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A Pilot Study to Determine the Effects of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 on Leukemia Cell Kinetics and Trafficking, Using Heavy Water Labeling in Subjects With Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)


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

Thank you

Trial Information

A Pilot Study to Determine the Effects of the Bruton's Tyrosine Kinase (Btk) Inhibitor PCI-32765 on Leukemia Cell Kinetics and Trafficking, Using Heavy Water Labeling in Subjects With Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)


Heavy Water Administration:

If you are found to be eligible to take part in this study, you will receive heavy water to
drink for 4 weeks. The vials of heavy water will be shipped to your home location.

On Days 1-5, you will drink the heavy water 3 times each day. You will drink 1 dose in the
morning, 1 dose in the afternoon, and 1 dose in the evening. You should take the doses at
least 3 hours apart. If you miss a dose, take it as soon as you remember. Make sure to wait
at least 3 hours between doses.

Starting on Day 6 and until your first study visit, you will drink the heavy water 1 time
each day in the evening.

You may choose to drink the heavy water with or without food.

You will be given a study diary to record your doses. If you miss a dose, take it as soon as
you remember. If you vomit a dose, you do not need to make it up. Just wait until the next
regularly scheduled dose and make a note of it in the diary.

Heavy Water Study Visits:

On Day 1 and during Weeks 2 and 4, blood (about 5 tablespoons) will be drawn for routine
tests and for heavy water testing. These blood samples will not be banked for future
research. The samples will only be used for research in this study and will be kept until
all DNA and protein analysis is complete. These Samples will be sent to our collaborators at
the Feinstein Institute for Medical Research and KineMed, Inc., in order to conduct the
heavy water analyses.

After Week 4, you will stop drinking the heavy water and will be followed either in the
clinic or by your local doctor for 6-12 weeks.

Every 2 weeks during the time after you stop drinking heavy water and before you start
taking ibrutinib, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of your vital signs.

- Blood (about 4 tablespoons) will be drawn for heavy water testing. This measures how
fast the cancer cells are making new protein and DNA.

- You will be asked about any drugs you may be taking.

Every 4 weeks during the time after you stop drinking heavy water and before you start
taking ibrutinib, blood (about 1 tablespoon) will be drawn for routine tests.

Ibrutinib Administration:

Beginning around Weeks 10-16, you will start taking ibrutinib. You will take 3 capsules by
mouth with 1 cup (8 ounces) of water 1 time a day. The dose should be taken at least 30
minutes before eating and at least 2 hours after a meal, at about the same time each day.

If you miss or vomit a dose, do not make up the dose. Take the next dose at your regularly
scheduled time and be sure to write it down in the study diary.

You will take the study drug for up to 12 cycles. Each cycle is 28 days. If the doctor
thinks it is in your best interest, you may continue taking the study drug even after 12
cycles.

You will also take allopurinol by mouth 1 time each day during the first 1-2 weeks of taking
ibrutinib to lower the risk of side effects.

Ibrutinib Study Visits:

At every study visit, you will be asked about any drugs you may be taking and about any side
effects you may be having.

On Days 1 and 3 of Week 1, and at the end of Weeks 2, 4, 6, 8, and 10:

- You will have a physical exam, including measurement of your vital signs.

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

- Blood (about 4 tablespoons) will be drawn for heavy water testing.

At the end of Week 12:

- You will have a physical exam, including measurement of your vital signs.

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

- Blood (about 4 tablespoons) will be drawn for heavy water testing.

- You will have computed tomography (CT) scans of the chest, abdomen, and pelvis to check
the status of the disease.

- You will have a bone marrow aspiration to check the status of the disease. To collect a
bone marrow aspirate, an area of the hip or other site is numbed with anesthetic, and a
small amount of bone marrow is withdrawn through a large needle.

At the end of Weeks 16 and 20:

- You will have a physical exam, including measurement of your vital signs.

- Blood (about 2 tablespoon) will be drawn for routine tests.

At the end of Weeks 24 and 36:

- You will have a physical exam, including measurement of your vital signs.

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

- You will have CT scans to check the status of the disease.

- You will have a bone marrow aspiration to check the status of the disease.

At the end of Week 48:

- You will have a physical exam, including measurement of your vital signs.

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

- You will have CT scans to check the status of the disease.

Length of Study Drug Dosing:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the end-of-study visits.

Follow-Up Visits:

If you continue taking the study drug past 12 cycles, you will come to the clinic for
follow-up visits every month. You will continue to have follow-up visits as long as you are
taking the study drug. At each visit, the following tests and procedures will be performed:

- You will have a physical exam, including measurement of you vital signs.

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

Whenever the doctor thinks it is needed, you will have the following tests and procedures:

- You may have CT scans to check the status of the disease.

- You may have a bone marrow aspiration to check the status of the disease.

End-of-Study Visits:

After your last dose of study drug, and then 1 more time during the next month, you will
have end-of-study visits. The following tests and procedures will be performed:

- You will have a physical exam, including measurement of you vital signs.

- You will be asked about any symptoms you may be having.

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

This is an investigational study. Ibrutinib is not commercially available or FDA approved.
It is currently being used for research purposes only.

Up to 30 patients will take part in this study. All will be enrolled at MD Anderson.


Inclusion Criteria:



1. A diagnosis of CLL/ SLL and have not been previously treated.

2. An indication for treatment by 2008 IWCLL Criteria.

3. Male and female subjects of age >/= 18 years at the time of signing informed consent
and requiring treatment within the next 2 to 6 months.

4. Understand and voluntarily sign an informed consent, and be able to comply with study
procedures and follow-up examinations.

5. Platelet counts at study entry must be greater than 50,000/µL and absolute neutrophil
counts at study entry must be greater than 750/µL.

6. Free of prior malignancies for 3 years with exception of currently treated basal
cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or
breast.

7. Subjects must be able to contribute the required amount of blood and/or tissue
without compromising their well-being or care and must weigh at least 110 pounds.

8. Adequate renal and hepatic function as indicated by all of the following: total
bilirubin ULN; and estimated creatinine clearance (CrCl) of > 30 mL/min, as calculated by the
Cockcroft-Gault equation.

9. Participants must be willing to be contacted again for consideration of additional
studies in the future, such as a blood draw or another action (e.g., bone marrow
aspiration and/or biopsy) that would be associated with their standard of care,
unless they consented to such for research purposes.

10. An ECOG/WHO performance status of 0-2.

11. Males and females of child bearing potential must have adequate birth control
protection while on study and for 30 days after the last dose of study drug. The
couple will use two forms of birth control for the entire time of the study and 30
days after finishing study. Conception control should include a hormonal method
(birth control pill, etc.), and a double-barrier methods (condoms with spermicidal,
sponge with spermicidal, or diaphragm with spermicidal), or abstinence (not having
sex) will be practiced.

12. Female subjects will need a negative pregnancy screening test if they are of child
bearing potential.

Exclusion Criteria:

1. Subjects less than 18 years of age.

2. A lymphocyte doubling time of < 3 months, or other clinical or laboratory signs
indicating that a treatment delay of 2 months or longer (due to heavy water labeling
and resting period) would result in a significant progression of the disease and be
detrimental to the subject, as determined by the treating physician.

3. Any prior treatment for CLL including chemotherapy, chemoimmunotherapy, monoclonal
antibody therapy, radiotherapy, or high-dose corticosteroid therapy (Prednisone > 60
mg daily or equivalent), or immunotherapy prior to enrollment or concurrent with this
trial.

4. Concomitant use of agents that have been described to affect the biology and/or
proliferation rate of CLL cells such as: PDE-inhibitors (e.g., sildenafil,
theophylline), immunosuppressive agents (e.g., prednisone, cyclosporin-A, rapamycin),
green tea extract, itraconazole, ketoconazole, clarithromycin, bupropion, and Cox-2
inhibitors.

5. Investigational agent received within 30 days prior to the first dose of study drug.
If received any investigational agent prior to this time point, drug-related
toxicities must have recovered to Grade 1 or less prior to first dose of study drug.

6. Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment).

7. Subjects with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune
thrombocytopenia (ITP).

8. Any other severe concurrent disease, or have a history of serious organ dysfunction
or disease involving the heart, kidney, liver or other organ system that may place
the subject at undue risk to undergo therapy with PCI-32765.

9. Any serious medical condition, laboratory abnormality, or psychiatric illness that
places the subject at unacceptable risk if he/she were to participate in the study.

10. History of intracranial hemorrhage or stroke within 6 months prior to the study.

11. Evidence of bleeding diathesis or coagulopathy.

12. Major surgical procedure, open biopsy, or significant traumatic injury, within 28
days prior to Day 1, anticipation of need for major surgical procedure during the
course of the study. (Minor surgical procedures, fine needle aspirations or core
biopsies within 7 days prior to Day 1. Bone marrow aspiration +/- biopsy is allowed).

13. Serious, non-healing wound, ulcer, or bone fracture.

14. Subjects receiving anticoagulation (for example heparin, Coumadin,
low-molecular-weight heparin (LMWH, such as Lovenox), and anti-platelet drugs (except
for low-dose aspirin) will be ineligible to participate in this study. Subjects who
recently received drugs for anticoagulation must be off those medications for at
least 7 days prior to start of the study.

15. Subjects who are known to be anemic, with hemoglobin <8.0g/dl.

16. Weight less than 110 pounds

17. Subjects who are known to be infected with HIV, or have signs of active Hepatitis B
or Hepatitis C.

18. Biliary obstruction, acute hepatitis, severe liver failure, or severely impaired
renal function.

19. PCI-32765 is contraindicated in subjects with clinically significant hypersensitivity
to any of the compound's structural components.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Impact of PCI-32765 on Leukemia Cell Trafficking and Death

Outcome Description:

Statistical analysis is characterization of pattern of labeled cells (LC) over time. Patterns analyzed both visually and using more formal statistical methods in an exploratory manner. First, pattern will be smoothed using a cubic spline interpolation (SAS Graph, SAS Institute, Cary, NC). This will facilitate the determination of shape and numbers and patterns of peaks by eliminating "noise" in the data. Second, based on the patterns observed after smoothing, the data will be fit to candidate regression models (e.g., parabolas, mixtures of parabolas, piecewise curves, etc.) and the best fitting model will be identified using common statistical methods such as R2, Akaike's information, etc. All curves will be fit on individual subjects, thereby permitting subjects to vary in the pattern of their LC response curves.

Outcome Time Frame:

12 weeks

Safety Issue:

No

Principal Investigator

Jan A. Burger, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

2012-0086

NCT ID:

NCT01752426

Start Date:

December 2012

Completion Date:

Related Keywords:

  • Leukemia
  • Leukemia
  • Chronic Lymphocytic Leukemia
  • CLL
  • Small Lymphocytic Lymphoma
  • SLL
  • PCI-32765
  • Ibrutinib
  • Btk inhibitor
  • Heavy water
  • 2H2O
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid

Name

Location

UT MD Anderson Cancer CenterHouston, Texas  77030