The p53 Colorectal Cancer Trial

Study Overview
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Brief Summary
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Single center, open labeled, phase 2 clinical trial, where patients with metastatic colorectal cancer are selected for treatment with dose dense Cyclophosphamide every second week based on TP53 mutation status; i.e. only patients with TP53 mutated tumors may be included in the treatment arm.

Official Title
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Treatment of Patients With Metastatic Colorectal Cancer Harboring TP53 Mutations With Dose-dense Cyclophosphamide - the p53 Colorectal Cancer Trial

Conditions
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Colorectal Cancer Metastatic, Colorectal Cancer Stage IV, TP53 Gene Mutation

Intervention / Treatment
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* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic colorectal cancer patients for whom conventional therapy has failed; defined as 2 lines of chemotherapy including oxaliplatin or irinotecan- containing regimens as well as an EGFR inhibitor if applicable. Tumor lesion suitable for biopsy Age >18 years Clinically or radiologically measurable tumor deposits according to the RECIST criteria WHO performance status 0-1 Radiology studies (CT thorax/abdomen/pelvis) and echo cor and ECG must be performed within 28 days prior to registration. Before patient registration in the trial, written informed consent must be given according to national and local regulations. Blood test requirements: Neutrophils > 1.0 e9/L Platelets > 75 e9/L Bilirubin < 20 µmol / L. Serum creatinine < 1.5 x ULN Exclusion Criteria: Co-morbidity including, but not limited to, impaired renal-, liver or bone marrow function, that based on the assessment of the treating physician, may preclude the use of cyclophosphamide at actual doses. Known hypersensitivity to the study drug, its metabolites or any excipients in the infusion solution. Psychological, familial, sociological or geographical condition(s) potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial Pregnant or lactating patients cannot be included. Clinical evidence of serious coagulopathy. Prior arterial/venous thrombosis or embolism does not exclude patients from inclusion, unless patient is considered unfit by study oncologist. Patient not able to give an informed consent or comply with study regulations as deemed by study investigator.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single center, open labeled, phase 2 clinical trial, where patients are selected for treatment based on upfront TP53 mutation status; i.e. only patients with TP53 mutated tumors may be included in the single treatment arm. The informed consent, however needs to be signed prior to a biopsy for TP53 mutation analyses; thus, all patients are formally enrolled in the study prior to tissue collection, and the full population tested will be accounted for despite the fact that only patients with TP53 mutated tumors may enter the single treatment arm.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide arm<br>Dose dense cyclophosphamide (1800 Mg/m2) administered intravenously every second week. | Drug: Cyclophosphamide<br>* Chemotherapy<br>* Other names: Sendoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Partial response (PR) or complete response (CR) as defined by the RECIST criteria | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Possible molecular markers of therapy response/resistance and survival outcome beyond TP53 mutations will be examined. | Tissue and blood sampling at baseline and whenever treatment is changed | 10 years | 
| Number of patients with treatment response among patients harboring TP53 mutations belonging to particular mutation subgroups | Tissue and blood sampling at baseline and whenever treatment is changed | 10 years | 
| Clinical benefit rate (CBR) | Stable disease (SD) >6 months, PR or CR | 5 years | 
| Recurrence-free and overall survival, compared to historical data | Survival analyses | All patients will be followed for 5 years or until death to record survival outcome | 
| Safety and tolerability of the study treatment including recording of number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Clinical examination and blood samples | Every second week during the treatment period from start of treatment, and thereafter every second month for 5 years or until death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cyclophosphamide, Colorectal Cancer Metastatic, TP53 Gene Mutation