Phase I Dose-finding and Preliminary Efficacy Study of the Istodax® in Combination With Doxil® for the Treatment of Adults With Relapsed or Refractory Cutaneous T-cell Lymphoma

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Brief Title

Phase I Dose-finding and Preliminary Efficacy Study of the Istodax® in Combination With Doxil® for the Treatment of Adults With Relapsed or Refractory Cutaneous T-cell Lymphoma

Official Title

A Multicenter Phase I Dose-finding and Preliminary Efficacy Study of the Histone Deacetylase Inhibitor Romidepsin (Istodax®) in Combination With Doxorubicin HCl Liposomal (Doxil®) for the Treatment of Adults With Relapsed or Refractory Cutaneous T-cell Lymphoma

Brief Summary

      This a multi-center, single arm, open-label, Phase I dose-finding and preliminary efficacy
      study of the combination of the histone deacetylase inhibitor romidepsin (Istodax®) in
      combination with doxorubicin HCl liposomal (Doxil®) for adult patients with relapsed or
      refractory cutaneous T-cell lymphoma after at least 2 lines of skin-directed therapy or one
      prior line of systemic therapy. Patients will be treated with Doxil 20mg/m2 on day 1 and
      romidepsin 8-14mg/m2 on days 1, 8 and 15, every 28 days, until 2 cycles beyond the best
      response, 8 cycles, disease progression or intolerability whichever comes first. Importantly,
      doxil is administered prior to romidepsin on day1 of each cycle. Patients will be followed
      until disease progression or death whichever comes first.

Detailed Description

      This a multi-center, single arm, open-label, Phase I dose-finding and preliminary efficacy
      study of the combination of the histone deacetylase inhibitor romidepsin (Istodax®) in
      combination with doxorubicin HCl liposomal (Doxil®) for adult patients with relapsed or
      refractory cutaneous T-cell lymphoma after at least one prior line of systemic therapy.



      MTD will be determined by standard "3+3" dose escalation of romidepsin with a fixed dose of
      doxorubicin HCl liposomal. Participants will be followed throughout therapy and all adverse
      events recorded, graded, and given likelihood of relevance to study therapies. Toxicity will
      be graded by the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.


        -  Response will be assessed by a global response score integrating change in skin disease
           as measured by the modified severity-weighted assessment tool (mSWAT) score, change in
           lymph node size, change in visceral disease, and changes in peripheral blood Sézary
           cells by flow cytometry. CR/PR assignment requires confirmatory assessment in 4 weeks.
           Skin scores, clinical lymph node, liver and spleen exam, and Sézary cell count
           assessment will occur on Day 1 of each cycle. Contrasted CT scan of the neck, chest,
           abdomen and pelvis will be performed at screening for all patients. In patients with
           lymphadenopathy and/or organomegaly at screening, contrasted CT scans of the neck,
           chest, abdomen, and pelvis will occur at the end of every third cycle of therapy, within
           1 week of cycle 8 completion, and every 6 months for one year after maximal response.
           All patients will have contrasted CT scans of the neck, chest, abdomen, and pelvis at
           the time of concern for disease progression in lymph nodes and/or viscera.TTR is the
           time of the first romidepsin dose to the time of documented objective response (PR/CR).
           DOR is the time from first objective response (PR or CR) until disease progression.

        -  TTP will be measured from the time of the first romidepsin dose until disease

        -  Pruritus will be assessed monthly using a 100 mm visual analog scale. Quality of life
           will be assessed monthly by Functional Assessment of Cancer Therapy- General (FACT-G),
           Skindex-29, and ItchyQOL questionnaires.


      Skin lesions will be punch biopsied (two contiguous 5mm biopsies) prior to beginning therapy
      as standard care of care. Any leftover tissue will be collected for research with consent of
      patient. Optional single 5mm punch biopsies will be obtained on day 15 of Cycle 2 after
      infusion of romidepsin, and at disease relapse.

Study Phase

Phase 1

Study Type


Primary Outcome

Maximum Tolerated Dose

Secondary Outcome

 Complete response (CR) rate





Study Arms / Comparison Groups

 Istodax, Doxil
Description:  Istodax; Intravenous; 8-14 mg/m2; Days 1, 8, and 15; over 4 hours
Doxil; Intravenous; 20 mg/m2; Day 1; over 1 hour


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

March 4, 2014

Completion Date

April 11, 2020

Primary Completion Date

July 13, 2018

Eligibility Criteria

        Inclusion Criteria:

          1. Able to understand and voluntarily sign an informed consent form.

          2. Age ≥18 years at the time of signing the informed consent form.

          3. Able to adhere to the study visit schedule and other protocol requirements.

          4. Biopsy-proven, measurable, Stage IB-IVB relapsed or refractory cutaneous T-cell
             lymphoma after 2 lines of skin-directed therapy or one prior line of systemic therapy
             (Note: extracorporeal photopheresis will be considered a systemic therapy for this

          5. All cancer therapy, including radiation, hormonal therapy and surgery, must have been
             discontinued at least 4 weeks prior to treatment in this study. The only exceptions
             are participants with erythroderma who have been on corticosteroids for prolonged
             periods of time (>60 days) without change may continue use of either low dose systemic
             steroid (equivalent to <10 mg per day of prednisone) or low potency topical steroids
             are eligible for this study if the frequency and dosage steroids has not changed for
             60 days prior to the study. These participants should continue on the same dose of
             systemic/topical steroid throughout the study period unless they achieve a complete
             response at which time steroids can be discontinued. Patients are allowed to continue
             any medications with known activity in T cell lymphomas at the pre-enrollment doses
             for conditions other than T cell lymphomas (ie, steroids for sarcoidosis) , as long as
             there is evidence of T cell lymphoma progression while patients were on these agents.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry.

          7. Laboratory test results within these ranges:

               -  Absolute neutrophil count ≥750/mm³

               -  Platelet count≥75,000/mm³

               -  Total bilirubin ≤ 2 x upper limit of normal (ULN)

               -  ULN and Aspartate Aminotransferase (ALT) (SGPT) ≤ 3 x ULN.

               -  Creatinine < 2 mg/dL

          8. Disease free of prior malignancies for ≥ 5 years with exception of currently treated
             basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or
             breast. Patients with early stage of prostate cancer under clinical surveillance
             without therapy are eligible

          9. Negative serum pregnancy test at the time of enrollment for females of childbearing

         10. For males and females of child-producing potential, use of effective contraceptive
             methods during the study to include 2 methods of contraception, one being a condom.

         11. Life expectancy >90 days.

        Exclusion Criteria:

          1. Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form.

          2. Pregnant or breast feeding females.

          3. Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study.

          4. Use of any other experimental drug or therapy within 28 days of baseline except
             topical therapy for mycosis fungoides which must be discontinued 14 days prior to
             initiation of study therapy.

          5. Prior allogeneic hematopoietic cell transplant.

          6. Prior solid organ transplant.

          7. Cumulative anthracycline exposure greater than 300 mg/m2 doxorubicin equivalents.

          8. Known active viral infection with human immunodeficiency virus (HIV), hepatitis B
             virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of prior
             hepatitis B virus vaccination are eligible.

          9. Central nervous system or meningeal involvement

         10. Any known cardiac abnormalities including:

               -  Congenital long QT syndrome

               -  Baseline QTc interval ≥ 480 milliseconds;

               -  Myocardial infarction within 6 months of Cycle 1 Day 1 (C1D1). Subjects with a
                  history of myocardial infarction between 6 and 12 months prior to C1D1 who are
                  asymptomatic and have had a negative cardiac risk assessment (treadmill stress
                  test, nuclear medicine stress test, or stress echocardiogram) since the event may

               -  Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV)
                  block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50

               -  Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II- IV. In
                  any patient in whom there is doubt, the patient should have a stress imaging
                  study and, if abnormal, angiography to define whether or not CAD is present

               -  An ECG recorded at screening showing evidence of cardiac ischemia (ST depression
                  of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the
                  patient should have a stress imaging study and, if abnormal, angiography to
                  define whether or not CAD is present

               -  Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class
                  II to IV definitions (see Appendix 10) and/or ejection fraction <40% by
                  Multigated Acquisition Scan (MUGA) scan or <50% by echocardiogram and/or MRI

               -  A known history of sustained ventricular tachycardia (VT), ventricular
                  fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently
                  addressed with an automatic implantable cardioverter defibrillator (AICD)

               -  Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or
                  other causes

               -  Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients with a
                  history of hypertension controlled by medication must be on a stable dose (for at
                  least one month) and meet all other inclusion criteria

               -  Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable
                  doses of beta-blockers)

               -  Any cardiac finding that is deemed ineligible at the discretion of the

         11. Patients taking drugs leading to significant QT prolongation and unable to stop drugs
             prior to treatment

         12. Concomitant use of CYP3A4 inhibitors or inducers unless able to stop medication(s)
             prior to starting study therapies




18 Years - N/A

Accepts Healthy Volunteers



Ai Wei, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

Weiyun Ai


 Celgene Corporation

Study Sponsor

Ai Wei, M.D., Principal Investigator, University of California, San Francisco

Verification Date

June 2020