Amrubicin as second- or third-line treatment for women with metastatic HER2-negative breast cancer: a Sarah Cannon Research Institute phase 1/2 trial.

Amrubicin is a synthetic anthracycline which has been shown in preclinical studies to have broad-spectrum anti-tumor activity and a lower potential for cardiotoxicity as compared to doxorubicin. We conducted a phase 1/2 trial of single-agent amrubicin as second- or third-line treatment for women with metastatic breast cancer. Women with metastatic HER2-negative breast cancer who had normal cardiac function and measurable disease, received intravenous (IV) amrubicin every 3 weeks. Prophylactic treatment with granulocyte colony-stimulating factors (G-CSFs) was recommended. Escalating amrubicin doses were administered in a 3 + 3 design in the phase 1 portion to determine the maximum tolerated dose. Achievement of a median PFS ≥4.5 months would warrant further development of amrubicin in this setting. Seventy-eight women (median age 58 years) were treated (phase 1, 15 patients; phase 2, 63 patients). An amrubicin dose of 110 mg/m(2) every 3 weeks was selected as the phase 2 dose, and 66 patients were treated. Twelve of 66 patients (18%) achieved objective response, and the clinical benefit rate was 42%. Median PFS was 4 months (95% CI 2.5, 5.8). Neutropenia was the most common grade 3/4 toxicity, observed in 29 patients (44%). One patient experienced an asymptomatic transient left ventricular ejection fraction decline (grade 3). Although the study did not meet the predefined PFS, amrubicin was well tolerated at 110 mg/m(2) IV when administered every 3 weeks with prophylactic G-CSF, and was an active second- or third-line treatment for metastatic HER2-negative breast cancer.

Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma.

INTRODUCTION/BACKGROUND: Inhibition of tumor angiogenesis by the interruption of VEGF pathway signaling is of therapeutic value in several solid tumors. Preclinical evidence supports similar importance of the pathway in non-Hodgkin lymphoma. In this randomized phase II trial, we compared the efficacy and toxicity of rituximab with bevacizumab versus single-agent rituximab, in patients with previously-treated follicular lymphoma. PATIENTS AND METHODS: Patients (n = 60) were randomized (1:1) to receive rituximab (375 mg/m(2) intravenously [I.V.] weekly for 4 weeks) either as a single agent or with bevacizumab (10 mg/kg I.V. on days 3 and 15). Patients with an objective response or stable disease at week 12 received 4 additional doses of rituximab (at months 3, 5, 7, and 9); patients who received rituximab/bevacizumab also received bevacizumab 10 mg/kg I.V. every 2 weeks for 16 doses. RESULTS: After a median follow-up of 34 months, PFS was improved in patients who received rituximab/bevacizumab compared with patients who received rituximab alone (median 20.7 vs. 10.4 months respectively; HR, 0.40 (95% confidence interval [CI], 0.20-0.80); P = .007). Overall survival was also improved numerically (73% vs. 53% at 4 years), but did not reach statistical significance (HR, 0.40 (95% CI, 0.15-1.05); P = .055). The addition of bevacizumab increased the toxicity of therapy, but both regimens were well tolerated (no grade 4 toxicity). CONCLUSION: The addition of bevacizumab to rituximab significantly improved PFS. The role of angiogenesis inhibition in the treatment of follicular lymphoma requires further definition in larger clinical trials.

Phase II study of neoadjuvant weekly nab-paclitaxel and carboplatin, with bevacizumab and trastuzumab, as treatment for women with locally advanced HER2+ breast cancer.

PURPOSE: Neoadjuvant treatment with chemotherapy plus trastuzumab is standard care for women with locally advanced, HER2-positive (HER2(+)) breast cancer. HER2 has been shown to stimulate angiogenesis through vascular endothelial growth factor upregulation. We investigated the feasibility and efficacy of bevacizumab in combination with trastuzumab, nab-paclitaxel, and carboplatin as neoadjuvant therapy for women with locally advanced HER2(+) breast cancer. PATIENTS AND METHODS: Twenty-eight women with locally advanced HER2(+) breast cancer received nab-paclitaxel (100 mg/m(2) intravenously [I.V.] days 1,8, and 15) and carboplatin (AUC = 6 I.V. day 1) every 28 days × 6 cycles. Concurrent with chemotherapy, trastuzumab (4 mg/kg loading dose, then 2 mg/kg) and bevacizumab (5 mg/kg I.V.) were administered weekly × 23 weeks. Patients then underwent mastectomy or breast-conserving surgery; pathologic responses were assessed. After surgery, trastuzumab 6 mg/kg and bevacizumab 15 mg/kg were administered every 3 weeks (54 weeks total); locoregional radiotherapy and/or antiestrogen therapy was administered per standard guidelines. RESULTS: Twenty-six patients (90%) completed neoadjuvant therapy, with objective responses in 86%. Pathologic complete response (pCR) was confirmed in 14 of the 26 patients (54%) who had surgery. However, bevacizumab-related complications were common postoperatively and during adjuvant trastuzumab/bevacizumab therapy. Ten patients had wound-healing delays or infections (6 patients discontinued therapy); 4 patients had left ventricular ejection fraction (LVEF) decreases (1 patient discontinued therapy). Other severe treatment-related toxicity was uncommon. Only 9 patients (31%) completed all protocol therapy. CONCLUSIONS: Neoadjuvant therapy with nab-paclitaxel, carboplatin, trastuzumab, and bevacizumab was feasible in most patients, producing a pCR rate comparable to that in chemotherapy/trastuzumab combinations. In contrast, prolonged bevacizumab/trastuzumab therapy after surgical treatment was not well tolerated, primarily due to bevacizumab-related toxicity. The role of bevacizumab in neoadjuvant therapy remains undefined.

A pilot study of adjuvant nanoparticle albumin-bound (nab) paclitaxel and cyclophosphamide, with trastuzumab in HER2-positive patients, in the treatment of early-stage breast cancer.

nab-Paclitaxel has shown favorable efficacy and toxicity profiles compared to other taxanes in the treatment of metastatic breast cancer. In this pilot trial, we evaluated a nab-paclitaxel-containing adjuvant regimen in patients with early stage breast cancer. Patients with node-positive or high-risk node-negative early-stage breast cancer were eligible following completion of standard primary therapy. All the patients received four cycles, at 21-day intervals, of nab-paclitaxel (100 mg/m(2) IV days 1, 8, and 15) and cyclophosphamide (600 mg/m(2) IV day 1). HER2-positive patients also received trastuzumab 8 mg/kg IV on cycle 1 day 1, followed by 6 mg/kg every 21 days for a total of 52 weeks. The purpose of this trial was to evaluate feasibility and toxicity of this nab-paclitaxel-containing adjuvant regimen. 62 patients were treated between 2/08 and 11/08. The majority of the patients (87%) were HER2-negative. This adjuvant regimen was well tolerated, and full doses of all agents were administered in >90% of cycles. Grade 3/4 neutropenia occurred in 53% of the patients; however, only one episode of febrile neutropenia occurred in a total of 249 cycles administered. Other grade 3/4 adverse events occurred in less than 5% of patients. After short follow-up, all the patients remain alive and disease-free. The combination of nab-paclitaxel and cyclophosphamide, with or without trastuzumab, is feasible and well tolerated in patients with early stage breast cancer. Further investigation of the role of nab-paclitaxel in adjuvant breast cancer therapy is indicated, but definitive evaluation will require randomized phase III trials.

Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab.

PURPOSE Tracheoesophageal fistulae are rare complications of thoracic cancers and their treatments. Novel antiangiogenic agents in cancer treatment such as bevacizumab potentially impact wound healing and may contribute to tracheoesophageal fistula development. PATIENTS AND METHODS We conducted two independent phase II clinical trials in small-cell lung cancer and non-small-cell lung cancer using bevacizumab in combination with chemotherapy and radiation. Both trials were intended to assess preliminary efficacy and safety outcomes. Results For the limited-stage small-cell lung cancer trial, 29 patients were enrolled beginning April 2006, and closed early due to toxicity in March 2007 (14-month median follow-up). The locally advanced, non-small-cell lung cancer trial opened with enrollment limited to five patients in February 2007, and closed early due to safety in December 2007. In each trial, we observed tracheoesophageal fistulae development and related morbidity and mortality, prompting early trial closures, US Food and Drug Administration warnings, and a change in bevacizumab labeling. CONCLUSION The current data from the final reports from these two trials suggest bevacizumab and chemoradiotherapy are associated with a relatively high incidence of tracheoesophageal fistulae formation in both small-cell lung cancer and non-small-cell lung cancer settings. Strategies to safely incorporate novel antiangiogenic agents into combined-modality therapy in lung cancer are needed.

Combination therapy with fludarabine and rituximab followed by alemtuzumab in the first-line treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase 2 trial of the Minnie Pearl Cancer Research Network.

BACKGROUND: The purpose of the current study was to evaluate the efficacy and toxicity of the combination of fludarabine and rituximab, followed by alemtuzumab, as first-line treatment for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). METHODS: In a nonrandomized phase 2 trial, 41 patients who had previously untreated CLL or SLL and required treatment received 4 cycles of the fludarabine and rituximab combination followed 5 weeks later by 4 weeks (12 doses) of intravenous alemtuzumab therapy. The response to treatment was evaluated after completion of treatment with fludarabine and rituximab, and again after the completion of alemtuzumab consolidation. RESULTS: Initial treatment with the combination of fludarabine and rituximab was well tolerated, and produced a 71% overall response rate (13% complete response). Thirty-four patients began treatment with intravenous alemtuzumab, but this drug was relatively poorly tolerated when given at a short interval after fludarabine and rituximab, and only 20 patients (49% of total) were able to complete the prescribed course. Five patients had an improvement in their response with alemtuzumab; the final complete response rate was 21%. The median progression-free survival for the entire group was 42 months. Toxicity with alemtuzumab included infusion-related toxicity, myelosuppression, and opportunistic infections. CONCLUSIONS: The intravenous schedule of alemtuzumab employed in the trial was relatively poorly tolerated in this community-based trial. The relatively low complete response rates after treatment with the combination of fludarabine and rituximab and after the completion of treatment suggest that these abbreviated courses may compromise efficacy. The generalized use of alemtuzumab as consolidation therapy cannot yet be recommended for community practice. However, optimization of the route of administration, duration of treatment, and interval after completion of induction therapy may improve efficacy, and further investigation is ongoing.

A Phase I trial of protracted oral fixed-dose temozolomide.

BACKGROUND: The current Phase I trial was conducted to determine the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended Phase II dose of oral fixed-dose temozolomide when administered for 5 of every 7 days on a continuous basis. METHODS: Patients received a fixed dose of temozolomide daily for 5 of every 7 days continuously. Four weeks of treatment were considered 1 treatment cycle. Patients were accrued at 7 different dose levels ranging from 100 mg/day to 360 mg/day. RESULTS: Forty-six patients received 111 cycles of therapy. DLT consisted of myelosuppression, particularly thrombocytopenia. The primary nonhematologic toxicities were nausea and emesis, which were easily controlled with antiemetics. CONCLUSIONS: Protracted administration of temozolomide at a fixed dose of 300 mg/day for 5 of every 7 days continuously was well tolerated and allowed greater dose intensity compared with various other schedules. This regimen could potentially increase antitumor activity as protracted temozolomide schedules inhibit DNA repair by depletion of the repair protein O6-methylguanine-DNA methyltransferase.

Combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site: a Minnie Pearl Cancer Research Network Phase II trial.

BACKGROUND: The current study was performed to evaluate the activity of combination chemotherapy with gemcitabine and irinotecan in patients with previously treated carcinoma of an unknown primary site. METHODS: Patients with carcinoma of an unknown primary site who had received one previous chemotherapy regimen were eligible for this study. All patients received gemcitabine at a dose of 1000 mg/m2 intravenously (i.v.) and irinotecan at a dose of 100 mg/m2 i.v. on Days 1 and 8; treatment courses were repeated every 21 days. Patients were evaluated for response after completing two courses of treatment; responders/stable patients continued treatment for a recommended six courses. RESULTS: Forty patients entered this multicenter, community-based Phase II trial between September 2000 and July 2003. Four of these 40 patients (10%) achieved objective responses (a partial response in 3 patients and a complete response in 1 patient). An additional 17 patients (43%) had stable disease/minor response at first reevaluation; 7 of these patients (18%) remained stable for longer than 6 months. The median survival for the entire group was 4.5 months, with 1-year and 2-year survival rates of 25% and 13%, respectively. The treatment was well tolerated by most patients. Neutropenia was the most common Grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria, version 3.0) (occurring in 36% of patients). Myelosuppression-related complications were uncommon, as were severe nonhematologic toxicities. CONCLUSIONS: The combination of gemcitabine and irinotecan has modest activity and is well tolerated in patients with recurrent/refractory carcinoma of an unknown primary site. Treatment-related toxicity, particularly myelosuppression, appears to be less severe than toxicity produced by the taxane and platinum regimens frequently used in the first-line therapy of these patients. Evaluation of the gemcitabine and irinotecan combination as first-line therapy is indicated.

A phase I/II study of exisulind in combination with docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer.

Exisulind is a sulfone derivative of sulindac that induces apoptosis and demonstrates synergy with docetaxel in lung cancer models. This study evaluated the safety, efficacy, and pharmacokinetic interactions of exisulind and docetaxel/carboplatin in patients with metastatic non-small-cell lung cancer (NSCLC). Fifty-seven patients received 218 cycles of docetaxel (75 mg/m2) and carboplatin (area under the curve, 5.0) in combination with exisulind (125-250 mg orally twice daily). Two complete responses and 9 partial responses were observed among the 47 patients assessable for response (overall response rate, 23%). The median duration of response was 5.9 months and median survival was 9.4 months. The 1- and 2-year survival rates are 35% and 14%, respectively. The hematologic toxicities were consistent with those previously reported with docetaxel/carboplatin. The most common nonhematologic toxicities were mild to moderate fatigue, anorexia, nausea, and vomiting. The addition of exisulind to the chemotherapy regimen did not interfere with the metabolism or elimination of docetaxel and vice versa, and docetaxel did not interfere with the pharmacokinetic parameters of exisulind. This trial did not allow direct comparison of patients receiving docetaxel/carboplatin with and without exisulind, but when compared with historical data of docetaxel/carboplatin alone, the addition of exisulind does not appear to enhance antitumor activity, duration of response, or survival. Although preclinical data demonstrate increased apoptosis and prolonged survival for the combination of exisulind and docetaxel, multiple clinical trials do not support further clinical development of this combination regimen in patients with advanced NSCLC.

Weekly paclitaxel, estramustine phosphate, and oral etoposide in the treatment of hormone-refractory prostate carcinoma: results of a Minnie Pearl Cancer Research Network phase II trial.

BACKGROUND: The objective of the current study was to evaluate the efficacy and toxicity of weekly paclitaxel, oral etoposide, and estramustine phosphate in the treatment of patients with advanced, hormone-refractory prostate carcinoma. METHODS: Patients with hormone-refractory prostate carcinoma who had received no more than one previous chemotherapy regimen were eligible for this trial. Forty-two patients were treated between February 1998 and March 2000. Toxicity was excessive in the first 3 patients treated (Grade 3-4 leukopenia, 3 patients; death due to sepsis, 1 patient); the remaining 39 patients received lower doses of etoposide and estramustine phosphate (paclitaxel 50 mg/m(2) as a 1-hour, intravenous infusion on Days 1, 8, 15; etoposide 50 mg orally twice daily on Days 1-10; and estramustine phosphate 280 mg orally 3 times daily on Days 1-10). Courses were repeated every 28 days. Patients were evaluated for objective and/or serologic response after two courses of treatment; responding patients continued treatment for six courses. RESULTS: Fourteen of 40 evaluable patients (35%) had either an objective response or a serologic response to treatment. The median survival for the entire group was 9.5 months, with 1-year, 2-year, and 3-year survival rates of 38%, 12%, and 10%, respectively. Neutropenia was the most common Grade 3-4 toxicity and occurred in 38% of patients (11% of courses). Thirteen patients (33%) had severe fatigue, and 2 patients had treatment-related deaths due to sepsis. CONCLUSIONS: Although the three-drug combination had activity in patients with hormone-refractory prostate carcinoma, the results did not appear any better than the results achieved with less toxic taxane/estramustine phosphate combinations. Further development of this three-drug regimen is not recommended.

Phase I. Trial of irinotecan plus carboplatin in two dose schedules.

A phase I study of carboplatin (Paraplatin) administered in two different dosing schedules (single dose every 4 weeks and weekly dosing) in combination with weekly irinotecan (CPT-11, Camptosar) was conducted in patients with relapsed or refractory advanced malignancies. Fifty-three patients with a variety of tumor types were randomly enrolled on the two different treatment regimens and have received a total of 163 cycles of treatment to date. Twenty-six patients received weekly irinotecan in combination with a single fixed dose of every-4-week carboplatin (arm 1). Initially, patients received irinotecan on days 1, 8, and 15, in combination with fixed-dose carboplatin at an area under the concentration-time curve (AUC) of 5.5 (Calvert formula) on day 1 every 28 days. Due to dose-limiting toxicities encountered at the first two dose levels, the protocol was amended to decrease the fixed dose of carboplatin to an AUC of 4.0 every 4 weeks. Dose-limiting toxicity was again encountered, so the day-15 dose of irinotecan was eliminated from the dosing regimen. The recommended phase II dose for heavily pretreated patients is irinotecan at 60 mg/m2 on days 1 and 8 in combination with carboplatin at AUC 4.0 on day 1 with cycles repeated every 28 days. Twenty-seven patients were treated with weekly irinotecan in combination with fixed-dose weekly carboplatin (arm 2). The initial dosing regimen consisted of irinotecan in combination with fixed-dose carboplatin at an AUC of 1.8 on days 1, 8, and 15, with treatment cycles repeated every 28 days. Due to the development of dose-limiting toxicities at the first two dose levels, the dosing regimen was subsequently amended to weekly irinotecan in combination with fixed-dose carboplatin at AUC 2.0 on days 1 and 8 only, and the dosing interval was shortened to every 21 days. With this amended regimen, the recommended phase II doses are irinotecan at 90 mg/m2 in combination with carboplatin at AUC 2.0 on days 1 and 8, with treatment cycles repeated every 21 days.

Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies.

This phase I study was conducted to determine the dose limiting toxicity, maximum tolerated doses, and recommended phase II doses of the combination of JM-216 and paclitaxel. Patients received paclitaxel intravenously over one hour on day 1 of each cycle. Oral JM-216 was administered on days 1-5 starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine different dosing combinations. JM-216 doses ranged from 10-80 mg/m2/day and were combined with paclitaxel doses of 150, 175, or 200 mg/m2. Forty-three patients were treated with 146 cycles of therapy. Dose-limiting toxicity, consisting of febrile neutropenia and grade 3 thrombocytopenia, was encountered in 2 patients at the seventh dose level (JM-216 80 mg/m2/day + paclitaxel 175 mg/m2). Two intermediate dose levels were explored. The first level (JM-216 70 mg/m2/day + paclitaxel 175 mg/m2) produced dose-limiting thrombocytopenia in 1 of 6 patients. However, two additional patients also demonstrated delayed recovery from thrombocytopenia following treatment. As a result, a second intermediate dose level (JM-216 60 mg/m2/day + paclitaxel 200 mg/m2) was filled with six patients. No dose-limiting toxicities were reported in any patients at this dose level. The combination of oral JM-216 and paclitaxel is well-tolerated with minimal non-hematologic and reversible hematologic toxicity. The recommended dose for phase II study is JM-216 60 mg/m2/day for 5 days and paclitaxel 200 mg/m2 on day 1 repeated every 21 days. Higher doses of JM-216 are associated with more severe thrombocytopenia and delayed hematologic recovery resulting in subsequent dosing delays.