A Multicenter Phase I/II Trial Evaluating the Safety and Efficacy of Lenalidomide (Revlimid, CC-5013) in Combination With Doxorubicin and Dexamethasone (RAD) in Patients With Relapsed or Refractory Multiple Myeloma
Multiple myeloma is an incurable disease that is characterized by the malignant
proliferation of plasma cells. It is the second most common hematological malignancy, is
invariable fatal. The primary approach for treatment of multiple myeloma is systemic
chemotherapy. Conventional chemotherapy with melphalan and prednisone (MP) has increased the
survival from 12-17 months to approximately 3 years. But several other studies have shown
that combination therapy with addition of other agents such as cyclophosphamide, nitroureas
or anthracyclins does not improve the prognosis of patients with multiple myeloma. During
the past few years it has been demonstrated that high dose chemotherapy followed by
autologous stem cell transplantation can prolong the overall survival of myeloma patients
and therefore became the standard of care for younger patients. Since it has been
demonstrated that high dose chemotherapy is also well tolerated by the elderly high dose
chemotherapy is recommended for patients up to an age of about 70 if there is no relevant
comorbidity. Thus, the development of more effective regimens for the teatment of relapsed
or refractory myeloma patients is urgently needed. Treatment with corticosteroids alone can
induce responses in both primarily resistant and relapsed patients with myeloma. High pulse
dexamethasone (40mg daily d1-4, 9-12 and 17-21) showed response rates of 27% in primarily
unresponsive patients and 21% in relapsed patients, which were initially responsive. In
combination with anthracyclins like in the VAD-regimen (vincristin, adriamycin,
dexamethasone)response rates of about 31% were achieved in primary unresponsive patients
whereas the response rate was 65% in patients who relapsed, but had previously responded to
therapy. Thus, the combination of dexamethasone with anthracyclines and vincristin achieve a
certain anti-myeloma activity in relapsed or refractory patients. Nevertheless due to the
neurotoxicity, treatment with vincristin of elderly patients is critical and limited.
Therefore substitution of vincristine by a less toxic agent with high anti-myeloma activity
like the new thalidomide analogues (see below) could reduce toxicity and improve the
therapeutic efficacy of anthracycline and dexamethasone containing regimens. Protocol DSMM
VII Page 7/52 29.09.2004 Version 1.1 dexamethasone containing regimens. One interesting drug
with substantial anti-myeloma activity in patients with relapsed or refractory myeloma is
thalidomide. Thalidomide has been demonstrated to induce remissions in about one third of
relapsed myeloma patients if given as a single agent therapy. Response rates evaluated in
phase-II studies could be improved up to 55% if thalidomide was administered in combination
with other drugs such as glucocorticoids. However substantial side effects were observed
such as somnolence, constipation and neuropathy. These observations led to development of
derivatives of thalidomide in order to reduce toxicity and to improve efficacy. The
thalidomide analogues represent a new class of active drugs based on immunmodulatory and
direct anti-myeloma effects which have been demonstrated to have a greater potency to
inhibit growth of MM and angiogenesis in vitro and in vivo than thalidomide. In a phase I
study heavily pretreated patients with relapsed or refractory myeloma were treated with
CC-5013 (RevlimidTM, lenalidomide). Revlimid at doses up to 25 mg/day was safe and well
tolerated. The dose-limiting toxicity (DLT) was myelosupression at a dose level of 50
mg/day. In contrast to thalidomide treatment with CC- 5013 showed no significant side
effects like somnolence, constipation or neuropathy. In addition 29 % of the subjects
achieved a > 50% paraprotein reduction, 71% a reduction of > 25%. Preliminary phase II data
showed in about 20 % of relapsed myeloma patients a > 50% reduction of paraprotein, a > 25%
reduction could be observed in about 50%. No additional toxicity was observed in combination
with dexamethasone. Thus, Revlimid as a single agent is well tolerated and has a profound
anti-myeloma activity in patients with refractory or relapsed disease. These data suggest
that Revlimid combined with chemotherapy could lead to enhanced anti-myeloma effects with
acceptable toxicities. The present study will investigate the safety and the efficacy of
intermittent dosing of CC-5013 (Revlimid) combined with Dexamethasone and Doxorubicin in the
treatment of relapsed or refractory myeloma. Objectives Primary Objectives
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Part A (phase I)
Ralf Bargou, MD
Principal Investigator
Dept. of Internal Medicine II, University of Wuerzburg
Germany: Federal Institute for Drugs and Medical Devices
DSMM VII
NCT00306813
September 2004
December 2008
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