A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This research study is studying a drug as a possible treatment for p53 mutant metastatic colorectal cancer. The drug involved in this study is: -Lamivudine

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. Investigational means that the drug is being studied. The FDA (the U.S. Food and Drug Administration) has not approved lamivudine for this specific disease but it has been approved for other uses. In this research study, the investigators are studying the effects of lamivudine on this type of cancer. This drug may help prevent the growth and spread of the cancer cells to other parts of the body. The investigators have discovered that this particular type of colon cancer, which has a p53 mutation may be sensitive to treatment with lamivudine by impairing the ability of the cancer cells to grow.

Official Title
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A Phase 2 Study of Lamivudine in Patients With p53 Mutant Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed adenocarcinoma of the colon that has metastasized (stage 4) and is TP53 mutant/deleted by a CLIA approved genetic test. Only known loss of function TP53 mutation/deletion will be eligible for this study. Participants must have measureable disease, defined as at least on lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20mm with conventional techniques or > 10 mm with spiral CT scan, MRI or calipers by clinical exam. See section 11 for evaluation of measurable disease Patients must be resistant to or intolerant of 5FU, oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab (if RAS wild type) Age 18 or older. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) Life expectancy of greater than 8 weeks. Participants must have normal organ and marrow function as defined below: absolute neutrophil count ≥1,200/mcL platelets ≥75,000/mcL total bilirubin ≤1.5 × institutional upper limit of normal within normal AST(SGOT)/ALT(SGPT) ≤5 × institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. The effects of lamivudine on the developing human fetus are known to be teratogenic. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of lamivudine administration. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosourea or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Participants who are receiving any other investigational agents. Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to lamivudine. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because lamivudine is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lamivudine, breastfeeding should be discontinued if the mother is treated with lamivudine. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with lamivudine HBV positive participants will be excluded given the known effects of lamivudine on HBV.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lamivudine<br>Lamivudine administered orally every 4 weeks Treatment cycles will last 28 consecutive days The dosage will be determine by the PI | Drug: Lamivudine<br>* This drug may help prevent the growth and spread of the cancer cells to other parts of the body.<br>* Other names: Combivir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT scan or MRI, complete response (CR) is the disappearance of all target lesions and partial response (PR) is a >/=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR) = CR + PR. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-Free Survival (PFS) is defined as the time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. | 2 years | 
| Overall Survival | Overall Survival (OS) is defined as the time from registration to death due to any cause, or censored at date last known alive. | 2 years | 
| Overall Disease Control Rate | Disease control rate (DCR) is a composite of overall response rate (ORR) and stable disease and is useful to measure the efficacy of therapies that have tumoristatic effects rather than tumoricidal effects. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer