RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

NCT01047293 | Completed Phase 1 Results DMC

• 1 other identifier: HCI38815
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 2

Brief Summary

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, RAD001 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.

Conditions

Colorectal Cancer

Keywords

colorectal cancer

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival at Six Months

  6 months

• Evaluate Safety of the Combination at a Daily Dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 Part)

  Number of patients who experienced a Dose Limiting Toxicity (DLT). DLT will be assessed in the first 28 days of dosing. Patients need to get dosed with 2 rounds/sessions of all chemotherapy agents in the first 28 days in order to be evaluable for DLT assessment. The primary endpoint is safety as summarized by dose limiting toxicity (DLT).

  December 2011

Study Arms (1)

All patients

EXPERIMENTAL

All participants enrolled.

Drug: RAD001; Drug: FOLFOX; Drug: Bevacizumab

Interventions

RAD001 DRUG

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.

Also known as: everlomius

All patients

FOLFOX DRUG

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.

Also known as: oxaliplatin + 5 FU + leucovorin

All patients

Bevacizumab DRUG

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

Also known as: Avastin

All patients

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Utah: lead
• Novartis: collaborator

Study Sites (2)

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Utah Cancer Specialists

Salt Lake City, Utah, United States

Location

Related Publications (1)

• Weldon Gilcrease G, Stenehjem DD, Wade ML, Weis J, McGregor K, Whisenant J, Boucher KM, Thorne K, Orgain N, Garrido-Laguna I, Sharma S. Phase I/II study of everolimus combined with mFOLFOX-6 and bevacizumab for first-line treatment of metastatic colorectal cancer. Invest New Drugs. 2019 Jun;37(3):482-489. doi: 10.1007/s10637-018-0645-2. Epub 2018 Oct 10.

  PMID: 30302599 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Everolimus; Folfox protocol; Oxaliplatin; Fluorouracil; Leucovorin; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; Coordination Complexes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Sunil Sharma
• Organization: Huntsman Cancer Institute

sunil.sharma@hci.utah.edu

801-587-5559

Study Officials

• Sunil Sharma, MD

  Huntsman Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2010
• First Posted: January 12, 2010
• Study Start: May 1, 2010
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: April 4, 2017
• Results First Posted: March 6, 2017

Record last verified: 2017-03

Locations

US (2)