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Targeted Therapies Formerly
BioOncology Watch www.tgt-therapies.com |
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june 2004 FARNESYL TRANSFERASE INHIBITION Tipifarnib. Three studies of the novel farnesyl transferase inhibitor (FTI)
tipifarnib were recently reported in the literature. FTIs are targeted
therapies that modulate tumor signaling cascades by inhibition of the enzyme,
farnesyl transferase. Farnesylation is critical to the activation of several
oncoproteins, including Ras proteins that are the products of mutant ras genes. In the first study Razelle
Kurzrock and colleagues enrolled 28 patients with intermediate-1- to
high-risk myelodysplastic syndromes (MDS) into a study of oral tipifarnib
(R115777) 600 mg bid given for 4 weeks every 6 weeks. Two patients achieved a
complete remission (bone marrow with < 5% blasts and resolution of
dysplasia; peripheral blood with no abnormal cells and granulocytes > 109/L
and platelets > 100 x 109/L for ≥ 4 weeks; and resolution
of pre-existing splenomegaly) and 1 patient had a partial remission. The
durations of the complete remissions (CRs) were 4 and 11 months and the
partial remission (PR) lasted for 2 months. None of the responders had ras mutations. Eleven patients (41%)
developed tipifarnib-related toxicity necessitating dose reduction in 4
patients and discontinuation of therapy in 7 patients within the first 12
weeks of treatment. Dose reductions to 300 mg bid were well tolerated. In a
second study, Melissa Alsina et al treated 43 consecutive patients with
previously treated and progressive multiple myeloma with tipifarnib 600 mg
bid for 3 weeks every 4 weeks. The treatment was found to suppress
farnesyltransferase activity in bone marrow and peripheral blood mononuclear
cells and to inhibit HDJ-2 protein farnesylation in mononuclear and myeloma
cells. Sixty-four percent of patients had disease stabilization, but no
patients showed a complete or partial response. The most common toxicity was
fatigue; other adverse events included diarrhea, nausea, neuropathy, anemia,
and thrombocytopenia. In addition, Eric Van Cutsem et al conducted a
double-blind, phase III study in which 688 patients with advanced pancreatic
adenocarcinoma were randomized to receive tipifarnib plus gemcitabine or
placebo plus gemcitabine. No differences in overall or progression-free
survival times were noted between treatment groups. However, combination
therapy was tolerated with acceptable toxicity. These studies demonstrated that:
oral tipifarnib can inhibit farnesylation clinically and has modest activity
against MDS; MDS patients did not tolerate 600 mg bid of tipifarnib; and
combining tipifarnib with standard cytotoxic chemotherapy is feasible for
solid tumor patients. However, in multiple myeloma, despite its apparent
inhibition of farnesylation, no clinical responses were noted in the trial. (Kurzrock
R, et al. J Clin Oncol 2004;22:1287-1292; Alsina M, et al. Blood 2004;103:3271-3277; Van Cutsem E, et al. J
Clin Oncol 2004;22:1430-1438) MONOCLONAL ANTIBODIES Cetuximab in refractory colorectal cancer. Cetuximab is a monoclonal antibody directed against
the ligand-binding site of the epidermal growth factor receptor (EGFR). When
bound to EGFR, cetuximab blocks the activation of EGFR tyrosine kinase by EGF
or TGF-a, thereby
inhibiting the growth of tumors overexpressing EGFR. A phase II study
demonstrated that the combination of cetuximab plus irinotecan achieved a
22.5% response rate in a population of 120 colorectal cancer patients in
clinical failure while on prior irinotecan therapy. These findings led
Leonard Saltz and associates to conduct a phase II study in which 57 patients
with EGFR-positive colorectal cancer who had previously received
irinotecan-based treatments and experienced clinical failure were given
weekly infusions of single-agent cetuximab (first dose was 400 mg/m2
infused over 2 hours followed by subsequent weekly treatments of 250 mg/m2
infused over 1 hour). Five patients (9%) achieved a PR and 21 patients had
minor responses or stable disease. The median survival time was 6.4 months.
The most common adverse events were an acne-like rash (86%) and a composite
of asthenia, fatigue, malaise, and lethargy (56%). Three patients experienced
grade 3 allergic reactions. This study showed that single-agent cetuximab has
modest activity and is well tolerated in patients with refractory colorectal
cancer. Further studies of cetuximab in combination with standard therapies
are warranted. (Saltz LB, et al. J Clin Oncol 2004;22:1201-1208) Alemtuzumab. Gerard Lozanski and others report the results of 36 consecutive patients
with fludarabine-refractory chronic lymphocytic leukemia (CLL) treated with
alemtuzumab, an anti-CD52 monoclonal antibody (Vysis Incorporated). Alemtuzumab
was administered by a stepped-up dosing schedule (3 mg Day 1, 10 mg Day 2,
and 30 mg Day 3 intravenously (i.v.), followed by 30 mg three times weekly
for a total of 12 weeks of treatment). Two patients (6%) attained a CR and 9
patients (25%) had a PR. The median duration of response was 10 months
(range, 3-36 months). In addition, a subpopulation of 15 patients with p53
mutations or deletions [del17 (p13.1)] were identified. Patients with p53
mutations or deletions have a poor prognosis and are known to be refractory
to chlorambucil, fludarabine, and rituximab treatments. Alemtuzumab treatment
resulted in clinical responses in 6 (40%) of these 15 patients with a median
response duration of 8 months (range, 3-17 months). These data suggest that
alemtuzumab may be effective therapy for patients with CLL associated with
p53 mutations or deletions. In a second study Gunilla Enblad and coworkers
treated 14 patients with refractory peripheral T-cell lymphoma (PTL) with
alemtuzumab therapy for 12 weeks using the rapidly escalating dose schedule
described previously. These patients have an extremely poor prognosis when
disease progression develops after or during conventional chemotherapy.
During this pilot study of alemtuzumab treatment, 3 patients achieved a CR and
2 patients had a PR (overall response rate of 36%). Cytomegalovirus
reactivation occurred in 6 patients, pulmonary aspergillosis in 2 patients,
and pancytopenia in 4 patients. EBV-related hemophagocytosis was seen in 2
patients and 5 patients died due to treatment-related causes. These
preliminary findings suggested that alemtuzumab has activity in patients with
advanced PTL; however it is associated with significant toxicity. Further
investigation is warranted in patients with less advanced disease. (Lozanski
G, et al. Blood 2004;103:3278-3281; Enblad G, et al. Blood 2004;103:2920-2924) |
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