Vorinostat Plus Lenalidomide and Dexamethasone or Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients Who Experience Biochemical Relapse During Lenalidomide Maintenance Therapy

Sponsor
Tiziana Marangon
Study ID
NCT01501370
Phase
PHASE2
Status
Withdrawn

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Vorinostat — DRUG
    Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle
  • Lenalidomide — DRUG
    Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days
  • Dexamethasone — DRUG
    Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.
  • Lenalidomide — DRUG
    Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days
  • Dexamethasone — DRUG
    Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Study Details

Histone deacetylase (HDAC) inhibitors represent a potential new class of antitumor agents. Vorinostat (suberoylanilide Hydroxamic acid, SAHA) inhibits the activity of all 11 known human class I and II HDACs. HDACs have many protein targets whose structure and function are altered by acetylation, including histones and non-histones proteins component of transcription factors controlling gene expression and proteins that regulate cell proliferation, migration and death (1). Vorinostat has undergone initial evaluation in several phase I and II clinical trials in both solid and hematologic malignancies. It has shown activity in hematologic malignancies including Hodgkin's disease and non Hodgkin's lymphomas (2-5); it has been approved for treatment of cutaneous manifestation in patients with primary cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies (6). HDAC function is critical for Multiple Myeloma (MM) cells by actively maintaining a transcriptional program indispensable for their uncontrolled proliferation and/or inappropriate resistance to pro-apoptotic stimuli. The pleiotropic anti-MM effects of Vorinostat and its ability to sensitize MM cellsto multiple conventional or novel agents (7) provide the framework for clinical trials of Vorinostat in MM. A phase I trial of oral Vorinostat alone in advanced MM shows modest activity, but treatment was generally well tolerated (common drug related adverse events (AEs) included fatigue, anorexia, dehydration, diarrhea and nausea and were mostly grade \< 2) (8). A phase I clinical trial of Vorinostat in association with Bortezomib in relapsed MM patients report a partial response (PR) rate of 42%, with responses occurring also in patients refractory to a previous Bortezomib based regimen. Treatment was generally well tolerated (main adverse events were myelosuppression, fatigue and diarrhea) (9). Lenalidomide is an active agent against MM, that as shown activity in both the relapse and newly diagnosed settings, in combination with chemotherapy or steroids only. The dose of Lenalidomide commonly used in the relapse setting, in association with steroids, is 25 mg/day on days 1-21 every 28 days (10, 11). A recent phase I study evaluated the safety and tolerability of Vorinostat in combination with Lenalidomide and Dexamethasone in relapsed patients:no dose limiting toxicities prohibited dose escalation, the maximum tolerated dose has not been reached and the maximum administered dose was Lenalidomide 25 mg/day on days 1-21, Dexamethasone 40 mg/day on days 1,8,15,22, Vorinostat 400 mg/day on days 1-7 and 15-21; each cycle was repeated every 28 days. Rate of at least PR was 51%, and activity was seen also in patients who received prior Lenalidomide therapy (clinical benefit reported in 69% of patients, including minimal response or better in 33% of Lenalidomide refractory patients). The most common drug related grade \> 3 AEs were neutropenia, thrombocytopenia, diarrhea, anemia and fatigue (12). Since Vorinostat has shown efficacy also in patients previously treated with Lenalidomide, and in patients refractory to Lenalidomide, the investigators hypothesis is that the addition of Vorinostat and low-dose dexamethasone to Lenalidomide (ZLd), in patients experiencing a biochemical relapse during a Lenalidomide maintenance ongoing therapy, can overcome Lenalidomide-drug resistance and result in a significant response rate, that can translate into a significant improvement in survival of MM patients. The second hypothesis is that, since the dose of Lenalidomide commonly administered in maintenance therapy, is 10 mg days 1-21 every 28 days, the increase in Lenalidomide dose to the standard dose used for relapsing patients, plus low-dose Dexamethasone (Ld), in patients experiencing a biochemical relapse during a Lenalidomide ongoing maintenance, can as well overcome Lenalidomide-drug resistance and determine a significant response rate, that can translate into a significant improvement in survival of MM patients. This is a multicenter non comparative, randomized, open label, phase II study. Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive: Cohort 1: ZLd association: Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle. Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days. Cohort 2: Ld association: Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days. Patients must have a -confirmed diagnosis of relapsed multiple myeloma. In this Phase II study, a total of up to 35 patients in the ZLd cohort and 48 in the Ld cohort will be enrolled. It is anticipated that full accrual to this study will take approximately 36 months.

Key Dates

Start date
Jan 31, 2012
Status verified
May 2016
Primary completion
Jan 31, 2012
Completion
Jan 31, 2012

Study Design

Enrollment
0 participants (actual)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: ZLd
    Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive: Cohort 1: ZLd association: * Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days * Vorinostat orally at the dose of 400 mg/day on days 1-7 and 15- 21 on a 28-day cycle. * Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.
  • Active Comparator: Ld
    Patients, who are receiving Lenalidomide maintenance treatment with or without prednisone, will be randomized to receive: Lenalidomide orally at the dose of 25 mg/day for 21 days every 28 days • Dexamethasone orally at the dose of 40 mg day 1,8, 15, 22 every 28 days.

Primary Outcome Measure

Rate of PR (PARTIAL RESPONSE) with the association of ZLd and Ld [ Time Frame: Responses will be evaluated after 112 days from enrollment of each patients (4 cycles of therapy) ]

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