An Open Label, International, Multi-centre, Phase I/IIa Study of Lenalidomide (Revlimid) and Romidepsin (Istodax) for Relapsed /Refractory Hodgkin Lymphoma, Mature T-cell Lymphoma and Multiple Myeloma. (RId Study)

1. All patients must have a biopsy-proven diagnosis of one of the following malignancies that meets the additional disease-specific inclusion criteria.

   A. Mature T-Cell lymphoma. The following entities are eligible. PTCL or CTCL (including MF and SS) but excluding adult T-cell leukemia/lymphoma, primary cutaneous CD30+ lymphoma, lymphomatoid papulosis, and NK or LGL leukemia.(The complete WHO classification of T-cell lymphoma can be found in the appendices).

   1. Peripheral T-cell lymphoma: patients must have relapsed or progressed after: at least one prior chemotherapy-based treatment, or not suitable for a conventional chemotherapeutic approach as judged by the investigator.
   2. Sezary syndrome/ Mycosis Fungoides: patients must have relapsed or progressed after at least one prior systemic therapy.

   B. Hodgkin lymphoma

   1. At least one prior chemotherapy-based treatment.
   2. Prior autograft in those eligible for autologous transplantation according to institutional guidelines.

   C. Myeloma

   1. Relapsed after at least one prior systemic therapy that includes thalidomide (unless intolerant or contraindicated) or lenalidomide. Those who have received prior lenalidomide must have had a response that exceeded 6 months.
   2. Patients who are candidates for autologous stem cell transplant in first remission are not eligible.
   3. Patients must have failed/relapsed after bortezomib therapy.
2. ECOG performance status \<2
3. Age >18 years.
4. Life expectancy ≥90 days.

5. Patients must have normal organ and marrow function as defined below:

   absolute neutrophil count >1.0 x109/L (or greater than 0.75x109/L if >50% plasma cells or >50% lymphoma in the bone marrow) Neutrophil count must not be supported by G-CSF prior to study entry. platelets >100 x109/L (or >75 x 109 if >50% plasma cells or >50% lymphoma in the bone marrow).

   (Transfusion to achieve these goals would not qualify the patient) total bilirubin \<1.5x the institutional upper limit of normal. (\<2.5x for Gilbert's disease).

   AST(SGOT)/ALT(SGPT) \<2.5 X institutional upper limit of normal

   Creatinine clearance >60 mL/min/1.73 m2 in the dose escalation phase, and >30 mL/min/1.73 m2 in phase II.

   Serum potassium \& magnesium Serum potassium ≥3.8 mmol/L Serum magnesium ≥1.8mg/dL /0.75mmol/L (supplementation is allowed)

6. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

Exclusion Criteria:

1. Patients receiving any other investigational agents within 4 weeks.
2. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not adequately recovered from grade III/IV adverse events due to agents administered more than 4 weeks earlier.
3. Prior exposure to lenalidomide, in patients with myeloma, except if a response (including stable disease) was maintained for at least 6 months. (Washout period of 4 weeks required)
4. Prior treatment with HDAC inhibitor (not including sodium valproate for neurological or psychiatric disorders), except if response (including stable disease) was maintained for at least 3 months. (Washout period of 4 weeks required)
5. Concomitant treatment with sodium valproate (washout 4 weeks required).
6. Central nervous system involvement by lymphoma or myeloma.
7. A history of allergic reaction to romidepsin or lenalidomide, boron or mannitol.
8. A history of Gr III/IV drug-related non-hematological toxicity, excluding thromboembolism or sepsis, in a prior exposure to either lenalidomide or a histone deacetylase inhibitor.
9. Concomitant corticosteroid except for patients on a stable dose of ≤10mg prednisone/day for at least 4 weeks prior to screening.
10. Congenital long QT syndrome, or a QTc interval >450 milliseconds
11. Patients who have had a myocardial infarction within twelve months of study entry.

12. Patients who have active coronary artery disease (for example NYHA class II or above angina).

    Any patient in whom coronary artery disease is suspected should be referred for a cardiology consultation and if active myocardial ischemia is demonstrated, the patient should be excluded. If a non-invasive imaging study is equivocal, it may be necessary to proceed to coronary angiography.

13. Patients with a baseline ECG showing evidence of cardiac ischaemia (ST depression of ≥2mm)
14. Patients with NYHA-class congestive heart failure ≥II
15. Patients with cardiac ejection fraction less than the institutional lower limited of normal by a gated heart-pool scan, or echocardiogram.
16. Patients with a history of sustained VT, VF, torsade de pointes or cardiac arrest unless that issue is currently managed with an implantable cardioverter defibrillator (AICD).
17. Patients with a cardiomyopathy of any cause.
18. Patients with uncontrolled hypertension ie. SBP ≥160mmHg or DBP ≥95mmHg
19. Patients with cardiac arrythmia requiring anti-arrythmic medication other than a beta blocker or calcium channel blocker. Patients in who digitalis can not be discontinued are excluded from the study.

20. Patients with mobitz-II second degree heart block that do not have a pacemaker.

    1. Patients with first degree or Mobitz-I second degree block, bradyarrhythmia or sick sinus syndrome require holter monitoring and evaluation for eligibility by a cardiologist.
    2. Patients with other cardiac disease may be excluded at the discretion of the PI following consultation with a cardiologist.
21. Patients who require concomitant use of drugs known to cause significant prolongation of the QT interval.
22. Patients who require concomitant use of warfarin, due to potential for drug interaction.
23. Pregnancy in female patients. Lactating females must agree not to breast feed while taking lenalidomide.
24. Patients with known HIV infection.
25. Patients with known Hepatitis B infection.
26. Prior allotransplantation, unless the patient has been completely weaned off immunosuppressive agents for ≥3 months.
27. Myeloma, patient who is a candidate for autologous stem cell transplant
28. Pre-existing motor or sensory neuropathy ≥ grade 3.
29. Other serious and / or uncontrolled medication condition

30. Prior diagnosis of cancer that was:

    1. more than 3 years prior to current diagnosis with estimated clinical expectation of progression greater than 10% within next 2 years.
    2. within 3 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma, carcinoma in situ of the cervix or localised cancer treated curatively with local therapy only.