To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, ...and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics.
The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed.
Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%.
ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.
Bevacizumab and erlotinib have been shown to improve survival in stage IV non-small-cell lung cancer (NSCLC). This phase I/II trial was designed to incorporate these agents with induction and ...concurrent chemoradiotherapy in stage III NSCLC.
Patients received induction chemotherapy (carboplatin area under the curve AUC 6, paclitaxel 225 mg/m(2), and bevacizumab 15 mg/kg on days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly with bevacizumab 10 mg/kg every other week for four doses) and thoracic conformal radiation therapy (TCRT) to 74 Gy. In the phase I portion, cohort 1 received no erlotinib, whereas cohorts 2 and 3 received erlotinib at 100 and 150 mg, respectively, Tuesday through Friday, during TCRT. Consolidation therapy with erlotinib (150 mg daily) and bevacizumab (15 mg/kg every 3 weeks) was planned 3 to 6 weeks later for six cycles.
Forty-five eligible patients were enrolled. The objective response rates to induction and overall treatment were 39% (95% CI, 24% to 55%) and 60% (95% CI, 44% to 75%), respectively. The median progression-free and overall survival times were 10.2 months (95% CI, 8.4 to 18.3 months) and 18.4 months (95% CI, 13.4 to 31.7 months), respectively. The principal toxicity was esophagitis (29% grade 3 or 4 esophagitis, with one patient with grade 3 tracheoesophageal fistula), which was often prolonged. Consolidation therapy with bevacizumab and erlotinib was not feasible.
The use of bevacizumab and erlotinib as administered in this trial is not recommended given the lack of an efficacy signal and the substantial risk of esophageal toxicity.
Purpose: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed
to the bcl-2 mRNA, with docetaxel in patients with ...hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic
and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy.
Experimental Design: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v.
over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen
and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression
pretreatment and post-treatment.
Results: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75
mg/m 2 i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients
with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration ( C ss ) was a significant determinant of antitumor activity; mean C ss values were higher in responders compared with nonresponders (6.24 ± 1.68 versus 4.27 ± 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral
blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen C ss or response.
Conclusions: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate
and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition,
and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies
to optimize oblimersen C ss .
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein, with an extracellular ligand-binding domain and intracellular tyrosine kinase domain. Ligand binding induces EGFR ...dimerization and autophosphorylation on several tyrosine residues in the intracellular domain, leading to mitogenic signal transduction. EGFR overexpression correlates with a poor prognosis and is often associated with malignant transformation in a variety of epithelial cancers. ABX-EGF is a high-affinity (dissociation constant KD = 5 × 10−11 M) fully human IgG2 monoclonal antibody against human EGFR. ABX-EGF binds EGFR and blocks receptor binding of EGF and transforming growth factor-α, inhibiting EGFR tyrosine phosphorylation and tumor cell activation. ABX-EGF prevents tumor formation and eradicates large, established A431 tumors in xenograft models. Tumor growth inhibition occurs at relatively low doses, without concomitant chemotherapy or radiotherapy. When combined with chemotherapeutic agents, ABX-EGF has resulted in additive antitumor activity. A Phase I clinical trial has demonstrated activity in several tumor types, and the results from a Phase II trial for renal cell cancer also showed modest activity. Therapy was generally well tolerated without statistically significant adverse events. Monoclonal antibody blockade of EGFR represents a new and exciting direction in cancer therapy.
To determine the maximum tolerated dose and pharmacokinetics of cantuzumab mertansine, an immunoconjugate of the potent maytansine derivative (DM1) and the humanized monoclonal antibody (huC242) ...directed to CanAg, intravenously (i.v.) once every 3 weeks and to seek evidence of antitumor activity.
Patients with CanAg-expressing solid malignancies were treated with escalating doses of cantuzumab mertansine administered i.v. every 3 weeks. The pharmacokinetic parameters of cantuzumab mertansine, the presence of plasma-shed CanAg, and the development of both human antihuman and human anti-DM1 conjugate antibodies also were characterized.
Thirty-seven patients received 110 courses of cantuzumab mertansine at doses ranging from 22 to 295 mg/m2. Acute, transient, and reversible elevations of hepatic transaminases were the principal toxic effects. Nausea, vomiting, fatigue, and diarrhea were common but rarely severe at the highest dose levels. Dose, peak concentration, and area under the concentration-time curve correlated with the severity of transaminase elevation. The mean (+/- SD) clearance and terminal elimination half-life values for cantuzumab mertansine averaged 39.5 (+/-13.1) mL/h/m2 and 41.1 (+/-16.1) hours, respectively. Strong expression (3+) of CanAg was documented in 68% of patients. Two patients with chemotherapy-refractory colorectal carcinoma had minor regressions, and four patients had persistently stable disease for more than six courses.
The recommended dose for cantuzumab mertansine is 235 mg/m2 i.v. every 3 weeks. The absence of severe hematologic toxic effects, preliminary evidence of cantuzumab mertansine tumor localization, and encouraging biologic activity in chemotherapy-refractory patients warrant further broad clinical development of this immunoconjugate in CanAg-expressing tumors.
Purpose: This study was designed to determine the safety, tolerability, and pharmacokinetics, and to seek preliminary evidence of
anticancer activity of trabectedin, a novel marine-derived DNA minor ...grove binder, when administered as a 1-hour or 3-hour
i.v. infusion for 3 consecutive weeks every 4 weeks in patients with advanced solid malignancies. The study also sought to
determine the maximum tolerated dose (MTD) levels of trabectedin on these schedules, as well as to recommend doses for disease-directed
studies.
Experimental Design: A total of 32 and 31 patients were treated in sequential cohorts with trabectedin on the 1-hour schedule (doses ranging from
0.46 to 0.80 mg/m 2 ) and on the 3-hour schedule (doses ranging from 0.30 to 0.65 mg/m 2 ).
Results: Neutropenia, transient elevations in hepatic transaminases and creatine phosphokinase, and fatigue precluded dose escalation
above 0.70 mg/m 2 (1-hour schedule) and 0.65 mg/m 2 (3-hour schedule), which were determined to be the MTD levels, respectively. The pharmacokinetics of trabectedin on both
schedules were characterized by a high clearance rate, a long terminal half-life, and a large volume of distribution. A patient
with soft tissue sarcoma had partial response, and several soft tissue sarcoma patients had prolonged (â¥6 months) stable disease.
Conclusions: The MTD levels of trabectedin given weekly for 3 weeks every 4 weeks is 0.61 mg/m 2 as a 1-hour infusion and 0.58 mg/m 2 as a 3-hour infusion. The manageable toxicities at the MTDs, preliminary evidence of antitumor activity, pharmacokinetic
profile, and the unique mechanistic aspects of trabectedin warrant further disease-directed evaluations on weekly schedules.
This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies.
...Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses.
Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m(2)/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and alpha-fluoro-beta-alanine, were not meaningfully altered by coadministration.
Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.
To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically ...modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity.
Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%.
Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m(2). Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m(2), whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m(2). Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 +/- 12.3 hours; the harmonic mean half-life (t(1/2)) of free CPT was long (t(1/2), 77.46 +/- 36.77 hours).
Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m(2) as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.
Purpose: To assess the feasibility of administering oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the
Bcl-2 mRNA, with docetaxel to patients with hormone-refractory ...prostate cancer; to characterize the pertinent pharmacokinetic
parameters, Bcl-2 protein inhibition in peripheral blood mononuclear cell(s) (PBMC) and tumor; and to seek preliminary evidence
of antitumor activity.
Experimental Design: Patients were treated with increasing doses of oblimersen sodium administered by continuous i.v. infusion on days 1 to 6
and docetaxel administered i.v. over 1 h on day 6 every 3 weeks. Plasma was sampled to characterize the pharmacokinetic parameters
of both oblimersen and docetaxel, and Bcl-2 protein expression was measured from paired collections of PBMCs pretreatment
and post-treatment.
Results: Twenty patients received 124 courses of the oblimersen and docetaxel combination at doses ranging from 5 to 7 mg/kg/day oblimersen
and 60 to 100 mg/m 2 docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day
oblimersen and 75 mg/m 2 docetaxel. Nausea, vomiting, and fever were common, but rarely severe. Oblimersen mean steady-state concentrations were 3.44
± 1.31 and 5.32 ± 2.34 at the 5- and 7-mg/kg dose levels, respectively. Prostate-specific antigen responses were observed
in 7 of 12 taxane-naïve patients, but in taxane-refractory patients no responses were observed. Preliminary evaluation of
Bcl-2 expression in diagnostic tumor specimens was not predictive of response to this therapy.
Conclusions: The recommended Phase II doses for oblimersen and docetaxel on this schedule are 7 mg/kg/day continuous i.v. infusion days
1 to 6, and 75 mg/m 2 i.v. day 6, respectively, once every 3 weeks. The absence of severe toxicities at this recommended dose, evidence of Bcl-2
protein inhibition in PBMC and tumor tissue, and encouraging antitumor activity in HPRC patients warrant further clinical
evaluation of this combination.
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