Pilot Study of Brentuximab Vedotin (SGN-35) in Patients With MF With Variable CD30 Expression Level

The purpose of this study is to learn the effects of an investigational medication, SGN 35, on patients with mycosis fungoides. Despite a wide range of therapeutic options, the treatments are associated with short response duration, thus this condition is largely incurable. This investigational drug may offer less toxicity than standard treatments and have better tumor specific targeting.

The purpose of this study is to learn the effects of an investigational medication, SGN 35, on patients with cutaneous T cell lymphoma (CTCL), specifically mycosis fungoides (MF) and Sezary syndrome (SS). Despite a wide range of therapeutic options, the treatments are associated with short response duration, thus this condition is largely incurable. This investigational drug may offer less toxicity than standard treatments and have better tumor specific targeting.

The primary objective is to explore the biologic activity of brentuximab vedotin (SGN-35) in patients with mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), where expression of CD30 is variable. SGN-35 has significant biologic activity in Hodgkin's disease (HD) where only a small numbers of CD30 positive tumor cells are present, as well as in lymphomas with large numbers of CD30-expressing tumor cells such as systemic anaplastic large cell lymphoma (sALCL).

This phase II exploratory study will evaluate the clinical response of brentuximab vedotin (SGN-35) in MF and SS where tumor cells express variable levels of CD30 target molecule. The grouping by CD30 expression levels (low, intermediate, high) is for accrual purposes only to ensure a wide range of CD30 expression. Given the exploratory nature of this study, it will be open-label, single-arm, and non-randomized trial.

One centers will be involved to complete the accrual, a total of 24 patients with MF and SS. Enrollment will be based on CD30 expression levels by tissue immunohistochemistry (IHC), defined as low, intermediate or high expressers. The investigators will target 8 patients in each group for total of 24 patients. Of these 8 patients per group, up to 3 may be patients with SS.

Each patient regardless of CD30 expression level will receive 1.8 mg/kg of SGN-35 IV every 21 days, up to 8 cycles of therapy. Patients with CR may receive 2 additional cycles. Patients who have PR may receive up to a maximum of 16 doses IF they are continuing to improve after 8 cycles. Patients who relapse within 6 months after CR maybe eligible for retreatment.

• Lymphoma, Non-Hodgkin
• Cutaneous Lymphoma
• Cutaneous T Cell Lymphoma
• Mycosis Fungoides
• Sezary Syndrome

Inclusion Criteria:

1. Patient has biopsy-proven MF/SS, stage IB-IVB, and failed one standard systemic therapy.

   • Skin biopsy will be obtained within 3 months of beginning study medication, for assessment of CD30 expression by immunohistochemistry (IHC). This data will be used to ensure equal enrollment of patients in the 3 groups of varying CD30 expression (low, intermediate, high). If patient has different lesion morphology (patch, plaque, tumor), a biopsy will be obtained from each morphologic lesion. If the patient has one type of lesion morphology, a biopsy from 2 separate anatomic sites will be obtained.
   • The highest CD30 expression value among biopsies will be used to determine which of the 3 groups the subject will be assigned to.

2. Patients must have the following minimum wash-out from previous treatments:

   • >= 3 weeks for local radiation therapy, systemic cytotoxic anticancer therapy, treatment with other anti-cancer investigational agents (including monoclonal antibody).
   • > 3 weeks for retinoids, interferons, vorinostat, romidepsin, denileukin diftitox.
   • > 3 wks for phototherapy.
   • > 2 wks for topical therapy (including topical steroid, retinoid, nitrogen mustard, or imiquimod).
3. At least 18 years of age.
4. ECOG performance status of <= 2.
5. Patients must be available for study treatment, blood sampling, study assessments, and management of toxicity at the treating institution.
6. Adequate baseline laboratory data: absolute neutrophil count (ANC) >= 1000/uL, platelets >= 50,000/uL, bilirubin <= 2X upper limit of normal (ULN) or <= 3X ULN for patients with Gilbert's disease, serum creatinine <= 2X ULN, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3X ULN.
7. Women of childbearing potential (WOCBP) must have a negative serum beta-HCG pregnancy test result within seven days of treatment.
8. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with mycosis fungoides (MF) with limited disease (stage IA) or central nervous system (CNS) disease.
2. Concomitant corticosteroid use, systemic or topical, for treatment of skin disease. Oral prednisone is allowed at <= 10 mg/day, if patient has been on a stable dose for at least 1 month prior to study entry.
3. Patients with known Grade 3 or higher (per NCI CTCAE v4.0 criteria) active systemic or cutaneous viral, bacterial, or fungal infection.
4. Patients who are known to be Hepatitis B or Hepatitis C antibody positive.
5. Patients who are HIV-positive, and have a measurable viral load while on antiretrovirals.
6. Patients with a known hypersensitivity to recombinant proteins or any excipient contained in the drug formulation.
7. Patients with a history of other malignancies during the past three years. (The following are exempt from the three-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, curatively treated localized breast cancer, resected thyroid cancer, cervical intraepithelial neoplasia or cervical carcinoma in situ on biopsy).
8. Patients who are currently pregnant or breastfeeding.
9. Patients with congestive heart failure, Class III or IV, by New York Heart Association (NYHA) criteria.
10. Patients with any serious underlying medical condition that would impair their ability to receive or tolerate the planned treatment.
11. Patients with dementia or altered mental status that would preclude understanding and rendering of informed consent.