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BioOncology Watch Timely Information for Practicing Physicians |
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JULY 2000 Monclonal Antibody Therapy rhuMAb VEGF in breast cancer. The novel antiangiogenesis agent, rhuMAb VEGF (Genentech,
Inc.), is a recombinant humanized monoclonal antibody that targets vascular
endothelial cell growth factor (VEGF) and prevents it from binding to
receptors on vascular endothelial cells.
George Sledge et al. reported the results of a phase II trial of
single-agent rhuMAb VEGF therapy of patients with progressive metastatic
breast cancer following at least one anthracycline- or taxane-based
chemotherapy regimen. The rhuMAb VEGF
was administered intravenously every 2 weeks at a dose of either 3 (n=18) or
10 mg/kg (n=41). One patient in the 3
mg/kg cohort achieved a partial response of 3 months duration and 4 patients
in the 10 mg/kg cohort had responses (1 CR) with a median duration >4.2
months. Four patients in the 3 mg/kg
group and 7 patients in the 10 mg/kg group developed grade 3 or 4
hypertension. This study provides
preliminary evidence that rhuMAb VEGF has activity in advanced breast
cancer. The greatest safety concern
has been the development of hypertension.
(Abstract 5C) rhuMAb VEGF in colorectal cancer. Emily Bergsland and colleagues
investigated the use of rhuMAb VEGF therapy in patients with metastatic
colorectal cancer who were previously untreated or had received adjuvant
therapy at least 12 months prior to enrollment. In this phase II study patients were randomized to receive
5-flourouracil (5-FU) 500 mg/m2 and leucovorin (LV) 500 mg/m2
alone (weekly x 6 every 8 weeks; n=36), or 5-FU/LV and low dose rhuMAb VEGF
(5 mg/kg every 2 weeks; n=35), or 5-FU/LV and high dose rhuMAb VEGF (10 mg/kg
every 2 weeks; n=33). For the
5-FU/LV, 5-FU/LV/low dose and 5 FU/LV/high dose groups response rates were
17%, 40% (p=.03), and 24% (p=.43), respectively; median times to disease
progression were 5.2, 9.0 (p=.005), and 7.2 (p=.217) months, respectively;
median survival was 13.8, > 17.3 (p=.08), and 16.1 (p=.97) months, respectively. Grade 3 or 4 hypertension was reported in
2 low dose and 8 high dose patients.
Grade 3 or 4 thrombotic events occurred in 5 low dose and 2 high dose
patients (including 1 fatal pulmonary embolism). The low dose rhuMAb VEGF/5-FU/LV group demonstrated the
greatest efficacy and safety was tolerable. (Abstract 939) rhuMAb VEGF in non-small-cell lung cancer (NSCLC). Russel DeVore and coworkers studied rhuMAb
VEGF therapy in patients with advanced NSCLC (stage IIIb with pleural
effusion, stage IV or recurrent disease) who were previously untreated. Patients were randomized to receive
carboplatin (C) AUC 6/paclitaxel (P) 200 mg/m2 alone (every 3
weeks; n=32), or CP and low dose rhuMAb VEGF (7.5 mg/kg every 3 weeks; n=32),
or CP and high dose rhuMAb VEGF (15 mg/kg every 3 weeks; n=35). Hemoptysis developed in 6 rhuMAb
VEGF-treated patients (4 with squamous cell histology) and was fatal in 4
patients. Objective response rates and
time to disease progression were greater in the CP/high dose rhuMAb VEGF group
compared to the CP alone and CP/low dose rhuMAb VEGF groups. However, the
only parameter to reach significance was the investigator-assessed time to
disease progression of the high dose group (7.4 months) compared to CP alone
(4.2 months). Survival for the CP,
CP/low dose, and CP/high dose groups were 14.9, 11.6 and 17.7 (p=.80) months,
respectively. These data show that
hemoptysis can be a life-threatening adverse event associated with rhuMAb
VEGF treatments in NSCLC and that rhuMAb VEGF at a dose of 15 mg/kg in
combination with CP may be an active therapy for advanced NSCLC with improved
tumor control. (Abstract 1896) Rituximab for Waldenstrom’s macroglobulinemia (WM). Stephen Treon et al. identified 28
evaluable patients with WM who received single-agent rituximab therapy. Rituximab therapy was associated with a
decrease in the mean IgM level (p=.0007), a decrease in the mean %
lymphoplasmacytic cell involvement of bone marrow (p=.0008), and an increase
in the mean Hct level (p=.0015) compared to baseline values. Eight (28.5%) patients experienced a >
50% reduction on the IgM serum concentration, 17 (60.7%) patients had an
increase in their Hct level, and 14 (50%) patients had a rise in their
platelet counts. The data from these
patients show that rituximab is a potentially effective treatment modality
for WM and future studies are planned.
(Abstract 13) Iodine I 131 tositumomab in follicular lymphoma (FL). Mark Kaminski et al. evaluated a single treatment
of iodine I 131 tositumomab (Coulter Pharmaceuticals, Inc.) as therapy for
patients with previously untreated advanced stage FL (n=76). Seven to 14 days following a dosimetric
dose (450 mg tositumomab and 5mCi [35 mg] iodine I 131 tositumomab) patients
were administered 450 mg of tositumomab and enough iodine I 131 tositumomab
to deliver a total body dose of 75 cGy I-131. Seventy-four (97%) patients achieved a response (63% CR) and
the median duration of response had not been reached after a median follow-up
of 16.2 months. The 3-year
progression-free survival was 68.2% (95% CI: 56 to 83%). Following B-cell recovery, 79% of the 34
patients who were PCR+ at baseline for the t(14;18) translocation were
PCR-. Forty-nine (65%) of patients
developed human anti-mouse antibodies and myelosuppression was moderate and
reversible. These results show that
Iodine I 131 tositumomab is an active first-line treatment for patients with
FL. (Abstract 11) Campath-1H in hematological malignancies. Alessandra Ferrajoli and colleagues
evaluated the use of Campath-1H in refractory hematological malignancies
which were found to express CD52 in >20% of neoplastic cells. Campath-1H was administered intravenously
(3 mg day 1, 10 mg day 2, 30 mg day 3, and 30 mg 3 x weekly for 12 weeks) to
45 patients (30 with B-CLL and 15 with differing NHL histologies). Three (9%) patients achieved a CR and 9
(26%) patients had a PR while 6 (18%) patients were observed to have stable
disease. The most common adverse
events were infusion related (30 [88%]) patients had fever/chills, 6 [18%]
patients had hypotension, 6 [18%] patients had dyspnea, and 4 [12%] patients
had an urticarioid rash). Lymphopenia
occurred in 25 (74%) patients and severe thrompocytopenia (platelet count
<10,000/mm3) occurred in 8 (24%) patients. Campath-1H is active in CD52+ refractory
hematological malignancies and has an acceptable safety profile. (Abstract 22) Gemtuzumab zogamicin in AML. Eric Sievers et al analyzed data from 142 patients with AML in
first relapse who were treated with gemtuzumab zogamicin (Wyeth-Ayerst
Research), a recombinant human anti-CD33 monoclonal antibody linked to the
cytotoxic agent calicheamicin, in 3 phase II studies. A remission (<5% marrow blasts with
adequate hematologic recovery) was obtained in 30% of patents (34% in
patients <60 years old [n=62], 26% in patients ³ 60
years old [n=80]). Median overall
survival was 5.9 months. Adverse
events included infusion-related symptoms, grade 4 marrow suppression, and
transient increases in liver function tests.
Gemtuzumab zogamicin is active in relapsed AML and there were no
observed differences in the efficacy or safety profiles for younger versus
older patients. (Abstract 23) Epratuzumab in NHL. John Leonard and colleagues reported the results of
dose-finding studies of epratuzumab (Immunomedics, Inc.), an anti-CD22
monoclonal antibody, in patients with relapsed/refractory NHL (n=44). The starting dose of intravenous
epratuzumab was of 120 mg/m2 weekly x 4. Twelve (48%) of 35 evaluable patients developed grade 1 or 2
adverse events associated with the first infusion (chills/rigors, nausea,
hypotension) and no grade 3 or 4 drug-related toxicity or human anti-human
antibody have been observed. Five
responses have occurred at dose levels of 240 to 480 mg/m2/week. These data show epratuzumab is well
tolerated and that there is evidence of efficacy in relapsed/refractory NHL.
(Abstract 60) Herceptin in metastatic breast cancer. C. Vogel et al. conduced a study of
intravenous Herceptin (trastuzumab), a humanized anti-HER2 monoclonal
antibody, as first-line treatment for patients with HER2 overexpressing
metastatic breast cancer (n=114).
Patients were randomized to standard low dose (4mg/kg loading and 2
mg/kg weekly) or high dose Herceptin (8 mg/kg loading and 4 mg/kg
weekly). Response rates for the low
dose group (LDG) compared to the high dose group (HDG) were similar (25% and
27%, respectively) and all responders overexpressed HER2 at the 3+
level. Median time to disease progression
(3.5 months LDG and 3.8 months HDG) and survival (22.9 months [95% CI:
16.0-37.1] LDG and 25.8 months [95% CI: 13.3-34.7] HDG) were also similar
between the treatment groups. Two
patients were reported to develop cardiac dysfunction. Herceptin is a potentially active
first-line agent in metastatic breast cancers that overexpress HER2. (Abstract 275) Tyrosine Kinase Inhibitor
Bcr-Abl positive acute leukemias. Moshe Talpaz and coworkers reported
results of the treatment of patients with Bcr-Abl positive acute leukemias
with an Abl tyrosine kinase inhibitor, STI 571 (Novartis
Pharmaceuticals.) The patient
population consisted of patients with chronic myelogenous leukemia (CML) in
myeloid blast crisis (n=21) and patients with either Bcr-Abl positive acute
lymphoblastic leukemia or CML in lymphoid blast crisis (n=12). Patients were treated with 300, 400, 500,
or 600 mg of STI 571 given as oral, daily, outpatient therapy. Responses (<15% marrow blasts) have
occurred in 55% of the patients with myeloid blast crisis (22% CRs) and in
82% of the patients with lymphoid leukemias (55% CRs). All the responding patients with lymphoid
leukemias relapsed between 45 and 81 days while 2 patients with myeloid blast
crisis had responses ongoing at 140 to 182 days. These data demonstrate that Bcr-Abl positive acute leukemias
respond to inhibition of Bcr-Abl kinase activity. (Abstract 6) IFN Therapy in CML
IFN vs. allogeneic bone marrow transplantation (BMT). R. Hehlmann et al. presented data from the
German CML Study Group trial concerning a subgroup of CML patients who had an
available related BMT donor. Patients
with an available donor were randomized within the first year of diagnosis to
receive either allogeneic BMT or INF-based therapy (n=524; 165 allogeneic BMT
and 389 IFN therapy). Allogeneic BMT
had been performed in 137 patients at the time of the report. During the first 4 years after diagnosis
survival was superior in the IFN arm due to early BMT-related mortality
(p=.014). The benefit occurred in
low-risk patients and no superiority for INF therapy was recognizable for
intermediate or high-risk patients.
After 4 years the survival curves converge and a crossing is expected
after 5 years. The results of this
study suggest that low-risk CML patients may benefit from an initial trial of
INF-based therapy prior to an allogeneic BMT procedure. (Abstract 10) Dendritic Cell Therapy
Idiotype-loaded dendritic cells in multiple myeloma. Frank Valone and coworkers conducted a
trial of therapy with APC8020 (Dendreon Corp.), an idiotype-loaded autologous
dendritic cell immunotherapy product, in patients with multiple myeloma.
APC8020 was infused on weeks 0, 4, 8, and 24 (n=33) or on weeks 0, 2, 4, and
16 (n=28). T cell immune responses
were observed in 1/3 of patients. Six
responses (3 CRs) were seen in 13 evaluable patients with low tumor
burden. No complete or partial
responses were observed in 38 patients with high tumor burden, however, 17
patients had stable disease for ³ 24 weeks. Only 2
of 186 infusions were reported to be associated with an adverse event
(dyspnea). These results suggest that
further studies of APC8020 are warranted.
(Abstract 1776) |
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