RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT01047293
• Collaborator: Novartis (Industry)
• Enrollment: 47
• Locations: 2
• Arm: 1
• Duration (Months): 63
• Patients Per Site: 23.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: RAD001; Drug: FOLFOX; Drug: Bevacizumab	Phase 1/Phase 2

Detailed Description

Patient population Phase I portion: Metastatic colorectal cancer. A total of 3 patients on each cohort. Additional 3 patients on the tolerable cohort. Total patient number: Minimum 6, Maximum: 12 Phase II portion: Metastatic colorectal cancer: A total of 33 patients will be treated in this portion. This will include the patients treated on the tolerable dose level from the phase I trial. The statistical justification is indicated in the Statistics section 7.

Overall study design Phase I Study: A three cohort dose escalation will be used. Cycle length will be 28 days.

Bevacizumab FOLFOX-6 RAD001 Cohort 1: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 2.5 mg PO qd Cohort 2: 5 mg/ kg Q 2weeks Standard Dose FOLFOX-6 5 mg PO qd Cohort 3: 5mg/kg Q 2 weeks Standard Dose FOLFOX-6 10 mg PO qd

Phase II Study:

For the Phase II portion the primary endpoint is Progression Free Survival at 6 months.

Study Objectives Primary

1. To evaluate the progression free survival (PFS) for a combination of FOLFOX+ Bevacizumab

• RAD001 in previously untreated metastatic or advanced colorectal cancers

1. To evaluate the safety of the combination at a daily dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 part) Secondary

2. To study the toxicity profile of the combination 2. To study the Response Rate (RR) of the combination 3. To determine the serum proteomic profiles of patients treated with combination therapy (Both phase I and II portions)

Dose selection for RAD001 In phase 1 clinical studies of RAD001 as a monotherapy agent in oncology patients, the side-effect profile is essentially mild to moderate adverse events with a low frequency of DLT at the daily dose of 10 mg/d. Based on the PK/PD model, a daily dose of 10mg RAD001 is assumed to provide a persistently high degree of target inhibition in the tumor [Investigators' Brochure-Section 4.1.1.3]. In addition, preliminary data from phase 1 studies, in which changes in molecular characteristics of tumor induced by treatment with RAD001 at the doses of 5 and 10 mg/d were investigated, confirm the pharmacodynamic activity predicted previously by PK/PD modeling [Investigators' Brochure-Section 4.1.1.3]. Therefore, a dose of 10 mg/d should ensure adequate drug target inhibition for most patients, taking into consideration the known inter-patient variability in drug levels (CV of approx 50%). In this study, we will begin with a RAD001 dose of 2.5 mg which is the lowest dose that can be administered on a daily basis. If the dose is tolerable (<1/6 DLTs), we will escalate to the dose of RAD001 (5 mg) and a third cohort of 10 mg. If cohort 1 is intolerable, study will be closed without any further expansion. On any dose level, 3 patients would be enrolled. If there are 0/3 DLTs, we would be able to escalate the dose level. If 1/3 DLTs are observed, 3 additional patients will be enrolled on the same dose level. The intent is to escalate dose levels only if < 1/6 DLTs are observed. In case 2 or more DLTs are observed on a particular dose level, no further dose escalation is possible. This dose level would be deemed intolerable and the lower dose level would be expanded. The definition of the Maximum Tolerated Dose (MTD) is the highest dose level at which RAD001 can be combined with FOLFOX/ Bevacizumab with < 1/6 DLTs.

FOLFOX/ Bevacizumab: FOLFOX6 and Bevacizumab will be given as previously described 28. mFOLFOX6 (oxaliplatin 85 mg/m2 IV with LV 350 mg IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2continuous infusion over 46 hours every 2 weeks) will be combined with Bevacizumab given at 5 mg/kg every 2 weeks. Dose modifications will be carried out for chemotherapy as per the label for oxaliplatin, fluorouracil and bevacizumab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of RAD001, FOLFOX and Bevacizumab in Treatment of Colorectal Carcinoma
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All patients All participants enrolled.

Drug: RAD001; 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 Names: 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 Names: 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 Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival at Six Months [6 months]

2. Evaluate Safety of the Combination at a Daily Dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 Part) [December 2011]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
2	Utah Cancer Specialists	Salt Lake City	Utah	United States

Sponsors and Collaborators

• University of Utah
• Novartis

Investigators

• Principal Investigator: Sunil Sharma, MD, Huntsman Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Utah
• ClinicalTrials.gov Identifier: NCT01047293
• Other Study ID Numbers: HCI38815
• First Posted: Jan 12, 2010
• Last Update Posted: Apr 4, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by University of Utah: colorectal cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Bevacizumab; Oxaliplatin; Everolimus

Study Results

Participant Flow

Arm/Group Title	ARM 1 RAD001 5 mg QOD	ARM 2 5mg RAD001 QD	ARM 3 10mg RAD001 QD	ARM 4 10mg RAD001 QD - Phase II
Arm/Group Description	Patients received 5mg RAD001 with FOLFOX and bevacizumab.	Patients received 5mg RAD001 QD with FOLFOX and bevacizumab.	Patients received 10mg RAD001 QD with FOLFOX and bevacizumab.	Patients received 10 mg RAD001 with FOLFOX and bevacizumab. - Patient in the Dose Expansion Cohort not Dose Escalation
Period Title: Overall Study
STARTED	4	8	9	26
COMPLETED	3	7	9	26
NOT COMPLETED	1	1	0	0

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description
Overall Participants	47
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Sex: Female, Male (Count of Participants)
Female	22 46.8%
Male	25 53.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival at Six Months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Progression free survival at six month was calculated using all patients receiving one dose of drug therapy at all of the different dosing levels. The six month progression free survival was determined using Kaplan Meier methods

Arm/Group Title	All Patients
Arm/Group Description
Measure Participants	47
Number (95% Confidence Interval) [percentage of participants]	87 185.1%

2. Primary Outcome

Title	Evaluate Safety of the Combination at a Daily Dosing of 2.5mg RAD001, 5 mg RAD001 or 10 mg RAD001 (Phase 1 Part)
Description	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).
Time Frame	December 2011

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ARM 1 RAD001 5 mg QOD	ARM 2 5mg RAD001 QD	ARM 3 10mg RAD001 QD
Arm/Group Description	Patients received 5mg RAD001 with FOLFOX and bevacizumab.	Patients received 5mg RAD001 QD with FOLFOX and bevacizumab.	Patients received 10mg RAD001 QD with FOLFOX and bevacizumab.
Measure Participants	3	7	9
Number [participants]	0 0%	1 NaN	1 NaN

Adverse Events

Arm/Group Title	All Patients
Arm/Group Description	All participants enrolled.
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	18/47 (38.3%)
Blood and lymphatic system disorders
anemia	3/47 (6.4%)	4
Deep Vein Thrombosis	2/47 (4.3%)	2
febrile neutropenia	3/47 (6.4%)	3
neutropenia	2/47 (4.3%)	3
Cardiac disorders
left ventricular systolic dysfunction	1/47 (2.1%)	1
pericarditis	1/47 (2.1%)	1
Gastrointestinal disorders
bowel perforation	4/47 (8.5%)	5
cholecystitis	1/47 (2.1%)	1
diarrhea	2/47 (4.3%)	2
fistula - small bowel	1/47 (2.1%)	1
mucositis	4/47 (8.5%)	4
nausea	1/47 (2.1%)	1
pain - abdominal	3/47 (6.4%)	3
pain - rectal/anal	1/47 (2.1%)	1
pancreatitis	2/47 (4.3%)	2
vomiting	1/47 (2.1%)	1
General disorders
fever	2/47 (4.3%)	2
pain - chest	1/47 (2.1%)	1
Infections and infestations
c-diff infection	2/47 (4.3%)	3
Infection - hepatic	1/47 (2.1%)	1
Infection - pseudomonas	1/47 (2.1%)	1
infection - urinary tract	2/47 (4.3%)	2
Infections and other systemic inflammatory syndrome	1/47 (2.1%)	1
thrush	1/47 (2.1%)	1
Investigations
failure to thrive	1/47 (2.1%)	1
weight loss	1/47 (2.1%)	1
Metabolism and nutrition disorders
dehydration	3/47 (6.4%)	3
lipase increased	1/47 (2.1%)	1
Musculoskeletal and connective tissue disorders
muscle weakness	1/47 (2.1%)	1
Nervous system disorders
confusion	1/47 (2.1%)	1
Renal and urinary disorders
Renal calculi	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
epistaxis	1/47 (2.1%)	1
hypoxia	2/47 (4.3%)	2
pneumonia - aspiration	1/47 (2.1%)	1
Vascular disorders
pulmonary emboli	3/47 (6.4%)	3
vasospasms	2/47 (4.3%)	2
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	47/47 (100%)
Blood and lymphatic system disorders
anemia	12/47 (25.5%)	22
leukopenia	16/47 (34%)	37
lymphopenia	5/47 (10.6%)	7
neutropenia	34/47 (72.3%)	102
thrombocytopenia	16/47 (34%)	50
Cardiac disorders
tachycardia - sinus	6/47 (12.8%)	8
Gastrointestinal disorders
anorexia	25/47 (53.2%)	52
constipation	12/47 (25.5%)	31
diarrhea	37/47 (78.7%)	86
dry mouth	3/47 (6.4%)	3
dysgeusia	18/47 (38.3%)	22
dysphagia	8/47 (17%)	9
flatulence	8/47 (17%)	8
hemorrhoids	5/47 (10.6%)	7
mucositis	40/47 (85.1%)	146
nausea	37/47 (78.7%)	83
pain - unspecified	3/47 (6.4%)	3
pain - rectal/anal	9/47 (19.1%)	16
vomiting	25/47 (53.2%)	39
General disorders
body aches	3/47 (6.4%)	4
edemia - penile/groin	17/47 (36.2%)	25
fatigue	43/47 (91.5%)	88
fever	12/47 (25.5%)	15
malaise	3/47 (6.4%)	3
nail changes	7/47 (14.9%)	7
night sweats	5/47 (10.6%)	5
pain - abdominal	21/47 (44.7%)	36
pain - back	14/47 (29.8%)	22
pain - chest	13/47 (27.7%)	17
pain - extremity	7/47 (14.9%)	11
pain - shoulders	3/47 (6.4%)	7
toothache	3/47 (6.4%)	3
voice changes	6/47 (12.8%)	7
Immune system disorders
allergic reaction - anaphylactic	4/47 (8.5%)	5
Infections and infestations
c-diff infection	3/47 (6.4%)	6
infection - gums	3/47 (6.4%)	4
infection - tooth	3/47 (6.4%)	3
infection - urine/yeast	13/47 (27.7%)	29
infection - vaginial	4/47 (8.5%)	8
thrush	9/47 (19.1%)	10
Injury, poisoning and procedural complications
bruising	4/47 (8.5%)	4
Investigations
Alanine aminotransferase increased	6/47 (12.8%)	8
Aspartate aminotransferase increased	5/47 (10.6%)	6
creatinine increased	4/47 (8.5%)	6
hypercholesterolemia	4/47 (8.5%)	5
weight loss	28/47 (59.6%)	59
Metabolism and nutrition disorders
alkaline phosphatase increased	6/47 (12.8%)	7
dehydration	20/47 (42.6%)	29
hyperglycemia	8/47 (17%)	13
hypertriglyceridemia	9/47 (19.1%)	15
hypocalcemia	6/47 (12.8%)	7
hypokalemia	17/47 (36.2%)	36
hyponatremia	3/47 (6.4%)	4
hypophosphatemia	12/47 (25.5%)	29
Musculoskeletal and connective tissue disorders
arthralgia	4/47 (8.5%)	4
myalgia	7/47 (14.9%)	7
Nervous system disorders
ataxia	3/47 (6.4%)	6
dizziness	7/47 (14.9%)	7
headache	22/47 (46.8%)	27
neuropathy	41/47 (87.2%)	95
Psychiatric disorders
anxiety	3/47 (6.4%)	4
confusion	3/47 (6.4%)	3
depression	8/47 (17%)	10
insomnia	10/47 (21.3%)	11
Renal and urinary disorders
dysuria	3/47 (6.4%)	4
hematuria	4/47 (8.5%)	5
proteinuria	8/47 (17%)	12
Respiratory, thoracic and mediastinal disorders
congestion - sinus	13/47 (27.7%)	14
cough	16/47 (34%)	28
dyspnea	11/47 (23.4%)	20
epistaxis	29/47 (61.7%)	39
hypoxia	5/47 (10.6%)	6
pleural effusion	4/47 (8.5%)	4
pneumonitis	3/47 (6.4%)	6
post nasal drip	8/47 (17%)	8
pulmonary emboli	5/47 (10.6%)	5
sore throat	14/47 (29.8%)	18
Skin and subcutaneous tissue disorders
alopecia	11/47 (23.4%)	12
dry skin	10/47 (21.3%)	12
Erythroderma	13/47 (27.7%)	23
rash	17/47 (36.2%)	25
rash - acneiform	3/47 (6.4%)	9
rash - pruritic	7/47 (14.9%)	8
Vascular disorders
deep vein thrombosis	6/47 (12.8%)	6
hemorrhage - rectal	3/47 (6.4%)	3
hypertension	12/47 (25.5%)	23

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.