PI Cetuximab w/ RO4929097/PII Cetuximab w/RO4929097 vs Cetuximab w/ Placebo (16245)

Condition(s) targeted: Colorectal

Intervention: RO4929097 (Drug); cetuximab (Drug)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: H. Lee Moffitt Cancer Center and Research Institute

Official(s) and/or principal investigator(s):
Emily Chan, M.D., Ph.D., Principal Investigator, Affiliation: Vanderbilt-Ingram Cancer Center

Overall contact:
Emily Chan, M.D., Ph.D., Phone: 615-322-4967, Email: emily.chan@vanderbilt.edu

Coordinating Center: Southeast Phase 2 Consortium (SEP2C), Moffitt Cancer Center

The purpose of this study is to determine if a new drug, RO4929097, can work with cetuximab, a drug already approved for colorectal cancer, to help fight the patient's cancer. Cancers arise as a result of abnormal control of gene expression. One of the pathways that gets abnormally regulated in some cancers is the Notch pathway. RO4929097 is an investigational drug that blocks the activation of the Notch pathway. It is hoped that by blocking this abnormal activation, this drug may be helpful in patients with cancer but the investigators do not yet know if that is true. Cetuximab is an antibody against epidermal growth factor receptor and is known to have activity in metastatic colorectal cancer. Recent studies have shown that people with colorectal cancers that contain a mutation in a gene called K-ras do not benefit from receiving cetuximab. It is unknown if adding RO4929097 to cetuximab would benefit patients who have tumors with this mutation.

Official title: Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer and Phase II Study of Cetuximab With RO4929097 vs Cetuximab With Placebo in Metastatic Colorectal Cancer

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Determination of the maximum tolerated dose (MTD) of the combination of cetuximab and RO4929097

Secondary outcome:

Safety and tolerability of the combination of cetuximab and RO4929097

Exploratory analyses of anti-tumor effect with the combination

Laboratory correlatives exploring response rate with notch receptors and ligand expression, correlation of response and toxicity profiles to expression of EGFR pathway components

Pharmacokinetic studies

Evaluation of serum and tissue markers of γ-secretase inhibitor activity

Detailed description: Phase I dose escalation: In this part of the study, the investigators are trying to find out what is the highest tolerated dose of RO4929097 that can be safely combined with cetuximab. The investigators will be testing two different cetuximab doses. One is the standard dose (Arm A) and one is a little less than the standard dose (Arm B). Everyone will get treated with cetuximab and R04929097 in this part of the study.

Patients in Arm A will receive cetuximab at the standard dose: 400 mg/m2 IV loading dose on Day 1 followed by cetuximab 250 mg/m2 IV weekly. The RO4929097 will be dose escalated starting at 20 mg given daily 3 days on, 4 days off, weekly. The dose levels of RO4929097 to be explored will be 20 mg, 30 mg, 45 mg, 90 mg, 140 mg given days 1-3 weekly. No intrapatient dose escalation will be allowed.

Patients in Arm B will receive cetuximab 200 mg/m2 IV weekly without a loading dose. The RO4929097 will be dose escalated starting at 20 mg given daily 3 days on, 4 days off, weekly. The dose levels of RO4929097 to be explored will be 20 mg, 30 mg, 45 mg, 90 mg, 140 mg given days 1-3 weekly. No intrapatient dose escalation will be allowed.

Phase I dose expansion: In this part of the study, the investigators will take the highest tolerated dose found in the phase I part of the study and test a small number of people with colorectal cancer to see if there is any activity with the combination of drugs. Everyone will get treated with cetuximab and RO4929097 in this part of the study. This part of the study will be restricted to patients whose tumors do not have a mutation in the K-ras gene. If there is sufficient data from laboratory studies to show that RO4929097 and 97 cetuximab work together, this dose expansion will not be performed and the study will go to phase II.

Phase II: If there is activity seen in laboratory studies or in the phase I dose expansion, then the investigators will conduct the phase II part of the study. This phase II study will be restricted to patients whose tumors do not have a mutation in the K-ras gene. In this part of the study, patients will be assigned to therapy with either cetuximab and RO4929097 or cetuximab and placebo. Neither the patient nor their study doctor can choose which treatment patients are assigned to and you will not be told which treatment patients have been assigned to until they come off the treatment. Patients will have a 2 to 1 chance of getting assigned to treatment with cetuximab and RO4929097. In other words, patients have a 2/3 chance of getting assigned to treatment with cetuximab and RO4929097. Everyone will receive cetuximab on this part of the study, but only 2 out of 3 people will receive RO4929097. If the patient's cancer grows on the treatment that they are assigned, they will stop therapy. At that time, patients can find out what therapy they were assigned to. If patients were assigned to cetuximab and placebo, they can choose to get therapy with cetuximab and RO4929097 if they want to. RO4929097 is an investigational anti-cancer agent that has not yet been approved by the Food and Drug Administration for use in colorectal cancer. Cetuximab is FDA approved for metastatic colorectal cancer.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed metastatic colorectal

adenocarcinoma.

- 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) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan.

- Must have received at least one prior therapy for metastatic disease. Prior therapy

with anti-EGFR antibody is allowed in the phase I portion only as long as patient did not require dose reductions of the anti-EGFR antibody because of poor tolerability. Prior EGFR inhibitor therapy is not allowed on the phase II portion.

- Life expectancy of greater than 3 months

- ECOG performance status ≤2 (Karnofsky ≥60%)

- Must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- total bilirubin within normal institutional limits if no liver metastases

- total bilirubin < 1. 5 X the institutional upper limit of normal if liver

metastases are present

- AST(SGOT)/ALT(SGPT) ≤2. 5 X institutional upper limit of normal (ULN) if no liver

metastases.

- AST(SGOT)/ALT(SGPT) <5 X institutional ULN if liver metastases are present.

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1. 73 m² for patients with creatinine levels

above institutional normal

- For the phase I dose expansion and the phase II portion, tumor must be KRAS wildtype.

- There must be available a tumor block or 20 unstained slides for correlative studies.

- The effects of RO4929097on the developing human fetus at the recommended therapeutic

dose are unknown. For this reason and because Notch signal pathway inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of childbearing potential (WOCBP) and men must use 2 forms of contraception at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment. For appropriate methods of contraception considered acceptable. Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately. Pregnancy Testing. WOCBP 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 or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097. A positive urine test must be confirmed by a serum pregnancy test. 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 teratogenic potential of RO4929097. WOCBP 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.

- Ability to swallow pills.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for

nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered to a grade 1 or less from adverse events due to agents administered more than 4 weeks earlier with the exception of alopecia and neuropathy.

- May not be receiving any other investigational agents.

- Patients with known brain metastases

- History of allergic reactions attributed to compounds of similar chemical or biologic

composition to RO4929097 or other agents (EGFR antibodies) used in the study.

- Patients taking medications with narrow therapeutic indices that are metabolized by

cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible.

- Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of

CYP3A4 enzyme activity. Caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors. Furthermore, Patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk. If such patients cannot be switched to alternative medications, they will be ineligible to participate in this study.

- Patients with malabsorption syndrome or other condition that would interfere with

intestinal absorption. Patients must be able to swallow tablets.

- Patients who are serologically positive for Hepatitis A, B or C, or have a history of

liver disease, other forms of hepatitis or cirrhosis are ineligible, with the exception of liver metastases.

- Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia,

hypophosphatemia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study.

- 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 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 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.

- Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec (female). 3. 2.14

Patients whose tumor contains a mutation in KRAS are not eligible for the phase I dose expansion portion of the study or for the phase II portion of the study.

- Patients with prior exposure to γ-secretase inhibitors.

- Patients with another active malignancy.

- For the phase II portion, prior EGFR inhibitor therapy is not allowed.

Emily Chan, M.D., Ph.D., Phone: 615-322-4967, Email: emily.chan@vanderbilt.edu

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States

Emory University Winship Cancer Institute, Atlanta, Georgia 30322, United States

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7305, United States

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, United States

Moffitt Cancer Center Clinical Trials website

Starting date: September 2010
Last updated: September 10, 2010