolerated dose is determined, other 12 patients will be assessed to evaluate safety and tolerability of the study drug when administered as monotherapy. | Up to one week after the administration of the first dose | 
| Number of patients with grade 3 or 4 systemic adverse events | Once the maximum tolerated dose is determined, other 12 patients will be assessed to evaluate safety and tolerability of the study drug when administered as monotherapy. | Up to one week after the administration of the first dose | 
| Number of withdrawn from treatment |  | Up to one week after the administration of the first dose | 
| Number of patients with partial or complete response in clinical endpoints | Clinical endpoints such us rectal bleeding, mucorrhea, evacuatory attempts and rectal pain will be assessed before and after treatment with the study drug. Response will be classified as complete or partial response. | Up to one week after the administration of the first dose |