Phase I Trial of Brentuximab Vedotin for Refractory Chronic Graft-vs.-Host Disease (GVHD)

This study is looking for the highest dose of the Brentuximab Vedotin that can be
administered safely without severe or unmanageable side effects in patients that have chronic
Graft vs. Host Disease, not everyone who participates in this research study will receive the
same dose of the study drug. The dose each patient will get depends on the number of
participants who have been enrolled in the study prior and how well they have tolerated their
doses.

Each patient will receive a dose of Brentuximab Vedotin every 3 weeks. Brentuximab Vedotin is
administered via intravenous infusion, or IV infusion, which means directly into the vein,
over a period of about 30 minutes.

Each cycle is 21 days long.

Each patient will undergo the following tests and procedures when they come into the clinic
to receive each dose of Brentuximab Vedotin:

Days 1, 8, and 15 of 1st 2 cycles:

- Physical exam, which includes height, weight, body surface area and vital signs.

- A medical history, which includes questions about your health, current medications, and
any allergies.

- Performance status, which evaluates how participant are able to carry on with your usual
activities.

- Routine blood tests to test overall health (about 1 teaspoon of blood) Assessment of
side effects- physician will evaluate the patient's current health and ask questions to
see there are any experienced side effects from taking the study drug.

Only Day 1 of 1st 3 cycles:

- Research blood draws for biomarker and PK assessments (pharmacokinetic assessments that
measure the level of drug in the patient's blood) (about 4 teaspoons of blood)

- Biomarker studies blood draw (about 4 teaspoons) Viral monitoring blood tests to make
sure each patient has not developed any new viruses as a result of treatment (about 4
teaspoons of blood)

- Chronic GVHD assessments: The patient's physician may need to perform other tests to
confirm the diagnosis of acute GVHD. These can include more blood tests, imaging
studies, and possibly biopsies of affected organs. The exact tests will be determined by
the patient's physician

Planned Follow-up: If the patient's physician believes the patient is responding well to
treatment, the patient may receive up to 16 cycles of Brentuximab Vedotin. The Investigator
would like to keep track of patient's medical condition for 12 months after the patient has
completed the first 2 cycles of treatment, no matter if the patient receives more doses or
not. The Investigator would like to do this by calling the patient on the telephone to see
how he/she is doing. Keeping in touch with patient and checking the condition helps the
Investigator look at the long-term effects of the research study.

Inclusion Criteria:

- Recipients of allogeneic hematopoietic cell transplantation (HCT) after either
myeloablative or reduced intensity conditioning regimens. Any donor source of stem
cells is eligible.

- Participants must be at least 100 days after HCT.

- Patients must have steroid refractory cGVHD, defined as having persistent signs and
symptoms of chronic GVHD (section 13.1) despite the use of prednisone at ≥ 0.25
mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks in the preceding 12
months (or equivalent dosing of alternate corticosteroids) without complete resolution
of signs and symptoms.

- Stable dose of corticosteroids for 4 weeks prior to enrollment

- No addition or subtraction of other immunosuppressive medications (e.g., calcineurin
inhibitors, sirolimus, mycophenolate mofetil) for 4 weeks prior to enrollment. The
dose of immunosuppressive medicines may be adjusted based on the therapeutic range of
that drug

- Serum Cr ≤ 3 gm / dL

- Adequate hepatic function (total bilirubin < 2.0 mg/dl, AST < 5x ULN), unless hepatic
dysfunction is a manifestation of presumed cGVHD. For patients with abnormal LFTs as
the sole manifestation of active cGVHD, documented cGVHD on liver biopsy will be
required prior to enrollment. Abnormal LFTs in the context of active cGVHD involving
other organ systems may also be permitted if the treating physician documents the
abnormal LFTs as being consistent with active hepatic cGVHD, and a liver biopsy will
not be mandated in this situation.

- Patients must have adequate bone marrow function as defined by ANC ≥ 1000 / µl and
platelets ≥ 20,000 / µl without growth factor or transfusional support

- Negative pregnancy test for females of child bearing age

- Age ≥ 18 - The safety and effectiveness of brentuximab vedotin has not been
established in the pediatric population. Clinical trials of brentuximab vedotin
included only 9 pediatric patients and this number is not sufficient to determine
whether they respond differently than adult patients.

- The effects of brentuximab vedotin on the developing human fetus are unknown. For this
reason and because chemotherapy agents are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Ongoing prednisone requirement > 1 mg/kg/day (or equivalent)

- Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.

- ECP therapy within 4 weeks prior to enrollment

- Active malignant disease relapse

- Active, uncontrolled infection

- Uncontrolled cardiac angina or symptomatic congestive heart failure (NYHA Class III or
IV).

- Karnofsky performance status < 30

- Prior use of brentuximab vedotin for GVHD is not allowed. Prior use of brentuximab
vedotn for the treatment of malignancy is allowed.

- Pregnant women are excluded from this study because brentuximab vedotin is a
chemotherapy agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk of adverse events in nursing infants
secondary to treatment of the mother with brentuximab vedotin, breastfeeding should be
discontinued if the mother is treated with brentuximab vedotin.