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A Phase I/II Study of RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Gastrointestinal Cancer

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Trial Information

A Phase I/II Study of RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer


- Since we are looking for the highest dose of the study drug that can be given safely
without severe or unmanageable side effects in participants with gastrointestinal
malignancies, not everyone who participates will receive the same dose of the study
drug. The dose will depend on the number of participants who have enrolled and how
well they tolerated their doses.

- Both RAD001 and AV-951 are pills that are taken orally. Each treatment cycle lasts 4
weeks during which time participants will be taking: RAD001: once a day, every day and
AV-951: once a day for 3 weeks followed by a 1 week break.

- Participants will be given a take home blood pressure machine and be instructed on how
to use it. They will be asked to keep a daily blood pressure diary.

- During all cycles participants will have a physical exam (including vital signs) and be
asked questions about their general health and specific questions about any problems
they may be experiencing.

- Every 8 weeks the tumor will be assessed by CT scan (or imaging tests).

- Blood tests will be done every other week while the participant is on study and a urine
test will be done every 4 weeks while the participant is on study.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the safety, tolerability, and maximally tolerated dose of RAD001 and AV-951 administered in combination to this patient population (Phase I).

Outcome Time Frame:

2 years

Safety Issue:

Yes

Principal Investigator

Brian Wolpin, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

09-276

NCT ID:

NCT01058655

Start Date:

February 2010

Completion Date:

Related Keywords:

  • Gastrointestinal Cancer
  • Colorectal Cancer
  • Colorectal Neoplasms
  • Gastrointestinal Neoplasms

Name

Location

Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617