Combination Chemotherapy and Bevacizumab With or Without RO4929097 in Treating Patients With Metastatic Colorectal Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Withdrawn

CT.gov ID

NCT01270438

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II clinical trial is studying how well giving combination chemotherapy and bevacizumab with or without RO4929097 works in treating patients with metastatic colorectal 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 or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy and bevacizumab is more effective with RO4929097 in treating patients with colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma of the Colon Adenocarcinoma of the Rectum Recurrent Colon Cancer Recurrent Rectal Cancer Stage IVA Colon Cancer Stage IVA Rectal Cancer Stage IVB Colon Cancer Stage IVB Rectal Cancer	Drug: FOLFOX regimen Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097 Biological: bevacizumab Drug: oxaliplatin Drug: leucovorin calcium Drug: fluorouracil	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To estimate the efficacy, as determined by progression-free survival, of FOLFOX6 and bevacizumab with versus without gamma-secretase inhibitor RO4929097 (RO4929097).

SECONDARY OBJECTIVES:

To estimate the clinical benefit of RO4929097 in combination with mFOLFOX6 and bevacizumab, as measured by objective response rate.
To evaluate the safety and tolerability of RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab.
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of RO4929097 in combination with mFOLFOX6 and bevacizumab.
To investigate PD response of RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab, as assessed by direct measurement of gamma-secretase enzyme activity, in tumor samples.
(Exploratory) To investigate the Notch signaling pathway genes targeted by RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with clinical outcome.
(Exploratory) To investigate the Ras signaling pathway genes targeted by RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with clinical outcome.
(Exploratory) To investigate putative colorectal cancer stem cells targeted by RO4929097 in combination with mFOLFOX6 chemotherapy and bevacizumab and correlate with clinical outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center, prior therapy (adjuvant/neoadjuvant vs none), and number of organs* involved by metastases (1 vs > 1). Patients are randomized to 1 of 2 treatment arms.

NOTE: *Lesions all in the liver would be considered as 1 organ involved.

ARM I: Patients receive FOLFOX6 regimen comprising oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10.

Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity (RO4929097 is given for up to 12 courses).

ARM II: Patients receive FOLFOX6 regimen and bevacizumab as in arm I.

Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients may undergo blood sample collection at baseline and periodically during study for pharmacokinetic, pharmacodynamic, and correlative studies.

After completion of study therapy, patients are followed up for 12 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2 Study of RO4929097 (NSC 749225) in Combination With FOLFOX Plus Bevacizumab Versus FOLFOX Plus Bevacizumab Alone for the First-Line Treatment of Patients With Metastatic Colorectal Cancer (NCI #8467)

Actual Study Start Date :

Dec 1, 2010

Actual Primary Completion Date :

Aug 1, 2011

Actual Study Completion Date :

Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (RO4929097, combination chemotherapy, bevacizumab) Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Drug: FOLFOX regimen Given IV Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097 Given orally Biological: bevacizumab Given IV Drug: oxaliplatin Given IV Drug: leucovorin calcium Given IV Drug: fluorouracil Given IV
Experimental: Arm II (combination chemotherapy, bevacizumab) Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.	Drug: FOLFOX regimen Given IV Biological: bevacizumab Given IV Drug: oxaliplatin Given IV Drug: leucovorin calcium Given IV Drug: fluorouracil Given IV

Arm

Intervention/Treatment

Experimental: Arm I (RO4929097, combination chemotherapy, bevacizumab)

Patients receive FOLFOX6 regimen comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, fluorouracil IV continuously over 46 hours, and bevacizumab IV over 30-90 minutes on days 1-2. Patients also receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: FOLFOX regimen

Given IV

Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097

Given orally

Biological: bevacizumab

Given IV

Drug: oxaliplatin

Given IV

Drug: leucovorin calcium

Given IV

Drug: fluorouracil

Given IV

Experimental: Arm II (combination chemotherapy, bevacizumab)

Patients receive FOLFOX6 regimen and bevacizumab as in arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: FOLFOX regimen

Given IV

Biological: bevacizumab

Given IV

Drug: oxaliplatin

Given IV

Drug: leucovorin calcium

Given IV

Drug: fluorouracil

Given IV

Outcome Measures

Primary Outcome Measures

Progression-free survival of patients treated with FOLFOX6 plus bevacizumab with or without gamma-secretase inhibitor RO4929097 [From start of treatment to time of progression, assessed up to 12 months]
Progression is defined as changes in RECIST 1.1-defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Secondary Outcome Measures

Objective response rate (complete or partial response) as measured by RECIST [Assessed up to 12 months]
Estimated using the binomial distribution and exact 95% confidence intervals (CI) will be provided.
Incidence of dose-limiting and non-dose-limiting toxicities [Assessed up to 12 months]
Summarized using descriptive statistics.
Pharmacokinetics and pharmacodynamics of gamma-secretase inhibitor RO4929097 [Baseline, and day 1 of courses 1 and 2]
Computed using non- compartmental methods for RO4929097 and will be correlated with clinical parameters using Cox regression model for association with survival and PFS and Wilcoxon rank sum test for response.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma of the colon or adenocarcinoma of the rectum
Metastatic disease by imaging
Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20mm by conventional techniques or as ≥ 10 mm by spiral CT scan
No known brain metastases
ECOG performance status 0-1
ANC ≥ 1,500/mm³
WBC ≥ 3,000/mm³
Platelet count ≥ 100,000/mm³ (without a platelet transfusion ≤ 14 days prior to study)
Hemoglobin ≥ 9 g/dL
Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
Urine protein:creatinine ≤ 0.5 or proteinuria < 1,000 mg on 24-hour urine collection
Total bilirubin ≤ 1.5 times ULN
AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN for patients with liver metastases)
Albumin ≥ 2.5 g/dL
Amylase ≤ 2 times ULN
Lipase ≤ 2 times ULN
PTT ≤ 1.2 times ULN
INR ≤ 1.2 times ULN
No patients with uncontrolled hypophosphatemia, hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution, despite adequateelectrolyte supplementation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use two forms of contraception (i.e., barrier contraception and one other method of contraception) prior to, during, and for ≥ 12 months after study participation
Patients must not have current evidence of or history of another malignancy except adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other curatively treated solid tumors with no evidence of disease for ≥ 3 years prior to enrollment
Able to swallow capsules
No malabsorption syndrome or other condition that would interfere with intestinal absorption
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to gamma-secretase inhibitor RO4929097 used in the study
No clinically important history of liver disease, including known viral, other hepatitis, or cirrhosis
No uncontrolled intercurrent illness including, but not limited to, any of the following:
Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
A history of torsades de pointes or other significant cardiac arrhythmias
Psychiatric illness and/or social situations that would limit compliance with study requirements
No baseline QTcF > 450 msec (male) or QTcF > 470msec (female)
No serious or non-healing wound, ulcer, or bone fracture
No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No significant traumatic injury within the past 28 days
No clinically significant cardiovascular disease, including any of the following:
Inadequately controlled hypertension (systolic BP > 160 mm Hg and/or diastolic BP

90 mm Hg despite antihypertension medication)

History of cerebrovascular accident within the past 6 months
Myocardial infarction or unstable angina within the past 6 months
NYHA grade II-IV congestive heart failure
Serious and inadequately controlled cardiac arrhythmia
No requirement for antiarrhythmics or other medications known to prolong QTc
No significant vascular disease (e.g., aortic aneurysm, requiring surgical repair, history of aortic dissection, or recent peripheral arterial thrombosis) within the past 6 months
No clinically significant peripheral vascular disease
No evidence of bleeding diathesis or coagulopathy
No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
Recovered to < NCI CTCAE grade 2 toxicities related to prior therapy
No prior adjuvant or neoadjuvant chemotherapy for colorectal cancers within 12 months of development of metastases
No prior chemotherapy or gamma-secretase inhibitors or other investigational agents for metastatic colorectal cancer
No prior radiotherapy for colorectal cancers including in the neoadjuvant or adjuvant setting within 12 months of development of metastases
No major surgical procedure or open biopsy within the past 28 days and no anticipation of need for major surgical procedures during the course of the study
No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
Patients who switch from warfarin sodium to alternative anti-coagulant agents allowed
No concurrent medications that are strong inducers, inhibitors, or substrates of CYP3A4, including ketoconazole and grapefruit juice
No concurrent combination antiretroviral therapy for HIV-positive patients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905
2	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
3	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio	United States	43210