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BioOncology Watch Timely Information for Practicing
Physicians |
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June 2002 highlights of the 38th
ASCO Annual Meeting May 18-21, 2002, Orlando, FL Imatinib Newly diagnosed
chronic myelogenous leukemia (CML). Brian Druker and the
International Randomized IFN vs. STI571 Study Group now report interim data
of a study investigating imatinib therapy in patients with newly diagnosed
CML. In this multicenter trial, 1,106
patients have been randomized to receive either imatinib 400 mg daily or
interferon 5 million IU/m2/day plus cytarabine 20 mg/m2/day
for 10 days monthly. Imatinib therapy
has resulted in a greater complete cytogenetic response rate (40% vs. 2%;
p<0.001) and a lower 6-month progression rate (1.4% vs. 10.3%;
p<0.001). Based on these results,
an independent data monitoring board has recommended that these data be
disclosed early. In a second
investigation of newly diagnosed CML patients, Hagop Kantarjian and
colleagues have evaluated two doses of imatinib. Fifty patients were given 400 mg daily and 33 patients have
received 800 mg daily (400 mg twice daily).
The 800 mg daily dose was associated with a higher complete
cytogenetic response rate after only 3 months of therapy (59% vs. 39%) and a
slightly higher incidence of manageable side effects (liver dysfunction
[20%], neutropenia [10%], thrombocytopenia [7%], muscle cramps [7%]). These studies demonstrate that imatinib is
effective in newly diagnosed CML patients.
(Druker BJ, et al. Abstract 1; Kantarjian H, et al. Abstract 1043) Farnesyl Transferase Inhibitor Zarnestra
(R115777). Jean-Luc Harousseau and associates
reported preliminary data from a study of the treatment of
relapsed/refractory AML patients with the oral farnesyl transferase
inhibitor, R115777. Of 42 evaluable
patients, remissions (marrow leukemic blasts <5%) were induced in 7 (17%)
patients. The most frequent
drug-related grade 3 or 4 adverse events were hypokalemia (n = 2), rash (n =
2), and hyperbilirubinemia (n = 2).
Accrual is ongoing to confirm these encouraging results. J. Gotlib et al. treated 7 patients with
myeloproliferative disorders (Bcr-Abl negative CML [n = 4], CMML [n = 2], and
Bcr-Abl positive CML after failing imatinib [n = 1]) with oral R115777. Clinical complete remissions (CRs) were
achieved in 2 patients and 2 patients had stable disease. In vitro clonogenic
culture studies demonstrated dose-related cytotoxicity of CFU-GMs with levels
of R115777 that are achievable in vivo. In addition, SRD Johnston and coworkers
conducted a phase II study in which 76 patients with advanced breast cancer
were treated with R115777 by either a continuous daily dosing schedule (400
or 300 mg twice daily; n = 41) or a cyclical regimen (300 mg twice daily for
21 days every 4 weeks; n = 35).
Efficacy was similar in the cyclical and continuous dosing groups (11%
and 10% partial response [PR] rates, respectively), but significantly less
grade 3/4 neutropenia (p = 0.003), grade 3/4 thrombocytopenia (p = 0.006),
and grade 2/3 neurotoxicity (p<0.0001) occurred in patients treated with
the cyclical regimen. Further studies
are warranted. (Harousseau J-L, et al. Abstract 1056; Gotlib J, et al.
Abstract 14; Johnston SRD, et al. Abstract 138) Radioimmunotherapy (RIT) Post-RIT
treatments feasible. Two studies have shown that effective
therapy can be delivered to patients with non-Hodgkin's lymphoma (NHL)
following RIT. At disease progression
following therapy with 90Y ibritumomab tiuxetan, a radiolabeled
anti-CD20 monoclonal antibody (mAb) conjugate, R.J. Schilder et al. reported
the clinical courses of 99 patients that were treated with a variety of regimens
including single-agent alkylators, CHOP, ESHAP, DHAP, and high-dose therapy
with stem cell rescue. Response rates
achieved were similar to those commonly obtained with salvage treatments in
NHL. A. Dosik et al. followed 63 NHL
patients with disease progression after RIT with iodine 131 tositumomab. Hematologic counts following RIT therapy
were similar to pre-RIT levels, except for a slightly low median platelet
count (140,000/ul). They observed
that 38 patients treated with salvage chemotherapy had disease improvement
while 15 patients died with refractory lymphoma. These results show that chemotherapy after RIT is feasible and
potentially effective. (Schilder RJ, et al. Abstract 1064; Dosik A, et al.
Abstract 1065) Radiolabeled J591.
N.H. Bander and coworkers studied a novel human mAb (J591) directed
against the extracellular domain of prostate specific membrane antigen and
radiolabeled with either 90yttrium or 177lutitium in
patients with advanced prostate cancer.
In this phase I study, the maximum-tolerated dose has not yet been
identified. In 25 evaluable patients
all lesions were successfully targeted and dose-related antitumor effects
have been observed (PSA declines in 3 patients and measurable PRs in 2
patients). No patient has developed
HAHA. Toxicity has been dose-related
and limited to reversible myelosuppression.
The study is ongoing. (Bander NH, et al. Abstract 18) Vaccines Idiotype vaccines.
Early data from a phase II trial investigating the use of recombinant
idiotype vaccines in previously untreated patients with follicular NHL was
reported by J. Timmerman and colleagues.
Eleven of 13 patients developed specific immune responses (9 humoral
and 2 cellular). Four of 6 patients
completing 5 immunizations have achieved mixed clinical responses or stable
disease. This is the first
demonstration of vaccine-induced immune responses in untreated NHL
patients. The study remains ongoing. (Timmerman J, et al. Abstract 13) Monoclonal Antibodies (mAb)
Bevacizumab.
Bevacizumab is a mAb directed against vascular endothelial growth
factor (VEGF). J.C. Yang et al.
performed a phase II trial in which 110 patients with metastatic renal cell
carcinoma were randomized in a double-blind fashion to receive either
high-dose (10 mg/kg) or low-dose (3 mg/kg) bevacizumab or placebo. An interim analysis revealed a significant
prolongation of time to tumor progression (TTP) for the high-dose group
compared to the placebo group (p = 0.001).
This finding satisfied early stopping criteria, however, only 3 PRs
were achieved by bevacizumab treatments (all occurred in the high-dose
arm). These results show that
antiangiogenic therapy can prolong TTP without inducing a substantial number
of tumor responses. In a second study, V.K. Langmuir et al. reported the
results of 28 patients with solid tumors who had received bevacizumab for at
least 1 year (median dose duration = 14 months; range, 11-36 months). Sixteen patients developed disease
progression during an off-bevacizumab therapy observation period. Eighteen patients received concomitant
chemotherapy. Two CRs and 12 PRs were
achieved and the median TTP was 13.7 months.
Median survival has not been reached.
Treatments were generally well tolerated, but 5 patients developed
deep venous thrombosis. These results
indicate that relapsing patients may benefit from bevacizumab
retreatment. (Yang JC, et al.
Abstract 15; Langmuir VK, et al. Abstract 32) Anti-prostate
specific membrane antigen (PSMA) mAb. M.I. Milowsky et al. are
studying the use of the anti-PSMA mAb, J591, to treat patients with
refractory solid tumors known to express PSMA on tumor neovasculature in a
phase I trial. Indium scanning showed
tumor localization of J591 in 6 of 9 patients. Tumor marker (CEA) decline and improvement in pain and
performance status have occurred, but no clinical tumor responses have been
achieved. Toxicity has been limited
to infusion reactions. This study is
ongoing with revised dosing schedules.
(Milowsky MI, et al. Abstract 29) Oregovomab (OV).
OV is a mAb with high binding affinity for CA125. OV-CA125 complex
formation has been found to induce numerous immune responses. T.G. Ehlen et al. randomized 345 patients
with stage III-IV ovarian cancer that had responded to surgery and
chemotherapy to OV or placebo in a double-blind study. OV was infused at baseline, every 4 weeks
for 2 months, and then every 12 weeks until relapse for up to 2 years. Robust immune responses were generated in
55% of OV-treated patients and were associated with a >2-fold prolongation
of the time to tumor relapse compared to those patients without an immune
response (p<0.001). These data
demonstrate the biological activity of OV in ovarian cancer. (EhlenTG, et al. Abstract 31) Erbitux
(IMC-C225). Erbitux is a chimeric mAb directed against
EGFR. A previous study (N = 120) has
demonstrated a tumor response rate of 22.5% in CPT-11-refractory EGFR+
colorectal cancer (CRC). In the
current phase II study, Leonard Saltz and associates treated 57 patients with
CRC refractory to both 5-FU and CPT-11 with single-agent Erbitux (20 mg test
dose, 400 mg/m2 loading dose, 250 mg/m 2 weekly). A PR was achieved in 6 (11%) patients and
13 patients had stable disease. With
a median follow-up of 4 months, the median survival has not been reached. The most common toxicities were rash and
asthenia. These data indicate that
single-agent Erbitux is active against EGFR+ refractory CRC. (Saltz L, et al. Abstract 504) Combination
epratuzumab and rituximab. J. P. Leonard and coworkers evaluated the
treatment of relapsed or refractory NHL patients with combination epratuzumab
(anti-CD22) 360 mg/m2 i.v. and rituximab (anti-CD20) 375 mg/m2
i.v. weekly for 4 doses. Patients had
not been previously treated with rituximab.
Of 19 evaluable patients, 10 (53%) patients achieved a response and
responses were ongoing in 9 patients with up to 13+ months of follow-up. The combination infusion therapy was well
tolerated. Epratuzumab plus rituximab
combination therapy represents a potentially effective treatment for patients
with progressive NHL. Although the
response rate observed was not better than responses observed with rituximab
therapy alone, the suggestion of increased durability of responses needs to
be confirmed in future trials. (Leonard JP, et al. Abstract 1060) Tyrosine Kinase Inhibitor Iressa (ZD 1839). Iressa is an
oral selective EGFR tyrosine kinase inhibitor. M.G. Kris et al. conducted a phase II study of Iressa (250
mg/day vs. 500 mg/day) in patients with locally advanced or metastatic non-small
cell lung cancer (NSCLC) that had failed at least 2 prior chemotherapy
regimens containing platinum and docetaxel (N = 216). The response rates were 11.8% and 8.8% for
the 250 mg/day and 500 mg/day treatment groups, respectively. Tumor response duration ranged from 3 to
7+ months. Disease-related symptom
response rates were 43% for the 250 mg/day group and 35% for the 500 mg/day
group. Approximately 60% of the
patients who had a symptom response did so by the second week of
therapy. The duration of symptomatic
responses ranged from 1 to 7.4+ months.
The median survival for the two treatment groups was similar (6.0 vs.
6.1 months for the 250 vs. 500 mg/day groups, respectively). Reported adverse events were mild
reversible diarrhea and rashes. These
results demonstrate that Iressa has activity against refractory NSCLC. No dose response was observed between the
250 and 500 mg/day dosing groups.
(Kris MG, et al. Abstract 1166) |
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