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

This study has been withdrawn prior to enrollment.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01270438
First received: January 4, 2011
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival of patients treated with FOLFOX6 plus bevacizumab with or without gamma-secretase inhibitor RO4929097 [ Time Frame: From start of treatment to time of progression, assessed up to 12 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: Assessed up to 12 months ] [ Designated as safety issue: No ]
    Estimated using the binomial distribution and exact 95% confidence intervals (CI) will be provided.

  • Incidence of dose-limiting and non-dose-limiting toxicities [ Time Frame: Assessed up to 12 months ] [ Designated as safety issue: Yes ]
    Summarized using descriptive statistics.

  • Pharmacokinetics and pharmacodynamics of gamma-secretase inhibitor RO4929097 [ Time Frame: Baseline, and day 1 of courses 1 and 2 ] [ Designated as safety issue: No ]
    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.


Enrollment: 0
Study Start Date: December 2010
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01270438

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Neil Segal Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01270438     History of Changes
Other Study ID Numbers: NCI-2011-02571, NCI-2011-02571, CDR0000692198, MSKCC-10191, 10-191, 8467, U01CA069856, N01CM62206
Study First Received: January 4, 2011
Last Updated: October 7, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Adenocarcinoma
Colonic Neoplasms
Colorectal Neoplasms
Rectal Neoplasms
Carcinoma
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Rectal Diseases
Bevacizumab
Fluorouracil
Levoleucovorin
Oxaliplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antidotes
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Immunologic Factors

ClinicalTrials.gov processed this record on October 21, 2014