Clinical trial NCT00255801
Conditions: Lymphoma
Keywords: stage I cutaneous T-cell non-Hodgkin lymphoma stage II cutaneous T-cell non-Hodgkin lymphoma stage III cutaneous T-cell non-Hodgkin lymphoma stage IV cutaneous T-cell non-Hodgkin lymphoma recurrent cutaneous T-cell non-Hodgkin lymphoma stage I mycosis fungoides/Sezary syndrome stage II mycosis fungoides/Sezary syndrome stage III mycosis fungoides/Sezary syndrome stage IV mycosis fungoides/Sezary syndrome recurrent mycosis fungoides/Sezary syndrome
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2005-11-01; Completion date: 2017-10-01
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as liposomal doxorubicin and bexarotene, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bexarotene may also cause cutaneous T-cell lymphoma cells to look more like normal cells, and to grow and spread more slowly. Giving liposomal doxorubicin followed by bexarotene may be an effective treatment for cutaneous T-cell lymphoma.

PURPOSE: This phase II trial is studying how well giving liposomal doxorubicin followed by bexarotene works in treating patients with cutaneous T-cell lymphoma.

Detailed description:
OBJECTIVES:

Primary

* Determine the progression-free survival of patients with stage IB-IV cutaneous T-cell lymphoma treated with doxorubicin HCl liposome followed by bexarotene.

Secondary

* Determine the complete and partial response rate in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter study.

Patients receive doxorubicin HCl liposome IV over 30-90 minutes once on day 1. Treatment repeats every 2 weeks for 8 courses. Beginning within 4 weeks after the last dose of doxorubicin HCl liposome, patients receive oral bexarotene once daily for at least 16 weeks. Patients who achieve a complete or partial response may continue to receive bexarotene in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 5 years.

Arms: arm 1: Patients will be treated with intravenous Doxil® every two weeks for 8 doses (16 weeks). Responses will be assessed. They will then receive Targretin® (bexarotene) orally for at least 16 weeks. Patients who achieve a CR or PR may continue on Targretin® (bexarotene) until relapse.
Interventions: intervention 1: Targretin® (bexarotene) intervention 2: pegylated liposomal doxorubicin hydrochloride
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
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Phase II Trial of Doxorubicin HCl Liposome injection (Doxil®) in Advanced Stage 
Cutaneous T-Cell Lymphoma Followed by Bexarotene (Targretin®) 
 
THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Coordinating Center: 
Memorial Sloan-Kettering Cancer Center 
 
Principal Investigator: 
David J. Straus, M.D. 
 
 
 
Co-Principal Investigator(s): Steven M. Horwitz, M.D. 
Patricia L. Myskowski, M.D.. 
 
Investigator(s): 
Andrew D. Zelenetz, M.D., Ph.D. 
Craig H. Moskowitz, M.D. 
Paul A.Hamlin, M.D. 
Ariela Noy, M.D. 
Carol S. Portlock, M.D. 
Klaus J. Busam, M.D. 
Howard T. Thaler, Ph.D. 
Lia Palomba, M.D. 
John Gerecitano, M.D., Ph.D. 
Matthew Matasar, M.D 
 
Consenting Professional(s): 
David J. Straus, M.D. 
Steven M. Horwitz, M.D. 
Andrew D. Zelenetz, M.D., Ph.D. 
Craig H. Moskowitz, M.D. 
Paul A.Hamlin, M.D. 
Ariela Noy, M.D. 
Carol S. Portlock, M.D. 
Lia Palomba, M.D. 
John Gerecitano, M.D., Ph.D. 
Matthew Matasar, M.D 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


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Subjects Education and Certification Program. 
 
 
 
 
 
 
Collaborating Institution (s): 
Madeleine Duvic, M.D. (Co-Principal Investigator) 
M.D. Anderson Cancer Center 
The University of Texas 
M.D. Anderson Cancer Center 
1515 Holcombe Blvd., Box 434 
Rm. FC5.3001 
Houston, TX 77030-4009 
Phone: (713)745-1113 
Fax: (713) 745-3597 
mduvic@mdanderson.org 
 
 
 
 
 
Kenneth Hymes, M.D. (Co-Principal Investigator) 
New York University Medical Center 
School of Medicine, Hematology 
Clinical Cancer Center 
160 East 34th Street, 7th Floor 
New York, NY 10016 
Phone: (212)731-5189 
Fax: (212)731-5540 
Kenneth.hymes@med.nyu.edu 


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André Goy, M.D. (Co-Principal Investigator) 
Hackensack University Medical Center 
The Cancer Center at Hackensack University Medical Center 
360 Essex Street, Ste 302 
Hackensack, NJ 07601 
Phone: (201)336-8957 
agoy@humed.com 
 
Francisco J. Hernandez-Ilizaturri, MD (Co-Principal 
Investigator) 
Roswell Park Cancer Institute 
Elm & Carlton Streets 
Buffalo, NY 14263 
Phone: (201)716-845-3221 
francisco.hernandez@roswellpark.org 


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Table of Contents 
 
 
 
THERAPEUTIC/DIAGNOSTIC PROTOCOL.............................................................................. 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA................................................................ 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.......................................................................... 5 
3.0 
BACKGROUND AND RATIONALE............................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................... 7 
4.1 
DESIGN .................................................................................................................. 7 
4.2 
INTERVENTION ................................................................................................... 7 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ....................................................................... 7 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ..................................................................... 11 
6.1 
SUBJECT INCLUSION CRITERIA.................................................................... 11 
6.2 
SUBJECT EXCLUSION CRITE RIA................................................................... 12 
7.0 
RECRUITMENT PLAN................................................................................................... 12 
8.0 
PRETREATMENT EVALUATION ................................................................................ 13 
9.0 
TRE AT ME NT/INTE RVE NTION PLAN ........................................................................ 13 
10.0 
EVALUATION DURING TREAT MENT/INTE RVE NTION ........................................ 16 
11.0 
TOXICITIES/SIDE EFFECT S ......................................................................................... 17 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT............... 18 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 21 
14.0 
BIOSTATISTICS ............................................................................................................. 22 
15.0 
SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES .................... 23 
15.1   SUBJECT REGISTRATION ................................................................................. 23 
15.2   RANDOMIZATION............................................................................................... 24 
16.0 
DATA  MANAGEMENT ISSUES .................................................................................. 24 
16.1 
QUALITY ASSURANCE .................................................................................... 25 
16.2 
DATA AND SAFETY MONITORING ............................................................... 25 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 26 
17.1 
PRIVACY ............................................................................................................. 26 
17.2 SERIOUS ADVERSE EVENT (SAE) REPORTING.............................................. 26 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................... 28 
18.1 
RESEARCH AUTHORIZATION........................................................................ 28 
19.0 
REFE RE NCE(S)...............................................................................................................  29 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Cutaneous T-cell lymphoma: TNM stages IB, IIA, IIB-IV, either newly diagnosed or previously 
treated with active measurable disease 
 
Sample Size: 37 patients 
 
Multi-Center Study : Participating sites include M.D. Anderson Cancer Center, Yale University 
School of Medicine, New York University Medical Center, Hackensack University Medical 
Center 
 
IND Status: Non-IND 
 
Criteria to be used for response evaluation: 
 
The evaluation of cutaneous tumor burden in CTCL is an evolving process. Skin tumor and lymph 
node assessments will be performed prior to treatment and after eight cycles of Doxil® according 
the Severity-Weighted Assessment Tool (SWAT) for CTCL response that is currently employed 
in IRB 02-078 and 04-051. Also the completion of treatment, history and general physical 
examination, Karnofsky performance status, CBC with Sézary cell count for patients with Sézary 
syndrome, and CT scans of the chest, abdomen and pelvis for patients with TNM stage IV CTCL 
will be obtained. These studies will also be obtained prior to treatment. If clinical complete 
remission of target skin lesions is suspected, skin biopsies will be repeated following completion 
of treatment. 
 
Dosing/Regimen: 
 
1. Doxil®Dose: 20mg/m2 intravenously. Frequency: 2 weeks.   Number of Cycles: 8 
2. Targretin®Dose: 300mg/m2 orally Frequency: Daily for at least 16 weeks 
 
Schema: 
 
Doxil® every 2 weeks x 8→response assessment→Targretin® x 16 weeks→response 
assessment, CR/PR→continue Targretin® until relapse. 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objective: To determine the progression-free survival in patients with CTCL treated by 
Doxil® followed by Targretin® 
 
Secondary Objective: To determine the major response rate (CR + PR) of Doxil® followed by 
Targretin® in the treatment of CTCL 


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3.0 
BACKGROUND AND RATIONALE 
 
Cutaneous T-cell lymphoma (CTCL) is a chronic lymphoma that is not curable with systemic 
treatment. Doxorubicin is one of many single agents with activity in CTCL 1. Doxorubicin 
HClliposome injection (Doxil®) is licensed for the treatment of Kaposi’s sarcoma. High 
concentrations are attained in skin lesions of Kaposi’s sarcoma following intravenous 
administration of Doxil®. At 48 and 96 hours post-infusion of Doxil® 20mg/m2  in 11 patients, 
the concentrations of Doxil® in biopsies of skin lesions of Kaposi’s sarcoma were several-fold 
higher than in those in normal skin. Adverse events led to discontinuation of Doxil® in only 5% 
of patients with Kaposi’s sarcoma treated at this dose.  Wollina et al.2 treated 34 CTCL patients 
with Doxil; 27 received Doxil at a dose of 20 mg/m2 every 2-4 weeks, 23 of whom were treated 
every 4 weeks. The major response rate was 88.2% with 15 patients achieving a CR or CRu (not 
confirmed by skin biopsy) and 15 a PR. Event-free survival was 12.0 months ± 9.5 months. Only 
6 patients experienced grade 3 or 4 toxicities. Prince and colleagues3 reported on two patients 
with CTCL who failed to respond to Doxil®. Both were refractory to other previously 
administered intravenous chemotherapy. Although the Package Insert for Doxil® recommends a 
dose of 20 mg/me administered every 3 weeks for Kaposi’s sarcoma, the safety and efficacy of 
this dose administered every two weeks has been recently established for breast cancer4,5. 
 
 
 
Bexarotene (Targretin®) is a synthetic retinoid that selectively activates retinoid X receptors 
(RXRs). These retinoid receptors have biologic activity distinct from that of retinoic acid 
receptors (RARs). Once activated, these receptors function as transcription factors that regulate 
the expression of genes that control cellular differentiation and proliferation. By mechanisms that 
are not known, activity has been found against CTCL, and the drug has been recently 
commercially released. The optimal dose was 300 mg/m2/day, and patients on the trials were 
treated for up to 97 weeks. At the optimal dose, in patients with refractory or persistent early 
stage CTCL, the overall response rate was 54% and was 45% for patients with refractory 
advanced stage disease 6,7. At this dose, most side effects were infrequent and included pruritus, 
headache, peripheral edema, leukopenia, hypothyroidism and rash. Grade 3 or 4 
hypertriglyceridemia and hypercholesterolemia were seen in 25%-30% of patients. These 
elevations are reversible with cessation of the drug, and some patients were continued on 
treatment with the addition of antilipemic treatment. 
 
 
 
 
There are no preclinical data on potential synergy of Doxil® and Targretin®. Sequential 
treatment with single agents in patients with CTCL has been as effective as and less toxic than 
the use of drug combinations 8. 


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Further organized phase II investigation of Doxil® followed by Targretin® treatment of CTCL 
seems warranted in view of the following considerations: 
1.   Treatment of patients with CTCL with both agents results in high response rates. 
2.   The high skin lesion concentrations and efficacy were seen in the treatment of Kaposi’s 
sarcoma with Doxil®. 
3.   Severe adverse events were infrequent in patients with Kaposi’s sarcoma or CTCL 
treated at the doses proposed in this study. 
4.   Although Doxil® alone results in a high overall response rate, the responses of at least 
50% of the patients are incomplete, and progression-free survival can be relatively short. 
5.   Although cardiotoxicity is less with Doxil® than doxorubicin, concern about eventual 
cardiac toxicity might limit the continuous use of Doxil® as a maintenance drug. The 
responses with Doxil® might be more rapid than with Targretin®. The latter agent might 
improve on initial responses to Doxil® and maintain complete and partial remissions for a 
longer time than a brief course of Doxil® alone. 
 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a phase II, multi-center, open-label, single arm trial. The goals are to prolong 
progression-free survival and improve response rate in patients with cutaneous T-cell 
lymphomas with the sequential use of Targretin after an optimal course of Doxil 
 
4.2 
Intervention 
 
Patients will be treated with intravenous Doxil® every two weeks for 8 doses (16 weeks). 
Responses will be assessed. They will then receive Targretin® orally for at least 16 weeks. 
Patients who achieve a CR or PR may continue on Targretin® until relapse. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
Doxil® (doxorubicin HCl liposome injection) 
Doxil® (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in 
STEALTH® liposomes for intravenous administration. The active ingredient of Doxil® is 
doxorubicin HCl, a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. 
caesius.  The mechanism of action of doxorubicin HCl is thought to be related to its ability to 
bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell 
penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic 
acid synthesis, and induction of mutagenesis and chromosomal aberrations. 
 
If at anytime the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 


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If at anytime the patient develops unacceptable toxicity he/she will be removed from study. 
 
If at anytime the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be 
removed from the study. 
 
Doxil® is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes. Liposomes 
are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating 
active drugs.  The STEALTH® liposomes of Doxil® are formulated with surface-bound 
methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect 
liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood 
circulation time. 
 
Doxil® (doxorubicin HCl liposome injection) is indicated for: 
 
 
DOXIL®  (doxorubicin HCl liposome injection) is indicated for the treatment of patients with 
ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. 
 
DOXIL® (doxorubicin HCl liposome injection) is also indicated for the treatment of AIDS- 
related Kaposi’s sarcoma in patients with disease that has progressed on prior combination 
chemotherapy or in patients who are intolerant to such therapy. 
 
These indications are based on objective tumor response rates. No results are available from 
controlled trials that demonstrate a clinical benefit resulting from this treatment, such as 
improvement in disease-related symptoms or increased survival. 
 
Doxil Study Drug Supplier/Accountability 
 
Doxil will be provided by Ortho Biotech Products, L.P. The investigator agrees not to supply the 
study drug to any person other than investigators, designated staff and the subjects participating in 
the study. It is the responsibility of the clinical investigator to ensure that all study drug received at 
the site will be inventoried and accounted for throughout the study. Records must be kept by the 
institution. Administration of the study drug must be recorded in the patient's permanent record. 
The study drug provided may not be used for any purpose other than what is outlined in this 
protocol, including other human studies, animal investigations or in vitro testing. Study drug will 
be stored in a limited access or locked area and under refrigeration. 
 
Doxil Storage and Handling 
Refrigerate unopened vials of Doxil® at 2°C to 8°C (36°F to 46°F).  Avoid freezing. Prolonged 
freezing may adversely affect liposomal drug products; however, short-term freezing (less than 1 
month) does not appear to have a deleterious effect on Doxil®. 


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Caution should be exercised in the handling and preparation of Doxil®. The use of gloves is 
required. If Doxil® comes into contact with skin or mucosa, immediately wash thoroughly with 
soap and water. 
 
Doxil® should be considered an irritant and precautions should be taken to avoid extravasation. 
With intravenous administration of Doxil®, extravasation may occur with or without an 
accompanying stinging or burning sensation, even if blood returns well on aspiration of the 
infusion needle. If any signs or symptoms of extravasation have occurred, the infusion should be 
immediately terminated and restarted in another vein. Doxil® must not be given by the 
intramuscular or subcutaneous route. 
 
Doxil® should be handled and disposed of in a manner consistent with other anticancer drugs. 
Several guidelines on this subject exist. 
 
Targretin® (bexarotene) 
Targretin® (bexarotene) is a member of a subclass of retinoids that selectively 
activate retinoid X receptors (RXRs). These retinoid receptors have biologic activity 
distinct from that of retinoic acid receptors (RARs). Each soft gelatin capsule for oral 
administration contains 75 mg of bexarotene. 
The chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- 
naphthalenyl) ethenyl] benzoic acid, and the structural formula is as follows: 
 
 
 
 
 
 
 
 
 
 
 
Bexarotene is an off-white to white powder with a molecular weight of 348.48 and a 
molecular formula of C24H28O2. It is insoluble in water and slightly soluble in 
vegetable oils and ethanol, USP. 
Each Targretin® (bexarotene) capsule also contains the following inactive 
ingredients: polyethylene glycol 400, NF, polysorbate 20, NF, povidone, USP, and 
butylated hydroxyanisole, NF. The capsule shell contains gelatin, NF, sorbitol 
special-glycerin blend, and titanium dioxide, USP. 
 
Bexarotene selectively binds and activates retinoid X receptor subtypes (RXRa, 
RXRb, RXRg). RXRs can form heterodimers with various receptor partners such as 
retinoic acid receptors (RARs), vitamin D receptor, thyroid receptor, and peroxisome 
proliferator activator receptors (PPARs). Once activated, these receptors function 
as transcription factors that regulate the expression of genes that control cellular 
differentiation and proliferation. Bexarotene inhibits the growth in vitro of some 
tumor cell lines of hematopoietic and squamous cell origin. It also induces tumor 


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regression in vivo in some animal models. The exact mechanism of action of 
bexarotene in the treatment of cutaneous T-cell lymphoma (CTCL) is unknown. 
 
Targretin® capsules were evaluated in 152 patients with advanced and early stage 
cutaneous T-cell lymphoma (CTCL) in two multicenter, open-label, historically controlled 
clinical studies conducted in the U.S., Canada, Europe, and Australia. 
The advanced disease patients had disease refractory to at least one prior systemic 
therapy (median of two, range one to six prior systemic therapies) and had been treated 
with a median of five (range 1 to 11) prior systemic, irradiation, and/or topical 
therapies. Early disease patients were intolerant to, had disease that was refractory 
to, or had reached a response plateau of six months on, at least two prior therapies. 
The patients entered had been treated with a median of 3.5 (range 2 to 12) therapies 
(systemic, radiation, and/or topical). 
 
The two clinical studies enrolled a total of 152 patients, 102 of whom had disease 
refractory to at least one prior systemic therapy, 90 with advanced disease and 12 
with early disease. This is the patient population for whom Targretin® capsules are 
indicated. Patients were initially treated with a starting dose of 650 mg/m2/day with a 
subsequent reduction of starting dose to 500 mg/m2/day. Neither of these starting 
doses were tolerated, and the starting dose was then reduced to 300 mg/m2/day. If, 
however, a patient on 300 mg/m2/day of Targretin® capsules showed no response 
after eight or more weeks of therapy, the dose could be increased to 400 mg/m2/day. 
Tumor response was assessed in both studies by observation of up to five baseline defined 
index lesions using a Composite Assessment of Index Lesion Disease 
Severity (CA). This endpoint was based on a summation of the grades, for all indexes 
lesions, of erythema, scaling, plaque elevation, hypopigmentation or 
hyperpigmentation, and area of involvement. Also considered in response 
assessment was the presence or absence of cutaneous tumors and extracutaneous 
disease manifestations. 
 
All tumor responses required confirmation over at least two assessments separated 
by at least four weeks. A partial response was defined as an improvement of at 
least 50% in the index lesions without worsening, or development of new cutaneous 
tumors or non-cutaneous manifestations. A complete clinical response required 
complete disappearance of all manifestations of disease, but did not require 
confirmation by biopsy. 
 
At the initial dose of 300 mg/m2/day, 1/62 (1.6%) of patients had a complete clinical 
tumor response and 19/62 (30%) of patients had a partial tumor response. The rate 
of relapse (25% increase in CA or worsening of other aspects of disease) in the 
20 patients who had a tumor response was 6/20 (30%) over a median duration of 
observation of 21 weeks, and the median duration of tumor response had not been 
reached. Responses were seen as early as 4 weeks and new responses continued 
to be seen at later visits. 


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Targretin® capsules are supplied as 75-mg off-white, oblong soft gelatin capsules, 
imprinted with “Targretin,” in high density polyethylene bottles with child-resistant 
closures. 
 
Bottles of 100 capsules........................................................................ NDC 64365-502-01 
 
Store at 2°-25°C (36°-77°F). Avoid exposing to high temperatures and humidity after 
the bottle is opened. Protect from light. 
 
Manufactured for: Ligand Pharmaceuticals Incorporated 
San Diego, CA 92121 
by: R.P. Scherer 
St. Petersburg, FL 33716 
 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
 
 
6.1 
Subject Inclusion Criteria 
 
• 
Patient ≥ 18 years of age. 
• 
Cutaneous T-cell lymphoma: TNM stages IB, IIA, IIB-IV with biopsy documentation 
within six weeks before treatment. Repeat biopsies are not required within six weeks 
before treatment for patients with Sézary syndrome and objective evidence of circulating 
cells. 
• 
KPS ≥ 60 
• 
Acceptable organ function: absolute neutrophil count ≥1500/μL, platelet count ≥ 
100,000/μ/L, bilirubin ≤1.5x upper limit of normal, creatinine ≤1.5x upper limit of 
normal, SGOT (AST) and SGPT (ALT) ≤2.5x upper limit of normal 
• 
MUGA or 2-d echocardiogram indicating an ejection fraction of ≥ 50% within 42 days 
prior to first dose of study drug. The method used at baseline must be used for later 
monitoring. 
• 
Patients previously treated with doxorubicin or epirubicin are eligible if the total 
cumulative dose does not exceed 300 mg/m2 for doxorubicin or 540 mg/m2 for 
epirubicin. 
• 
Negative pregnancy test. Effective birth control measures. 
• 
Topical corticosteroids, with the exception of those with high potency (class 1), will be 
allowed for patients with erythroderma-Sézary syndrome (T4) and tumor stage (T3) with 
intense pruritus. Therapy with non-prescription emollients will also be allowed on study. 


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6.2 
Subject Exclusion Criteria 
 
• 
Pregnant or lactating women 
• 
No acute intercurrent disease including active potentially life-threatening infection or 
heart disease, with New York Heart Association Class II or greater, or clinical evidence 
of congestive heart failure. 
• 
History of hypersensitivity reactions attributed to a conventional formulation of 
doxorubicin HCL or components of Doxil 
• 
No demonstrated resistance to prior treatment with Targretin®. 
• 
Patients using class 1 high potency topical therapy will not be allowed on to the study. 
 
 
 
Please note copies of source documentation confirming eligibility for patients enrolling at 
outside institutions must be provided to the MSKCC CTO registrar at the time of registration. 
Please fax to 212-557-0786. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
The trial will require 37 patients to meet study endpoints. With the targeted annual accrual of 10- 
15 patients, this study will require about 3 years to complete accrual. 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC- 
Lead Center), M. D. Anderson Cancer Center, New York University Medical Center, Hackensack 
University Medical Center, and Roswell Park Cancer Institute. If the investigator is a member of 
the treatment team, s/he will screen their patient’s medical records for suitable research study 
participants and discuss the study and their potential for enrolling in the research study. Potential 
subjects contacted by their treating physician will be referred to the investigator/research staff of 
the study. 
 
Consent Process 
 
Participation is voluntary. The patient must be aware of the nature of his/her disease and 
willingly consent after being informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side effects, risks and discomforts. All patients 
will be required to sign a statement of informed consent that conforms to IRB guidelines. 
Informed consent will be documented by the use of a written consent form that has been 
approved by the institution’s IRB. Three copies of the informed consent will be signed and dated 
by the patient or the patient’s legally authorized representative. One copy will be given to the 
patient, one copy will be filed in the patient’s medical record, and one copy will be retained in 
the Protocol Participant Registration (PPR) Office. Written consent will be obtained by either 
the principal investigators or participating investigators. 


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8.0 
PRETREATMENT EVALUATION 
 
• History and physical examination. Karnofsky Performance Status. A dermatologist will 
make skin score determination. A two item self-reported pruritus questionnaire will be 
administered. (to be done within 14 days prior to entry into the study) 
 
• 
Laboratory Evaluations: 
 
Ƅ CBC, platelet count, differential count with absolute neutrophil count (to 
be done within 14 days prior to entry into the study) 
Ƅ Serum chemistry panel: electrolytes, BUN, creatinine, SGOT (AST), 
SGPT (ALT), alkaline phosphatase, LDH, total bilirubin, albumin, total 
protein, calcium, amylase, uric acid. After at least an eight-hour fast: 
glucose, cholesterol, triglycerides (to be done within 14 days prior to entry 
into the study) 
Ƅ T4, TSH (to be done within 14 days prior to entry into the study) 
Ƅ Patients must have a MUGA scan or 2-d echocardiogram indicating an 
ejection fraction of > 50% within 42 days prior to first dose of study drug. 
The method used at baseline must be used for later monitoring. 
• 
Urinalysis (to be done within 7 days prior to entry into the study) 
 
 
 
•  Patients with stage IV disease (TNM): CT of chest, abdomen and pelvis (to be done 
within 6 weeks prior to entry into the study) 
 
•  For women of child bearing potential: beta-HCG pregnancy test (to be done within 7 
days prior to entry into the study) 
 
• Patients with Sézary syndrome will have a Sézary cell count and/or flow cytometry panel 
(to be done within 14 days prior to entry into the study) 
 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Dosing/Regimen: 
 
Doxil®Dose: 20mg/m2 intravenously. Frequency: 2 weeks.  Number of Cycles: 8 (16 
weeks) 
 
To minimize the risk of infusion-related reactions, the first infusion of DOXIL should be 
administered over 90 minutes as follows: 
 
10 mL over 1st 10 minutes 


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20mL over next 10 minutes 
40mL over next 10 minutes 
then, complete the infusion over a total of 90 minutes 
 
 
 
Targretin®Dose: 300mg/m2 orally Frequency: Daily for at least 16 weeks to be started 
within 2 weeks of tumor assessment (It is recommended that patients be treated 
prophylactically with an agent to lower triglycerides such as fenofibrate or atorvastatin) 
 
Schema: 
 
Doxil® every 2 weeks x 8→response assessment→within 2 weeks of tumor assessment: 
Targretin® x 16 weeks→response assessment, CR/PR→continue Targretin® until relapse. 
 
Dose Modification Guidelines 
 
 
 
Patients should be carefully monitored for toxicity. Adverse events, such as palmar-plantar 
erythrodysthesia (hand-foot syndrome), hematologic toxicities, and stomatitis may be 
managed by dose delays and adjustments. Following the first appearance of Grade 1 
toxicity, patients will be prescribed topical betamethasone diproprionate (Diprolene) 0.05% 
gel to use twice daily on hands and feet only until signs and symptoms resolve. Following 
the first appearance of a Grade 2 or higher adverse event, the dosing should be adjusted or 
delayed as described in the following tables. Once the dose has been reduced, it should not 
be increased at a later time. 
 
 
 
PALMAR – PLANTAR ERYTHRODYSESTHESIA 
Toxicity Grade 
Dose Adjustment 
1 
(mild erythema, swelling, or 
desquamation not interfering 
with daily activities) 
Redose unless patient has experienced previous Grade 3 or 4 toxicity.  If so, 
delay up to 2 weeks and decrease dose by 25%.  Return to original dose 
interval. 
2 
(erythema, desquamation, or 
swelling interfering with, but 
not precluding normal physical 
activities; small blisters or 
ulcerations less than 2 cm in 
diameter.) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  If after 2 weeks 
there is no resolution, Doxil® should be discontinued. 


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3 
(blistering, ulceration, or 
swelling interfering with 
walking or normal daily 
activities; cannot wear regular 
clothing) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 
25% and return to original dose interval. If after 2 weeks there is no resolution, 
Doxil® should be discontinued. 
4 
(diffuse or local process 
causing infectious 
complications, or a bed ridden 
state or hospitalization) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 
25% and return to original dose interval. If after 2 weeks there is no resolution, 
Doxil® should be discontinued. 
 
 
HEMATOLOGICAL TOXICITY 
GRADE 
ANC 
PLATELETS 
MODIFICATION 
1 
1500 – 1900 
75,000 - 150,000 
Resume treatment with no dose 
reduction 
2 
1000  - <1500 
50,000 - <75,000 
Wait until ANC > 1,500 and platelets > 
75,000; redose with no dose reduction 
3 
500 – 999 
25,000 - <50,000 
Wait until ANC > 1,500 and platelets > 
75,000; redose with no dose reduction 
4 
<500 
<25,000 
Wait until ANC > 1,500 and platelets > 
75,000; redose at 25% dose reduction or 
continue full dose with cytokine support. 
 
 
 
STOMATITIS 
Toxicity Grade 
Dose Adjustment 
1 
(painless ulcers, 
erythema, or mild 
soreness) 
Redose unless patient has experienced previous Grade 3 or 4 toxicity.  If so, 
delay up to 2 weeks and decrease dose by 25%.  Return to original dose 
interval. 
2 
(painful erythema, 
edema, or ulcers, but 
can eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1. If after 2 weeks 
there is no resolution, Doxil® should be discontinued. 


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3 
(painful erythema, 
edema, or ulcers, and 
cannot eat) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  Decrease dose by 
25% and return to original dose interval. If after 2 weeks there is no 
resolution, Doxil® should be discontinued. 
4 
(requires parenteral or 
enteral support) 
Delay dosing up to 2 weeks or until resolved to Grade 0-1.  Decrease dose by 
25% and return to original dose interval. If after 2 weeks there is no 
resolution, Doxil® should be discontinued. 
 
 
 
Myeloid and erythroid growth factor support will be permitted according to institutional or 
National Comprehensive Cancer Network (NCCN) guidelines. 
 
In the event of Targretin® dose-limiting toxicity (NCI toxicity grade 3 or 4 or serum 
triglycerides ≥800 mg/dL), the 300 mg/m2/day dose may be reduced to 200 mg/m2/day, or a 
200 mg/m2/day dose may be reduced to 100 mg/m2/day. Suspension of Targretin capsules 
treatment may accompany dose reductions for up to 14 days, if necessary for recovery from 
toxicity. Patients with dose-limiting toxicities at the 100 mg/m2/day dose level should be 
withdrawn from the study. 
 
 
 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 Treatment visits every 2 weeks for Doxil® administration for 16 weeks. At each visit: 
history, physical exam, KPS, toxicity assessment, CBC, platelet count. 
 
10.2 Tumor assessment within 2 weeks following the last dose of Doxil®, optimally between 
7 and 14 days. For patients with stage IV disease (TNM) with baseline 
lymphadenopathy on CT scans of chest, abdomen and pelvis: repeat CT scans of chest, 
abdomen and pelvis. Patients with Sezary syndrome will have Sézary cell count and/or 
flow cytometry. Patients who have a CCR should have a biopsy to document a 
pathological CR. Two item self-reported pruritus questionnaire will be administered at 
time of tumor assessment. The details for tumor assessments at 16 and 32 weeks are 
described in Section 12.0 and in the Table in Appendix 3. 
 
 
 
10.3 Cardiac Safety Monitoring 
All patients will be monitored for a decrease in LVEF based on the criteria below: 
Baseline Left Ventricular Ejection Fraction (LVEF) determinations will be performed 
on all patients prior to enrollment in the trial. Patients will not be enrolled if LVEF 
<50%. If during treatment the LVEF falls to ≤ 45%, or the ejection fraction (LVEF) 
falls by 20% from the baseline level, Doxil® will be discontinued. The investigator 


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may verify the LVEF from a MUGA by obtaining an ECHO with cardiac consultation. 
If there is no evidence of cardiac damage determined by ECHO the patient may 
continue on treatment. 
MUGA or ECHO (LVEF) Schedule for all patients: 
Ƅ Cumulative anthracycline dose of < 350mg/m2: physicians discretion 
Ƅ Cumulative anthracycline dose of ≥ 350mg/m2: every two cycles 
 
10.4 Within 2 weeks of tumor assessment: history, physical exam, KPS, CBC, platelet count, 
total bilirubin, SGOT (AST), SGPT (ALT), creatinine, uric acid, fasting triglycerides 
and cholesterol, T4, TSH. 
 
10.5 Within 2 weeks after tumor assessment begin oral Targretin® for 16 weeks. 
 
10.6 Followup visits: at 2 weeks, 4 weeks, 8 weeks, 12 weeks,16 weeks: history, physical 
examination, KPS, CBC, platelet count, total bilirubin, SGOT (AST), SGPT (ALT), 
creatinine, uric acid, fasting triglycerides and cholesterol, T4, TSH. Tumor assessment 
at 16 weeks on Targretin® including self-reported pruritus questionnaire. Imaging 
with CT scans of the chest, abdomen and pelvis will be repeated at 16 weeks for stage 
IV patients if initial lymphadenopathy was present. Patients with Sézary syndrome will 
also have Sézary cell counts and/or flow cytometry repeated at 16 weeks. Responding 
patients may continue on Targretin® until progression. Followup visits will be at least 
every 3 months for 5 years or until signs or symptoms of tumor progression. 
 
 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Toxicity will be described according to NCI Common Toxicity Criteria (Version 3.0) 
 
11.1 Doxil® 
Ƅ Cardiac toxicity: cardiomyopathy and/or congestive heart failure. Possibly non- 
specific arrhythmias 
Ƅ Myelosuppression. Leukopenia more common than thrombocytopenia and anemia 
Ƅ Infusion reactions: shortness of breath, facial swelling, headache, chills, chest pain, 
back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash ,cyanosis, 
syncope, bronchospasm, asthma, apnea and/or hypotension, anaphylaxis 
Ƅ Palmar-plantar erythrodysesthesia (hand-foot syndrome) 
Ƅ Stomatitis 
Ƅ Pregnancy, Category D risk 
Ƅ Injection site reactions. An irritant, not a vesicant. 
Ƅ Asthenia 
Ƅ Nausea/vomiting 
 
11.2 Targretin® 


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Ƅ Hyperlipidemia: hypertriglyceridemia more common than hypercholesterolemia 
Ƅ Hypothyroidism 
Ƅ Headache 
Ƅ Fever 
Ƅ Asthenia, myalgia, arthralgia 
Ƅ Rash 
Ƅ Pancreatitis (associated with hypertriglyceridemia) 
Ƅ Reversible liver function abnormalities 
Ƅ Leukopenia/neutropenia 
Ƅ Anemia 
Ƅ Pregnancy, Category X risk 
 
11.2.1 Serious Adverse Event (SAE) Reporting 
 
For Participating Sites: 
 
Any SAE will be reported to the local institution’s IRB. In addition, it will need to be sent to 
MSKCC as the coordinating center and Ortho Biotech as soon as possible but no later than 5 
days from the onset of the event. 
 
Ortho Biotech will be notified of SAEs within 24 hours by faxing a completed MedWatch 
3500 form to 908-541-4565; this form must also be faxed to the MSKCC principal 
investigator, David Straus, MD (phone: 212-639-8365; fax :646-422-2291; email: 
strausd@mskcc.org). The sites should fax to Ortho Biotech and MSKCC at the same time. 
 
The Study PI will fax a copy of all SAE’s within 5 days to outside site principal investigators 
to report to their own local IRB’s. 
 
Participating sites should send the following information to the coordinating center: 
 
1. The initials of the subjects, patient MRN #, MSKCC protocol # and title 
2. The date the event occurred 
3. A description of the SAE 
4. An explanation of how the SAE was handled 
5. A description of the subject's condition 
6. Indication if the subject remains on the study 
7. Indication if the event is considered related to the treatment (drug, device,intervention) 
8. Indication if an amendment will need to be made to the protocol and/or consent form as a 
result of the SAE. 
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 At 16 weeks (completion of Doxil® treatment) and after 16 weeks of Targretin® 
treatment: CT scans of chest, abdomen and pelvis for TNM stage IV patients who 
had positive findings prior to treatment. 


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12.2 History and physical examination including skin assessment 
 
12.3 Karnofsky performance status. 
 
12.4 CBC with Sézary cell count and/or flow cytometry in patients with Sézary 
syndrome. 
 
12.5 Assessment of response status and any residual toxicity will be performed 4 weeks 
after completion of treatment. 
 
12.6 Biopsy of residual lesions 4 weeks after the completion of treatment if clinical 
complete remission is suspected. 
 
12.7 Dermatologic evaluation of response 
 
Dermatologic responses will be determined by the Severity-Weighted Assessment Tool 
(SWAT), a standardized approach to measuring the extent and severity of overall skin 
disease in patients with CTCL. It will be briefly described and full details are provided in 
an appendix. The purpose of this description is to optimize intra-observer objectivity and 
to minimize the potential for intra-observer and inter-observer variability in the 
measurement of overall skin disease. Only physicians who received training will be 
permitted to conduct SWAT assessments during the clinical study. It is essential that 
physicians adhere as closely as possible to the prescribed procedures so as to reduce 
measurement error and variability. All efficacy assessments should be performed by the 
same physician for each patient whenever possible. Physicians will be instructed not to 
examine previous SWAT assessments and full body photographs prior to conducting the 
current SWAT assessment. 
 
1.   Total Body Surface Area (TBSA) Involvement by Skin Disease 
 
The body is divided into 12 regions with pre-assigned %TBSA based on the burn 
literature. The extent of skin disease in each region is quantified by using the 
patient’s palm to measure the %TBSA involvement within region: 
Patient’s palm with 4 fingers (excluding the thumb) is 1% of TBSA 
Patient’s palm without fingers is 0.5% of TBSA. 
 
The patient’s palm with 4 fingers is traced on a transparency sheet at the baseline 
visit, using a permanent marker that will not rub off or smear. The transparency of 
the patient’s palm should be used in all SWAT assessments during the course of the 
clinical study. The transparency will be labeled with the patient’s study ID number 
kept in the patient’s study file on site. Using the baseline visit transparency of the 
patient’s palm, the investigator will measure and record on the case report form 
(Example of table from CRF is given below) the %TBSA for each lesion type within 
each of the 12 regions. 
 
2.   Severity Weighting Factor 
 
The severity weighting factors will be the following: 


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1= patch (flat erythema or erythema with mild infiltration) 
2=plaque (elevated erythema or erythema with moderate infiltration) 
 
4= tumor or ulceration (erythema with fissuring, ulceration or tumor) 
Patch is defined as abnormal skin not elevated from normal skin. A plaque is defined 
as abnormal skin elevated from normal skin by < 5 mm. A plaque elevated ≥5 mm is 
a tumor. 
 
3.  Calculating Skin Scores 
 
The sum of %TBSA by lesion is derived by summing the %TBSA from all regions 
affected by the lesion. The sum of %TBSA across lesion types (patches, plaques and 
tumors) within each region can not exceed the %TBSA for the region. For example, 
the %TBSA for the head region is 7%.  The sum of %TBSA across lesion types from 
head can only range from 0-7%.  The skin score subtotal by lesion type are derived by 
multiplying the sum of %TBSA for patches from all regions by 1, sum of %TBSA of 
plaques from all regions by 2, and the sum of %TBSA of tumors or ulcers from all 
regions by 4.  The skin score total is derived from summing the skin score subtotals 
for patches, plaques and tumors or ulcers. The skin score total is dimensionless with 
a scale of 0 to 400. 
 
 
 
 


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Responses will be determined by the criteria described in the table below. Progression of 
disease while on treatment should be confirmed by a second assessment 1-4 weeks later so 
that patients who experience a temporary flare of disease due to skin infection or other 
intercurrent illnesses are not removed from the study prematurely. 
 
 
Assessment 
Description 
Status 
Completely clear 
No evidence of disease; 100% improvement 
CCR 
Marked Improvement 
Greater than or equal to 50% decrease in skin scores compared 
to baseline and improvement is maintained for 4 weeks 
PR 
Slight Improvement 
Less than 50% decrease in skin scores compared to baseline 
SD 
Worse 
≥25% increase in skin scores compared to baseline while the 
patient is actively taking the study drug 
or 
≥50% increase in the sum of the products of the greatest 
diameters of pathologically positive lymph nodes (should be 
documented by biopsy) compared to baseline while the patent is 
actively taking the study drug. 
PD 
 
Assessment of Overall Skin Disease 
 
 
 
Pruritus Relief (Appendix 1) 
 
The intensity of pruritus will be evaluated by the patient at baseline, at the week 16 (end of 
treatment with Doxil®) and week 32 (after 16 weeks of treatment with Tagretin®) using a 1- 
10 point scale, where 0 is no pruritus and 10 is the worst imaginable pruritus. A 3-point 
decrease in pruritus intensity confirmed by a second assessment at least 4 weeks later without 
an increase in the use of anti-pruritic medications is considered clinically significant in those 
whose pruritus score is ≥3 on the 0-10 point scale at baseline. 
 
 
 
4. As a secondary goal, index lesion severity will be evaluated by a modified Composite 
Assessment Scale (Appendix 2). These are measurements of skin disease that have been employed 
and validated in the phase II-III studies of Targretin® and in the current MSKCC trial of 
Targretin® of Intron-A® (IRB #01-128) in CTCL. Up to 4 index skin lesions will be chosen from 
representative patch, plaque and tumor lesions, and erythrodermic lesions. For erythrodermic 
patients, a 10x10 cm. area, easily identified by anatomic landmarks will be chosen and assessed 
by the same scale. These index lesions will be photographed and assessed at the same time as the 
SWAT assessment. 
 
In the Phase II-III studies of Targretin capsules in CTCL, the Composite Assessment (CA) of 
Index Lesion Disease Severity was based on a core element of the summation of index lesion 


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clinical signs .  Up to a maximum of five (5) cutaneous T-cell lymphoma lesions were designated 
as index lesions. If the patient had five or fewer CTCL lesions, then all CTCL lesions were 
designated as index lesions. If the patients had more than five CTCL lesions, then five lesions that 
were representative of the patient’s overall cutaneous disease were designated as index lesions. 
The index lesions were preferably separate and distinct from other lesions in order to minimize the 
chance of lesion confluence. Individual index lesion clinical signs and symptoms were to have 
been graded at each visit according to a 0-to-8 point scale (see Table). A CA summation was 
generated by summing the grades for each index lesion for each clinical sign. 
To determine the area of each index lesion, the longest diameter and the longest diameter 
perpendicular to this diameter of each index lesion were to have been measured to the nearest 
millimeter. The area in square centimeters was then converted to a 0-to-18 scale in order to 
provide a means for integrating the area into the CA summation of grades (see Table). The 
summation of CA grades at baseline was divided into the summation of CA grades at each 
subsequent post-baseline study visit to determine the CA ratio to provide an objective measure of 
the patient’s response to treatment (e.g., a CA ratio <1.0 indicated improvement in disease and a 
ratio >1.0 indicated a worsening of disease). This CA score was found to correlate with the 
Physicians Global Assessment, which is replaced by SWAT in this study. 
 
 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at anytime the patient develops progressive disease he/she will be taken off study and 
referred for alternative therapy. 
If at anytime the patient develops unacceptable toxicity he/she will be removed from study. If 
at anytime the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be 
removed from the study. 
 
 
 
14.0 
BIOSTATISTICS 
 
This is a phase II, multi-center, open-label, single arm trial. The goal of this trial is to improve 
response rate and prolong progression-free survival in patients with cutaneous T-cell lymphomas 
with the sequential use of Targretin® after an optimal course of Doxil®. The primary endpoint is 
progression-free survival at 12 months. Based on historical data, the median progression-free is 
12 months for treatment of CTCL with Doxil®. With the new treatment, this trial will be 
considered as promising if the probability of progression-free at 12 months is 70%. Thirty seven 
patients are needed in this trial with conventional type I error 0.05 and power 0.8. This trial 
would be considered to be promising for further study if 24 or more patients are progression free 
at one year. There is 80% chance of observing 24 or more progression-free out of 37 patients if 
the true rate is 70% or better. 


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The second endpoints are complete response and partial response rates. 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1   Subject Registration (at Memorial Sloan-Kettering Cancer Center) 
 
The following person(s) can obtain informed consent: MSKCC: David J. Straus, M.D., Steven M. 
Horwitz, M.D., Andrew D. Zelenetz, M.D., Ph.D., Craig H. Moskowitz, M.D., Paul A. Hamlin. 
M.D., Ariela Noy, M.D., Carol S. Portlock, M.D., Lia Palomba, M.D., John Gerecitano, M.D., 
Ph.D, and Matthew Matasar, M.D 
 
Confirm with electronic medical record that the patient has received the Notice of Privacy 
Practice. This must be obtained before the eligibility confirmation and obtaining of the research 
informed consent. 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain written informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
All patients must be registered through the Protocol Patient Registration (PPR) at Memorial 
Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am - 5:30pm 
at telephone (646)735-8000, fax (646) 735-0008. The completed signature page of the informed 
consent form, the completed signature page of the Research Authorization and a completed 
Eligibility Checklist must be faxed to PPR at the time of registration. 
 
For Participating Centers: 
The following person(s) can obtain informed consent: 
M.D. Anderson Cancer center: Madeleine Duvic, M.D., New York University Medical Center:: 
Kenneth Hymes, M.D.; Hackensack University Medical Center: André Goy, M.D., Roswell Park 
Cancer Institute: Francisco J. Hernandez-Ilizaturri, M.D. 
 
 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer Center. To 
complete registration and enroll a patient from an outside center, the study coordinator will fax to 
Clinical Trials Office at MSKCC the completed MSKCC eligibility checklist, the last page of the 
signed informed consent, the signature page of the Research Authorization, and supporting 
source documentation for eligibility questions. If the patient meets all criteria, the patient will be 
enrolled and then the patient will be assigned a MSKCC study number. The MSKCC registrar 
will fax back an enrollment confirmation. Patients from all sites must be registered with the 
Protocol Patient Registration (PPR) at MSKCC before starting therapy, Telephone 646-735- 


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8000, Fax 646-735-0008, Hours of operation 8:30 am to 5:30 pm (Eastern Time) Monday 
 
 
through Friday. 
 
 
 
During the registration process registering individuals will be required to answer specific 
eligibility questions and provide the following information: 
 
Registering Individual 
[Last, First Name] 
Notice of Privacy Status 
[Yes, No, N/A] 
Research Authorization 
[Date] 
MSKCC IRB Protocol# 
Attending of Record (if applicable)  [Last, First Name] 
Consenting Professional                    [Last, First Name] 
Informed Consent Date 
Patient's Full Name 
[Last, First Name] 
Patient MRN 
 
 
 
15.2 
Protocol Patient Number 
 
Once eligibility has been established, the patient is assigned an MSKCC Clinical Research 
Database (CRDB) patient number. This number is unique to the patient and must be written 
on all data and correspondence for the patient. 
 
 
 
15.3   Randomization 
 
NA 
 
 
 
16.0     DATA  MANAGEMENT ISSUES 
 
 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
The data collected for this study will be entered into a secured database (Clinical Research 
Database, CRDB) at Memorial Sloan-Kettering Cancer Center. 
 
Standardized Case Report Forms (CRFs) have been generated for this study. Affiliate sites will 
be responsible for filling out these MSKCC case report forms. Blank case report forms will be 
sent to the data managers at each site (for photocopying and use).  These forms and the 


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required source documentation must be submitted to MSKCC in a timely fashion (please see 
Appendix 4 for schedule of data collection forms). When a patient goes off-study all CRFs are 
required to be sent to MSKCC no later than 4 weeks after the off-study date. Participating sites 
must fax case report forms bimonthly to: (212) 557-0787 to the attention of the RSA. Forms 
can also be mailed to the address below. 
 
Memorial Sloan-Kettering Cancer Center 
Clinical Trials Office 
Dorothy Lin 
633 Third Avenue – 15th floor 
New York, NY 10017 
 
 
 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action 
 
Random-sample data quality and protocol compliance audits will be conducted by the 
study team, at a minimum of once a year, more frequently if indicated. 
 
 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.  The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and 


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II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for 
it’s level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) Will 
be addressed and the monitoring procedures will be established at the time of protocol 
activationInclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited 
and because the majority are already accessed by a nationwide pediatric cancer research 
network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on 
the Inclusion of Children as Participants in Research Involving Human Subjects. 
 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited 
and because the majority are already accessed by a nationwide pediatric cancer research 
network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on 
the Inclusion of Children as Participants in Research Involving Human Subjects. 
 
17.1 
Privacy 
 
It is the responsibility of the Research Staff to ensure that protocol patients have received 
the Center’s Notice of Privacy Practices. If the subject has not already done so, MSK 
personnel must try to obtain acknowledgment before the patient participates in this study. 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board. 
 
17.2 Serious Adverse Event (SAE) Reporting 
 
At Memorial Sloan-Kettering Cancer Center: 
 
Any SAE must be reported to the IRB as soon as possible but no later than 5 calendar 
days. The IRB requires a Clinical Research Database (CRDB) AE report to be delivered 
to the Institutional SAE Manager (307 East 63rd Street, 1st Floor) containing the following 
information: 


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Fields populated from the CRDB: 
• Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• Medical record number 
• Disease/histology (if applicable) 
• Protocol number and title 
 
Data needing to be entered: 
• The date the adverse event occurred 
• The adverse event 
• Relationship of the adverse event to the treatment (drug, device, or intervention) 
• If the AE was expected 
• The severity of the AE 
• The intervention 
• Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
All serious adverse events regardless of severity or relationship must be reported to Ortho 
Biotech Products, L.P. within 24 hours of the investigational staff’s knowledge. 
SAE Fax Number: 908-541-4565 
 
*Serious Adverse Event (SAE): 
Any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (The patient was at risk of death at the time of the event. It does not refer 
to an event which hypothetically might have caused death if it were more severe.), 
• requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Hospitalizations that do not meet these criteria are: 
• reasons described in the protocol, e.g., drug administration, protocol-required testing 
• social reason in the absence of an AE 
• surgery or procedure planned prior to entry into the trial 
• results in persistent or significant disability/incapacity, 
or 
• is a congenital anomaly/birth defect. 
 
Note:  Medical  and  scientific  judgment should  be  exercised in  deciding  whether  expedited 
reporting is appropriate in other situations, such as important medical events that may not be 


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immediately life-threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the outcomes listed in the definition above. 
 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
All Patients will be required to sign a statement of informed consent that has been approved 
by both the sponsor and by the local Institutional Review Board. The principal investigator is 
responsible for verifying compliance with all aspects of both the protocol and the informed 
consent process, which must indicate that the patient has received adequate information to 
make such informed consent. 
 
Patients willing to enroll will be required to sign three copies of the consent form; one will be 
returned to the patient, one will be filed in the patient’s chart, and one copy will be filed with 
Protocol Patient Registration (PPR) at the Office of Clinical Research. 
 
18.1 
Research Authorization 
 
Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, investigators and/or designated staff will fully explain the 
details of the protocol, study procedures, and the aspects of patient privacy concerning 
research specific information. In addition to signing the IRB Informed Consent, all 
patients must sign the Research Authorization component of the informed consent form. 
The Research Authorization requires a separate set of signatures from the patient. The 
original signed documents will become part of the patient’s medical record, and each 
patient will receive a copy of the signed documents. 


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19.0 
REFERENCE(S) 
 
 
 
1. 
Broder S, Bunn PA, Jr.: Cutaneous T-cell lymphomas. Semin Oncol 7:310-31, 
1980 
2. 
Wollina U, Dummer R, Brockmeyer NH, et al: Multicenter study of pegylated 
liposomal doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 
98:993-1001, 2003 
3. 
Prince HM, Seymour JF, Ryan G, et al: Pegylated liposomal doxorubicin in the 
treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol 44:149-50, 2001 
4. 
Luck HJ, Rossner D, Hollwitz B, et al: Treatment of metastatic breast cancer with 
a bi-weekly schedule of PEG-liposomal doxorubicine. A phase II study. 27th 
Annual San Antonio Breast cancer Symposium, 2004 
5. 
Schmid P, Schulz-C-O, Dieling A, et al: Biweekly pegylated liposomal doxorubin 
(Caelyx/Doxil) in heavily pretrweated patients with metastatic breast cancer. 27th 
Annual San Antonio Breast Cancer Symposium, 2004 
6. 
Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe for treatment 
of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II- 
III trial results. J Clin Oncol 19:2456-71, 2001 
7. 
Duvic M, Martin AG, Kim Y, et al: Phase 2 and 3 clinical trial of oral bexarotene 
(Targretin capsules) for the treatment of refractory or persistent early-stage 
cutaneous T-cell lymphoma. Arch Dermatol 137:581-93, 2001 
8. 
Kaye FJ, Bunn PA, Jr., Steinberg SM, et al: A randomized trial comparing 
combination electron-beam radiation and chemotherapy with topical therapy in 
the initial treatment of mycosis fungoides. N Engl J Med 321:1784-90, 1989 


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IRB#: 05-098 A(6) 
 
 
Appendix 1: Patient Questionnaire 
 
Patient Name   
 
Study Site Name:   
 
 
In this questionnaire, you will be asked about your itching and the use of anti-itching medications over the past week. Please complete 
this questionnaire before seeing your doctor. 
 
(1) Overall, how badly has your skin itched over the past week? Please circle only one number. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
No Itching 
Itching as 
bad as it 
can be 
 
(2) Overall, how has your use of prescribed or over the counted medications against itching, e.g., pills, creams, changed in the past 
week compared to the previous week? Please circle only one item. 
 
(A) I did not use any medications against itching in the past week 
 
(B) I used medication against itching in the past week, but the use is less than the previous week 
 
(C) I used medication against itching in the past week, but there is no change in the use 
 
(D) I used medication against itching in the past week, but the use is more than the previous week 
 
 
Patient Signature:   
 
Month  
Day  
Year  
 
 
Study staff: This questionnaire must be completed, signed and dated by the patient before the patient is seen by the treating physician. 


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IRB Protocol 
IRB#: 05-098 A(6) 
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Appendix 2:  Grading Scales for Composite Assessment (CA) 
of Index Lesion Disease Severity 
Page 1 of 2 
SCALING 
0 - No evidence of scaling on the lesion 
1* 
2 - Mild:  Mainly fine scales; lesion partially covered 
3* 
4 - Moderate:  Somewhat coarser scales; lesion partially covered 
5* 
6 - Severe: Coarse, thick scales; virtually all of the lesion covered; rough 
surface 
7* 
8 - Very severe:  Coarse, very thick scales; all of the lesion covered; very 
rough surface 
ERYTHEMA 
0 - No evidence of erythema, possible brown hyperpigmentation 
1* 
2 - Mild:  Light red lesion 
3* 
4 - Moderate: Red lesion 
5* 
6 - Severe:  Very red lesion 
7* 
8 - Very severe:  Extremely red lesion 
PLAQUE/TUMOR 
0 - 0 mm:  No evidence of plaque above normal skin level 
ELEVATION 
1 - ≥0 to <0.5 mm:  Minimal but definite plaque elevation above normal 
skin level 
2 - ≥0.5 to <1 mm:  Slight but definite plaque elevation 
3 - ≥1 to <1.5 mm:  Mild elevation 
4 - ≥1.5 to <2 mm:  Moderate elevation 
5 - ≥2 to <2.5 mm:  Moderate to marked elevation 
6 - ≥2.5 to <3 mm:  Marked elevation 
7 - ≥3 to <3.5 mm:  Very marked elevation 
8 - ≥3.5 mm:  Extreme elevation 
* 
For scaling and erythema, intermediate intervals 1, 3, 5 and 7 were to serve as mid-points between the defined grades 0, 2, 4, 
6 and 8. 


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IRB Protocol 
IRB#: 05-098 A(6) 
Amended:  9/9/08 
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Table 
Grading Scales for Composite Assessment (CA) 
of Index Lesion Disease Severity (continued) 
Page 2 of 2 
HYPO-/HYPER- 
PIGMENTATION 
To have been used only when hypopigmentation or hyperpigmentation was 
the clinical manifestation of CTCL. 
0 - No evidence of pigmentation change. 
1* 
2 - Mild:  25% lighter pigmentation or noticeably darker pigmentation 
compared to the patient’s normal skin pigmentation. 
3* 
4 - Moderate:   50% lighter pigmentation or twice as dark 
pigmentation compared to the patient’s normal skin 
pigmentation. 
5* 
6 - Severe: 75% lighter pigmentation or three times as dark 
pigmentation compared to the patient’s normal skin 
pigmentation. 
7* 
8 - Very severe:  Nearly complete absence of pigmentation or nearly as 
dark a pigmentation as could be observed compared 
to the patient’s normal skin pigmentation. 
* 
Intermediate intervals 1,3,5 and 7 are to serve as mid-points between the defined grades 0, 2, 4, 6 and 8. 
INDEX LESION AREA 
0 - 0 cm2 (no measurable area) 
1 - > 0 and ≤ 4 cm
2  
2 - > 4 and ≤ 10 cm
2  
3 - >10 and ≤ 16 cm
2  
4 - >16 and ≤ 25 cm
2  
5 - >25 and ≤ 35 cm
2  
6 - >35 and ≤ 45 cm
2  
7 - >45 and ≤ 55 cm
2  
8 - > 55 and ≤ 70 cm
2 
9 - >70 and ≤ 90 cm
2  
10 - >90 and ≤ 110 cm
2  
11 - >110 and ≤ 130 cm
2  
12 - >130 and ≤ 155 cm
2  
13 - >155 and ≤ 180 cm
2  
14 - >180 and ≤ 210 cm
2  
15 - >210 and ≤ 240 cm
2  
16 - >240 and ≤ 270 cm
2  
17 - >270 and ≤ 300 cm
2  
18 - >300 cm
2  


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Appendix  3: S c hedule  of Protocol  Ev en ts 
W  e ek  
P reR x 
W  .2 
W  .4 
W  .6 
W  .8 
W  .10 
W  .12 
W  .1 4 
W  .14-16  W  .14 -1 6 
W  .16-18  
W  .1 8 -2 0 
W  .22 -24  
W  .26-28  
W  .30-32  
R x D  o s e 1 
D o se 2 D o se 3 D o se 4 D o se 5 D o se 6 D o se 7 D o s e 8 
R x D  a y 1 R x W  .2 
R x W  .4 
R x W  .8 
R x W  .12  
R x W  .16  
R es p . E val . 
X 
X 
R x 
D o x il 
D o x il 
D o x il 
D o x il 
D o x il 
D o x il 
D o x il 
D o x il 
T a rg ret in T a rg ret in T arg re t in T arg ret in T a rg ret in T a rg ret in 
H x /P x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
K P S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T o x i c i ty a s s e s s . 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tum or  
X 
X *** 
X *** 
m e a s ur e m en ts 
/S k in s c or e 
P r uritus q u es tionna ir e 
X 
X 
X 
C B C  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fas ting : 
X 
X 
X 
X 
X 
X 
X 
T rig l.**** C  hole s t. 
L yte s , B U N ,  
X 
X 
X 
X 
X 
X 
X 
C r ., A S T , 
A L T , a l k . ph o s., 
bili., T P , 
alb ., C  a , a m yl ase,  
U A , g luc  
U ri n an a l. 
X 
T4,T S H  
X 
X 
X 
X 
X 
X 
X 
Ec ho /M U G A 
X 
C T c/a /p*  
X 
X 
X 
S é zar y c e ll C  T /F lo w 
***** X 
X 
X 
be ta -H C G ** 
X 
X 
*P ts . w ith s tag e IV (T N M ) 
**p re m e nop a usal w o m en  w i thi n 7 da ys 
***biops y  of r e sidual lesions  i f C  C  R  
****fasting  trig l yc . ob tain e d a t e ach M D visit 
*****P ts . w i th S ézar y s ynd ro m e 
Schedule of Protocol Events 


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IRB#: 05-098 A(6) 
 
 
Appendix 4 
 
DATA COLLECTION FORM SCHEDULE 
 
 
 
FORM 
BASELINE 
CYCLE 
OFFSTUDY 
W HEN 
APPLICABLE 
Demographic, Disease & Prior 
Treatment Form 
X 
Comorbidity Form 
X 
Original Pathology Reports* 
X 
Original Radiology Reports 
X 
Treatment & Treatment 
Modification Form 
X 
X 
Physical Exam Form 
X 
X 
Laboratory Form 
X 
Toxicity Form 
X 
X 
Concomitant Drug Form 
X 
X 
X 
Hospitalization Form 
X 
Patient Status & Outcome Form 
X 
 
* Pathology report must be faxed to the MSKCC Clinical Trials Office (212) 557-0786 at the 
same time as patient registration that confirms patient has Cutaneous T-Cell Lymphoma. 
 
Schedule: 
 
Baseline: Forms to be submitted within two weeks of registration. 
Cycle: To be completed after each cycle and submitted every 4 weeks. 
Off-study: To be submitted within four weeks of the protocol completion. 
 
 
 
 
Please submit forms to: 
Dorothy Lin, Research Study Assistant 
Memorial Sloan-Kettering Cancer Center 
633 3rd Avenue, l 5th Floor 
New York, NY 10017 
Fax: 212-557-0787