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Phase I Study of TheraSphere and Everolimus Among Patients With Neuroendocrine Tumors and Liver Only or Liver Dominant Disease


Phase 1
18 Years
N/A
Not Enrolling
Both
Liver Cancer

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Trial Information

Phase I Study of TheraSphere and Everolimus Among Patients With Neuroendocrine Tumors and Liver Only or Liver Dominant Disease


Study Groups:

If patient is are found to be eligible to take part in this study, they will be assigned to
a dose level of everolimus based on when they joined this study. Up to 3 dose levels of
everolimus will be tested. Up to 6 participants will be enrolled at each dose level. The
first group of participants will receive the low dose level. Each new group will receive a
higher dose than the group before it, if no intolerable side effects were seen. If
intolerable side effects are seen, the dose may be lowered. This will continue until the
highest tolerable dose of everolimus is found. After that, 10 additional participants will
be enrolled at the highest tolerable dose that was found.

All participants will receive the same dose level of TheraSphere.

Study Drug Administration:

Each study cycle is 28 days.

On Day 1 of Cycle 1, 2 weeks before the TheraSphere procedure, patient will start taking
everolimus.

Patient will take 1-2 tablets of everolimus by mouth 1 time every day. Patient will take
the everolimus tablets with a glass of water in the morning at the same time every day. The
tablets should be swallowed whole and not chewed or crushed. The tablets may be taken
either always with or always without food.

If patient vomits after taking their dose, they should not take another tablet that day. It
is very important that patients take the tablets given to them just as the study doctor
tells them and that they do not miss any tablets. If patient does forget to take it one
day, they should not take any extra doses the next day. Instead, patient should contact
their doctor and ask for advice.

On the days of patient's study visits, they should take their dose of everolimus at the
clinic, not at home.

TheraSphere Administration:

About 2 weeks before the TheraSphere procedure, patient will have an angiogram. An
angiogram is an imaging test that uses contrast dye to help the doctor look at the body's
blood vessels. Patient will be given drugs by vein in their arm or hand to help them relax,
but patient will stay awake during the procedure. An area in patient's groin will be numbed
with anesthetic.

During the procedure, the doctor will insert a catheter into a blood vessel in patient's
groin that leads to their liver. Dye will be injected into the catheter, and a series of
x-rays will be taken that will allow the doctor to see the blood vessels in patient's liver.
At the end of the procedure, the catheter will be removed from patient's groin area. The
x-rays taken will be looked at by patient's doctor to plan for their TheraSphere procedure.
The angiogram procedure should take about 1½ to 3 hours.

On Day 15 of Cycle 1, patient will receive TheraSphere. Before the procedure, patient will
be given drugs by vein in their arm or hand to help them relax, but patient will stay awake
during the procedure. An area in patient's groin will be numbed with anesthetic. Patient
may ask the study staff for information about how the anesthesia drugs are given and their
risks.

The doctor will insert a catheter into a blood vessel in patient's groin that leads to their
liver. Based on the planning from patient's angiogram procedure, the doctor will guide the
catheter to the target blood vessel. Once the catheter is in the proper blood vessel, the
TheraSphere microspheres containing Y-90 will be injected into the catheter to reach the
tumor in the liver. After the TheraSphere microspheres are injected, the catheter will be
removed from patient's groin. The entire procedure will take about 1½ to 3 hours.

After receiving the TheraSphere microspheres, patient will stay in the recovery area for
several hours so that the staff can check patient for possible side effects. If patient has
any serious side effects, they may be admitted to the hospital to be checked on and for
treatment, if needed.

Study Visits:

Before all visits, patient must fast starting at midnight the night before.

On Day 1 of Cycle 1, if the tests have not been done in the last 5 days:

- Patient will have a physical exam, including measurement of their weight and vital
signs.

- Patient will be asked about any symptoms they may have had and any drugs they may be
taking.

- Patient's performance status will be recorded.

- Blood (about 4 tablespoons) will be drawn for routine tests and tumor marker testing.

- Urine will be collected for routine tests.

- If patient's doctor thinks it is needed, blood (about 2 teaspoons) will be drawn to
check for hepatitis B and/or C.

On Day 14 or 15 of Cycle 1:

- Patient will have a physical exam, including measurement of their weight and vital
signs.

- Patient will be asked about any side effects they may have had.

- Patient's performance status will be recorded.

- Blood (about 3 tablespoons) will be drawn for routine tests.

On Day 1 of Cycles 2 and beyond:

- Patient will have a physical exam, including measurement of their weight and vital
signs.

- Patient will be asked about any side effects they may have had and any drugs they may
be taking.

- Patient's performance status will be recorded.

- Blood (about 1 tablespoon) will be drawn for routine tests.

On Day 1 of Cycles 2 and 3 and every 3-6 weeks after that, blood (about 2 teaspoons) will be
drawn to check for hepatitis B and/or C if the doctor thinks it is needed.

On Day 1 of Cycles 2, 4, and every 3 cycles after that, blood (about 2 tablespoons) will be
drawn for tumor marker testing and additional routine tests.

On Day 1 of Cycles 4 and beyond, urine will be collected for routine tests.

On Day 1 of Cycle 4 and every 3 cycles after that, patient will have a CT scan, MRI, and/or
x-ray to check the status of the disease.

Length of Dosing:

Patient will receive TheraSphere on Day 15 of Cycle 1 and they may continue taking
everolimus for up to 12 cycles, as long as the doctor thinks it is in patient's best
interest. Patient will no longer be able to take everolimus if the disease gets worse, if
intolerable side effects occur, or if they are unable to follow study directions.

Patient's participation on the study will be over once they have completed the follow-up.

End-of-Dosing Visit:

Within 1 week after patient stops taking the study drug, the following tests and procedures
will be performed. Patient must fast starting at midnight the night before this visit.

- Patient will have a physical exam, including measurement of their weight and vital
signs.

- Patient will be asked about any side effects they may have had.

- Patient's performance status will be recorded.

- Blood (about 3 tablespoons) will be drawn for routine tests and tumor marker testing.
This blood draw will include a pregnancy test if patient can become pregnant.

- Urine will be collected for routine tests.

- Patient will have a CT scan, MRI, and/or x-ray to check the status of the disease.

Follow-up:

At least 1 time a week by phone or at the clinic for up to 30 days after patient's last
everolimus dose, the study staff will follow up with patient. Patient will be asked about
any side effects they may have had. The call should last about 10-15 minutes.

If patient left the study because of a side effect, they will continue to be contacted by
the study staff until the side effect has gone away or become stable.

This is an investigational study. Everolimus is commercially available and FDA approved to
treat advanced pancreatic NETs and other types of cancer. The combination of everolimus and
TheraSphere in this study is investigational.

TheraSphere is commercially available and FDA approved as a radiation treatment for liver
cancer. The use of TheraSphere in this study is investigational.

Up to 22 participants will be enrolled in this study. All will take part at MD Anderson.


Inclusion Criteria:



1. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study.

2. Patients must have histologically or cytologically confirmed low or intermediate
grade neuroendocrine tumor, for which standard curative measures do not exist.
Patients with neuroendocrine tumors associated with multiple endocrine neoplasia type
1 (MEN1 syndrome) will be eligible.

3. Patients must have liver-only or liver-dominant disease.

4. Patient deemed suitable for TheraSphere therapy after review of anatomic imaging by
an Interventional Radiologist.

5. No prior biliary enteric anastomosis.

6. Intact portal vein and hepatic artery.

7. Age >/= 18 years of age.

8. World Health Organization (WHO) performance status of 0 or 1.

9. Patients must have normal organ and marrow function as defined below: a) leukocytes
>/= 3,000/mcL; b) absolute neutrophil count >/= 1,500/mcL; c) hemoglobin >/= 9 g/dL*;
d) platelets >/= 100,000/mcL; e) total bilirubin (ULN); f) AST (SGOT) and ALT (SGPT) test [LFT] elevations due to liver metastases); g) creatinine ULN OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels
above institutional normal. *Eligibility level for hemoglobin may be reached by
transfusion.

10. The patient must have fasting serum glucose
11. Fasting serum cholesterol patient can only be included after initiation of appropriate lipid lowering
medication.

12. The effects of TheraSphere and everolimus on the developing human fetus are unknown.
For this reason, women of child-bearing potential must agree to use highly effective
contraception from the time of study enrollment continuing for the duration of study
therapy and for 8 weeks after the last dose of TheraSphere and/or everolimus. Women
of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, must use highly effective contraception during the study and for 8 weeks
after stopping treatment. Highly effective contraception is defined as either: 1)
Total abstinence: When this is in line with the preferred and usual lifestyle of the
subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of contraception.];

13. Continuation of # 12: 2) Sterilization: have had surgical bilateral oophorectomy
(with or without hysterectomy) or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment; 3) Male partner
sterilization (with the appropriate post-vasectomy documentation of the absence of
sperm in the ejaculate). [For female subjects on the study, the vasectomised male
partner should be the sole partner for that subject.]; 4) Use of a combination of any
two of the following (a+b or a+c or b+c): a. Use of oral, injected, implanted or
other hormonal methods of contraception; b. Placement of an intrauterine device (IUD)
or intrauterine system (IUS); c. Barrier methods of contraception: Condom or
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/vaginal suppository.

14. Continuation of # 13: In case of use of oral contraception, women should have been
stable on the oral agent before taking study treatment. Sexually active males must
use a condom during intercourse while taking the drug and for 8 weeks after stopping
treatment and should not father a child in this period. A condom is required to be
used also by vasectomised men in order to prevent delivery of the drug via seminal
fluid. Female partners of male patients must also be advised to use one of the
following contraception methods: Use of (1) oral, injected, implanted or other
hormonal methods of contraception, or (2) intrauterine device (IUD) or intrauterine
system (IUS), or (3) prior male/female sterilization.

15. Women of childbearing potential must have a serum pregnancy test within 7 days prior
starting study treatment.

16. Patients must have at least one measurable site of disease according to RECIST in
liver.

17. Patients may have received prior systemic anti-neoplastic therapy. There are no
limitations on the number of prior regimens. At least 28 days must have elapsed since
last treatment. Prior somatostatin analogs use is allowed. The patients on 3 months
of stable dose of concurrent somatostatin analogs will be allowed to continue while
on study treatment.

18. Patients must have international normalized ratio (INR)
Exclusion Criteria:

1. Patients may not be receiving any other treatment-related investigational agents.

2. Uncontrolled intercurrent illness including but not limited to: a) ongoing or active
infection requiring parenteral therapy at the time of study registration; b) liver
disease such as cirrhosis or severe hepatic impairment (Child-Pugh class B or C)
Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be
done at screening for all patients. Testing required at screening for all patients
with a positive medical history based on risk factors and/or confirmation of prior
HBV/HCV infection; c) symptomatic congestive heart failure resulting in a resting O2
saturation of < 92% on room air; d) unstable angina or pectoris myocardial infarction
within 6 months of start of study drug; e) serious uncontrolled cardiac arrhythmia;
f) known severely impaired lung function as defined as spirometry and DLCO that is
50% of the normal predicted value and/or oxygen saturation that is 88% or less at
rest on room air. Pulmonary function test (PFT) is not required at study entry.

3. Patients currently receiving anticancer therapies or who have received anticancer
therapies within 4 weeks of the start of study drug (including chemotherapy,
radiation therapy, antibody based therapy, etc.).

4. Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study.

5. Patients who previously received liver directed therapy, with either radiofrequency
ablation (RFA), transarterial hepatic embolization (TACE) with or without
chemotherapy must have >/= 60 days elapsed since last treatment.

6. A known history of human immunodeficiency virus (HIV) seropositivity.

7. Chronic treatment with systemic steroids or another immunosuppressive agent.

8. Female patients who are pregnant or breast feeding, or of reproductive potential who
are not using effective birth control methods.

9. Patients with a known history of allergic reactions and/or hypersensitivity
attributed compounds of similar chemical or biologic composition to everolimus or
other rapamycins (sirolimus, temsirolimus).

10. Known history of brain or leptomeningeal metastases.

11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study.

12. Patients who have had hormonal therapy (other than replacement) within 4 weeks prior
to entering the study.

13. Not recovered from adverse events related to previous treatment (excluding alopecia)
to active Common Terminology Criteria for Adverse Events (CTCAE) Ver. 4
14. With the exception of tumor common to a single genetic cancer syndrome (ie MEN1,
MEN2, von Hippel-Lindau [vHL], tuberous sclerosis complex [TSC] etc), patients with
evidence of more than one active malignancy are excluded. Active malignancy is
defined as the presence of primary, regional nodal, or distant metastatic neoplasm
that has not undergone definitive therapy.

15. The patient has poorly controlled diabetes mellitus. Patients with a history of
diabetes mellitus are allowed to participate, provided that their blood glucose is
within 1.3 X institutional upper limit of normal and that they are on a stable
dietary or therapeutic regimen for this condition.

16. Patients who have received prior treatment with everolimus or an mTOR inhibitor
(sirolimus, temsirolimus, everolimus).

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Dose Limiting Toxicities (DLT) for Combination of TheraSphere and Everolimus

Outcome Description:

Dose limiting toxicity (DLT) defined as any toxicity occurring during the first 56 days of therapy with definite, possible or probable attribution to TheraSphere and/or Everolimus and meets CTCAE version 4.0 criteria.

Outcome Time Frame:

56 days

Safety Issue:

Yes

Principal Investigator

Nageshwara V. Dasari, MBBS

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2011-1205

NCT ID:

NCT01864070

Start Date:

November 2013

Completion Date:

Related Keywords:

  • Liver Cancer
  • Liver cancer
  • Neuroendocrine tumors
  • NET
  • Liver dominant disease
  • TheraSphere
  • Yttrium-90
  • Y-90
  • Everolimus
  • Afinitor
  • Zortress
  • RAD001
  • Microspheres
  • Liver Neoplasms
  • Neuroendocrine Tumors

Name

Location

University of Texas MD Anderson Cancer CenterHouston, Texas  77030