Bone Marrow Stromal Cells for Inflammatory Bowel Diseases

Crohn s disease (CD) and ulcerative colitis (UC), the 2 major sub-types of inflammatory bowel
disease (IBD), are chronic, life-long conditions characterized by relapsing inflammation of
the gastrointestinal tract. CD has a predilection for the small bowel and the proximal large
bowel; however, it can affect the gastrointestinal tract discontinuously anywhere. UC mainly
affects the distal colon but can involve the entire colon as well. In spite of advances in
IBD therapeutics, a significant number of patients continue to have symptoms while on
conventional medications. The current protocol proposes to study infusions of allogenic bone
marrow stromal cells (BMSCs) for the treatment of active IBD.

The purpose of this study is to evaluate the safety of BMSC infusions in subjects with IBD
and to examine the host clinical and immunologic response to BMSCs. BMSCs possess
multi-lineage differentiation potential in bone marrow, and aid in the repair of damaged
tissue. They suppress the lymphocyte immune response and target sites of inflammation to
promote healing through tissue regeneration. Studies are underway examining the utility of
BMSCs to treat several conditions including neurologic disorders, myocardial infarctions,
rheumatologic disorders, and gastrointestinal disorders including acute
graft-versus-host-disease and IBD. Progress in the understanding of the cell populations
involved in the pathogenesis of IBD and the discovery of the potential immunologic and
regenerative characteristics of BMSCs have created a new potential direction for IBD therapy.

This phase I study will enroll subjects with moderate-to-severe IBD who are refractory to or
intolerant of standard therapy. Under the guidance of the NIH Bone Marrow Stromal Cell
Transplantation Center, the Cell Processing Section of the Department of Transfusion Medicine
at the Clinical Center has developed a procedure for collecting, expanding, and
cryopreserving clinical grade BMSCs under an FDA Drug Master File. Marrow will be aspirated
from volunteer donors participating on protocol 10-CC-0053 who have passed the standard
screening for blood and marrow donors; BMSCs will be expanded in vitro. Since it is not
necessary to HLA-match BMSC donors with their recipients, a BMSC repository will be used as
the source of BMSCs for this study.

In Arm 1, the safety of the BMSC infusion dosage (4 x 106 cells/kg/dose 10%) and schedule
(once a week for 4 weeks) will be evaluated in 3 non-overlapping IBD subjects. Once safety is
established in these subjects, subsequent subjects in Arm 2 will be enrolled without overlap
restriction. Subjects will return to the clinic for safety and response assessments at 28,
56, 84, and 112 days after the first infusion. Additional safety visits will be performed at
180, 360 and 720 days after the first infusion. Safety will be monitored by a Data and Safety
Monitoring Board. Response to study drug will be assessed in all patients by changes in
symptom scores, endoscopic/histologic findings, quality of life scores, and
immunologic/laboratory parameters. Fifty subjects will be evaluated over a 5-year period.

- SUBJECT INCLUSION CRITERIA:

Subjects who meet ALL of the following criteria will be considered for enrollment into this
study:

1. Be 18 to 65 years of age, inclusive, as of the date of enrollment.

2. Be willing to take appropriate measures to avoid pregnancy during the study period.
Subject to the judgment and discretion of the PI, participants who meet ANY of the
criteria listed immediately below, as well as male participants who are in a
monogamous relationship with a woman who meets ANY of the criteria below, may not be
required to take any pregnancy avoidance measures (e.g. barrier methods). Such
participants will be counseled on risks at the time of consent and at appropriate
points (e.g. when pregnancy testing occurs) during the study:

1. Females who have had their uterus, and/or BOTH ovaries removed

2. Females who have had BOTH fallopian tubes surgically tied or removed

3. Females who have undergone other permanent birth control procedures, such as
endometrial ablation or sterilization (such as Essure or Novasure), and have had
any required follow up testing to confirm the effectiveness of the permanent
birth control procedure.

4. Females who are above the age of 50 and have spontaneously had no menses at any
point during the past 12 or more consecutive months (i.e. have reached
menopause).

5. Females who, in the conservative and reasonable judgment of the PI (e.g. due to
sexual orientation, or serious life choice), from the time of enrollment until

12 weeks after the last BMSC infusion, will NOT participate in any potentially
reproductive sexual contact (i.e. sexual intercourse with a male partner).

6. Males who have had a vasectomy and have had the follow-up testing confirming zero
sperm count in their semen.

3. Any subject who does NOT meet the criteria listed in #2 above, will be appropriately
counseled on reproductive risks and pregnancy avoidance, and will be required to
adhere to the following measures, as agreed upon by the subject and the PI until at
least 12 weeks after the last BMSC infusion:

1. A highly effective hormonal method to prevent pregnancy [e.g. CONSISTENT,
CONTINUOUS use of contraceptive pill, patch, ring, implant or injection], and/or
IUD or equivalent.

IN ADDITION TO

2. A barrier method to be used at the time of potentially reproductive sexual
activity (e.g. [male/female condom, cap, or diaphragm] + spermicide).

3. Male participants will be appropriately counseled on risks and must agree to
consistently use effective contraception with female sexual partners through the
Day 112 study visit to avoid a pregnancy that could be affected by the study
drug. Appropriate measures to avoid pregnancy and trial related risks in sexual
partners, per the PI s judgment, must be agreed to and practiced.

NOTE: Most of the above interventions to prevent pregnancy must be implemented at a
particular time in the menstrual cycle, and may not be immediately effective. Trial
activity that may pose a reproductive risk may NOT occur until the above contraceptive
measures are fully effective and must continue until at least 12 weeks after the last
BMSC infusion.

4. Have a diagnosis of CD or UC that has been endoscopically or radiographically
confirmed at least 6 months prior to screening.

5. Have either active CD symptoms as defined by a CDAI score between 220 and 450,
inclusive, as measured for 7 consecutive days during screening, or active UC as
defined by a SCCAI score greater than or equal to 6.

6. The patient must have demonstrated an inadequate response to, loss of response to, or
intolerance of at least 1 of the following agents as defined below:

- Corticosteroids

- Signs and symptoms of persistently active disease despite a history of at
least one 4-week induction regimen that included a dose equivalent to
prednisone 30 mg daily orally for 2 weeks or intravenously for 1 week OR

- Two failed attempts to taper corticosteroids to below a dose equivalent to
prednisone 10 mg daily orally on 2 separate occasions OR

- History of intolerance of corticosteroids (including, but not limited to
Cushing s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia,
infection)

- Immunomodulators

- Signs and symptoms of persistently active disease despite a history of at
least one 8 week regimen of oral azathioprine (greater than or equal to 1.5
mg/kg) or 6-mercaptopurine mg/kg (greater than or equal to 0.75 mg/kg) OR

- Signs and symptoms of persistently active disease despite a history of at
least one 8 week regimen of methotrexate (greater than or equal to 12.5
mg/week) OR

- History of intolerance of at least one immunomodulator (including, but not
limited to nausea/vomiting, abdominal pain, pancreatitis, LFT abnormalities,
lymphopenia, TPMT genetic mutation, infection)

- TNF alpha antagonists

- Signs and symptoms of persistently active disease despite a history of at
least one 4 week induction regimen of 1 of the following agents

- Infliximab: 5 mg/kg IV, 2 doses at least 2 weeks apart

- Adalimumab: one 80 mg SC dose followed by one 40 mg dose at least 2
weeks apart

- Certolizumab pegol: 400 mg SC, 2 doses at least 2 weeks apart OR

- Recurrence of symptoms during scheduled maintenance dosing following prior
clinical benefit (discontinuation despite clinical benefit does not qualify)
OR

- History of intolerance of at least 1 TNF antagonist (including, but not
limited to infusion-related reaction, demyelination, congestive heart
failure, infection)

7. May be receiving a therapeutic dose of the following drugs:

- Oral 5-ASA compounds provided that the dose has been stable for the 2 weeks
immediately prior to enrollment

- Oral corticosteroid therapy (prednisone at a stable dose less than or equal to 30
mg/day, budesonide at a stable dose less than or equal to 9 mg/day, or equivalent
steroid) provided that the dose has been stable for the 4 weeks immediately prior
to enrollment if corticosteroids have just been initiated, or for the 2 weeks
immediately prior to enrollment if corticosteroids are being tapered

- Probiotics (e.g., Culturelle, Saccharomyces boulardii) provided that the dose has
been stable for the 2 weeks immediately prior to enrollment

- Antidiarrheals (e.g., loperamide, diphenoxylate with atropine) for control of
chronic diarrhea

- Azathioprine or 6-mercaptopurine provided that the dose has been stable for the 8
weeks immediately prior to enrollment

- Methotrexate provided that the dose has been stable for the 8 weeks immediately
prior to enrollment

- Antibiotics used for the treatment of CD (i.e., ciprofloxacin, metronidazole)
provided that the dose has been stable for the 2 weeks immediately prior to
enrollment

8. Subjects must agree to have samples of their blood and tissue samples stored for
potential future research use.

9. Be willing to take appropriate measures to avoid pregnancy until at least 12 weeks
after the last BMSC infusion. All subjects will be informed of the potential risks of
BMSC during pregnancy and counseled on pregnancy avoidance appropriate to the subject
s circumstances (e.g. fertility status, medical contraindications to hormonal birth
control, and/or personal or religious beliefs regarding pregnancy avoidance). Subject
to thejudgement and discretion of the PI, some subjects may not need to take pregnancy
avoidance measures.

10. Subjects must have a primary medical care provider.

SUBJECT EXCLUSION CRITERIA

Subjects who meet ANY of the following criteria will be excluded from participation in this
study:

1. Subjects who are currently taking greater than or equal to 20 mg of prednisone per
day. Subjects on corticosteroids must be on a stable dose for at least 4 weeks.

2. Concomitant treatment with anti-TNF therapy (or other biological therapy) or with
Entyvio/vedolizumab. The following washout period will be required for subjects to be
eligible to participate in the trial:

1. Three months washout prior to baseline for certolizumab or natalizumab.

2. Two months washout prior to baseline for adalimumab, etanercept, infliximab, and
Entyvio/vedolizumab.

3. One month washout prior to baseline for cyclosporine, mycophenolate,

pimecrolimus, tacrolimus, and any other systemic immunosuppressants.

3. Pregnant or breastfeeding. Serum pregnancy test must be negative at screening for
female subjects of childbearing potential. Urine pregnancy test must remain negative
at each of the four infusion visits.

4. Subject does not agree to pregnancy avoidance measures required to prevent pregnancy
during participation in the study, or meet criteria that would exempt them from
contraceptive measures.

5. Has clinically significant systemic infection (e.g., chronic or acute infection,
urinary tract infection, upper respiratory tract infection) within one month of
screening and no opportunistic infection within six months of screening. Has a history
or presence of recurrent or chronic infection (e.g. viral infections [including
hepatitis B or C, HIV], bacterial infections, systemic fungal infections, or
syphilis).

6. Has a positive Quantiferon-TB Gold (QFT-G) test, indicating tuberculosis infection, at
time of screening. A QFT-G will not be done in a subject who has received tuberculosis
vaccination; these subjects will be eligible to participate if latent tuberculosis can
be excluded with a chest x-ray (CXR).

7. Received an agent not approved by the FDA for marketed use in any indication or any
small molecule inhibitors (e.g., Naltrexone) within 90 days of beginning the screening
CDAI diary or at any time during the screening window. This includes medications used
to treat IBD as an off-label use (at the discretion of the investigator).

8. Has abnormal hematological and biochemical parameters, including:

- Neutrophil count <1500 cells/mm(3).

- Hemoglobin <9 g/dL.

- Platelet count less than or equal to150,000 cells/mm(3).

- Creatinine greater than or equal to1.2 times the upper limit of normal (ULN).

- Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) greater
than or equal to2 times ULN.

- Prothrombin time-International Normalized Ratio (PT-INR) >2 and/or on chronic
anticoagulation medications.

- If total bilirubin is greater than 1.2 mg/dL, then direct bilirubin can be no
more than 70% of the total, up to a direct bilirubin of 2.0 mg/dL.

9. Has active infection with enteric pathogens as evidenced by positive microbiological
culture of stool.

10. Has active cytomegalovirus (CMV) infection. CMV polymerase chain reaction (PCR)
testing will be performed on biopsies taken during the time of initial colonoscopy in
order to exclude CMV.

11. Has a history of low-grade or high-grade colonic mucosal dysplasia.

12. Has a history of uveitis or iritis within the previous two months. This is due to the
concern that BMSCs may home to sites of active inflammation.

13. Had bowel surgery other than perianal (e.g., fistulotomy, seton placement, abscess
drainage) within 6 months prior to beginning the CDAI screening diary or drawing
screening blood samples.

14. Has surgical changes to gut anatomy that preclude administration of clinical activity
indicies including but not limited to ileostomy, colostomy, or subtotal colectomy with
ileorectal anastomosis.

15. Has known or suspected short bowel syndrome.

16. Requires parenteral or total parenteral nutrition.

17. Has a history of cancer, other than non-melanomatous cancer of the skin, within the
past 5 years.

18. Unwillingness or inability to comply with study requirements.

19. Has any medical or psychiatric condition that, in the opinion of the investigator,
contraindicates participation in this protocol.

20. Has only small bowel IBD that is inaccessible by standard colonoscopy to obtain
research biopsies. For this reason patients with only upper gastrointestinal IBD are
also excluded.

21. Refuses to abstain from using COX-2 inhibitors or NSAIDs throughout the 4 week study
drug infusion period.