Low-dose (12 Gy) TSEBT+Vorinostat Versus Low-dose TSEBT Monotherapy in Mycosis Fungoides

Vorinostat is a histone deacetylase inhibitor (HDAC) that is FDA-approved for treatment of
mycosis fungoides (MF), and has shown activity as a radiation-sensitizer in preclinical
studies. Treatment of various cell lines [glioblastoma multiforme (GBM), non-small cell lung
cancer (NSCLC), melanoma] has shown that pretreatment with vorinostat had a significant
effect on radiation kill. This effect is believed to be secondary to multiple mechanisms that
may involve antiproliferative growth inhibition and effects on DNA repair after exposure to
radiation. A histone deacetylase inhibitor such as vorinostat may act as a radiosensitizer by
modulating the expression of single- and double-strand DNA repair proteins such as KU67,
KU86, H2AX, and Rad50. These DNA repair proteins are enzymes of that repair radiation-induced
damage. The decrease in these DNA repair enzymes is thought to be the key mechanism of
sensitization. Down-regulation of several key proteins involved in the nonhomologous end
joining pathway is thought to generate a G2/M checkpoint blockade. Vorinostat may also cause
an "open chromatin" structure increasing the effect of radiation damage to DNA. This is
exemplified by the finding that there is a prolonged H2AX phosphorylation and H2AX foci
formation. The mechanism producing this prolongation of H2AX foci is thought to contribute to
the damage, and thus killing effect of the radiation.

In the pivotal phase 2 trial of vorinostat, an overall response rate of nearly 30% was
reported. The median time to progression was 4.9 months overall, and 9.8 months for MF stage
IIB or higher responders. Through hyperacetylation of both histone and non-histone proteins,
vorinostat is felt to exert its anti-tumor activity via several mechanisms, including cell
cycle arrest, induction of apoptosis, reactive oxygen species generation, cell
differentiation, and angiogenesis inhibition. Importantly, a number of pre-clinical studies
have reported on the potential of vorinostat to enhance radiosensitivity of several different
human tumor cell lines. The rational for clinical trial investigating combination of
vorinostat and TSEBT not only comes from their underlying mechanism for potential synergy as
suggested by prior in-vitro studies but also due to general therapeutic advantage derived
from their non-overlapping toxicities.

Recent results from a phase 1 dose-escalation trial combining palliative pelvic radiation (30
Gy in 3 Gy fractions over 2 weeks) and vorinostat in study participants with
histologically-confirmed intrapelvic gastrointestinal carcinoma. Sixteen participants were
enrolled into cohorts of escalating vorinostat dose (100 mg, 200 mg, 300 mg, and 400 mg
daily). The most common adverse events were grade 1 and 2, among which fatigue and
gastrointestinal events were most common. Grade 3 adverse events included fatigue (n = 5),
hyponatremia (n = 1), hypokalemia (n = 1), and acneiform rash (n = 1). Of these, treatment
related grade 3 events [ie, dose limiting toxicities (DLT)] were observed in 1 of 6
participants at vorinostat 300 mg daily (fatigue and anorexia), and in 2 of 6 participants at
the 400 mg daily dose. As a result, the maximum tolerated dose of vorinostat in combination
with palliative radiotherapy was determined to be 300mg daily. The study concluded that
vorinostat can be safely combined with short term palliative radiotherapy. It should be noted
that the adverse events observed in the combination trial overlap with the toxicity profile
of vorinostat listed in the package insert.

Anecdotal experience in a patient who was failing standard course of TSEBT is relevant and is
described here. This patient's skin lesions were progressing towards the latter half of his
TSEBT course, thus, vorinostat was initiated and overlapped with TSEBT in the last 2 weeks.
The patient tolerated the combination well without any worsening skin reactions and his skin
lesions cleared completely. At one year follow-up, his skin is still in complete remission.
Another patient received a combination of romidepsin, another (HDAC) inhibitor, and low-dose
(12 Gy) TSEBT. He had CR after the addition of TSEBT, while his skin lesions were stable on
romidepsin alone.

Based on preclinical, early clinical data and anecdotal experience, it is anticipated that
vorinostat in combination with TSEBT can be administered safely and will be tolerated in
participants with MF. In addition, within the recognized limits of a phase 1-2 clinical
trial, this study may provide an assessment of the anti-tumor activity of vorinostat in
combination with TSEBT in participants with MF and thus allow us to evaluate the
radiation-enhancing potential of vorinostat.

This study is a multicenter phase 1-2, randomized, 2-arm trail exploring the efficacy of
TSEBT 12 Gy alone vs TSEBT 12 Gy + vorinostat. 12 Gy was selected for this study because it
is effective as a rapid debulking agent (with overall response rates of near 100% in the
retrospective study and ongoing clinical trial) and can be administered conveniently over 3
weeks. Because of the diminished clinical CR rates associated with TSEBT doses < 30 Gy, it is
proposed that combining TSEBT 12 Gy with vorinostat will lead to significantly higher
complete response (CR) rates, longer time-to-progression (TTP), and improved quality of life
as compared to TSEBT 12 Gy alone. Based on the retrospective study and preliminary experience
in the ongoing 12 Gy TSEBT trial, it is hypothesized that 12 Gy is an adequate dose to
achieve clinically meaningful outcomes and that the vorinostat may enhance its clinical
efficacy while minimizing radiation-associated toxicities due to the shortened treatment
duration.

Participants are stratified by MF stage as follows.

- Stage IB: ~10 % skin involvement, with up to 1000/mm3 clone+ Sezary cells in blood.

- Stage IIA: Up to 10 % skin involvement, with up to 1000/mm3 clone+ Sezary cells in blood
and clinically abnormal peripheral lymph nodes.

- Stage IIB: One or more tumors 1 cm in diameter, with up to 1000/mm3 clone+ Sezary cells
in blood and clinically abnormal peripheral lymph nodes.

- Stage IIIB: Skin erythema >80 % body surface area, with up to 1000/mm3 clone+ Sezary
cells in blood and clinically abnormal peripheral lymph nodes.

For detailed staging information, see References: Olsen E, et al. Blood. 2007;110:1713-1722.
PMID: 17540844

INCLUSION CRITERIA

- Biopsy-confirmed mycosis fungoides (MF); clinical stage IB; IIA; IIB; or IIIB.

- Patients must have failed or have been intolerant to at least one prior systemic or
skin-directed therapy. This may include topical steroids if used as primary therapy
for MF.

- 18 years of age or older.

- Eastern Cooperative Oncology Group (ECOG) of ≤ 2.

- White blood cell (WBC) > 2000/uL

- Platelet count > 75,000/mm3

- Absolute neutrophil count (ANC) > 1000.

- Bilirubin ≤ 1.5 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST) ≤ 2.5 x UNL

- Alanine aminotransferase (ALT) ≤ 2.5 x UNL

- Alkaline phosphatase (liver fraction) ≤ 2.5 x ULN

- Creatinine ≤ 1.5 x UNL OR creatinine clearance ≤ 60 mL/min for patients with
creatinine levels > 1.5 x institutional ULN

- Potassium level between 3.5 and 4.5

- Magnesium level between 1.5 and 2.5

- Required washout period for prior therapies

- Topical therapy: 2 weeks

- Systemic biologic, monoclonal antibody, or chemotherapy: 4 weeks

- Phototherapy or radiotherapy (excluding TSEBT): 4 weeks

- Other investigational therapy: 4 weeks

- Note: patients with rapidly progressive disease may be treated earlier than
required washout period; however, such circumstance must be discussed and
approved by the protocol director at the primary site (Stanford).

- Women of child-bearing potential (WOCBP) must have negative serum pregnancy test.

- WOCBP must agree to use effective contraception, defined as oral contraceptives,
intrauterine devices, double barrier method (condom plus spermicide or diaphragm) or
abstain from sexual intercourse. WOCBP includes any female who has experienced
menarche and who has not undergone successful surgical sterilization or is not
postmenopausal (defined as amenorrhea for 12 consecutive months).

- Male subjects must be willing to use an appropriate method of contraception (eg,
condoms) or abstain from sexual intercourse and inform any sexual partners that they
must also use a reliable method of contraception (eg, birth control pills) during the
study.

- Ability to understand and sign a written informed consent document.

- Ability to comply with the treatment schedule

EXCLUSION CRITERIA

- Prior courses of TSEBT (Note : localized skin-directed radiotherapy is allowed if
administered at least 4 weeks prior to initiation on study).

- Concomitant use of any anti-cancer therapy or immune modifier.

- Receiving colony stimulating factors.

- Prior allogeneic or autologous transplant.

- Active infection or have received intravenous antibiotics, antiviral, or antifungal
agents within 2 weeks prior to the start of the study drug.

- Known history of human immunodeficiency virus (HIV), hepatitis B or C.

- History of prior malignancy with the exception of cervical intraepithelial neoplasia,
non-melanoma skin cancer, and adequately treated localized prostate carcinoma (PSA <
1.0). Patients with a history of other malignancies must have undergone potentially
curative therapy and have no evidence of that disease for 5 years.

- Uncontrolled intercurrent illness, condition, or circumstances that could limit
compliance with the study, including, but not limited to the following: active
infection, acute or chronic graft versus host disease, symptomatic congestive heart
failure, unstable angina pectoris, medically significant cardiac arrhythmia,
uncontrolled diabetes mellitus or hypertension, or psychiatric conditions.

- Medically significant cardiac event in prior 6 months (ie, myocardial infarction,
cardiac surgery.

- Congenital long QT syndrome.

- QTc interval > 480 msec on screening ECG.

- Proven or suspected stage IV disease including patients with B2 (Sezary syndrome); N3
(frank LN disease); or M1 (visceral disease) categories; presence of reactive or
dermatopathic lymphadenopathy (N1-2) or limited blood involvement (B1) is permitted.

- Pregnant or lactating.

- Unwilling to use reliable birth control methods.

- Any other medical issue, including laboratory abnormalities, deemed by the
Investigator to be likely to interfere with patient participation.

- Unwilling or unable to provide informed consent.