TITAN: phase III study of doxorubicin/cyclophosphamide followed by ixabepilone or paclitaxel in early-stage triple-negative breast cancer.

PURPOSE: Ixabepilone is a microtubule stabilizer with activity in taxane-refractory metastatic breast cancer and low susceptibility to taxane-resistance mechanisms including multidrug-resistant phenotypes and high ß-III tubulin expression. Since these resistance mechanisms are common in triple-negative breast cancer (TNBC), ixabepilone may have particular advantages in this patient population. This study evaluated the substitution of ixabepilone for paclitaxel following doxorubicin/cyclophosphamide (AC) in the adjuvant treatment of early-stage TNBC. METHODS: Patients with operable TNBC were eligible following definitive breast surgery. Patients were randomized (1:1) to receive four cycles of AC followed by either four cycles (12 weeks) of ixabepilone or 12 weekly doses of paclitaxel. RESULTS: 614 patients were randomized: 306 to AC/ixabepilone and 308 to AC/paclitaxel. At a median follow-up of 48 months, 59 patients had relapsed (AC/ixabepilone, 29; AC/paclitaxel, 30). The median time from diagnosis to relapse was 20.8 months. The 5-year disease-free survival (DFS) rates of the two groups were similar [HR 0.92; ixabepilone 87.1% (95% CI 82.6-90.5) vs. paclitaxel 84.7% (95% CI 79.7-88.6)]. The estimated 5-year overall survival (OS) rates were also similar [HR 1.1; ixabepilone 89.7% (95% CI 85.5-92.7) vs. paclitaxel 89.6% (95% CI 85.0-92.9)]. Peripheral neuropathy was the most common grade 3/4 event. Dose reductions and treatment discontinuations occurred more frequently during paclitaxel treatment. CONCLUSIONS: Treatment with AC/ixabepilone provided similar DFS and OS in patients with operable TNBC when compared to treatment with AC/paclitaxel. The two regimens had similar toxicity, although treatment discontinuation, dose modifications, and overall peripheral neuropathy were more frequent with AC/paclitaxel. TRIAL REGISTRATION: Clinical Trials.gov Identifier, NCT00789581.

Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study.

In anecdotal reports, some patients with immune thrombocytopenia (ITP) maintained platelet counts after discontinuing romiplostim. Here, we examined rates of platelet response (≥50 × 10(9) /l), remission, splenectomy and adverse events in patients with primary ITP duration ≤6 months who were treated with romiplostim for ≤12 months. The starting dose of romiplostim was 1 µg/kg; concomitant and rescue treatments were permitted to maintain platelet counts. Patients with platelet counts ≥50 × 10(9) /l at the end of 12 months entered a dose taper in which the romiplostim dose was decreased as long as platelet counts were maintained. Remission (platelet count ≥50 × 10(9) /l for 24 consecutive weeks with no ITP treatments) was evaluated in patients once romiplostim was discontinued. Over the 12 months, a high response rate (>90%) was observed. Platelet response occurred quickly (median, ~2 weeks) and was observed for a cumulative median of 11 months. Remission was observed in 24 patients (32%); there were no significantly predictors of remission. Most (20/24) patients had remission start before the forced taper. No new safety signals were identified. Thus, in patients with early-stage ITP, romiplostim was well tolerated and induced rapid responses, with remission occurring in approximately one-third of patients (NCT01143038, Amgen 20080435).

Phase I/II trial of neoadjuvant sunitinib administered with weekly paclitaxel/carboplatin in patients with locally advanced triple-negative breast cancer.

The purpose of the study is to evaluate the feasibility and efficacy of adding sunitinib to paclitaxel/carboplatin in the neoadjuvant therapy of patients with triple-negative breast cancer (TNBC). Patients had histologically proven, previously untreated, triple-negative adenocarcinoma, with disease limited to the breast and axilla (clinical T1-T3, N0-N2, M0; T1N1M0 excluded). Following determination of the maximum tolerated doses in the phase I portion, patients in the phase II study received paclitaxel 70 mg/m(2) IV days 1, 8, and 15; carboplatin AUC 5.0 IV day 1; sunitinib 25 mg orally daily; treatment was administered for six 28-day cycles followed by definitive surgery. Sunitinib was resumed postoperatively to complete a 52-week course. Pathologic complete response (pCR) rate was the primary endpoint. Fifty-four patients enrolled; 41 received treatment in the phase II study. Sixteen patients (39 %) were able to complete six cycles of neoadjuvant therapy; 18 additional patients had surgery after completing 2-5 cycles of treatment. The pCR rate in these 34 evaluable patients was 35 %. The toxicity of the regimen was considerable, with myelosuppression resulting in numerous dose reductions and/or omissions of paclitaxel and carboplatin. Eleven patients (27 %) discontinued sunitinib during neoadjuvant therapy, and six patients (14 %) completed 52 weeks of single-agent sunitinib. In the neoadjuvant treatment of patients with TNBC, the combination of paclitaxel, carboplatin, and sunitinib was difficult to administer, and produced a pCR rate comparable to other less toxic regimens. This combination is not recommended for further evaluation. At present, sunitinib has no defined role in the treatment of breast cancer.

Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute.

Amplified PI3K/Akt/mTOR signaling is common in metastatic breast cancer (MBC). The mTOR inhibitor everolimus improves progression-free survival (PFS) when added to steroidal aromatase inhibitor therapy. This randomized phase II trial compares the efficacy of paclitaxel/bevacizumab/everolimus and paclitaxel/bevacizumab/placebo as first-line treatment for MBC. Patients with untreated HER2-negative MBC were randomized (1:1) to receive 28-day cycles of paclitaxel 90 mg/m(2) IV (days 1, 8, and 15) and bevacizumab 10 mg/kg IV (days 1, 15) with either everolimus 10 mg (Arm 1) or placebo (Arm 2) daily. Treatment continued (evaluation every 8 weeks) until progression or unacceptable toxicity. Treatment of 110 patients allowed detection of an improvement in median PFS from 11 to 16 months (70 % power, α = 0.10). Between August 2009 and June 2011, 113 patients (median age 58 years; 88 % ER or PR positive) were randomized (Arm 1, 56; Arm 2, 57). Patients in both arms received a median of six treatment cycles. Median PFS (95 % CI) was 9.1 months (6.8-18.8) for Arm 1, and 7.1 months (5.6-10.8) for Arm 2 (p = 0.89). Comparisons of other efficacy endpoints were also similar in the two treatment arms. Patients receiving everolimus had more anemia, stomatitis, diarrhea, rash, and arthralgia/myalgia, although the overall incidence of severe (grade 3/4) toxicity was similar. The addition of everolimus did not improve the efficacy of weekly paclitaxel/bevacizumab as first-line treatment for patients with HER2-negative MBC. These results contrast with the demonstrated efficacy of adding everolimus to either hormonal or HER2-targeted therapy in previously treated patients.

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.

Phase II trial of preoperative pemetrexed plus carboplatin in patients with stage IB-III nonsquamous non-small cell lung cancer (NSCLC).

OBJECTIVES: The combination of pemetrexed and carboplatin is a standard first-line treatment for patients with advanced NSCLC. In this pilot phase II trial, we evaluated the feasibility of using pemetrexed and carboplatin as neoadjuvant therapy, prior to definitive surgical resection, for patients with localized NSCLC. PATIENTS AND METHODS: Patients with potentially resectable, previously untreated, clinical stage IB-III, nonsquamous NSCLC were eligible for this trial. All patients received 4 cycles of pemetrexed (500 mg/m2) and carboplatin (AUC 6.0) administered at 21 day intervals. Three to 6 weeks after completion of chemotherapy, definitive surgical resection was attempted. The primary endpoint of this trial was the 3-year survival rate. RESULTS: Forty-six patients began protocol treatment, and 40 completed 4 courses of pemetrexed/carboplatin. Surgical resection was performed in 27 patients (59%); all had pathologic partial responses. The estimated 3-year survival rate for the entire group was 46%. Toxicity of neoadjuvant therapy was consistent with toxicity previously reported with pemetrexed/carboplatin. CONCLUSIONS: Administration of 4 courses of pemetrexed/carboplatin was feasible. The efficacy was similar to neoadjuvant regimens previously investigated. A significant number of patients 19 of 46 (41%) in this trial did not have surgical resection after neoadjuvant therapy. Further investigation of the role of neoadjuvant pemetrexed/carboplatin requires a larger, randomized clinical trial.

Concurrent radiotherapy and temozolomide followed by temozolomide and sorafenib in the first-line treatment of patients with glioblastoma multiforme.

BACKGROUND: The current study was conducted to evaluate the efficacy of sorafenib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, when added to standard radiotherapy and temozolomide in the first-line treatment of patients with glioblastoma multiforme. METHODS: After initial surgical resection or biopsy, patients with newly diagnosed glioblastoma multiforme received concurrent radiotherapy (2.0 grays [Gy]/day; total dose, 60 Gy) and temozolomide (at a dose of 75 mg/m2 orally daily), followed by 6 months of maintenance therapy with temozolomide (at a dose of 150 mg/m2 orally on Days 1-5 every 28 days) and sorafenib (at a dose of 400 mg orally twice daily). Patients were re-evaluated every 2 months; the primary endpoint of the trial was progression-free survival (PFS). RESULTS: A total of 47 patients were treated; 34 had undergone previous debulking surgery. Nineteen patients withdrew from treatment before the initiation of maintenance therapy with temozolomide and sorafenib (12 because of early tumor progression). Twenty-eight patients (60% of enrolled patients) received 4 months of maintenance therapy with temozolomide and sorafenib, and 9 patients (19%) completed the planned 6 months of maintenance therapy. The median PFS for the entire group was 6 months (95% confidence interval [95% CI], 3.7-7 months), with a 1-year PFS rate of 16%. The median overall survival was 12 months (95%CI, 7.2-16 months). Maintenance therapy with temozolomide and sorafenib was found to be well tolerated by most patients, with no grade 3/4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) reported to occur in >10% of patients. CONCLUSIONS: The addition of sorafenib did not appear to improve the efficacy of treatment when compared with the results expected with standard therapy. A substantial percentage of patients (40%) did not receive any maintenance sorafenib, most often because of early disease progression. The administration of angiogenesis inhibitors concurrently with radiotherapy and temozolomide may optimize the opportunity to improve therapy.