RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by University of Utah
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
University of Utah
ClinicalTrials.gov Identifier:
NCT01047293
First received: January 8, 2010
Last updated: May 9, 2014
Last verified: May 2014
  Purpose

RAD001 (everolimus) is a novel oral derivative of rapamycin. RAD001 has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in a number of countries, including the majority of the European Union. RAD001 has been in development for patients with various malignancies since 2002.

RAD001 is being investigated as an anticancer agent based on its potential to act:

  • Directly on the tumor cells by inhibiting tumor cell growth and proliferation
  • Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is well established, and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGFR signaling in endothelial cells.

At weekly and daily schedules and at various doses explored, RAD0001 is generally well tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) associated with RAD001 therapy are manageable. Non-infectious pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and reversible.

Both FOLFOX and bevacizumab are well established for treatment of metastatic colorectal carcinomas. FOLFOX-6 can be combined safely with Bevacizumab and is currently in phase 3 testing for adjuvant therapy and is commonly used as a first line treatment regimen for metastatic colorectal cancers 25. There is an enhanced interest in development of more effective regimens for colorectal cancers. RAD001 is a mTOR inhibitor that has preclinical and clinical activity in colorectal cancers. RAD001 downregulates the mTOR pathway which can lead to direct antiproliferative effects as well as decreased production of Vascular Endothelial Growth Factor. A combination of RAD001 at 10 mg per day in combination with Bevacizumab 10 mg/kg every 2 weeks has been shown to be efficacious and safe. In another trial, RAD001 was shown to have many patients with stable disease and clearly needs to be given in combination therapy.


Condition Intervention Phase
Colorectal Cancer
Drug: RAD011
Drug: FOLFOX
Drug: Bevacizumab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Study of RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Evaluate PFS for combination of FOLFOX+ Bevacizumab + RAD001 in previously untreated metastatic or advanced colorectal cancers [ Time Frame: December 2011 ] [ Designated as safety issue: No ]
  • Evaluate safety of the combination at a daily dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 part) [ Time Frame: December 2011 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To study the toxicity profile of the combination [ Time Frame: December 2011 ] [ Designated as safety issue: No ]
  • To study the Response Rate (RR) of the combination [ Time Frame: December 2011 ] [ Designated as safety issue: No ]
  • To determine the serum proteomic profiles of patients treated with combination therapy (Both phase I and II portions) [ Time Frame: December 2011 ] [ Designated as safety issue: No ]

Estimated Enrollment: 45
Study Start Date: May 2010
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: All patients
All participants enrolled.
Drug: RAD011

RAD001 (everolimus) is a novel oral derivative of rapamycin.

RAD001 is being investigated as an anticancer agent based on its potential to act:

  • Directly on the tumor cells by inhibiting tumor cell growth and proliferation
  • Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-induced proliferation of endothelial cells). The role of angiogenesis in the maintenance of solid tumor growth is well established, and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGFR signaling in endothelial cells.
Other Name: everlomius
Drug: FOLFOX
FOLFOX regimens combine oxaliplatin and leucovorin with bolus and infusional 5-fluorouracil (5-FU). 1 Oxaliplatin is a DNA cross-linking agent consisting of a platinum ion chelated with1, 2-diaminocyclohexane (DACH) and an oxalate ligand. It undergoes spontaneous activation in aqueous solutions via displacement of the labile oxalate ligand by water. The activated compounds bind with DNA, resulting in inter- and intra-strand platinum-DNA crosslinks. 5-FU is an anti-metabolite that blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, causing thymidine-less cell death in rapidly growing cells. Leucovorin is reduced folic acid that modulates the activity of 5-FU by stabilizing the ternary 5-FdUMP/ thymidylate synthetase complex. Side effects associated with FOLFOX include neuropathy including pharyngo-laryngodysesthesia, diarrhea, nausea, vomiting, and mild myelosuppression.
Other Name: oxaliplatin + 5 FU + leucovorin
Drug: Bevacizumab
Bevacizumab, a monoclonal antibody directed against VEGF (vascular endothelial growth factor) has been studied in a multitude of Phase I, II, and III clinical trials in more than 5000 patients in multiple tumor types. Phase III data in metastatic cancers
Other Name: Avastin

  Show Detailed Description

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with advanced or metastatic colorectal cancers for whom chemotherapy is indicated
  • Patients must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy
  • Patients must have at least one measurable site of disease according to RECIST (version 1.1) criteria that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation
  • Age ≥ 18 years
  • Minimum of four weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy)
  • ECOG performance status £ 2
  • Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hgb > 9 g/dL
  • Adequate liver function as shown by: serum bilirubin ≤ 1.5 x upper limit of normal (ULN), and serum AST and ALT ≤ 2.5 x ULN. With the exception of serum AST and ALT (< 5 x ULN) if the patient has liver metastases
  • Adequate renal function, serum creatinine < 2 x ULN or creatinine clearance > 50 cc/hr
  • Fasting serum cholesterol ≤300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In cases where one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
  • Signed informed consent
  • INR and PTT < 1.5 (Anticoagulation is allowed if target INR < 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at time of randomization)

Exclusion Criteria:

  • History of severe and uncontrolled allergic reactions to bevacizumab
  • Symptomatic congestive heart failure of New York heart association Class III or IV
  • Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)
  • DVT and hypertension controlled < 6 months
  • Prior treatment with any investigational drug within the preceding 4 weeks
  • Chronic treatment with systemic steroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed
  • Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry
  • Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
  • Other malignancies that are active at the time of enrollment/ treatment on the protocol
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
  • unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
  • severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
  • uncontrolled diabetes as defined by fasting serum glucose >1.5x ULN
  • any active (acute or chronic) or uncontrolled infection/ disorders
  • nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
  • known liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
  • A known history of HIV seropositivity
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 in the judgment of the investigator (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
  • Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose Coumadin)
  • Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.
  • Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
  • History of noncompliance to medical regimens
  • Patients unwilling to or unable to comply with the protocol
  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: NCT01047293

Contacts
Contact: Marlene Mitchell, RN 801-587-4779 marlene.mitchell@hci.utah.edu
Contact: Cindy Davidson, APRN 801-587-5581 cynthia.davidson@hci.utah.edu

Locations
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Marlene Mitchell, RN    801-587-4779    marlene.mitchell@hci.utah.edu   
Contact: Cindy Davidson, RN    801-587-5581    cynthia.davidson@hci.utah.edu   
Principal Investigator: Sunil Sharma, MD         
Utah Cancer Specialists Recruiting
Salt Lake City, Utah, United States
Contact: Jonathan Wisenant, MD    801-263-3416      
Sponsors and Collaborators
University of Utah
Novartis
Investigators
Principal Investigator: Sunil Sharma, MD Huntsman Cancer Institute
  More Information

No publications provided

Responsible Party: University of Utah
ClinicalTrials.gov Identifier: NCT01047293     History of Changes
Other Study ID Numbers: HCI38815
Study First Received: January 8, 2010
Last Updated: May 9, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Utah:
colorectal cancer

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Oxaliplatin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 22, 2014