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All Drugs and Chemicals

Vorinostat

Histone Deacetylase Inhibitors

Enzyme Inhibitors

Total skin electron beam therapy (TSEBT) will be performed per institution guidelines.

Vorinostat will be administered at a dose of 400 mg/day, starting one day prior to the initiation of TSEBT. During TSEBT, vorinostat should be taken in the morning and preferably prior to TSEBT.

Total skin electron beam therapy (TSEBT) will be administered according to the Stanford 6-field technique or equivalent technique per institutional standards. Patients will receive a planned total skin dose of 12 grey (Gy) fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment); 4 days each week; for a total of 3 weeks. Supplements will routinely be applied to the perineum and soles as well as any other "shadowed" sites involved by disease, such as the inframammary regions (1-2 Gy fractions to a total dose of 12 Gy). Discrete tumors may receive additional "boost" treatment not to exceed 12 Gy.

TSEBT is administered as 12 Gy fractionated at 2 grey (Gy)/cycle (each cycle requiring 2 days of treatment); 4 days each week; for 3 weeks.

Total skin electron beam therapy (TSEBT)

Starting doses of is vorinostat 400 mg/day, continuing for 8 weeks.

Youn H Kim

The purpose of this study is to determine if vorinostat combined with low-dose total skin electron beam therapy (TSEBT) offers superior clinical benefit (efficacy \& safety) over low-dose TSEBT alone in participants with mycosis fungoides (MF)

Treatment in this study is TSEBT +/- vorinostat, with participants stratified by MF stage.

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

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

A Multicenter, Open-label, Randomized, Phase I/II Study Evaluating the Safety and Efficacy of Low-dose (12 Gy) Total Skin Electron Beam Therapy (TSEBT) Combined With Vorinostat Versus Low-dose TSEBT Monotherapy in Mycosis Fungoides (MF)

Complete Clinical Response (CCR) at week 8 as determined by an Modified Severity-Weighted Assessment Tool (mSWAT) score of 0. mSWAT is an objective, quantitative, severity-weighted method to assess the extent of mycosis fungoides (MF) lesions, and is determined by total body surface area (%TBSA) of the lesion by a severity-weighting factor (1 = patch; 2 = plaque; 4 = tumor). O% TBSA produces a product of 0, indicating complete response.

Adverse events occurring at least 10% out of evaluable participants, and it's corresponding rate in the opposing arm.

Clinical Response Rate (CRR) at week 8 as determined by an Modified Severity-Weighted Assessment Tool (mSWAT) score of 0, consisting of complete response (CR) rate; partial response (PR) rate; stable disease (SD) rate; or progressive disease (PD) rate.

CR = 100% clearance of skin disease (mSWAT score = 0) PR = 50%to \<100% clearance of skin disease as measured by \> 50% decrease of mSWAT score compared with baseline SD = Not CR, PR, or PD

PD = Whichever is met first of:

1. \> 25% increase in skin disease from baseline as measured by \> 25% increase of mSWAT score compared with baseline
2. New tumor (T3) lesions in patients without prior T3 lesions (T1, T2, T4) or
3. In responders (confirmed), increase in skin disease over nadir by 50% of baseline as measured by mSWAT score of \> \[nadir + \> 50% of baseline\]
4. Relapse applies to any new disease after confirmed CR

Duration of clinical benefit represents the period of time that clinical response was maintained. Duration of clinical benefit is reported as the median period of time from the initiation of treatment until progressive disease, as measured by the mSWAT skin assessment, and censored at the final per-protocol assessment (48 weeks)

Duration of clinical benefit represents the period of time that clinical response was maintained. Duration of clinical benefit is reported as the median period of time from the initiation of treatment or until progressive disease, as measured by the mSWAT skin assessment.

Stanford University

Professor of Medicine

TSEBT (12Gy) per institutional guidelines.

TSEBT Only

TSEBT (12Gy) per institutional guidelines.

Vorinostat 400 mg daily starting one day prior to the initiation of TSEBT.

TSEBT & Vorinostat

• TSEBT as 12 grey (Gy), fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment); 4 days each week; for a total of 3 weeks.

* TSEBT as 12 grey (Gy), fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment); 4 days each week; for a total of 3 weeks.
* Vorinostat 400 mg/day concurrent and continuing for 8 weeks total.

TSEBT Plus Vorinostat

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Participants are stratified by MF stage as follows.

* Stage IB: \~10 % skin involvement, with up to 1000/mm3 clone+ Sezary cells in blood. No abnormal lymph nodes.
* Stage IIA: Up to 10% skin involvement, with up to 1000/mm3 clone+ Sezary cells in blood \& 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 \& clinically abnormal peripheral lymph nodes.
* Stage IIIB: Skin erythema \>80 % body surface area, with up to 1000/mm3 clone+ Sezary cells in blood \& clinically abnormal peripheral lymph nodes.

Clinical Stage

Youn H Kim, MD

Complete Clinical Response (CCR)

Alopecia

Fatigue

Extremity Pain

Nausea

Dysgeusia

Nail Changes

Diarrhea

Ocular Irritation

Radiation Dermatitis

Thrombocytopenia

Anorexia

Dizziness

Lymphopenia

Pedal Edema

Skin Pain

Vomiting

Xerosis/Dry Skin

Safety and Tolerability as Measured by Severity and Frequency of Adverse Events

Clinical Response Rate (CRR)

The data are reported for the per-protocol period of follow-up (48 weeks).

Duration of Clinical Benefit (Per Protocol Follow-up)

The data are reported for the full period for which participant data are available.

Duration of Clinical Benefit (Supplemental Follow-up)

* TSEBT as 12 grey (Gy), fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment); 4 days each week; for a total of 3 weeks.
* Vorinostat 400 mg/day continuing for 8 weeks total.

Overall Study

Syndrome

Sezary Syndrome

Interleukin-12

Adjuvants, Immunologic

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

The LD-TSEBT treatment will start on Day 1 of the study. NM-IL-12 will be administered subcutaneously.

NM-IL-12 and TSEBT

In the proposed study, NM-IL-12 will be evaluated as immunotherapy to increase antitumor efficacy against CTCL, while reducing skin-related toxicity, when combined with low-dose TSEBT therapy. Determination of the maximum tolerated dose (MTD) for NM-IL-12 is not planned in this study, rather, a pre-defined starting dose will be explored; this dose is based on two safety and tolerability studies of NM-IL-12 in healthy volunteers.

This is a single arm, open-label, non-randomized study with NM-IL-12 dosed in combination with low dose TSEBT in CTCL patients. This study is planned to be conducted in 10 patients, 18 years or older in age, undergoing low dose TSEBT of 12 Gy over a 3-week period.

The study will initially enroll 4 patients and then will be expanded to enroll 6 additional patients (total 10 patients) depending on the presence or absence of Dose Modifying Criteria (DMC). Decision whether to de-escalate will be made after first 4 patients are followed up for 28 days from the first dose of NM-IL-12.

Safety monitoring will continue throughout the whole period of drug administration and the treatment will be discontinued if intolerable toxicity or disease progression occurs during this period.

NM-IL-12 in Cutaneous T-Cell Lymphoma (CTCL) Undergoing Total Skin Electron Beam Therapy (TSEBT)

A Single Arm, Open-Label Study To Evaluate The Safety, Tolerability And Preliminary Efficacy Of NM-IL-12 (rHuIL-12) In Patients With Cutaneous T Cell Lymphoma (CTCL) Undergoing Low Dose Total Skin Electron Beam Therapy (TSEBT)

General safety: Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and physical examination.

Toxicity according to the NCI CTCAE (v4.03) for AEs and clinical laboratory profile; AEs will be collected in all patients who received at least one dose of NM-IL-12 and up to four weeks post last NM-IL-12 dose.

Immunogenicity of NM-IL-12 will be evaluated by the presence of anti-drug antibody (ADA)

Exploratory skin clinical responses measured by a modified severity-weighted assessment tool (mSWAT)

Progression free survival based on every 4 week follow up after the monthly dose until one of the events below occurs first:

* Progressive disease is documented
* Another treatment for CTCL is administered (topical or systemic)
* 107 weeks are completed after the patient's first dose of NM-IL-12

National Cancer Institute (NCI)

Neumedicines Inc.

Mechlorethamine

Alkylating Agents

Antineoplastic Agents, Alkylating

All subjects enrolled in the study will receive two weeks of low dose total skin electron beam therapy (TSEBT) (12 Gy total divided into 6 fractions delivered over two weeks) followed by a weekly maintenance mechlorethamine gel 0.016% regimen for one year. The initiation of the mechlorethamine gel regimen is dependent on their disease stage downgrading to IA and IB following low dose TSEBT.

TSEBT will be given in 6 fractions at 2 Gy per fraction every Monday, Wednesday, and Friday over the course of 2 weeks (total TSEBT dosage is 12 Gy). Supplements up to 8 Gy will routinely be applied to the perineum and soles as well as any other "shadowed" sites involved by disease, such as the inframammary regions, scalp, etc. Discrete tumors may receive additional "boost" up to 8 Gy.

The maintenance period for this study includes one year of weekly mechlorethamine gel 0.016%. This period will not begin until the observation period (30 days) has been completed. During the first week of the maintenance period, patients will apply mechlorethamine gel to the entire body surface daily. After the first week, patients will apply mechlorethamine gel to entire body surface one time per week for the rest of the maintenance period.

mechlorethamine gel 0.016%

Kelly Knoblauch

The clinical efficacy of mechlorethamine gel (Valchlor) as a maintenance therapy after low dose total skin electron beam therapy (TSEBT) for the treatment mycosis fungoides cutaneous T-cell lymphoma will be evaluated in this study. Subjects will be treated with low dose TSEBT (12 Gy total) over a period of two weeks. After a 30 day observation period and confirmation that their disease stage has been downgraded to IA or IB, subjects will use Valchlor as a maintenance therapy over the course of one year. The efficacy of Valchlor as a maintenance drug will be followed clinically through Modified Severity Weight Assessment Tool (mSWAT) and percent body surface area measurements (%BSA). Furthermore, subjects will be followed histopathologically through skin biopsies performed at the screening visit, immediately after observation period, one month after the start of the maintenance period, and twelve months after the start of the maintenance period (4 biopsies total).

Low Dose Total Skin Electron Beam Treatment (TSEBT) Followed by Maintenance Valchlor for Patients With Mycosis Fungoides

Phase II Study of Low Dose Total Skin Electron Beam Treatment (TSEBT) Followed by Maintenance Valchlor for Patients With Mycosis Fungoides

To assess the time to progression of patients treated with total skin electron beam therapy (TSEBT) followed by the year-long maintenance Valchlor regimen.

To assess the response rate (CR and PR) of patients treated with total skin electron beam therapy (TSEBT) followed by the year-long maintenance Valchlor regimen. . CR and PR are defined as the standard oncology criteria for complete response (100% reduction from the baseline score) and partial response (50% to \<100% reduction from the baseline score).

Actelion

Thomas Jefferson University

Prospective assignment to receive 12 Gy total skin electron beam therapy (TSEBT) for mycosis fungoides

The purpose of the study is to examine the efficacy and safety of total skin electron beam therapy to a dose of 12 Gray (TSEBT 12 Gray) in patients who have mycosis fungoides (MF) staged as IB to IIIB.

Total Skin Electron Beam Therapy (TSEBT)

Richard T. Hoppe

To examine the efficacy and safety of total skin electron beam therapy to a dose of 12 Gray (TSEBT 12 Gy) in patients who have mycosis fungoides (MF) staged as IB to IIIA.

Total skin electron beam therapy will be administered in the Department of Radiation Oncology according to the Stanford six-field technique. Patients will receive a planned total skin dose of 12 Gy fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment) 4 days each week, for 3 weeks. Supplements will routinely be applied to the perineum and soles as well as any other "shadowed" sites involved by disease, such as the inframammary regions (1-2 Gy fractions to a total dose of 12 Gy). Discrete tumors may receive additional "boost" treatment not to exceed 12 Gy. During the course of TSEBT patients will be evaluated weekly in the Department of Radiation Oncology for determination of adverse events and toxicity grading according the NCI Common Toxicity Criteria (CTC) Version 3.0.

A baseline evaluation will occur on the first day of TSEBT at which time the following procedures will be performed: (This visit may be waived if TSEBT is initiated within one week of the screening visit AND there is no clinical evidence of disease progression). After the completion of TSEBT, patients will be followed every 4 weeks until 24 weeks , and then every 8 weeks for a total of 12 months or until there is disease progression, relapse, or the initiation of a new anti-cancer therapy. Patients who withdraw during the treatment period due to intolerance to radiotherapy will be followed weekly until toxicities have reverted to Grade ≤ 2 or has stabilized in the opinion of the Investigator, at which point a final visit will be scheduled. A final visit should be attempted for all patients who are lost to follow-up.

2 x 5mm punch biopsies taken at enrollment and during follow up.

Phase 2 Total Skin Electron Beam Therapy (TSEBT 12 Gy) in Stage IB-IIIA Mycosis Fungoides

A Phase II Study of Total Skin Electron Beam Therapy (TSEBT) to Dose of 12 Gy in Stage IB-IIIA Mycosis Fungoides

After the completion of TSEBT, patients will be followed every 4 weeks until 24 weeks ,and then every 8 weeks for a total of 12 months or until there is disease progression, relapse, or the initiation of a new anti-cancer therapy.

The primary endpoint for the trial was the clinical response rate as defined by the modified severity weighted assessment tool (mSWAT) Partial response was defined as 50% improvement in the mSWAT. Complete response was complete disappearance of disease.

Henry S. Kaplan-Harry Lebeson Professor of Cancer Biology

Total skin electron beam therapy will be administered in the Department of Radiation Oncology according to the Stanford six-field technique. Patients will receive a planned total skin dose of 12 Gy fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment) 4 days each week, for 3 weeks. Discrete tumors may receive additional "boost" treatment not to exceed 12 Gy. .

12 Gy TSEBT

Total skin electron beam therapy will be administered in the Department of Radiation Oncology according to the Stanford six-field technique. Patients will receive a planned total skin dose of 12 Gy fractionated at 2 Gy/cycle (each cycle requiring 2 days of treatment) 4 days each week, for 3 weeks. Discrete tumors may receive additional "boost" treatment not to exceed 12 Gy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Low-dose (12 Gy) TSEBT+Vorinostat Versus Low-dose TSEBT Monotherapy in Mycosis Fungoides	NCT01187446	Cutaneous Lymph... Cutaneous T-cel...	Total skin elec... Vorinostat	18 Years -	Stanford University
Low-dose (12 Gy) TSEBT+Vorinostat Versus Low-dose TSEBT Monotherapy in Mycosis Fungoides	NCT01187446	Cutaneous Lymph... Cutaneous T-cel...	Total skin elec... Vorinostat	18 Years -	Stanford University
NM-IL-12 in Cutaneous T-Cell Lymphoma (CTCL) Undergoing Total Skin Electron Beam Therapy (TSEBT)	NCT02542124	Cutaneous T Cel... Mycosis Fungoid... Sézary Syndrome	NM-IL-12 and TS...	18 Years -	Neumedicines Inc.
Low Dose Total Skin Electron Beam Treatment (TSEBT) Followed by Maintenance Valchlor for Patients With Mycosis Fungoides	NCT02881749	Mycosis Fungoid... Cutaneous T-cel...	Total skin elec... mechlorethamine...	18 Years -	Thomas Jefferson University
Low-dose (12 Gy) TSEBT+Vorinostat Versus Low-dose TSEBT Monotherapy in Mycosis Fungoides	NCT01187446	Cutaneous Lymph... Cutaneous T-cel...	Total skin elec... Vorinostat	18 Years -	Stanford University
Phase 2 Total Skin Electron Beam Therapy (TSEBT 12 Gy) in Stage IB-IIIA Mycosis Fungoides	NCT00985140	Mycosis Fungoid... Lymphomas: Non-... Lymphomas: Non-... Lymphomas: Non-...	Total Skin Elec...	18 Years -	Stanford University
Low Dose Total Skin Electron Beam Treatment (TSEBT) Followed by Maintenance Valchlor for Patients With Mycosis Fungoides	NCT02881749	Mycosis Fungoid... Cutaneous T-cel...	Total skin elec... mechlorethamine...	18 Years -	Thomas Jefferson University
Phase 2 Total Skin Electron Beam Therapy (TSEBT 12 Gy) in Stage IB-IIIA Mycosis Fungoides	NCT00985140	Mycosis Fungoid... Lymphomas: Non-... Lymphomas: Non-... Lymphomas: Non-...	Total Skin Elec...	18 Years -	Stanford University

Spots Global Cancer Trial Database for total skin electron beam therapy (tsebt)