Haematologica 2003 - Supplements

11.5 CC 4047, PS 341 and arsenic trioxide
366
CC4047 (Actimid), a new immunomodulatory agent is
well tolerated and has anti-myeloma activity in patients
with relapsed / refractory multiple myeloma
Matthew Streetly,Richard W Jones,Rebecca
Sampson,Kavita Raj,Stephen A Schey
Department of Haematology, Guys Hospital, Guys and St.
Thomas` NHS Trust, London, UK SE1 9RT
The anti-myeloma activity of thalidomide is well established.
However side effects such as somnolence, constipation and
neuropathy are common thereby limiting its usefulness. CC4047
(Actimid) is a synthetic analogue of thalidomide with
immunomodulatory activity. It has been observed to have a 5000
fold greater inhibition of Tumour Necrosis Factor Alpha activity
than thalidomide and an excellent toxicity and safety profile in
human volunteer studies. We present the results of a Phase I dose
escalation study of this agent (1mg, 2mg, 5mg, 10mg) in patients
with relapsed /refractory myeloma to identify the maximum
tolerated dose of CC4047 when given orally for 4 weeks. The
secondary endpoint was disease response.
24 patients with a median age 66 years (range 49 – 82) and a
median of 3 (range 1 – 6) previous treatment regimens including
previous high dose therapy (5 patients) and/or thalidomide (7
patients) entered the study. During the study period the maximum
tolerated dose was established at 2mg/day. Grade IV
neutropaenia developed in 2/3 patients on 10mg/day, 1/6 patients
on 5mg/day and 2/9 patients on 2mg/day. Neutropaenia resolved
in all patients within 4 weeks of discontinuation of treatment.
Furthermore 1 patient developed a lower limb deep venous
thrombosis (DVT) at 3 weeks and was withdrawn from the study
(the patient was subsequently shown to have malignant
melanoma related lymphadenopathy proximal to the site of
thrombosis). Following the study period 20/24 patients continued
treatment on a compassionate use basis (patients on 10mg during
trial reduced dose to 5mg). Treatment was withdrawn in 7 of
these patients (4 due to neutropaenia, 2 due to DVT, 1 due to
renal failure) and 1 patient withdrew from the study. The median
duration of treatment was 25 weeks (3-96 weeks).
All 24 patients are eligible for assessment of response on an
intention to treat basis. 13/24 patients (54%) achieved >50%
reduction in paraprotein, of these 4 patients (16%) had complete
disappearance of paraprotein and 2 patients (8%) had a 75-99%
reduction in paraprotein. A further 3/24 patients (24%) achieved a
25-50% reduction and 8/24 patients (33%) had stable disease for
at least 4 weeks. The median time to achieve maximum response
(>25% reduction) was 23 weeks (4 – 51) and the median duration
of response was 11 weeks (0 – 53). Although quality of life was
not formally assessed most patients reported a subjective
improvement in wellbeing irrespective of response. 6/24 (25%)
patients developed progressive disease whilst on treatment (1
previous CR, 1 previous VGPR, 2 previous PR and 2 stable
disease).
Conclusion: CC4047 is well tolerated with acceptable side effect
profile. There is good evidence for anti-myeloma activity. Studies
are ongoing to further define the optimum dosing schedule and
further studies are justified to fully assess the efficacy of this drug
both as a single agent or in combination with other treatments.
367
THALIDOMIDE ANALOGUE CC-4047 IS EFFECTIVE IN
THE TREATMENT OF PATIENTS WITH RELAPSED AND
REFRACTORY MULTIPLE MYELOMA (MM) AND
INDUCES T CELL ACTIVATION AND IL-12
PRODUCTION
M Streetly1, JB Marriot2, PA Fields1, RW Jones1, K Raj1,
IA Clarke2, K Dredge2, AG Dalgleish2 & SA Schey1
1Guy’s & St Thomas’ NHS Trust, London, UK and 2Division of
Oncology, St George’s Hospital Medical School, London, UK.
Multiple myeloma presently remains an incurable disease.
Because of this newer treatment strategies have been sought to
help improve outcome. One such strategy is immunomodulation,
which has shown promise in this disorder based on studies with
thalidomide. The immunomodulatory drug CC-4047 (Celgene,
ACTIMID) is a promising anti-tumour agent and is likely to
enhance the anti-myeloma effects observed during the treatment
of patients with thalidomide. It has been previously shown to be
anti-angiogenic in vivo, and can augment tumour specific
immunity in vivo and may also induce cell cycle arrest and
apoptosis of multiple myeloma (MM) cells in vitro. It has an
excellent toxicity and safety profile in human volunteer studies,
although it has not previously been assessed in patients with MM.
Our group conducted a phase I dose escalation study for a period
of 4 weeks of treatment with CC-4047 (1mg-10mg/day) in the
first 18 patients on study with relapsed/refractory MM. The
objectives were to 1) Identify the maximal tolerated dose (MTD)
and to evaluate the safety of CC4047 when given for 4 weeks
duration at doses ranging from 1-10mg or the MTD, whichever is
lower in patients with refractory or relapsed MM. 2) to evaluate
activity of CC-4047 in patients with MM; and 3) to identify the
effects of CC-4047 on cytokine production. MTD was established
at 2mg/day. All patients reported a subjective improvement in
their quality of life while on treatment. The M-protein response
was 25-50% in 7/18 (39%) and >50% in
3/18 (17%). On a named patient basis (after 4 weeks treatment),
8/18 developed >50% response, including one complete response
(CR) and two near CRs. We assessed the effect of CC-4047 on
immunological activation in these patients. In 17/18 patients,
peripheral blood CD4+ve and CD8+ve T cells greatly increased
their expression of the memory cell and activation marker
CD45RO, while expression of the mutually exclusive isoform,
CD45RA was strongly decreased. Serum levels of sIL-2 receptor
were increased, indicating IL-2 mediated T cell costimulation and
increased levels of IL-12, most probably from monocytes and
dendritic cells, were observed suggesting the generation of a CD4
induced Th1-type response. There was also evidence of increased
numbers of CD56+, CD3- NK cells in some subjects. However,
there were no effects on serum levels of IL-6 nor on the levels of
the pro-angiogenic factors, IL-8, VEGF or βFGF. In conclusion,
CC-4047 appears to be safe and highly effective in the treatment
of patients with relapsed/refractory MM and induced immune
activation in the majority of patients. Further ongoing studies are
being performed to dissect out and immune characterise of these
effects.
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