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Revlimid® (lenalidomide)
Author: Howard Hansen
Definitions
Revlimid® -
Trade name of an immunomodulatory
thalidomide analogue.
Lenalidomide - Generic name of Revlimid®;
CC5013 is an earlier name.
Introduction
Thalidomide is an anti-angiogenic drug that is FDA
approved for multiple myeloma and malignant cachexia. Lenalidomide/
Revlimid® is an immunomodulatory thalidomide analogue that is FDA approved
for treating a subtype of myelodysplastic syndrome and multiple myeloma.
Both thalidomide and Revlimid are used "off-label" for HRPC. Off-label use
is legal as long as your doctor explains the risks, benefits, and
alternatives. An excellent review article by Jeanny B. Aragon-Ching, et
al.(1) covers both thalidomide and Revlimid. See also an earlier article by
E. Crane and A. List (1b). While thalidomide has been extensively
studied in HRPC and other cancers, Revlimid is relatively new and there are
fewer clinical trials information to go on as far as use.
Revlimid is supposed to offer an improved side-effect
profile as well as having more potent immunomodulatory and antiangiogenic
activity than thalidomide. A list of notable side effects of thalidomide
would include somnolence, constipation, venous thromboembolism, peripheral
neuropathy and fatigue. With Revlimid, there is supposed to be less
peripheral neuropathy and pro-thrombotic effects. However that does
not mean they still don't exist to some extent -- as indicated by the
pro-thrombotic effects when combined with dexamethasone.
Due to the somnolence concern with thalidomide, it is
normally taken at bedtime. For Revlimid, at least one of the clinical
trials (RA Sharma et al (2)) had the patients taking it in the morning.
So potentially, we have a drug that is more potent than its predecessor and
has fewer side effects.
Below, are a summary of phase I and II
clinical trials for Revlimid as well as the combinations of Revlimid plus taxotere
and Revlimid plus Leukine (gm-csf)
-- with the focus on HRPC disease. Side effects are noted as available in
the tables.
Phase I Results of Single Agent
lenalidomide
A Phase I study of Revlimid by itself
was published in 2006 by RA Sharma, et al, for patients with solid malignancies. (2)
Of the 3 dose cohorts, they recommended II and III for further trials.
Table 1. Phase I studies of
single agent lenalidomide - some HRPC patients.
|
Reference |
Phase of
trial.
No. Pts. |
Type of
Cancer |
Doses |
Results |
Results |
|
RA Sharma
et al., Eur J. Can 2006 (2) |
Phase I, 2 center, open-label, 55
pts., 26 completed the study.
Once daily, 12 weeks. |
Metastatic solid
tumors. Refractory to
std. chemos. |
(I) 25 mg daily for the first 7 d, the
daily dose increased by 25 mg each week up to a maximum daily dose
of 150 mg;
(II) 25mg daily for 21 d followed by a
7-d rest period, the 4-week cycle repeated for 3 cycles; (III) 10 mg
daily continuously. |
Cohort I
Grade 3/4
Neutropenia, 4 Pts. |
Cohort II
Grade 3/4 Neutropenia, 4 Pts. |
|
TM Tohnya et al., ASCO 2006 (3) |
I, 45 Pts., 37 male, 8 female. |
Refractory metastatic. 36 of the 37
males had Prostate Cancer. |
5mg, 10, 15, 20, 25, 30, and 35mg.
40mg planned.
Daily dose changed to 21 of 28 days. |
Grade 1 or 2 toxicity:
nausea
(43%); myalgia
(38%); pruritis/rash (54%);
fatigue
(38%);
neutropenia (30%). |
Grade 3 or 4 toxicity:
nausea
(43%);
myalgia
(38%); pruritis/rash (54%);
fatigue
(38%);
neutropenia (30%). |
Reference 2 continues with the following list
of results: "Two patients experienced a grade 3
hypersensitivity rash. In 2 patients with predisposing medical
factors, grade 3 cardiac dysrhythmia was recorded. Grade 1 neurotoxicity was
detected in 6 patients. One complete and two partial radiological responses
were measured by computed tomography scanning; 8 patients had stable disease
after 12 weeks of treatment. Fifteen patients remained on treatment as named
patients; 1 with metastatic melanoma remains in clinical remission 3.5 years
from trial entry."
Phase I trials of lenalidomide and taxotere (docetaxel).
Table 2. Phase I trials of lenalidomide and
taxotere - HRPC/AIPC patients. Taxotere and thalidomide have previously shown activity
in AIPC, hence providing rationale for this trial.
|
Reference |
Phase of
trial.
No. Pts. |
Type of
Cancer and characteristics |
Doses and schedule |
Results - tumor |
Results -
toxicity |
|
RA Moss, et al,
ASCO PCa Symposium 2007, abstract #89 (4). |
AIPC,
I, 21 pts, 19 evaluable as of 1/31/07.(4) |
Measurable
disease or rising PSA. No more than 2
prior chemotherapies.
8 pts (42%) had
received prior chemotherapy (3 with 2 prior).
|
Taxotere:
q3 wks., 60mg/m2 and 75 mg/m2.
Prednisone 5mg BID.
Lenalidomide: 14 of 21 days with
escalating doses of 10 mg, 15 mg, 20
mg and 25 mg. |
Ten pts (52.6%)
had a > 50% decline in serum PSA with a median duration of 137 days.
13 pts with measurable disease, 5 (38.5%) achieved a
partial response (PR) with 1 of these pts having had previous chemotherapy
and 7 pts (53.9%) had stable disease
with 4 of these pts having had previous chemotherapy.
|
DVT: 1pt at 10mg.
Fatigue: 5 pt, 3 at 15mg, 1 gr 2, 2 gr 3;
1 at 20mg, gr 2, 1 at 25mg gr 2.
Neuropathy: 1 pt at 15mg, gr 3.
Neutropenia: 6 pt, 2 pt at 10mg, gr 2; 3 pt at
15mg, gr 3; 1 pt at 20mg gr 3.
Pneumonia: 1 pt at 15mg.
Prophylactic anticoagulation used at
investigators discretion.
|
|
MM Cooney et al, ASCO PCa
2006 (5). * |
I, 7 pts, 6 male and 1 female.
There was 1 PCa patient as of this abstract. |
Advanced, solid tumors. |
Taxotere: day 1, q21 days. Lenalidomide orally days 1
through 14 of the 21 day cycle. |
- |
5 patients;
Taxotere 75mg/m2 + lenalidomide at 5
mg days 1-14: two dose limiting toxicities:
neutropenic fever and grade 3 nausea
and vomiting.
7 patients; Taxotere 50mg/m2;
lenalidomide 5mg days 1-14: 4 of 6 had grade 3/4 neutropenia. |
|
SL Sanborn et al, 2007 ASCO annual
mtg. (6). |
I, 19 pts (14 male, 5 female).
Of the 14 males, 7 were PCa pts.
|
Advanced solid tumors. Fourteen
patients had zero or one prior treatment regimens (range 0 to 6). |
Taxotere: day 1, q21 days. Lenalidomide orally days 1-14 of the 21 day cycle.
*** |
For 75mg/m2 = 5mg lenalidomide days
1-14: 7 stable disease; 1 PCa pts > 95% drop in PSA. |
Taxotere 75mg/m2 q3wks + Lenalidomide
5mg days 1-14: 8 of 9 grade 3/4 neutropenia; 1 grade 3
nausea/vomiting, one grade 4 neutropenia with fever. G-CSF added no
neutropenia next 7 pts. ** |
* with the prevalence of grade 3/4
neutropenia they are exploring adding g-csf on day 2 of each cycle.
**Other grade 3 and 4 toxicities
included leukopenia (31%), lymphopenia (19%), as well as nausea, vomiting,
fatigue, anemia, infection, hyponatremia, and hypokalemia (6% each.)
*** Escalating dose to 75mg/m2 and 10mg plus pegfilgrastim
support day 2.
Phase II Studies of Revlimid
Table 3. Revlimid with GM-CSF (leukine) -
HRPC patients.
|
Reference |
Phase of
trial.
No. Pts. |
Type of
Cancer and characteristics |
Doses and schedule |
Results - tumor |
Results -
toxicity |
|
Dreicer R, et al, ASCO 2007, abs 15515
(7) |
I/II, |
HRPC, no prior immunotherapy or
chemotherapy. |
GM-CSF: 250 µg SC three times weekly along with lenalidomide 25
mg/day orally on days 1-21 of a 28-day cycle. Primary endpoints were safety
and objective and PSA responses. |
13 of 17 pts (76%)
experienced a reduction in PSA (<20%
2/17; 20-40% 7/17, >50% 4/17)
Objective RR 2 17 pts.
|
Grade 1-2 toxicities for all 17
pts included neutropenia 20%,
thrombocytopenia 13%, diarrhea 43%, dizziness 25%, and fatigue 90%.
Three pts developed Grade 4 toxicities (PE, neutropenia, and emesis).
|
SC = subcutaneously;
µg = microgram; RR = response rate; Objective
RR: RR of measurable disease other than bone mets; PE = pulmonary embolism;
emesis = vomiting.
Other safety information
The US FDA has had a "black" box warning placed on the
labels of Revlimid bottles. This warns of 1, potential birth defects
(similar to thalidomide); 2, a risk of neutropenia and thrombocytopenia; 3,
a risk of developing deep venous thrombosis (DVTs) and pulmonary embolisms
(PE). The DVTs and PEs may potentially be avoided by therapeutically
anti-coagulating with coumadin or a low-molecular weight heparin(8.)
Reference (8) says, "VTE rates were 8.5% to 75% in multiple myeloma treated
with lenalidomide and dex or
erythropoietin; rates were <3.4% when aspirin prophylaxis was added."
Thalidomide vs Revlimid
There appears to be enough phase I data available to
provide dose and schedule guidelines for Revlimid - except where it is
combined with taxotere. Hopefully this will be sorted out in further
phase II clinical trials (see table 2.)
Taxotere and thalidomide is much better characterized,
an example of which is found in references 9 and 10. In that study,
there were 59 patients, taxotere weekly 3 out of 4 weeks at 30mg/m2.
Patients were chemo-naive, but metastatic AIPC. 35% (6 of 17) of the
patients receiving only taxotere and 53% (19 of 36) of those receiving both
docetaxel and thalidomide had a PSA decline of at least 50%. Thrombotic
events have been seen in the combination arm for which LMWH was then used.
Updated in 2005, an analysis of this trial showed an improvement in the
18-month survival in the combination arm vs. taxotere alone arm (69.3%
versus 47.2%, P < 0.05), with a median survival time of 25.9 months in the
combination arm versus 14.7 months in the single agent arm [76,77].
Until phase II trials are done with Revlimid and
Taxotere, one might want to go slowly in adopting this drug. However, the
results for (4) look promising. The results from the phase II study
combining Leukine (gm-csf) and Revlimid look promising enough at this time
to be worthy of consideration.
Author: Howard Hansen 18 December 2007
References
1. Jeanny B. Aragon-Ching, Haiqing Li, Erin R. Gardner,
and William D. Figg, Thalidomide Analogues as Anticancer Drugs, Recent
Patents Anticancer Drug Discov. 2007 June ; 2(2): 167–174.
1b. Edward Crane & Alan List, Lenalidomide: an
immunomodulatory drug, Future Oncology Oct 2005, Vol. 1, No. 5, Pages 575 -
583, doi:10.2217/14796694.1.5.575).
2. Sharma RA, Steward WP, Daines CA, Knight RD, O'Byrne,
Toxicity profile of the immunomodulatory thalidomide analogue, lenalidomide:
phase I clinical trial of three dosing schedules in patients with solid
malignancies, Eur J Cancer. 2006
Sep;42(14):2318-25. Epub 2006 Aug 8.
3. T. M. Tohnya, J. Gulley, P. Arlene, A. Sparreboom, J. Venitz, C.
Parker, K. Fedenko, H. Parnes, W. D.
Figg, W. Dahut, Phase I study of lenalidomide, a novel thalidomide
analog, in patients with refractory metastatic cancer.
Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings
Part I. Vol 24, No. 18S (June 20
Supplement), 2006: 13038.
See also: Tohnya TM, Ng SS, Dahut WL, et al. A phase I study
of oral CC-5013 (lenalidomide, Revlimid), a thalidomide derivative, in
patients with refractory metastatic cancer. Clin Prostate Cancer
2004;2:241–3. [PubMed: 15072608]. This is an earlier status of this study.
4. R. A. Moss, S. G. Mohile, G. Shelton, J. Melia, D. P. Petrylak,
A phase I open-label study using lenalidomide and docetaxel in androgen
independent prostate cancer (AIPC),
Meeting: 2007 Prostate Cancer Symposium,
Abstract No: 89.
A preliminary report on this phase I trial was given at ASCO 2006 annual meeting(Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings
Part I. Vol 24, No. 18S (June 20
Supplement), 2006: 14618.)
5. M. M. Cooney, J. Gibbons, J. Brell, P. Savvides, S. Krishnamurthi,
A. Dowlati, N. Horvath, K. Robertson,
P. Fu, S. C. Remick,
Phase I trial of daily lenalidomide and docetaxel given every three weeks in
patients with advanced solid tumors, 2006 ASCO Prostate Cancer Symposium,
Abstract No: 265.
6.
S. L. Sanborn, M. Cooney, J. Gibbons, J. Brell, P. Savvides, S.
Krishnamurthi, J. Bokar, N. Horvath, A. Ness, S. Remick,
Phase I trial of daily lenalidomide and docetaxel given every three weeks in
patients with advanced solid tumors.
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings
Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3570.
7.
R. Dreicer, J. Garcia, S. Smith, P. Elson, P. Triozzi, S. Hodnick,
B. Rini, E. Klein,
Phase I/II trial of GM-CSF and lenalidomide in patients with hormone
refractory prostate cancer (HRPC), Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings
Part I. Vol 25, No. 18S (June 20
Supplement), 2007: 15515.
8. C. Angelotta, A. J. Lurie, A. J. Lurie, P. R. Yarnold, S. Singhal,
J. Mehta, E. A. Lyons, C. L. Bennett,
Black box warning on lenalidomide-associated venous thromboembolism (VTE) in
off-label setting: A preemptive and unusual safety initiative, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings
Part I. Vol 24, No. 18S (June 20
Supplement), 2006: 6074.
9. Figg WD, Arlen P, Gulley J, et al. A randomized
phase II trial of docetaxel (taxotere) plus thalidomide in
androgen-independent prostate cancer. Semin Oncol 2001;28:62–6. [PubMed:
11685731]
10. Retter AS, Ando Y, Price DK, et al. Follow-up analysis of a randomized
phase II study of docetaxel and thalidomide in androgen-independent prostate
cancer: Updated survival data and stratification by CYP2C19 mutation status.
Proceedings of the Prostate Cancer Symposium. 2005 Abstract 265
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