A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors.

This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations.

Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma.

The Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST) demonstrated substantial activity with two dose levels of bortezomib (1.0 and 1.3 mg/m(2)), alone or with dexamethasone, in relapsed or refractory multiple myeloma. We present updated survival analyses after prolonged follow-up (median >5 years). One- and 5-year survival rates were 82% and 32%, respectively, in the 1.0 mg/m(2) group (n = 28), and 81% and 45%, respectively, in the 1.3 mg/m(2) group (n = 26). Notable survival, response, and time-to-progression data suggest that a bortezomib starting dose of 1.3 mg/m(2) is preferred. If bortezomib dose reduction is required, the 1.0 mg/m(2) dose still offers patients a substantial survival benefit.

A phase 2 study of bortezomib in relapsed, refractory myeloma.

BACKGROUND: Bortezomib, a boronic acid dipeptide, is a novel proteasome inhibitor that has been shown in preclinical and phase 1 studies to have antimyeloma activity. METHODS: In this multicenter, open-label, nonrandomized, phase 2 trial, we enrolled 202 patients with relapsed myeloma that was refractory to the therapy they had received most recently. Patients received 1.3 mg of bortezomib per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles (24 weeks). In patients with a suboptimal response, oral dexamethasone (20 mg daily, on the day of and the day after bortezomib administration) was added to the regimen. The response was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation and confirmed by an independent review committee. RESULTS: Of 193 patients who could be evaluated, 92 percent had been treated with three or more of the major classes of agents for myeloma, and in 91 percent, the myeloma was refractory to the therapy received most recently. The rate of response to bortezomib was 35 percent, and those with a response included 7 patients in whom myeloma protein became undetectable and 12 in whom myeloma protein was detectable only by immunofixation. The median overall survival was 16 months, with a median duration of response of 12 months. Grade 3 adverse events included thrombocytopenia (in 28 percent of patients), fatigue (in 12 percent), peripheral neuropathy (in 12 percent), and neutropenia (in 11 percent). Grade 4 events occurred in 14 percent of patients. CONCLUSIONS: Bortezomib, a member of a new class of anticancer drugs, is active in patients with relapsed multiple myeloma that is refractory to conventional chemotherapy.

Phase II study of neoadjuvant docetaxel/ vinorelbine followed by surgery and adjuvant doxorubicin/cyclophosphamide in women with stage II/III breast cancer.

BACKGROUND: The purpose of this study was to evaluate the combination of docetaxel plus vinorelbine as neoadjuvant chemotherapy for stage II/III locally advanced breast cancer. PATIENTS AND METHODS: Eligible women with stage IIA-IIIB or locoregional stage IV breast cancer were treated before surgery with 6 cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2, repeated every 2 weeks with granulocyte colony-stimulating factor and quinolone prophylaxis. Pathologic complete response (pCR), viewed as an early surrogate for disease-free and overall survival, was the primary efficacy endpoint. Sixty patients were enrolled; 60% had T3 or T4 lesions, 67% had clinically palpable lymph nodes, and 52% were hormone receptor positive. RESULTS: Fifty-nine patients were evaluable for pathologic response; 16 (27%) exhibited pCR in the breast alone (T0 Tis NX), 20% exhibited a pCR in the breast and lymph nodes (T0 Tis N0), 24 (41%) had < 5 mm of residual tumor, and 28 (47%) had node-negative disease at surgery. Relative dose intensity was 96% for docetaxel and 95% for vinorelbine. The clinical response rate was 98% (59 of 60 patients), including 38 complete responses (63%). Grade 3/4 neutropenia (95%), neutropenic fever (22%), mucositis (5%), and pulmonary toxicity (5%) occurred in >or= 5% of patients. Constipation was seen early but became insignificant after incorporating a prophylactic laxative regimen. Other toxicities have been minimal. CONCLUSION: With a clinical response rate of 98% and an in-breast pCR rate of 27%, docetaxel/vinorelbine is among the most active neoadjuvant regimens reported for locally advanced breast cancer. Docetaxel/vinorelbine can be administered in a dose-dense fashion while maintaining relative dose intensity. However, there was a significant incidence of fever and neutropenia despite the use of prophylactic growth factors and quinolones, indicating that lower doses of docetaxel/vinorelbine should be evaluated in future studies.

Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial.

PURPOSE: Local control rates at conventional radiotherapy doses (60 to 66 Gy) are poor in stage III non-small-cell lung cancer (NSCLC). Dose escalation using three-dimensional thoracic conformal radiation therapy (TCRT) is one strategy to improve local control and perhaps survival. PATIENTS AND METHODS: Stage III NSCLC patients with a good performance status (PS) were treated with induction chemotherapy (carboplatin area under the curve [AUC] 5, irinotecan 100 mg/m(2), and paclitaxel 175 mg/m(2) days 1 and 22) followed by concurrent chemotherapy (carboplatin AUC 2 and paclitaxel 45 mg/m(2) weekly for 7 to 8 weeks) beginning on day 43. Pre- and postchemotherapy computed tomography scans defined the initial clinical target volume (CTV(I)) and boost clinical target volume (CTV(B)), respectively. The CTV(I) received 40 to 50 Gy; the CTV(B) received escalating doses of TCRT from 78 Gy to 82, 86, and 90 Gy. The primary objective was to escalate the TCRT dose from 78 to 90 Gy or to the maximum-tolerated dose. RESULTS: Twenty-nine patients were enrolled (25 assessable patients; median age, 59 years; 62% male; 45% stage IIIA; 38% PS 0; and 38% > or = 5% weight loss). Induction CIP was well tolerated (with filgrastim support) and active (partial response rate, 46.2%; stable disease, 53.8%; and early progression, 0%). The TCRT dose was escalated from 78 to 90 Gy without dose-limiting toxicity. The primary acute toxicity was esophagitis (16%, all grade 3). Late toxicity consisted of grade 2 esophageal stricture (n = 3), bronchial stenosis (n = 2), and fatal hemoptysis (n = 2). The overall response rate was 60%, with a median survival time and 1-year survival probability of 24 months and 0.73 (95% CI, 0.55 to 0.89), respectively. CONCLUSION Escalation of the TCRT dose from 78 to 90 Gy in the context of induction and concurrent chemotherapy was accomplished safely in stage III NSCLC patients.

Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.

INTRODUCTION: This phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer. METHODS: Patients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint. RESULTS: In total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively. CONCLUSIONS: There was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00511459.

Recurrent primary fibrosarcoma of the brain treated with the GliaSite brachytherapy system: case report.

BACKGROUND: Primary brain sarcomas are rarely curable with surgery and standard radiation therapy. They typically recur locally within 6 months of treatment. This case report describes a novel treatment approach for primary or recurrent brain sarcomas with intracavitary brachytherapy. CASE DESCRIPTION: This 34-year-old female presented with a large and rapidly recurrent primary fibrosarcoma in the right fronto-parietal brain only 1 month postinitial total resection. She was reoperated, again with an MRI-documented gross total resection, but at this second surgery a GliaSite RTS (a recently FDA-approved balloon catheter system for intracranial intracavitary brachytherapy) was inserted into the surgical cavity. Over four days a radiation dose of 152 Gy was delivered at the balloon surface dose and 50.0Gy was delivered at a depth of 7 mm from balloon surface. The patient received subsequent treatment with external beam radiation and chemotherapy. The patient tolerated her treatment well and has shown no evidence of tumor recurrence with a follow up of 18 months. CONCLUSIONS: Boost intracavitary brachytherapy can play a critical role in preventing local recurrence and early death in patients with primary brain sarcomas.

Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2­positive breast cancer: an NSABP Foundation Research Program phase I study.

PURPOSE: Neratinib is an oral, small-molecule inhibitor that irreversibly binds to pan-HER (ErbB) receptor tyrosine kinases. Studies suggest that dual anti-HER therapies utilized in breast cancer patients are more efficacious than single agents in both the metastatic and neoadjuvant settings. In this phase I study, neratinib was combined with trastuzumab and paclitaxel in metastatic HER2-positive patients. METHODS: Twenty-one patients entered this dose-escalation study to determine the maximum-tolerated dose, safety, and efficacy of neratinib (120 up to 240 mg/day) with trastuzumab (4 mg/kg IV loading dose, then 2 mg/kg IV weekly), and paclitaxel (80 mg/m(2) IV days 1, 8, and 15 of a 28-day cycle) in women with HER2-positive metastatic breast cancer previously treated with anti-HER agent(s) and a taxane. RESULTS: The recommended phase II dose of neratinib with trastuzumab and paclitaxel was 200 mg/day. Common grade 3/4 adverse events were diarrhea (38 %), dehydration (14 %), electrolyte imbalance (19 %), and fatigue (19 %). With mandated primary diarrheal prophylaxis, ≥grade 3 diarrhea was not observed. Objective responses, complete (CR) and partial (PR), occurred in eight patients (38 %), with a clinical benefit of CR + PR+ stable disease (SD) ≥24 weeks in 11 patients (52 %). Median time-to-disease progression was 3.7 months. CONCLUSIONS: Dual anti-HER blockade with neratinib and trastuzumab resulted in significant clinical benefit despite prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple lines of chemotherapy. In selected populations, inhibiting multiple ErbB-family receptors may be more advantageous than single-agent inhibition. Based on favorable tolerance and efficacy, this three-drug combination will be further assessed in a randomized phase II neoadjuvant trial (NSABP FB-7:NCT01008150).

Assessing quality of life following neoadjuvant therapy for early stage non-small cell lung cancer (NSCLC): results from a prospective analysis using the Lung Cancer Symptom Scale (LCSS).

BACKGROUND: The assessment of the impact of neoadjuvant therapy on quality of life (QL) has rarely been prospectively planned and evaluated, although validated QL instruments are available-such as the Lung Cancer Symptom Scale (LCSS) used in this study. The modest but significant survival gains reported with neoadjuvant and adjuvant approaches need to be viewed in terms of the added risks and toxicities associated with two or three modalities of treatment. MATERIALS AND METHODS: The objective was to compare patient-determined QL ratings from baseline (prior to neoadjuvant chemotherapy) with those in subsequent months of follow-up. All patients had clinical stage I or II non-small cell lung cancer (NSCLC) and participated in one of two similar randomized protocols. Patients received preoperative chemotherapy (three cycles) of gemcitabine plus carboplatin or paclitaxel in one trial or gemcitabine plus carboplatin or cisplatin in the second. Patients completed the LCSS at baseline, every 3 weeks preoperatively, and every 3 months postoperatively up to 12 months. RESULTS: Full QL data are available for 43 patients with at least one postsurgical evaluation and for 23 patients with evaluation at 1-year postsurgery. In patients with at least one postsurgical evaluation, 84% had an ECOG performance status of 0, 93% had a complete resection, and 67% (95% CI = 52, 81) of patients experienced improved or stable symptoms. A subgroup of patients (14 of 43) reported worsening of QL (33%). These patients experienced a mean worsening of 66% in individual symptom parameters, with an average of seven of nine LCSS symptom parameters declining. CONCLUSIONS: Most patients reported improved or stable QL. Prospectively planned QL assessment is feasible with neoadjuvant trials and adds useful information not otherwise attainable.

Neoadjuvant chemotherapy with gemcitabine-containing regimens in patients with early-stage non-small cell lung cancer.

BACKGROUND: Surgical resection alone remains suboptimal for patients with early-stage (I or II) non-small cell lung cancer. Two similar randomized phase II trials were conducted to define an active preoperative regimen in this disease state. METHODS: In the first study, patients were randomized to receive gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 80 mg/m2 on day 1 (GC) or gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1 (GCb). In the second trial, patients received the same regimen of GCb or gemcitabine 1000 mg/m2 on days 1 and 8 plus paclitaxel 200 mg/m2 on day 1 (GP). Cycles were repeated every 21 days for three cycles. The primary end point was pathologic complete response (pCR) rate. RESULTS: Eighty-seven eligible patients were randomized (GC n = 12, GP n = 35, and GCb n = 40), and 71 (82%) underwent surgery after chemotherapy. The confirmed pCR rate was 2.3% (2 of 87, 95% confidence interval 0.3-8.1). Clinical response rate was 28.7%, complete resection rate was 91.5% (65 of 71 patients), and perioperative mortality rate was 2.8%. As of October 2006, median survival for all patients was 45 months (65.5% censored), with 87.2% alive at 1 year and 69.8% alive at 2 years. DISCUSSION: Neoadjuvant chemotherapy with gemcitabine was feasible and well tolerated, and outcomes were similar to other reports of this treatment strategy. However, no regimen achieved the predefined pCR rate that would be sufficient to warrant further evaluation in the phase III setting. This trial design provides an efficient way of providing a rationale for choosing or rejecting regimens of potential value.

Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer.

PURPOSE: To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)--overexpressing breast cancer. PATIENTS AND METHODS: Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast. RESULTS: Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). CONCLUSION: With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.

Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer.

PURPOSE: To evaluate the efficacy and toxicity of bortezomib +/- docetaxel as second-line therapy in patients with relapsed or refractory advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomly assigned to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus docetaxel 75 mg/m2 (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1. Patients could receive unlimited cycles. The primary end point was response rate. RESULTS: A total of 155 patients were treated, 75 in arm A and 80 in arm B. Baseline characteristics were comparable. Investigator-assessed response rates were 8% in arm A and 9% in arm B. Disease control rates were 29% in arm A and 54% in arm B. Median time to progression was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and median survival was 7.4 and 7.8 months in arms A and B, respectively. Adverse effect profiles were as expected in both arms, with no significant additivity. The most common grade > or = 3 adverse events were neutropenia, fatigue, and dyspnea (4% and 53%, 19% and 26%, and 17% and 14% of patients in arms A and B, respectively). CONCLUSION: Bortezomib has modest single-agent activity in patients with relapsed or refractory advanced NSCLC using this schedule, with minor enhancement in combination with docetaxel. Additional investigation of bortezomib in NSCLC is warranted in combination with other drugs known to be active, or using different schedules.

A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme.

Two types of chemotherapy used in the treatment of patients with malignant glioma are carboplatin and Gliadel wafer [(3.85% 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)]. To date there have been no published data examining their concurrent use in this disease. The purpose of this study was to evaluate combination chemotherapy with Gliadel wafer and carboplatin in patients with high-grade, malignant glioma. In this prospective phase I study, 16 patients underwent surgery, Gliadel wafer implantation (up to 8 wafers), intravenous carboplatin given postoperatively (day 3 or 4) at a dose escalation range of area under the curve (AUC)=2-6, and external beam radiation. Median age was 55 years (range 27-66 years). Fourteen (88%) patients had glioblastoma multiforme and 2 (12%) had anaplastic astrocytoma. Performance status was as follows: Eastern Cooperative Oncology Group (ECOG)=0 (2 patients), ECOG=1 (13 patients), and ECOG=2 (2 patients). Three patients were treated at each dosing level (AUC=2-6), and 4 patients were treated at an AUC=5. Carboplatin was administered to all patients by postoperative day 4. Radiation was begun on day 14-36. No grade 3 or 4 toxicities were noted in this study. Median progression-free and overall survival was 266 and 679 days, respectively. We conclude that administering systemic carboplatin is safe and well tolerated in the postoperative period immediately following resection and implantation of Gliadel wafer for the treatment of malignant glioma. Further evaluation in a phase II setting, at maximal carboplatin dose to establish potential efficacy, with this combination is warranted.