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)

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Brief Title

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)

Official Title

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)

Brief Summary

      The study hypothesis is that lenalidomide and romidepsin (and dexamethasone for patients with
      myeloma) will have an acceptable toxicity profile and that in combination will have
      sufficient activity in the target population (including those previously refractory to HDACi
      monotherapy) to warrant further investigation.
    

Detailed Description

      Summary of rationale:

        1. As individual agents, both the histone deacetylase inhibitors and lenalidomide have
           significant activity in each of the diseases in this study;

        2. There is potential for the agents to synergize (to improve upon the response rates as
           there are both overlapping and disparate mechanisms of action.) Both agents may
           synergize to induce cell death through caspase 8-mediated and other mechanisms; both
           induce p21 and cell cycle arrest; both agents have anti-angiogenic effects; both are
           likely to interfere with PI3K/Akt signaling. One particularly attractive aspect of this
           combination is the potential for synergistic immunological effects, particularly related
           to T-cell polarization, NK cell activation, STAT signaling and cytokine production, as
           discussed above;

        3. With respect to PTCL, CTCL and HL, there is a clear path for further drug development
           and registration if this trial proves that this is a safe and efficacious combination;

        4. Myeloma is incurable and this is due to the persistence of a drug-resistant sub-clone of
           tumor-propagating cells that is drug insensitive. Preclinical data suggests that both
           HDACi and lenalidomide may target these tumor-propagating cells. This argues for
           examining this combination as part of early treatment in these diseases. This trial is
           the first step to examine the feasibility of combining an HDACi with what is front-line
           therapy in myeloma in the USA - lenalidomide.

        5. Incorporating three separate arms (as opposed to three separate studies) will allow;

           i. The investigators to accumulate data on this novel combination across the three
           groups and evaluate the toxicity profiles to make informed decisions around
           dose-escalation. Because it is a single study, valid comparisons can be made across the
           groups, which would not be possible if they were separate studies.

           ii. combined and simplified collection of correlative tests across the three studies.

           This study was terminated and Phase 2 portion never was initiated.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

Overall Rate of Clinical Response (Complete Response + Partial Response)

Secondary Outcome

 Rate of Overall survival (OS)

Condition

Hodgkin's Lymphoma

Intervention

lenalidomide (Revlimid) and romidepsin (Istodax)

Study Arms / Comparison Groups

 Arm L: subjects with lymphoma
Description:  The following dosing steps will be applied to the dose-escalation, phase-I component of the study for patients with lymphoma who are eligible to enter Arm L:
Dose Level Arm L Lenalidomide dose Oral Romidepsin Dose Intravenous
2 10mg D1-7, D15-21 6mg D1, 8, 15
1 10mg D1-7, D15-21 8mg D1, 8, 15
10mg D1-21 8mg D1, 8, 15 2 15mg D1-21 8mg D1, 8, 15 3 15mg D1-21 10mg D1, 8, 15 4 15mg D1-21 12mg D1, 8, 15 5 15mg D1-21 14mg D1, 8, 15 6 25mg D1-21 14mg D1, 8, 15
The first patient in arm L will be entered into the study at dosing level one.

Publications

* 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

Drug

Estimated Enrollment

12

Start Date

October 2012

Completion Date

August 2016

Primary Completion Date

August 2016

Eligibility Criteria

        Inclusion Criteria:

          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.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Francine Foss, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01742793

Organization ID

1112009392

Secondary IDs

115541

Responsible Party

Principal Investigator

Study Sponsor

Yale University

Collaborators

 Peter MacCallum Cancer Centre, Australia

Study Sponsor

Francine Foss, MD, Principal Investigator, Yale University


Verification Date

February 2017