Susana M. Campos

Clinical Activity of Trastuzumab and Vinorelbine in Women With HER2-Overexpressing Metastatic Breast Cancer

PURPOSE To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

Trastuzumab and Vinorelbine as First-Line Therapy for HER2-Overexpressing Metastatic Breast Cancer: Multicenter Phase II Trial With Clinical Outcomes, Analysis of Serum Tumor Markers as Predictive Factors, and Cardiac Surveillance Algorithm

PURPOSE Trastuzumab-based therapy improves survival for women with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. We conducted a multicenter phase II study to evaluate the efficacy and safety of trastuzumab combined with vinorelbine, and to assess cardiac surveillance algorithms and tumor markers as prognostic tools. PATIENTS AND METHODS Patients with HER2-positive (immunohistochemistry [IHC] 3+-positive or fluorescence in situ hybridization [FISH]-positive) metastatic breast cancer received first-line chemotherapy with trastuzumab and vinorelbine to determine response rate. Eligibility criteria were measurable disease and baseline ejection fraction >or= 50%. Serial testing for HER2 extracellular domain (ECD) was performed. RESULTS Fifty-four women from 17 participating centers were entered onto the study. The overall response rate was 68% (95% confidence interval, 54% to 80%). Response rates were not affected by method of HER2 status determination (FISH v IHC) or by prior adjuvant chemotherapy. Median time to treatment failure was 5.6 months; 38% of patients were progression free after 1 year. Concurrent therapy was quite feasible with maintained dose-intensity. Patients received both chemotherapy and trastuzumab on 90% of scheduled treatment dates. Two patients experienced cardiotoxicity in excess of grade 1; one patient experienced symptomatic heart failure. A surveillance algorithm of screening left ventricular ejection fraction (LVEF) at 16 weeks successfully identified women at risk for experiencing cardiotoxicity. Other acute and chronic side effects were tolerable. Lack of decline in HER2 ECD during cycle 1 predicted tumor progression. CONCLUSION Trastuzumab and vinorelbine constitute effective and well-tolerated first-line treatment for HER2-positive metastatic breast cancer. Patients with normal LVEF can be observed with surveillance of LVEF at 16 weeks to identify those at risk for cardiotoxicity.

Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases

BACKGROUND Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.

Cediranib, an Oral Inhibitor of Vascular Endothelial Growth Factor Receptor Kinases, Is an Active Drug in Recurrent Epithelial Ovarian, Fallopian Tube, and Peritoneal Cancer

PURPOSE Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. PATIENTS AND METHODS We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included <or= two lines of chemotherapy for recurrence. End points included response rate (via Response Evaluation Criteria in Solid Tumors [RECIST] or modified Gynecological Cancer Intergroup CA-125), toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS Forty-seven patients were enrolled; 46 were treated. Clinical benefit rate (defined as complete response [CR] or partial response [PR], stable disease [SD] > 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. CONCLUSION Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs.

Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer

PURPOSE Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

Unexpected Association between Induction of Immunity to the Universal Tumor Antigen CYP1B1 and Response to Next Therapy

Purpose: The carcinogen activator cytochrome P450 1B1 (CYP1B1) is expressed on almost all human tumors with rare expression on normal tissues. Anti-CYP1B1–specific T cells kill CYP1B1-expressing tumors, providing the rationale to examine CYP1B1 as a target for immunotherapy. Experimental Design: ZYC300, a plasmid DNA of CYP1B1 encapsulated in biodegradable poly-dl-lactide-coglycolide microparticles, was used in a phase I clinical trial to treat 17 patients with advanced stage, progressive cancer. ZYC300 was administered i.m. at a fixed dose of 400 μg every other week for up to 12 doses. Results: Thirteen patients received six vaccinations and five received all 12 doses. No significant adverse events were observed. Six patients developed immunity to CYP1B1, three of whom developed disease stabilization. All but 1 of 11 patients who did not develop immunity to CYP1B1 progressed and did not respond to salvage therapy. Five patients who developed immunity to CYP1B1 required salvage therapy for progressive metastatic disease and showed marked response to their next treatment regimen, most of which lasted longer than 1 year. Conclusions: The association between immunity to CYP1B1 and response to next salvage therapy was not expected. Because six of the seven patients who had clinical benefit regardless of the nature of salvage therapy had developed immunity to CYP1B1, it seems highly unlikely that this occurred by chance alone. Regardless of the mechanism(s) that induced tumor regression, these findings force us to rethink how the generation of antitumor immunity might be integrated into the treatment of cancer.

VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy.

Background: Anti-vascular endothelial growth factor therapy (VEGF) is an important new treatment modality in oncology. We sought to determine the efficacy and safety of the humanized monoclonal anti-VEGF antibody, bevacizumab, and vinorelbine as treatment for refractory breast cancer and to explore the role of plasma VEGF as a predictor of treatment outcome. Experimental Design: Eligible patients had received one or two prior chemotherapy regimens for metastatic breast cancer or recurred within 12 months of adjuvant therapy and had measurable disease and adequate end-organ function. Patients received bevacizumab 10 mg/kg every 2 weeks, and vinorelbine each week, until tumor progression or prohibitive toxicity. Plasma VEGF was measured at baseline. Results: Among 56 women treated on protocol, bevacizumab and vinorelbine yielded a 34% response rate (95% confidence interval, 22-48%) and median time to progression of 5.5 months. Activity was observed regardless of tumor hormone receptor status or type or extent of prior chemotherapy. Side effects included uncomplicated neutropenia, hypertension, nasal congestion/epistaxis, and neuropathy, consistent with well-described side effects of the respective agents. Three patients had impaired wound healing following surgical procedures. There were only rare instances of thrombosis or clinically significant proteinuria. Lower levels of baseline VEGF were associated with longer time to progression. Conclusions: Bevacizumab and vinorelbine are well tolerated and effective as treatment for refractory breast cancer. Plasma VEGF warrants further evaluation as a prognostic marker for treatment outcome in advanced breast cancer patients receiving anti-VEGF therapy.

Multicenter, Randomized Phase II Trial of Oral CI-1033 for Previously Treated Advanced Ovarian Cancer

PURPOSE To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells. PATIENTS AND METHODS This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated--a 50-mg and a 200--mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status. RESULTS One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest. CONCLUSION CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.

Phase II Study of Carboplatin, Paclitaxel, and Bevacizumab With Maintenance Bevacizumab As First-Line Chemotherapy for Advanced Müllerian Tumors

PURPOSE New strategies are needed to improve outcomes for patients with advanced ovarian cancer. Bevacizumab is a recombinant humanized monoclonal antibody that neutralizes vascular endothelial growth factor but is associated with GI perforations (GIPs) in patients with recurrent disease. PATIENTS AND METHODS An open-label, phase II clinical trial was conducted in newly diagnosed patients with stage > or = IC epithelial müllerian tumors. Patients received intravenous (IV) carboplatin (area under the curve = 5), paclitaxel (175 mg/m(2) IV), and bevacizumab (15 mg/kg IV) for six to eight cycles on day 1 every 21 days. Bevacizumab was omitted in the first cycle and continued as a single agent for 1 year. Results Sixty-two women participated in this study. Fifty-one patients (82%) were optimally surgically cytoreduced before treatment. The median age was 58 years (range, 18 to 77 years). Forty-five women (73%) had ovarian cancer, 10 (16%) had peritoneal cancer, four (6%) had fallopian tube cancers, and three (5%) had uterine papillary serous tumors. The majority of patients (90%) had stage III or IV disease. A median of 17 maintenance cycles (range, 0 to 25+ cycles) of bevacizumab (556 cycles) were administered with mild toxicity. Treatment was associated with two pulmonary embolisms and two GIPs, all occurring during the chemotherapy phase of treatment (364 total cycles). No grade 4 toxicities were seen during maintenance bevacizumab treatment. Radiographic responses were documented in 21 (75%) of 28 women with measurable disease (11 complete responses and 10 partial responses), with CA-125 responses in 76% of patients (11 complete responses, 21%; and 35 partial responses, 55%). The progression-free survival rate at 36 months was 58%. CONCLUSION The regimen of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab is feasible, safe, and worthy of future study in advanced ovarian cancer.

A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens

The objective of this study was to determine the objective response rate in patients with platinum-sensitive and platinum-resistant recurrent ovarian cancer to treatment with trabectedin (Yondelis®) administered as a 3-h infusion weekly for 3 weeks of a 4-week cycle. We carried out a multicentre Phase II trial of trabectedin in patients with advanced recurrent ovarian cancer. Trabectedin (0.58 mg m−2) was administered via a central line, after premedication with dexamethasone, to 147 patients as a 3-h infusion weekly for 3 weeks followed by 1-week rest. Major eligibility criteria included measurable relapsed advanced ovarian cancer and not more than two prior platinum-containing regimens. Patients were stratified according to the treatment-free interval (TFI) between having either platinum-sensitive (⩾6 months TFI) or platinum-resistant disease (<6 months TFI)/platinum-refractory disease (progression during first line therapy). In the platinum-sensitive cohort, 62 evaluable patients with measurable disease had an overall response rate (ORR) of 29.0% (95% CI: 18.2–41.9%) and median progression-free survival (PFS) was 5.1 months (95% CI: 2.8–6.2). Four patients with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) criteria had no follow-up scans at the end of treatment. In the platinum-resistant/refractory cohort, 79 patients were evaluable with an ORR of 6.3% (95% CI: 2.1–14.2%). Median PFS was 2.0 months (95% CI: 1.7–3.5 months). Two patients with measurable disease per RECIST criteria had no follow-up scans at the end of treatment. The most frequent (⩾2% of patients) drug-related treatment-emergent grade 3/4 adverse events were reversible liver alanine transferase elevation (10%), neutropaenia (8%), nausea, vomiting, and fatigue (5% each). Trabectedin is an active treatment, with documented responses in patients with platinum sensitive advanced relapsed ovarian cancer, and has a manageable toxicity profile.