RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01058655
• Collaborator: Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), Beth Israel Deaconess Medical Center (Other), Novartis (Industry), AVEO Pharmaceuticals, Inc. (Industry)
• Enrollment: 56
• Locations: 3
• Arms: 4
• Duration (Months): 61.9
• Patients Per Site: 18.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Research has shown that anti-angiogenic agents can be effective therapies to treat cancer. Anti-angiogenic agents target the blood vessels required for tumors to grow. Vascular endothelial growth factor (VEGF) is one of the cell pathways used for this blood vessel growth. When the investigators interfere with the VEGF pathway, the investigators inhibit this blood vessel growth which is required by tumors. One of the study drugs being used, tivozanib (AV-951), selectively interferes with the VEGF pathway. The second study drug being used, everolimus (RAD001) interferes with the mTOR pathway. The mTOR pathway is another pathway involved in blood vessel and tumor cell growth. By combining these two drugs the investigators hope to slow or reverse tumor cell growth in patients whose tumors have become resistant to other therapies for their disease.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Cancer	Drug: Everolimus; Drug: Tivozanib	Phase 1/Phase 2

Detailed Description

Primary Objective

Phase I

• To determine the safety, tolerability, and maximally tolerated dose (MTD) of everolimus and tivozanib administered in combination to patients with advanced gastrointestinal tumors.

Phase II

• At the MTD, to assess progression-free survival associated with everolimus and tivozanib in patients with refractory, metastatic colorectal cancer.

Secondary Objectives

Phase II

• To assess tumor response rate.

• To assess overall survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Drug: Everolimus; Other Names: RAD001 Afinitor ; Drug: Tivozanib; Other Names: AV-951
Experimental: Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Drug: Everolimus; Other Names: RAD001 Afinitor ; Drug: Tivozanib; Other Names: AV-951
Experimental: Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Drug: Everolimus; Other Names: RAD001 Afinitor ; Drug: Tivozanib; Other Names: AV-951
Experimental: Phase II: Everolimus 10 mg + Tivozanib 1 mg Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Drug: Everolimus; Other Names: RAD001 Afinitor ; Drug: Tivozanib; Other Names: AV-951

Outcome Measures

Primary Outcome Measures

1. Everolimus Maximum Tolerated Dose (MTD) [Phase I] [Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.]

   The everolimus MTD in combination with tivozanib is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

2. Tivozanib Maximum Tolerated Dose (MTD) [Phase I] [Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.]

   The tivozanib MTD in combination with everolimus is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.

3. Dose Limiting Toxicity (DLT) [Phase I] [Patients were assessed continuously for toxicity while on study. The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.]

   A DLT was defined as a treatment-related (attribution possible, probable, definite) adverse event that meets any of the following criteria: Grade 3 (G3) or higher non-hematologic toxicity (excluding, nausea, vomiting, diarrhea, alopecia, hypertension, hypercholesterolemia, or hypertriglyceridemia); G3 diarrhea, nausea or vomiting lasting > 48 hours or leading to hospitalization, despite aggressive anti-diarrheal or anti-emetic medications; G4 diarrhea, despite aggressive anti-diarrheal medications; G4 vomiting, despite aggressive anti-emetic medications; G3 hypertension, for which blood pressure cannot be reduced to <150/100 with anti-hypertensive therapies; G4 hypertension or severe hypertension, as defined by systolic blood pressure >180 mmHg or diastolic blood pressure > 110 mmHg; G4 hypercholesterolemia or hypertriglyceridemia lasting > 7 days, despite appropriate use of anti-hyperlipidemic medications; G4 hematologic toxicity lasting for >5 days, including leukopenia, neutropen

4. Progression-Free Survival (PFS) [Phase II] [Disease was assessed radiographically to document clinical progression every 2 cycles on treatment. Participants were followed for up to 16 months since study entry.]

   PFS based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the earliest date of last disease assessment. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Secondary Outcome Measures

1. Disease Control Rate (DCR) [Phase II] [Disease was assessed every 2 cycles on treatment. Median treatment duration on this study cohort was 2 months (range 1-16).]

   Disease Control Rate is defined as the percentage of patients who achieve confirmed stable disease (SD) or better on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started. SD is neither PR nor PD. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

2. Overall Survival (OS) [Phase II] [Long-term follow-up for survival was not specified per protocol. Participants were followed for up to 20 months on this study.]

   OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

For the Phase I component:

Inclusion Criteria:

• 18 years of age or older

• Histologic confirmation of a gastrointestinal malignancy, limited to cancer of the esophagus, stomach, small bowel, liver, biliary tract, gallbladder, pancreas, large bowel, appendix, rectum and anus.

• Locally advanced or metastatic disease

• Disease that: a) has recurred or progressed following standard therapy, b) for which no standard therapy currently exists, or c) for which the subject is not a candidate for or unwilling to undergo standard therapy. There is no limit to the number of prior regimens received by the patient.

• ECOG Performance Status of 0, 1 or 2

• Life expectancy of at least 12 weeks

• Adequate organ function as outlined in the protocol

• At least 4 weeks is required from : a) previous regimen of chemotherapy, b) immunotherapy or biological therapy, c) other investigational agents, and d) radiotherapy.

• At least 4 weeks is required from treatment of bevacizumab

• At least 4 weeks is required from prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors

• If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment.

Exclusion Criteria:

• Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed).

• Clinically apparent CNS metastases or carcinomatous meningitis

• Clinically significant cardiovascular disease

• Major surgery within 4 weeks of the start of study treatment or patients who have not recovered from the side effects of any major surgery.

• Active bleeding diathesis or history of Grade 2 or greater clinically significant bleeding within 3 months of enrollment

• Active infection requiring antibiotics

• Participants with a known positive history of chronic Hepatitis B viral infection or known positive HBV-DNA test are excluded.

• History of interstitial pneumonitis or severely impaired lung function defined as 88% or less O2 saturation at rest in room air

• Immunocompromise or chronic use of immunosuppressant medications

• Uncontrolled serious medical or psychiatric illness

• Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures

• Significant proteinuria, defined as urine dipstick protein of 3+ or greater

• Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy

• Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose

• Patients who are pregnant or lactating

• Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs

• Inability to swallow pills

For the phase II component, only patients with metastatic colorectal cancer will be enrolled.

For the Phase II component:

Inclusion Criteria (Phase II):

• 18 years of age or older

• Histologic confirmation of colorectal cancer

• Stage IV disease

• At least one site of disease measurable by RECIST criteria

• Receipt of or intolerance to a fluoropyrimidine (fluorouracil or capecitabine), irinotecan, oxaliplatin, bevacizumab, and a monoclonal antibody to epidermal growth factor receptor (cetuximab or panitumumab). If a patient's tumor was K-RAS mutation positive, then previous treatment with cetuximab or panitumumab is not required.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

• Life expectancy of at least 12 weeks

• Adequate organ function as outlined in the protocol

• At least 3 weeks is required from: (a) previous regimen of chemotherapy, (b)immunotherapy or biological therapy, (c) other investigational agents, and (d) radiotherapy. Of note, concomitant radiotherapy is NOT allowed, while a patient is on protocol.

• At least 3 weeks is required from prior treatment with bevacizumab

• At least 3 weeks is required since prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors.

• Negative pregnancy test for women of child bearing potential

Exclusion Criteria (Phase II):

• Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed)

• Clinically apparent CNS metastases or carcinomatous meningitis, as determined by physical examination and imaging studies

• Clinically significant cardiovascular disease, defined as follows:

(A)Symptomatic congestive heart failure, (B)Symptomatic coronary artery disease or myocardial infarction within 3 months of enrollment, (C)Cardiac arrhythmias not controlled with medication, (D)Deep venous thrombosis or pulmonary embolus within the last 6 months, (E) Cerebrovascular accident within the last 12 months, (F)Poorly controlled hypertension, defined as systolic pressure > 150 mmHg or diastolic pressure > 100 mmHg documented on 2 consecutive measurements taken at least 24 hours apart, (G)Symptomatic peripheral vascular disease, defined as claudication on walking ≤

1 block

• Major surgery within 4 weeks of the start of study treatment or patients who have not recovered from the side effects of any major surgery. Major surgery defined as those surgeries that require general anesthesia

• Active bleeding diathesis or history of grade 2 or higher clinically significant bleeding (hemoptysis, hematemesis, hematochezia, or melena) within 3 months of enrollment

• Active infection requiring antibiotics

• Participants with a known positive history of chronic Hepatitis B viral infection or known positive HBV-DNA test are excluded.

• History of interstitial pneumonitis or severely impaired lung function defined as less than or equal to 88% O2 saturation at rest in room air.

• Immunocompromise or chronic use of immunosuppressant medications (prednisone ≤ 10 mg daily or the equivalent of a comparable steroid is allowed, if deemed necessary by a study investigator)

• Uncontrolled serious medical or psychiatric illness

• Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures

• Significant proteinuria, defined as urine dipstick protein 3+ or greater

• Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy.

• Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose.

• Patients who are pregnant or lactating

• Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs

• Inability to swallow pills

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Massachusetts General Hospital
• Beth Israel Deaconess Medical Center
• Novartis
• AVEO Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Brian Wolpin, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Brian Wolpin, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01058655
• Other Study ID Numbers: 09-276
• First Posted: Jan 29, 2010
• Last Update Posted: Apr 13, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Brian Wolpin, MD, MPH, Principal Investigator, Dana-Farber Cancer Institute: Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Gastrointestinal Neoplasms; Everolimus

Study Results

Participant Flow

Recruitment Details	Patients enrolled from February 2010 through June 2011.

Arm/Group Title	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg	Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg	Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg	Phase II: Everolimus 10 mg + Tivozanib 1 mg
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Period Title: Overall Study
STARTED	3	3	8	42
Evaluable	3	3	6	40
COMPLETED	0	0	0	0
NOT COMPLETED	3	3	8	42

Baseline Characteristics

Arm/Group Title	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg	Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg	Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg	Phase II: Everolimus 10 mg + Tivozanib 1 mg	Total
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Total of all reporting groups
Overall Participants	3	3	8	42	56
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58	47	63	56	59
Sex: Female, Male (Count of Participants)
Female	0 0%	2 66.7%	3 37.5%	23 54.8%	28 50%
Male	3 100%	1 33.3%	5 62.5%	19 45.2%	28 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	1 2.4%	1 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 33.3%	0 0%	1 12.5%	2 4.8%	4 7.1%
White	2 66.7%	3 100%	7 87.5%	38 90.5%	50 89.3%
More than one race	0 0%	0 0%	0 0%	1 2.4%	1 1.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%	3 100%	8 100%	42 100%	56 100%

Outcome Measures

1. Primary Outcome

Title	Everolimus Maximum Tolerated Dose (MTD) [Phase I]
Description	The everolimus MTD in combination with tivozanib is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.
Time Frame	Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.

Outcome Measure Data

Analysis Population Description

All PI patients who received at least one dose of the study drug were evaluable for MTD unless patient withdrew before completing 1 cycle of therapy for reason other than dose-limiting toxicity.

Arm/Group Title	Phase I: Evaluable
Arm/Group Description	All phase I patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle according to the established dose escalation schedule. Patients who withdrew before completing 1 cycle of therapy for reason other than dose-limiting toxicity were not evaluable and replaced.
Measure Participants	12
Number [mg daily for 4 weeks of a 4 week cycle]	10

2. Primary Outcome

Title	Tivozanib Maximum Tolerated Dose (MTD) [Phase I]
Description	The tivozanib MTD in combination with everolimus is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.
Time Frame	Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.

Outcome Measure Data

Analysis Population Description

All PI patients who received at least one dose of the study drug were evaluable for MTD unless patient withdrew before completing 1 cycle of therapy for reason other than dose-limiting toxicity.

Arm/Group Title	Phase I: Evaluable
Arm/Group Description	All phase I patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle according to the established dose escalation schedule. Patients who withdrew before completing 1 cycle of therapy for reason other than dose-limiting toxicity were not evaluable and replaced.
Measure Participants	12
Number [mg daily for 3 weeks of a 4 week cycle]	1.0

3. Primary Outcome

Title	Dose Limiting Toxicity (DLT) [Phase I]
Description	A DLT was defined as a treatment-related (attribution possible, probable, definite) adverse event that meets any of the following criteria: Grade 3 (G3) or higher non-hematologic toxicity (excluding, nausea, vomiting, diarrhea, alopecia, hypertension, hypercholesterolemia, or hypertriglyceridemia); G3 diarrhea, nausea or vomiting lasting > 48 hours or leading to hospitalization, despite aggressive anti-diarrheal or anti-emetic medications; G4 diarrhea, despite aggressive anti-diarrheal medications; G4 vomiting, despite aggressive anti-emetic medications; G3 hypertension, for which blood pressure cannot be reduced to <150/100 with anti-hypertensive therapies; G4 hypertension or severe hypertension, as defined by systolic blood pressure >180 mmHg or diastolic blood pressure > 110 mmHg; G4 hypercholesterolemia or hypertriglyceridemia lasting > 7 days, despite appropriate use of anti-hyperlipidemic medications; G4 hematologic toxicity lasting for >5 days, including leukopenia, neutropen
Time Frame	Patients were assessed continuously for toxicity while on study. The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.

Outcome Measure Data

Analysis Population Description

All PI patients who received at least one dose of the study drug were evaluable for DLT. The 2 DLTs experienced by participants in dose level cohort 3 were grade 3 fatigue and dehydration.

Arm/Group Title	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg	Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg	Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	3	3	6
Number [Participants with DLT]	0 0%	0 0%	2 25%

4. Primary Outcome

Title	Progression-Free Survival (PFS) [Phase II]
Description	PFS based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the earliest date of last disease assessment. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time Frame	Disease was assessed radiographically to document clinical progression every 2 cycles on treatment. Participants were followed for up to 16 months since study entry.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all evaluable phase II patients.

Arm/Group Title	Phase II: Everolimus 10 mg + Tivozanib 1 mg [Evaluable]
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	40
Median (95% Confidence Interval) [months]	3.0

5. Secondary Outcome

Title	Disease Control Rate (DCR) [Phase II]
Description	Disease Control Rate is defined as the percentage of patients who achieve confirmed stable disease (SD) or better on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started. SD is neither PR nor PD. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time Frame	Disease was assessed every 2 cycles on treatment. Median treatment duration on this study cohort was 2 months (range 1-16).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all evaluable phase II patients.

Arm/Group Title	Phase II: Everolimus 10 mg + Tivozanib 1 mg [Evaluable]
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	50 1666.7%

6. Secondary Outcome

Title	Overall Survival (OS) [Phase II]
Description	OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive.
Time Frame	Long-term follow-up for survival was not specified per protocol. Participants were followed for up to 20 months on this study.

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all evaluable phase II patients.

Arm/Group Title	Phase II: Everolimus 10 mg + Tivozanib 1 mg [Evaluable]
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Measure Participants	40
Median (95% Confidence Interval) [months]	5.6

Adverse Events

Time Frame	Adverse events (AEs) were assessed continuously throughout treatment. Treatment duration was a median of 2 months (range 1-16 months) in this study cohort.
Adverse Event Reporting Description	AEs with treatment-attribution of possibly, probably or definitely were classified as serious if maximum grade 3-5 or other if grade 1-2 per CTCAEv3.
Arm/Group Title	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg		Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg		Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg		Phase II: Everolimus 10 mg + Tivozanib 1 mg
Arm/Group Description	Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.		Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.		Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.		Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of the 4 week cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
All Cause Mortality
	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg		Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg		Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg		Phase II: Everolimus 10 mg + Tivozanib 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/8 (0%)		5/42 (11.9%)
Serious Adverse Events
	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg		Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg		Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg		Phase II: Everolimus 10 mg + Tivozanib 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		1/3 (33.3%)		3/8 (37.5%)		30/42 (71.4%)
Blood and lymphatic system disorders
Hemoglobin	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Eye disorders
Retinal detachment	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		0/42 (0%)
Gastrointestinal disorders
Abdomen- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Constipation	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Diarrhea w/o prior colostomy	0/3 (0%)		0/3 (0%)		0/8 (0%)		6/42 (14.3%)
Muco/stomatitis (symptom) oral cavity	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Muco/stomatitis by exam- oral cavity	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Nausea	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Obstruction- small bowel NOS	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Rectum- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Stenosis (incl anastomotic) biliary tree	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Varices (esophageal)- hemorrhage	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Vomiting	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		0/42 (0%)
General disorders
Chest/thoracic pain NOS	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Death - disease progression NOS	0/3 (0%)		0/3 (0%)		0/8 (0%)		5/42 (11.9%)
Fatigue	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		5/42 (11.9%)
Infections and infestations
Infection w/ unk ANC kidney	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Injury, poisoning and procedural complications
Intra-op injury	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Intra-op injury Colon	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Intra-op injury Spinal cord	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Investigations
ALT- SGPT	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
AST- SGOT	0/3 (0%)		0/3 (0%)		0/8 (0%)		5/42 (11.9%)
Alkaline phosphatase	0/3 (0%)		0/3 (0%)		2/8 (25%)		2/42 (4.8%)
Bilirubin	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Creatinine	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Lymphopenia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Neutrophils	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Platelets	0/3 (0%)		0/3 (0%)		0/8 (0%)		10/42 (23.8%)
Metabolism and nutrition disorders
Dehydration	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		4/42 (9.5%)
Hyperglycemia	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		4/42 (9.5%)
Hypermagnesemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hyperuricemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hypokalemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hyponatremia	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		2/42 (4.8%)
Hypophosphatemia	1/3 (33.3%)		1/3 (33.3%)		0/8 (0%)		11/42 (26.2%)
Musculoskeletal and connective tissue disorders
Back- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Chest wall- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Nervous system disorders
Head/headache	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		0/42 (0%)
Psychiatric disorders
Confusion	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Renal and urinary disorders
Renal failure	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Reproductive system and breast disorders
Breast- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Vascular disorders
Hypertension	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		3/42 (7.1%)
Other (Not Including Serious) Adverse Events
	Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg		Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg		Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg		Phase II: Everolimus 10 mg + Tivozanib 1 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/3 (33.3%)		6/8 (75%)		32/42 (76.2%)
Blood and lymphatic system disorders
Hemoglobin	1/3 (33.3%)		1/3 (33.3%)		1/8 (12.5%)		20/42 (47.6%)
Lymph node- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Cardiac disorders
Atrial tachycardia/PAT	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Ear and labyrinth disorders
External ear- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Gastrointestinal disorders
Abdomen- pain	1/3 (33.3%)		1/3 (33.3%)		0/8 (0%)		15/42 (35.7%)
Ascites (non-malignant)	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Constipation	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		5/42 (11.9%)
Dental/teeth/peridontal- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Diarrhea w/o prior colostomy	2/3 (66.7%)		1/3 (33.3%)		4/8 (50%)		13/42 (31%)
Distention/bloating- abdominal	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Dry mouth	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		1/42 (2.4%)
Dyspepsia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Enteritis	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Flatulence	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		0/42 (0%)
Lip- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Muco/stomatitis (symptom) oral cavity	2/3 (66.7%)		1/3 (33.3%)		2/8 (25%)		7/42 (16.7%)
Muco/stomatitis by exam- oral cavity	0/3 (0%)		0/3 (0%)		0/8 (0%)		9/42 (21.4%)
Nausea	0/3 (0%)		0/3 (0%)		3/8 (37.5%)		14/42 (33.3%)
Rectum- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		0/42 (0%)
Stenosis (incl anastomotic) duodenum	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Stomach- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Vomiting	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		5/42 (11.9%)
General disorders
Edema head and neck	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Edema limb	1/3 (33.3%)		1/3 (33.3%)		1/8 (12.5%)		4/42 (9.5%)
Extremity-lower (gait/walking)	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Fatigue	2/3 (66.7%)		1/3 (33.3%)		3/8 (37.5%)		17/42 (40.5%)
Fever w/o neutropenia	0/3 (0%)		0/3 (0%)		0/8 (0%)		3/42 (7.1%)
Rigors/chills	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Immune system disorders
Allergic reaction	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infections and infestations
Infection Gr0-2 neut- bronchus	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infection Gr0-2 neut- dental-tooth	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infection Gr0-2 neut- oral cavity	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infection Gr0-2 neut- sinus	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infection Gr0-2 neut- urinary tract	0/3 (0%)		0/3 (0%)		0/8 (0%)		3/42 (7.1%)
Infection w/ unk ANC bronchus	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Infection w/ unk ANC vagina	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Injury, poisoning and procedural complications
Bruising	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		0/42 (0%)
Investigations
ALT- SGPT	1/3 (33.3%)		0/3 (0%)		2/8 (25%)		7/42 (16.7%)
AST- SGOT	3/3 (100%)		0/3 (0%)		1/8 (12.5%)		17/42 (40.5%)
Alkaline phosphatase	0/3 (0%)		0/3 (0%)		0/8 (0%)		16/42 (38.1%)
Bilirubin	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		4/42 (9.5%)
Creatinine	0/3 (0%)		0/3 (0%)		0/8 (0%)		5/42 (11.9%)
Leukocytes	0/3 (0%)		0/3 (0%)		0/8 (0%)		4/42 (9.5%)
Lymphopenia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Neutrophils	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		9/42 (21.4%)
Platelets	1/3 (33.3%)		0/3 (0%)		4/8 (50%)		16/42 (38.1%)
Weight loss	1/3 (33.3%)		1/3 (33.3%)		2/8 (25%)		4/42 (9.5%)
Metabolism and nutrition disorders
Anorexia	0/3 (0%)		0/3 (0%)		0/8 (0%)		11/42 (26.2%)
Dehydration	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		0/42 (0%)
Hypercalcemia	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		4/42 (9.5%)
Hypercholesterolemia	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		13/42 (31%)
Hyperglycemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		18/42 (42.9%)
Hyperkalemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hypertriglyceridemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		15/42 (35.7%)
Hyperuricemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		3/42 (7.1%)
Hypoalbuminemia	1/3 (33.3%)		0/3 (0%)		1/8 (12.5%)		19/42 (45.2%)
Hypocalcemia	2/3 (66.7%)		1/3 (33.3%)		1/8 (12.5%)		16/42 (38.1%)
Hypoglycemia	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hypokalemia	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		11/42 (26.2%)
Hypomagnesemia	0/3 (0%)		1/3 (33.3%)		2/8 (25%)		14/42 (33.3%)
Hyponatremia	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		5/42 (11.9%)
Hypophosphatemia	2/3 (66.7%)		0/3 (0%)		3/8 (37.5%)		7/42 (16.7%)
Obesity	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Musculoskeletal and connective tissue disorders
Back- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		6/42 (14.3%)
Bone- pain	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		1/42 (2.4%)
Chest wall- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Joint- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Muscle- pain	2/3 (66.7%)		0/3 (0%)		1/8 (12.5%)		1/42 (2.4%)
Neck- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Nonneuropathic generalized weakness	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		1/42 (2.4%)
Nervous system disorders
CNS- hemorrhage	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		0/42 (0%)
Depressed level of consciousness	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Dizziness	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		2/42 (4.8%)
Head/headache	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		6/42 (14.3%)
Mental status	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Psychiatric disorders
Anxiety	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Depression	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Insomnia	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		1/42 (2.4%)
Renal and urinary disorders
Cystitis	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Hemoglobinuria	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Proteinuria	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		7/42 (16.7%)
Urethra- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Urinary frequency/urgency	0/3 (0%)		0/3 (0%)		0/8 (0%)		3/42 (7.1%)
Urinary hemorrhage NOS	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Reproductive system and breast disorders
Pelvic- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Vaginal discharge (non-infectious	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm- wheezing	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Cough	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		6/42 (14.3%)
Dyspnea	0/3 (0%)		0/3 (0%)		0/8 (0%)		6/42 (14.3%)
Nose- hemorrhage	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		4/42 (9.5%)
Pneumothorax	0/3 (0%)		0/3 (0%)		1/8 (12.5%)		0/42 (0%)
Throat/pharynx/larynx- pain	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Voice changes/dysarthria	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Skin and subcutaneous tissue disorders
Dry skin	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Erythema multiforme	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hand-foot reaction	1/3 (33.3%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Nail changes	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Pruritus/itching	0/3 (0%)		0/3 (0%)		0/8 (0%)		3/42 (7.1%)
Rash/desquamation	0/3 (0%)		0/3 (0%)		0/8 (0%)		7/42 (16.7%)
Rash: acne/acneiform	0/3 (0%)		1/3 (33.3%)		0/8 (0%)		5/42 (11.9%)
Vascular disorders
Hematoma	0/3 (0%)		0/3 (0%)		0/8 (0%)		1/42 (2.4%)
Hypertension	3/3 (100%)		0/3 (0%)		3/8 (37.5%)		17/42 (40.5%)
Hypotension	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)
Thrombosis/thrombus/embolism	0/3 (0%)		0/3 (0%)		0/8 (0%)		2/42 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.