TSEB and Brentuximab for Treatment of Mycosis Fungoides & Sezary Syndrome

This study is a 2-cohort, open-label, phase 1B trial to evaluate the cutaneous toxicity,
overall toxicity, and treatment response associated with administering concurrent low-dose
TSEB and brentuximab vedotin in patients with mycosis fungoides or Sézary Syndrome. Duration
of complete skin response, DOCB, and tumor response in lymph nodes and blood will also be
evaluated. Additionally, skin-related QOL and neurotoxicity will be assessed.

Patients will be enrolled in 1 of 2 cohorts based on disease stage.

Cohort A will include patients with earlier stage disease (selected Stage IB in patients who
have had one previous course of therapy) and Stages IIA through IIIA [if N0-1]).

Cohort B will include patients with more advanced disease (Stage IIA through IIIA [if N2-3],
Stage IIIB, Stage IVA, and transformed CTCL) who are candidates for low-dose TSEB and/or
systemic therapy.

A standard dose of brentuximab vedotin will be administered to all patients by intravenous
infusion 3 weeks prior to initiation of low-dose TSEB and then every 3 weeks for a total of 3
cycles. Cohort A patients will complete brentuximab vedotin after 3 cycles; patients in
Cohort B will continue brentuximab vedotin until disease progression or unacceptable
toxicity, whichever occurs first. In the absence of progression or unacceptable toxicity, the
patient may receive brentuximab vedotin for up to 2 years as a study participant. A total of
12 Gy TSEB (ie, low-dose TSEB) will be administered to both cohorts per standard protocol in
6 fractions (2 fractions per week) beginning 3 weeks after the first dose of brentuximab
vedotin.

The Modified Severity Weighted Assessment Tool (mSWAT) (16), completed by the investigator,
will be used to determine skin involvement at baseline and skin response to treatment
beginning after administration of the 3 doses of brentuximab vedotin and low-dose TSEB.
Skindex-16, a patient-completed form that measures symptoms and perceptions of toxicity in
patients with skin disease will be used to assess skin-related QOL. Additionally, Form NTX
will be completed by patients in Cohort A to assess symptoms of CIPN which is a side effect
of brentuximab vedotin.

The sample size for this study will be a maximum of 15 patients for a total of 12 evaluable
patients with no more than 6 patients in Cohort B. However, if the number of patients with
severe toxicity exceeds the established acceptable incidence, accrual will end before
reaching the sample size goal of 12 evaluable patients.

Inclusion Criteria:

- Histologically confirmed CD30-positive (defined in this study as ≥ 1% expression)
Mycosis Fungoides (including large cell transformation variant) or Sezary Syndrome who
have either:

- Received prior systemic therapy (for whom commercial supply of brentuximab
vedotin is available) OR

- Not received prior systemic therapy (who will receive brentuximab vedotin free of
charge)

- Any of the disease stages listed below

- Stage IB disease that meets one of the following criteria:

- Plaque disease (ie,T2b staging)

- Diffuse skin involvement with indication for TSEB (plaque disease with or without
patches)

- Not appropriate for treatment with focal therapies

- One prior course of low-dose TSEB or one prior course of systemic chemotherapy
regimens (excluding brentuximab)

- Stage IIA, IIB, or IIIA that meets ONE or BOTH of the following criteria:

- Patient is a candidate for treatment with low-dose TSEB

- Patient is a candidate for systemic therapy

- IIIB or IVA disease requiring systemic therapy

- Transformed CTCL

- Candidate for TSEB based on investigator determination

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3, if the
performance status of 3 is due to skin disease involvement

- Adequate bone marrow function as defined below:

- Absolute neutrophil count (ANC) ≥ 1000/mm3

- Platelets > 75,000/mm3

- Hemoglobin ≥ 9 g/dL

- Note: Patients requiring transfusion to meet the hemoglobin requirement are
not eligible for the study.

- Calculated creatinine clearance (CrCl) > 30 mL/min.

- Adequate hepatic function as defined below:

- Total bilirubin ≤ 1.5 x ULN for the laboratory

- Aspartate aminotransferase (AST) ≤ 2 x ULN for the laboratory

- Alanine aminotransferase (ALT) ≤ 2 x ULN for the laboratory

- Prothrombin time with INR ≤ ULN for the laboratory

- A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age
and has not had a hysterectomy, must have a documented negative serum pregnancy test
14 days prior to study registration

- Note: If study treatment is not initiated within 7 days after the pregnancy test,
the pregnancy test must be repeated.

- A WCBP and a male patient with a partner who is a WCBP must agree to use a medically
accepted method for preventing pregnancy for the duration of study treatment and for
at least 6 months following completion of study treatment

- Ability to understand and willingness to sign the consent form

Exclusion Criteria:

- Previous TSEB therapy with total dose > 20 Gy

- Previous brentuximab treatment

- Any of the following within 4-3 weeks prior to initiating study treatment

- Systemic biologic therapy

- Monoclonal antibody

- Chemotherapy

- TSEB

- Phototherapy

- Other investigational therapy

- Anticancer topical therapy, including therapeutic doses of steroids, within 2 weeks
prior to initiating study treatment

- Note: Topical steroids at doses intended for symptom management are permitted
prior to study enrollment and may continue during study treatment.

- Peripheral sensory neuropathy or peripheral motor neuropathy ≥ grade 2 per NCI CTCAE
v4.0

- Diabetic neuropathy (any grade)

- Demyelinating form of Charcot-Marie-Tooth Syndrome

- History of progressive multifocal leukoencephalopathy

- Active or clinically significant cardiac disease including any of the following:

- Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months
prior to initiating study treatment

- Myocardial infarction within 6 months prior to initiating study treatment

- New York Heart Association (NYHA) class III or IV congestive heart failure
(Appendix 4)

- Active ≥ grade 3 (per NCI CTCAE v4) viral, bacterial, or fungal infection within 2
weeks prior to initiation of study treatment

- Known human immunodeficiency virus (HIV) infection

- Known or suspected active hepatitis B or C infection

- Known cirrhosis

- Known Gilbert's Syndrome

- Planned ongoing treatment with another drug that may potentially have adverse
interactions with brentuximab vedotin; if such a drug has been used, it must be
discontinued at least 1 week prior to initiating study treatment (see Section 6.6);
examples of potential interactions include:

- Coadministration of strong inhibitors of CYP3A4 (eg, ketoconazole, ritonavir,
clarithromycin)

- Coadministration of CYP3A4 inducers (eg, rifampin)

- Concomitant treatment with strong inhibitors of P-glycoprotein (P-gp)

- Known hypersensitivity to any excipient contained in the brentuximab formulation

- Prior malignancy or myelodysplastic syndrome (active within 3 years of screening)
except completely excised non-invasive basal cell or squamous cell carcinoma of the
skin, and in situ squamous cell carcinoma of the cervix

- Pregnancy or breastfeeding

- Medical, psychological, or social condition that, in the opinion of the investigator,
may increase the patient's risk or limit the patient's adherence with study
requirements