RO4929097 in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well RO4929097 works in treating patients with metastatic colorectal cancer. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective radiographic response rate associated with RO4929097 in patients with metastatic colorectal cancer who have progressed following at least two prior treatments in the metastatic setting. SECONDARY OBJECTIVES: I. To determine the progression-free survival (PFS) and overall survival (OS) associated with this agent. II. To determine the safety and tolerability of RO4929097 in this patient population. III. To assess whether response correlates with up regulation of the Notch pathway, to be determined through immunohistochemical analysis of Notch1, ICN and HES1 on available paraffin-embedded tissue samples (exploratory aim). OUTLINE: Participants will take 20 mg of RO4929097 by mouth at home in the morning for 3 days and then not take it for 4 days, continuously. The tablet is to be taken at approximately the same time the days they take it on an empty stomach, 1 hour before a meal or 2 hours after a meal. Participants will be asked to keep a pill diary recording each dose of study drug (including missed, skipped, or vomited doses) and return the diary to the study staff each visit. Participants will be informed that tablets should not be broken or opened; that they should avoid eating grapefruits or drinking grapefruit juice while on the study; that if they miss a dose of study drug, they should not try to make up that dose; that instead, they should wait until their next scheduled dose. Participants will see their study doctor and undergo standard blood work (approximately 12 mL) every 4 weeks. During these visits, participants will be asked about side effects of the RO4929097 and undergo a physical examination. Participants will continue taking the RO4929097 as long as they are tolerating it and as long as the cancer is shrinking or remains stable.

Official Title
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A Phase 2 Open-Label Study of RO4929097 in Metastatic Colorectal Cancer

Conditions
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Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer

Intervention / Treatment
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* Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed colorectal cancer (NOS 10010029) with evidence of stage 4 disease (distant metastases) Patients must have measurable disease, defined as at least one 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 >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan Patients must have received at least two prior lines of treatment in the metastatic setting; patients must have received 5-Fluorouracil (5-FU) or capecitabine, oxaliplatin and irinotecan, either in the adjuvant or metastatic setting; at least 4 weeks must have elapsed since prior chemotherapy or radiation therapy (6 weeks if the last regimen included mitomycin C) Life expectancy of greater than 3 months ECOG performance status =<2 (Karnofsky >= 60%) Absolute neutrophil count >= 1,000/mcL Platelets >= 100,000/mcL Hemoglobin >= 9 g/dL Total bilirubin =< 1.5 x institutional upper limit of normal AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal (or =< 5 x institutional upper limit of normal in patients with liver metastases) Creatinine =< 1.5 x institutional upper limit of normal The effects of RO4929097 on the developing human fetus at the recommended therapeutic dose are unknown; Notch signal pathway inhibitors are known to cause interruption of the embryonic signaling pathway and may lead to serious or life-threatening birth defects, including brain deformities, facial malformation, heart problems, or abnormal organs; therefore, women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 3 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 3 months after study participation, the patient should inform the treating physician immediately Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the potential of RO4929097 to cause serious or life-threatening birth defects; female patients of childbearing potential are defined as follows: Patients with regular menses Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding Women who have had tubal ligation Female patients may be considered to NOT be of childbearing potential for the following reasons: The patient has undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy or bilateral oophorectomy The patient is medically confirmed to be menopausal (no menstrual period) for 24 consecutive months Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 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 Patients may not be receiving any other investigational agents Patients with known brain or leptomeningeal 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 Patients receiving any medications or substances that are inhibitors or inducers of CYP3A4 are ineligible Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption; patients must be able to swallow tablets Known history of cirrhosis or clinically significant liver dysfunction Clinically significant hypocalcemia, hypomagnesemia or hypophosphatemia despite electrolyte supplementation Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic, stable atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because RO4929097 is a Notch pathway inhibiting agent with the potential for serious or life-threatening birth defects or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with RO4929097, breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with RO4929097; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female) Patients who have not recovered to < CTCAE grade 2 toxicities related to prior therapy are not eligible to participate in this study

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: Treatment (RO4929097)<br>See detailed description. | Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097<br>* Given orally<br>* Other names: RO4929097;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Objective Radiographic Response (ORR) | To determine the objective radiographic response rate associated with RO4929097 in patients with metastatic colorectal cancer who have progressed following at least 2 prior treatments in the metastatic setting. Radiologic assessment of tumor burden (CT scans of the chest, abdomen and pelvis, or MRI of the abdomen and pelvis and CT of the chest) was scheduled every 8 weeks. Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) were used for evaluation of the primary endpoint. | 2 months from enrollment for each participant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Overall Survival (OS) Rate | Overall Survival defined as the time from start of treatment until death as a result of any cause, with patients censored at the date of last follow-up if still alive. The Kaplan-Meier method was used to estimate all time-to-event functions. Statistical analysis was performed using Stata SE 9.0 software and SAS 9.2 software. | Study duration of 12 months | 
| Participant Progression Free Survival (PFS) Rate | Progression-Free Survival defined as the time from start of treatment until disease progression or death as a result of any cause. Patients were re-evaluated for response every 8 weeks. Response and progression were evaluated using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. | Study duration of 12 months | 
| Number of Related Serious Adverse Events (SAEs) | Study drug related grade 3-4 toxicities. To measure Adverse Events, investigators used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | Study duration of 12 months |