A Phase Ib Study of Safety and Pharmacokinetics of Ramucirumab in Combination With Paclitaxel in Patients With Advanced Gastric Adenocarcinomas

Lessons Learned

• The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies.
• This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated.

Background.

This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum.

Methods.

Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m² on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6).

Results.

No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4–42.7 weeks) and 12.2 weeks (range: 11.0–41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t_1/2) was 138 to 225 hours, and steady-state volume of distribution (V_ss) was ∼3 L.

Conclusion.

The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.     

nab‐Paclitaxel in Combination With Weekly Carboplatin With Concurrent Radiotherapy in Stage III Non‐Small Cell Lung Cancer

Lessons Learned

• The concomitant use of weekly nab-paclitaxel and carboplatin with concurrent radiotherapy was demonstrated to be a safe therapeutic approach in this phase I trial of 10 evaluable patients with stage III NSCLC.
• Despite the lack of systemic glucocorticoids, there were no reported infusion reactions or cases of peripheral neuropathy in this trial, both of which are known to occur with the use of paclitaxel.

Background.

Unresectable stage III non-small cell lung cancer (NSCLC) has a 5-year survival rate of 20%, and concurrent chemoradiotherapy results in significant toxicity with the use of current chemotherapeutic agents. nab-Paclitaxel was approved by the U.S. Food and Drug Administration in October 2012 for use along with carboplatin in advanced NSCLC. This study was undertaken to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of weekly nab-paclitaxel given in combination with carboplatin and concurrent radiotherapy in patients with unresectable stage III NSCLC.

Methods.

Escalating doses of once-weekly nab-paclitaxel were given along with once-weekly carboplatin area under the plasma concentration time curve (AUC) of 2 and concurrent radiotherapy 66 Gy in 33 fractions, followed by 2 cycles of carboplatin and nab-paclitaxel consolidation chemotherapy.

Results.

Eleven patients were enrolled and received treatment per protocol, with 10 evaluable for efficacy and toxicity. At dose level 1 (nab-paclitaxel 60 mg/m²), 2 DLTs were observed: esophagitis and radiation dermatitis. Six patients were enrolled at dose level 0 (nab-paclitaxel 40 mg/m²) with no DLTs. Nine of 10 evaluable patients had a partial response.

Conclusion.

Concurrent chemoradiotherapy with nab-paclitaxel 40 mg/m² and carboplatin AUC 2 is a safe and well-tolerated therapeutic regimen in patients with stage III NSCLC. A separate phase I/II study to evaluate the efficacy of this regimen is under way.     

Open-label feasibility study of pazopanib, carboplatin, and paclitaxel in women with newly diagnosed, untreated, gynaecologic tumours: a phase I/II trial of the AGO study group

Introduction:

Although most patients with advanced gynaecologic malignancies respond to first-line treatment with platinum-taxane doublets, a significant proportion of patients relapse. Combining targeted agents that have non-overlapping mechanisms of action with chemotherapy may potentially increase the disease-free interval. Accordingly, this study evaluated the feasibility of combining pazopanib, an oral angiogenesis inhibitor, with paclitaxel and carboplatin.

Methods:

This open-label, phase I/II study planned to evaluate the safety and efficacy of paclitaxel 175 mg m^–2 plus carboplatin (AUC5 (Arm A) or AUC6 (Arm B)) once in every 3 weeks for up to six cycles with either 800 or 400 mg per day pazopanib.

Results:

Dose-limiting toxicities (DLTs) were observed in two of the first six patients enrolled at pazopanib 800 mg plus paclitaxel 175 mg m^–2 plus carboplatin AUC5. Of the six patients enrolled in the next and lowest dosing level planned in the study, pazopanib 400 mg plus paclitaxel 175 mg m^–2 plus carboplatin AUC5, two patients also experienced DLTs and the study was terminated. Two of the 4 DLTs observed overall were gastrointestinal perforations. Severe myelotoxicity was reported in 6 of 12 patients.

Conclusion:

Combining either 800 or 400 mg per day pazopanib with standard carboplatin/paclitaxel chemotherapy is not a feasible treatment option.     

Stress hormones reduce the efficacy of paclitaxel in triple negative breast cancer through induction of DNA damage

Background:

The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy.

Methods:

We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel.

Results:

We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel.

Conclusion:

We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.     

Randomized Phase II Trial Comparing Carboplatin Plus Weekly Paclitaxel and Docetaxel Alone in Elderly Patients With Advanced Non‐Small Cell Lung Cancer: North Japan Lung Cancer Group Trial 0801

Background.

Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial.

Methods.

Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile.

Results.

Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%–69%) and 24% (95% confidence interval: 11%–37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm.

Conclusion.

The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.     

Phase I trial of axitinib combined with platinum doublets in patients with advanced non-small cell lung cancer and other solid tumours

Background:

This phase I dose-finding trial evaluated safety, efficacy and pharmacokinetics of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, combined with platinum doublets in patients with advanced non-small cell lung cancer (NSCLC) and other solid tumours.

Methods:

In all, 49 patients received axitinib 5 mg twice daily (b.i.d.) with paclitaxel/carboplatin or gemcitabine/cisplatin in 3-week cycles. Following determination of the maximum tolerated dose, a squamous cell NSCLC expansion cohort was enroled and received axitinib 5 mg b.i.d. with paclitaxel/carboplatin.

Results:

Two patients experienced dose-limiting toxicities: febrile neutropenia (n=1) in the paclitaxel/carboplatin cohort and fatigue (n=1) in the gemcitabine/cisplatin cohort. Common nonhaematologic treatment-related adverse events were hypertension (36.7%), diarrhoea (34.7%) and fatigue (28.6%). No grade⩾3 haemoptysis occurred among 12 patients with squamous cell NSCLC. The objective response rate was 37.0% for patients receiving axitinib/paclitaxel/carboplatin (n=27) and 23.8% for patients receiving axitinib/gemcitabine/cisplatin (n=21). Pharmacokinetics of axitinib and chemotherapeutic agents were similar when administered alone or in combination.

Conclusion:

Axitinib 5 mg b.i.d. may be combined with standard paclitaxel/carboplatin or gemcitabine/cisplatin regimens without evidence of overt drug–drug interactions. Both combinations demonstrated clinical efficacy and were well tolerated.     

PARP inhibitor reduces proliferation and increases apoptosis in breast cancer cells

Objective： Apoptosis is a reliable marker of chemotherapeutic efficacy. Olaparib and paclitaxel inhibit proliferation and induce apoptosis in a variety of cancers. We investigated the effects of paclitaxel combined with olaparib on apoptosis in breast cancer Bcap37 cells. Methods： Proliferation and apoptosis were detected by MTT assay and PI staining. Degradation of procaspase-3 and poly（ADP-ribose） polymerase （PARP） was analyzed by Western blotting. Results： Compared with paclitaxel alone, paclitaxel combined with 100 mg olaparib significantly reduced survival in Bcap37 cells at all tested treatment durations （P〈0.05）; inhibition increased with increasing olaparib dose and treatment time （P〈0.01）. Combined treatment yielded significantly higher rates of apoptosis （P〈0.05）, which also increased with time （P〈0.01）. Fluorescence micrographs showed that early and late apoptotic cells increased with treatment time. Pro-caspase-3 and PARP degradation was induced by paclitaxel and enhanced by olaparib in a dose-dependent manner. Thus, combined treatment was substantially more effective than treatment with paclitaxel alone. Conclusions： Our findings suggest that paclitaxel and olaparib inhibit breast cancer Bcap37 cell proliferation and induce apoptosis. Combined treatment further reduced cell growth and enhanced apoptosis, suggesting that this combination therapy may be a promising treaunent for breast cancer.     

Investigation of Adverse‐Event‐Related Costs for Patients With Metastatic Breast Cancer in a Real‐World Setting

Background.

Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2).

Materials and Methods.

Patients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated.

Results.

On average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0%) to $5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs.

Conclusion.

Chemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported.     

Phase II multi-institutional prospective randomised trial comparing S-1+paclitaxel with S-1+cisplatin in patients with unresectable and/or recurrent advanced gastric cancer

Background:

A combination of S-1 and cisplatin has been shown to be effective with acceptable safety for the first-line treatment of far-advanced gastric cancer in Japan. This is the first randomised phase II trial to compare S-1+paclitaxel with S-1+cisplatin in this setting.

Methods:

Patients with unresectable and/or recurrent advanced gastric cancer were randomly assigned to receive one of the two regimens: S-1 (40 mg m⁻² twice daily) on days 1–14 plus paclitaxel (60 mg m⁻²) on days 1, 8, and 15 of a 4-week cycle (S-1+paclitaxel) or S-1 (40 mg m⁻² twice daily) on days 1–21 plus cisplatin (60 mg m⁻²) on day 8 of a 5-week cycle (S-1+cisplatin). The primary end point was the response rate (RR). Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results:

A total of 83 patients were eligible for safety and efficacy analyses. In the S-1+paclitaxel and S-1+cisplatin groups, RRs (52.3% vs 48.7% P=0.74) and median PFS (9 vs 6 months; P=0.50) were similar. The median OS was similar in the S-1+paclitaxel and S-1+cisplatin groups (16 vs 17 months; P=0.84). The incidence of grade 3 or higher haematological toxicity was 19.0% with S-1+paclitaxel and 19.5% with S-1+cisplatin. The incidence of grade 3 or higher non-haematological toxicity was 14.2% with S-1+paclitaxel and 17.1% with S-1+cisplatin.

Conclusion:

S-1+paclitaxel was suggested to be a feasible and effective non-platinum-based regimen for chemotherapy in patients with advanced gastric cancer. Our results should be confirmed in multicenter, phase III-controlled clinical trials.     

Synergistic effects of the sesquiterpene lactone,EPD, with cisplatin and paclitaxel in ovarian cancer cells

Background

Ovarian cancer remains still the leading cause of death of gynecological malignancy, in spite of first-line chemotherapy with cisplatin and paclitaxel. Although initial response is favorably, relapses are common and prognosis for women with advanced disease stays poor. Therefore efficacious approaches are needed.

Methods

Previously, an anti-cancer agent, EPD exhibited potent cytotoxic effects towards ovarian cancer and not towards normal cells. Cell viability and cell cycle analysis studies were performed with EPD, in combination with cisplatin and/or paclitaxel, using the ovarian carcinoma cell lines: SK-OV-3, OVCAR-3, JC, JC-pl and normal fibroblasts. Cell viability was measured using Presto Blue and cell cycle analysis using a flow cytometer. Apoptosis was measured in JC and JC-pl , using the caspase 3 assay kit.

Results

In JC-pl, SK-OV-3 and JC, synergistic interactions between either EPD and cisplatin or EPD and paclitaxel were observed. For the first time the effects of EPD on the cell cycle of ovarian cancer cells and normal cells was studied. EPD and combinations of EPD with cisplatin and/ or paclitaxel showed cell cycle arrest in the G₂/M phase. The combination of EPD and cisplatin showed a significant synergistic effect in cell line JC-pl, while EPD with paclitaxel showed synergistic interaction in JC. Additionally, synergistic drug combinations showed increased apoptosis.

Conclusions

Our results showed a synergistic effect of EPD and cisplatin in an ovarian drug resistant cell line as well as a synergistic effect of EPD and paclitaxel in two other ovarian cell lines. These results might enhance clinical efficacy, compared to the existing regimen of paclitaxel and cisplatin.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0157-2) contains supplementary material, which is available to authorized users.     

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII‐Tubulin Expression as a Predictive Marker

Background.

This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated.

Patients and Methods.

Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m² (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m² (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. βIII-Tubulin expression was assessed using immunohistochemistry.

Results.

There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6–30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4–31.7). βIII-Tubulin-positive patients obtained higher pCR rates compared with βIII-tubulin-negative patients in both treatment arms; however, βIII-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy.

Conclusions.

Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among βIII-tubulin-positive patients.     

A Phase II Trial of Neoadjuvant Chemotherapy with Genexol? (Paclitaxel) and Epirubicin for Locally Advanced Breast Cancer

Purpose

Neoadjuvant chemotherapy (NC) is yet to be established as the definitive treatment regimen for locally advanced breast cancer (LABC). The aim of this study was to determine the efficacy and toxicity of NC with epirubicin and paclitaxel.

Methods

Between March 2007 and January 2009, 50 patients with LABC were enrolled in an open-label, phase II, multicenter study carried out at five distinct institutions. All patients were scheduled to receive four cycles of 60 mg/m² epirubicin and 175 mg/m² paclitaxel every 3 weeks, preoperatively, unless they developed profound side effects or disease progression. After curative surgery, two additional cycles of chemotherapy were administered to patients who had shown a positive response to NC.

Results

In all, 196 cycles of chemotherapy were administered preoperatively; 47 of the 50 patients (94%) underwent all four cycles of designated treatment. Complete disappearance of invasive foci of the primary tumor, and negative axillary lymph nodes were confirmed in eight patients (16.0%), post operation. The cumulative 5-year disease-free survival rate was 70.0% for patients with complete remission (CR) and partial remission (PR), and 33.3% for patients with stable disease (SD) and progressive disease (PD) (p=0.018). The cumulative 5-year overall survival was 90.0% for patients who achieved CR and PR and 55.6% for patients who had SD and PD (p=0.001). Neutropenia (42.0%) was the most common grade 3/4 toxicity. However, none of the toxicities resulted in cessation of the treatment.

Conclusion

The encouraging pathologic response observed in the patients treated with epirubicin plus paclitaxel NC in this study suggests that epirubicin could be a substitute for doxorubicin, which is the most cardiotoxic agent.     

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

Background:

The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell''s response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel.

Methods:

Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches.

Results:

We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2↓) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2↓ cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2↓ cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2↓ MCF7 cell line after paclitaxel reflecting the observed increase in senescence.

Conclusion:

Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.     

Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer

Objective

The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer.

Methods

To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 µL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls.

Results

Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses).

Conclusion

Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model.     

Temsirolimus Maintenance Therapy After Docetaxel Induction in Castration‐Resistant Prostate Cancer

Lessons Learned.

Temsirolimus maintenance therapy after docetaxel induction chemotherapy

• is safe in patients with castration-resistant prostate cancer, although biochemical or tumor responses are rare;
• does not diminish quality of life; and
• delays radiological and/or symptomatic progression by approximately 6 months.

Background.

No standard therapy is available for men with castration-resistant prostate cancer (CRPC) who have responded to docetaxel and do not yet have disease progression. Hence, we designed a single-arm phase II trial to explore whether the mTOR inhibitor temsirolimus can maintain the response to docetaxel without compromising quality of life.

Methods.

After successful docetaxel induction (75 mg/m² every 3 weeks; 6–10 cycles), 21 CRPC patients underwent temsirolimus maintenance treatment (25 mg weekly; 4 weeks per cycle). The primary endpoint was the time to treatment failure (TTTF) (i.e., radiological and/or symptomatic progression). The secondary endpoints included the tumor response rate (RECIST 1.0), safety (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0), quality of life (Functional Assessment of Cancer Therapy-Prostate [FACT-P]), pain (Present Pain Intensity [PPI] scale), prostate-specific antigen (PSA) parameters, including time to PSA progression (TTPP) according to Prostate Cancer Clinical Trials Working Group criteria, and serial enumeration of circulating endothelial cells (CECs) and endothelial progenitor cells (CEPs).

Results.

Patients received a median of 7 cycles of temsirolimus (range, 1–28), resulting in a median TTTF of 24.3 weeks (95% confidence interval [CI], 16.1–33.0), 1 partial tumor response (4.8%), 1 PSA response (4.8%), and a median TTPP of 12.2 weeks (95% CI, 7.8–23.9). Grade 3-4 adverse events were infrequent, and FACT-P and PPI scores remained stable during treatment. CECs did not predict clinical benefit, and CEPs were not consistently detectable.

Conclusion.

Temsirolimus maintenance therapy after successful docetaxel induction is feasible, does not adversely affect quality of life, and, in this exploratory single-arm phase II study, resulted in a median TTTF of 24.3 weeks.     

Bosutinib in Combination With the Aromatase Inhibitor Exemestane: A Phase II Trial in Postmenopausal Women With Previously Treated Locally Advanced or Metastatic Hormone Receptor‐Positive/HER2‐Negative Breast Cancer

Background.

Bosutinib is an oral, selective Src/Abl tyrosine kinase inhibitor with activity in breast cancer (BC). We evaluated bosutinib plus exemestane as second-line therapy in previously treated hormone receptor-positive (HR+) locally advanced or metastatic BC.

Methods.

This was a phase II study with patients enrolled in a single-arm safety lead-in phase. Patients receiving bosutinib at 400 mg or 300 mg/day (based on toxicity) plus exemestane at 25 mg/day were monitored for adverse events (AEs) and dose-limiting toxicities for 28 days, and initial efficacy was assessed. After the lead-in and dose-determination phase, randomized evaluation of combination therapy versus exemestane was planned.

Results.

Thirty-nine of 42 patients (93%) experienced treatment-related AEs including diarrhea in 28 (67%) and hepatotoxicity in 11 (26%); overall serious treatment-related AEs were recorded in 4 (10%). No liver toxicity met Hy’s law criteria. Dose-limiting toxicities occurred in 5 of 13 patients receiving 400 mg (38%) and 3 of 26 patients receiving 300 mg (12%) of bosutinib; all resolved on treatment discontinuation. One patient (300 mg/day) achieved confirmed partial response; three (400 mg/day, n = 2; 300 mg/day, n = 1) maintained stable disease for >24 weeks; a best response of progressive disease occurred in 15 of 42 patients (36%). Median progression-free survival was 12.3 weeks (80% confidence interval: 11.0–15.6).

Conclusion.

The risk-benefit profile of bosutinib at 300 mg/day plus exemestane resulted in early study termination before the randomized portion. Alternative bosutinib regimens merit investigation in BC.     

A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum-based therapy

Background

The appropriate second-line therapy for patients with advanced gastroesophageal (GE) or esophageal (E) cancer after failure of first-line platinum-based therapy is unclear. Pralatrexate and docetaxel have independently been shown to have efficacy in the treatment of these cancers. Thus, we performed a clinical trial examining the efficacy of the combination of these agents in the treatment of GE and E cancer.

Methods

A Fleming phase II design with a single stage of 32 patients was planned. Pralatrexate 120 mg/m² and docetaxel 35 mg/m² were administered on day 1 of 14-day cycles. The primary end-point was to evaluate the overall response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and secondary end-points were to evaluate for progression-free survival (PFS) and overall survival (OS).

Results

The study was halted prematurely due to loss of funding after the accrual of six patients. Two patients had stable disease (SD) and four patients had disease progression per RECIST. When applying PERCIST criteria in four evaluable patients, two had a partial response (PR) and two had SD. Median PFS was 1.9 months (95% CI, 0.8-7.2) and median OS was 5.5 (0.8-11.7) months.

Conclusions

Pralatrexate and docetaxel as therapy in refractory esophageal and GE adenocarcinoma did not demonstrate meaningful preliminary activity. PERCIST may prove to better assess the meaningfulness of anatomic SD.     

A Phase I/II Study Combining Erlotinib and Dasatinib for Non‐Small Cell Lung Cancer

Background.

EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC.

Methods.

The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed.

Results.

MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes.

Conclusion.

The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.     

Health-related quality of life in patients with metastatic colorectal cancer treated with panitumumab in first- or second-line treatment

Background:

Panitumumab in combination with chemotherapy was evaluated in two pivotal clinical trials in first- and second-line treatment of metastatic colorectal cancer (mCRC), respectively. This analysis compared the health-related quality of life (HRQoL) of patients with or without panitumumab in the two trials.

Methods:

Patients with mCRC were randomised to FOLFOX (first-line trial) or FOLFIRI (second-line trial)±panitumumab. The EuroQoL 5-Dimensions Health State Index (EQ-5D HSI) and Visual Analogue Scale (EQ-5D VAS) were assessed at baseline and monthly follow-up until disease progression. Patients with wild-type KRAS mCRC with baseline and post-baseline HRQoL scores were included. Difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models.

Results:

In the first-line trial, 576 patients with wild-type KRAS mCRC (284 panitumumab+FOLFOX4 and 292 FOLFOX4 alone) were included in the HRQoL analyses. In the second-line trial, 530 patients with wild-type KRAS mCRC were included in these analyses (263 panitumumab+FOLFIRI and 267 FOLFIRI alone). There was no significant difference in the change in EQ-5D HSI and VAS scores between treatment groups in either trial.

Conclusion:

The addition of panitumumab to FOLFOX4 or FOLFIRI in first- or second-line treatment of wild-type KRAS mCRC significantly improved progression-free survival without compromising HRQoL.     

A Phase Ib dose-escalation study to evaluate safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) to paclitaxel in patients with advanced solid tumours

Background:

This Phase Ib dose-escalating study investigated safety, maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and clinical antitumour activity of tosedostat (CHR-2797), an orally bioavailable aminopeptidase inhibitor, in combination with paclitaxel.

Methods:

A total of 22 patients received paclitaxel (135–175 mg m⁻²) intravenously, administered once every three weeks for up to six cycles, with oral tosedostat (90–240 mg) daily.

Results:

One DLT (grade 3 dyspnoea) was observed in one patient with tosedostat 180 mg combined with paclitaxel 175 mg m⁻². A high number of paclitaxel infusion reactions was noted during the second administration (59%) and this prompted interruption of tosedostat dosing for 5 days around every second and subsequent paclitaxel infusion. No formal MTD was determined because of the high frequency of paclitaxel infusion reactions that may have been influenced by tosedostat. Most frequently observed drug-related adverse events were alopecia, fatigue (95% each), peripheral sensory neuropathy (59%), paclitaxel hypersensitivity (59%) and rash (55%). One patient died because of eosinophilic myocarditis, possibly related to study medication. There was no PK interaction between tosedostat and paclitaxel. In all, 3 patients had a partial response and 12 patients had stable disease lasting >3 months.

Conclusion:

The combination of tosedostat with paclitaxel was well tolerated except for the high incidence of paclitaxel-related infusion reactions.