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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

Phase 1/Phase 2
18 Years
Not Enrolling
Relapse, Refractory Multiple Myeloma

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Trial Information

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

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to be eligible for enrollment
into the study

1. Understand and voluntarily sign an informed consent form.

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

3. Multiple myeloma with Durie-Salmon stage II or III and considered to have disease
progression after at least 1 previous anti-myeloma regimen (examples: induction
chemotherapy followed by stem cell collection and high dose chemotherapy and
autologous PBSCT; MP; anthracycline-containing regimen > 3 months ago, any other
conventional regimen including thalidomide- or bortezomib containing regimens.

4. Subjects must have not have recieved more than 3 previous anti-myeloma regimens and
must be relapsed or refractory following at least one regimen of anti-myeloma

5. No anthracycline-containing regimen (e.g. VAD) within the last 3 months of study.

6. Subjects may have been previously treated with thalidomide or bortezomib.

7. Radiation therapy after start of the protocol will be considered as treatment failure
except when given to treat pathological fractures or preexisting osteolytic lesions.

8. Patients must have measurable levels of myeloma paraprotein in serum (>0.5 g/dl) or
urine (>0.2 g excreted in a 24-hour collection sample).

9. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

10. Women of childbearing potential must have a negative serum or urine pregnancy test
within 7 days of starting each cycle. Men and WCBP must agree to use adequate
contraceptive methods.

11. Must have a 2-d echocardiogram indicating LVEF ≥ 55% within 42 days prior to first
dose of study drug.

12. Life extpectancy > 3 months.

Exclusion criteria:

The presence or any of the following will exclude a subject from study enrollment.

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that
makes the patient ineligeble for the study. Uncontrolled medical problems such as
diabetes mellitus, coronary artery disease, hypertension, unstable angina,
arrhythmias), pulmonary, hepatic and renal diseases unless renal insufficiency is
felt to be secondary to multiple myeloma.

2. Pregnant or lactating females.

3. Heart failure (EF < 55%).

4. Any of the following laboratory abnormalities Absolute neutrophil count (ANC)
<1500/mm3 (1x109/L) Platelet count (PLT) <100000/mm3 Serum creatinine> 2.5 mg/dL SGOT
and SGPT > 3 x upper limit of normal (ULN) Serum total bilirubin >1.2 mg/dL

5. Prior history of any other malignancies except for adequately treated basal cell,
insitu cervical or breast cancer or other for which the patient has been disease free
for 5 years.

6. Known hypersensitivity to thalidomide, dexamethasone and/or anthracyline.

7. Prior use of Revlimid.

8. Anthracycline-containing regimen (e.g. VAD) within the last 3 months of study.

9. Any history of thrombembolic events

10. Use of any standard or experimental anti-myeloma drug therapy within 28 days of study

11. Major surgery or radiotherapy within 4 weeks of study enrolment.

12. Active infection requiring antibiotic therapy.

13. Subjects who have received > 300 mg/m2 lifetime cumulative dose of doxorubicin alone,
or Doxil® alone, or doxorubicin plus Doxil®.

14. History of cardiac disease, with New York Heart Association Class II or greater (See
Appendix VII).

15. Known HIV or hepatitis B or C positive.

16. No more than 3 prior anti-myeloma regimens.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Part A (phase I)

Principal Investigator

Ralf Bargou, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dept. of Internal Medicine II, University of Wuerzburg


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

September 2004

Completion Date:

December 2008

Related Keywords:

  • Relapse
  • Refractory Multiple Myeloma
  • refractory or relapsed multiple myeloma
  • CC-5013
  • Revlimid
  • lenalidomide
  • RAD
  • Multiple Myeloma
  • Neoplasms, Plasma Cell