Overview

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

Status:
Completed
Trial end date:
2015-04-01
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Dana-Farber Cancer Institute
Collaborators:
AVEO Pharmaceuticals, Inc.
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Massachusetts General Hospital
Novartis
Treatments:
Everolimus
Sirolimus
Criteria
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