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

This was an open-label, single-arm Phase II study of lamivudine in patients who had progressed on systemic therapy for advanced colorectal cancer with TP53 mutations. The phase II study had a two-stage design, with a target accrual of 20 evaluable patients for the first stage and a total of 32 patients for the whole study. The first 9 patients were treated with lamivudine at 150 mg PO bid continuously for 28-day cycles. Subsequent patients (10-32) received a higher dose of 600 mg PO bid continuously for 28-day cycles. Tumor assessments were performed every 8 weeks until documented disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) or drug intolerance. Whole genome sequencing (WGS) and total RNA-seq were performed on pre- and post- treatment biopsies on this trial.]]>
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 measurable 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. Patients must be resistant or intolerant to 5-fluorouracil (5-FU), oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab (if RAS wild type).Age 18 or olderECOG performance status ≤2 (Karnofsky ≥60%)
Life expectancy of greater than 8 weeksParticipants must have normal organ and marrow function as defined below:absolute neutrophil count ≥1,200/mcLplatelets ≥75,000/mcL total bilirubin ≤1.5 × institutional upper limit of normal within normal AST(SGOT)/ALT(SGPT) ≤5 × institutional upper limit of normalcreatinine within normal institutional limits ORcreatinine 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. If a woman becomes 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.  ]]>