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All Conditions

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Oxaliplatin

Bevacizumab

Leucovorin

Fluorouracil

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Levoleucovorin

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Folate

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Cola

Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in Arm A and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Leucovorin Calcium

Al B Benson

This randomized phase III trial studies oxaliplatin, leucovorin calcium, fluorouracil, and bevacizumab to see how well they work compared to oxaliplatin, leucovorin calcium, and fluorouracil in treating patients who have undergone surgery for stage II colon cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving combination chemotherapy together with bevacizumab is more effective than combination chemotherapy alone in treating colon cancer.

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in 3-year disease-free survival for high-risk stage II colon cancer patients randomly assigned to 5-FU (fluorouracil), leucovorin (leucovorin calcium), oxaliplatin versus 5-FU, leucovorin, oxaliplatin and bevacizumab.

SECONDARY OBJECTIVES:

I. To compare overall survival between the regimens. II. To further define the toxicity profiles of the regimens. III. To prospectively determine the impact of tumor biological characteristics on the survival of patients with stage II colon cancer.

IV. To assess the association between oxaliplatin exposure, allelic variants in candidate genes, and neurotoxicity. (Pharmacogenetic ancillary objective)

OUTLINE: Patients with high-risk disease are randomized to 1 of 2 treatment arms (Arms A and B). Patients with low-risk disease are assigned to Arm C.

ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in Arm A and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab alone for 12 additional courses in the absence of disease progression or unacceptable toxicity.

ARM C: Patients undergo observation.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 10 years.

Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer

A Randomized Phase III Study Comparing 5-FU, Leucovorin and Oxaliplatin Versus 5-FU, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Stage II Colon Cancer at High Risk for Recurrence to Determine Prospectively the Prognostic Value of Molecular Markers

We will tabulate and report adverse events by treatment arm and note those events that differ statistically between arms. No formal type I error adjustment will be done for the toxicity analyses.

Analysis of tumor biological characteristics and their relationship to overall survival will be conducted between high and low risk populations.

National Cancer Institute (NCI)

Rectal Neoplasms

Disease Attributes

Rectal Diseases

Cetuximab

2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide

Gamma Secretase Inhibitors and Modulators

Enzyme Inhibitors

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.

Gamma-Secretase Inhibitor RO4929097

Pharmacological Study

Emily Chan

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.

PRIMARY OBJECTIVES:

I. Determination of the maximum tolerated dose (MTD) of the combination of cetuximab and RO4929097.

SECONDARY OBJECTIVES:

I. Safety and tolerability of the combination of cetuximab and RO4929097. II. Exploratory analyses of anti-tumor effect with the combination. III. Laboratory correlatives exploring response rate with notch receptors and ligand expression, correlation of response and toxicity profiles to expression of EGFR pathway components, and evaluation of serum and tissue markers of gamma-secretase inhibitor activity.

IV. Pharmacokinetic studies.

OUTLINE: This is a dose-escalation study of gamma-secretase/Notch signalling pathway inhibitor RO4929097.

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.

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. RO4929097 is an investigational anti-cancer agent that has not yet been approved by the Food and Drug Administration (FDA) for use in colorectal cancer. Cetuximab is FDA approved for metastatic colorectal cancer.

After completion of study treatment, patients are followed up every 3 months.

Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer

Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Akt Inhibitor MK2206

Edmund Kopetz

This phase II trial studies how well v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor MK2206 works in treating patients with previously treated colon or rectal cancer that has spread from the primary site to other places in the body or nearby tissue or lymph nodes and cannot be removed by surgery. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the response rate to MK-2206 (Akt inhibitor MK2206), defined as complete response (CR) + partial response (PR).

SECONDARY OBJECTIVES:

I. To determine response rate to MK-2206 in patients with phosphatase and tensin homolog (PTEN) loss or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation in a pretreatment biopsy from a metastatic site.

II. To determine progression-free survival (PFS) and overall survival (OS). III. To determine the time to treatment failure (TTF), and duration of tumor response (DR).

IV. To determine the safety profile and tolerability of this regimen in this patient population.

V. To determine effect of PTEN, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), PIK3CA, and AKT mutations and semi-quantitative grading of PTEN expression on clinical response.

OUTLINE:

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery

A Phase 2 Study of MK-2206 in Previously Treated Metastatic Colorectal Cancer Patients Enriched for PTEN Loss and PIK3CA Mutation

Samples will be analyzed using the Wilcoxon rank test. Chi-square or Fisher's exact test where appropriate will be used to determine whether high levels of marker expression correlate with PTEN status.

Complete Response (CR): Disappearance all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. Partial Response (PR): \> 30% decrease in sum diameters of target lesions, reference baseline sum diameters. Progressive Disease (PD): \> 20% increase in sum diameters of target lesions, reference smallest sum on study (includes baseline sum if smallest on study). In addition to relative increase of 20%, sum must demonstrate absolute increase of \>5 mm. (Note: appearance of 1/\> new lesions also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum diameters while on study.

Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for DR.

Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for OS.

Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for PFS.

Akt inhibitor MK2206 orally on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Treatment (Akt Inhibitor MK2206)

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Scott Kopetz/Associate Professor, GI Medical Oncology

Overall Response Rate (CR+PR) Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Outcome data not collected, no analysis to be performed as participants had related tumor response.

Duration of Tumor Response (DR)

Overall Survival (OS)

Progression-free Survival (PFS)

Given the lack of response seen in this study, biomarker validation and correlation of biomarker enrichment with clinical outcome is not feasible. Data were not collected.

Validation of the Enrichment Biomarker Signature in Metastatic Sites

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Bevacizumab in Treating Patients Who Have Undergone Surgery for Stage II Colon Cancer	NCT00217737	Colon Mucinous ... Colon Signet Ri... Lynch Syndrome Stage IIA Colon... Stage IIB Colon... Stage IIC Colon...	Bevacizumab Fluorouracil Laboratory Biom... Leucovorin Calc... Oxaliplatin	18 Years -	National Cancer Institute (NCI)
Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer	NCT01198535	Colon Mucinous ... Colon Signet Ri... Rectal Mucinous... Rectal Signet R... Recurrent Colon... Recurrent Recta... Stage IVA Colon... Stage IVA Recta... Stage IVB Colon... Stage IVB Recta...	Cetuximab Gamma-Secretase... Laboratory Biom... Pharmacological...	18 Years -	National Cancer Institute (NCI)
Phase I Study of Cetuximab With RO4929097 in Metastatic Colorectal Cancer	NCT01198535	Colon Mucinous ... Colon Signet Ri... Rectal Mucinous... Rectal Signet R... Recurrent Colon... Recurrent Recta... Stage IVA Colon... Stage IVA Recta... Stage IVB Colon... Stage IVB Recta...	Cetuximab Gamma-Secretase... Laboratory Biom... Pharmacological...	18 Years -	National Cancer Institute (NCI)
Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery	NCT01802320	Colon Mucinous ... Colon Signet Ri... Rectal Mucinous... Rectal Signet R... Recurrent Colon... Recurrent Recta... Stage IIIA Colo... Stage IIIA Rect... Stage IIIB Colo... Stage IIIB Rect... Stage IIIC Colo... Stage IIIC Rect... Stage IVA Colon... Stage IVA Recta... Stage IVB Colon... Stage IVB Recta...	Akt Inhibitor M... Laboratory Biom... Pharmacological...	18 Years -	National Cancer Institute (NCI)

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