Prophylactic G-CSF Support Research Articles

Phase 1 trial of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced non-small cell lung cancer

ObjectivesAXL, a transmembrane receptor tyrosine kinase, is highly expressed and associated with poor prognosis in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324), a selective orally bioavailable small molecule AXL inhibitor, synergizes with docetaxel in preclinical models. We performed a phase I trial of bemcentinib plus docetaxel in previously treated advanced NSCLC. Materials and MethodsEscalation of two dose levels of bemcentinib (200 mg load × 3 days then 100 mg daily, or 400 mg load × 3 days then 200 mg daily) in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a 3+3 study design. Due to hematologic toxicity, prophylactic G-CSF was added. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic and pharmacokinetic effects alone and in combination. Plasma protein biomarker levels were measured. Results21 patients were enrolled (median age 62 years, 67% male). Median treatment duration was 2.8 months (range 0.7–10.9 months). The main treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (57%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever occurred in 8 (38%) patients. The maximum tolerated dose was docetaxel 60 mg/m2 with prophylactic G-CSF support plus bemcentinib 400 mg load × 3 days followed by 200 mg daily thereafter. Bemcentinib and docetaxel pharmacokinetics resembled prior monotherapy data. Among 17 patients evaluable for radiographic response, 6 (35%) patients had partial response and 8 (47%) patients had stable disease as best response. Bemcentinib administration was associated with modulation of proteins involved in protein kinase B signaling, reactive oxygen species metabolism, and other processes. ConclusionBemcentinib plus docetaxel with G-CSF support demonstrates anti-tumor activity in previously treated, advanced NSCLC. The role of AXL inhibition in the treatment of NSCLC remains under investigation.

Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC.

9081 Background: AXL, a transmembrane receptor tyrosine kinase, is overexpressed and associated with poor prognosis and treatment resistance in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324) is a selective orally bioavailable small molecule inhibitor of AXL, currently in phase 2 clinical development, that has demonstrated synergistic activity with docetaxel in in vivo models of NSCLC. This phase I dose escalation and expansion trial assessed the safety, tolerability, and preliminary efficacy of bemcentinib in combination with docetaxel in previously treated advanced NSCLC. Methods: Dose escalation of daily bemcentinib in combination with docetaxel (60 or 75 mg/m2 every 3 weeks) followed a standard 3+3 design. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic effects alone and in combination. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) pre-dose (C1D-7), C1D1, and C2D1. Results: A total of 21 patients (pts) were enrolled with median age 62 (range 39-84) and 67% male. A median of 3 (range 1-13) cycles of therapy were administered. Principal treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (52%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever ≥G3 occurred in 7 (33%) pts. The maximum tolerated dose was 60 mg/m2 docetaxel plus 200 mg bemcentinib daily with prophylactic G-CSF support. Pharmacokinetics of bemcentinib alone and in combination with docetaxel were highly similar. Among 15 evaluable pts, 4 (27%) pts had partial response and 9 (60%) pts had stable disease as the best radiographic response. Bemcentinib treatment resulted in changes in plasma levels of proteins associated with regulation of sterol synthesis and AKT signaling. Conclusions: Bemcentinib in combination with docetaxel and prophylactic G-CSF support has a manageable safety profile, leads to decreases in systemic factors associated with tumor growth and metastasis, and demonstrates evidence of anti-tumor activity in previously treated, advanced NSCLC. Further studies to identify the patient population most likely to benefit from this regimen are warranted. Clinical trial information: NCT02922777.

Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG)

Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. In this randomized, non-inferiority, phase III trial, women with HER2-negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC → D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. Six hundred and fifty women were randomized to either FEC → D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC → D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC → D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC → D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. NCT01985724.

Abstract P1-12-02: Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group

Abstract Purpose: To compare the sequential versus the concurrent administration of epirubicin and docetaxel as adjuvant therapy in high risk axillary node negative women with early breast cancer. Patients and treatment: Women 18-75 years old with invasive breast adenocarcinoma surgically resected with no infiltrated axillary lymph nodes and absence of metastatic disease were randomized to receive 4 cycles of epirubicin 90mg/m2 followed by 4 cycles of docetaxel 75mg/m2 (sequential regimen) or 6 cycles of epirubicin 75mg/m2 followed by docetaxel 75mg/m2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with prophylactic G-CSF support for days 3-10 only for the concurrent regimen. Stratification was based on menopausal status, tumor size and hormone receptor expression. By protocol amendment in 2008 women with HER2 positive tumors were excluded. The primary endpoint of the study was to compare the disease-free survival (DFS) at 5 years and 329 patients were scheduled to enroll on each arm. Results: Between 2001-2013, 658 women were randomized and received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 and 52 years, premenopausal status 43.8% versus 44.1%, tumor size &amp;lt;2cm in 44.1% versus 44.4%, histological grade 3 tumor in 52% versus 53.5% and hormone receptor negative disease in 33.1% versus 37.4% of patients in the sequential and concurrent regimens, respectively. After a median follow up of 70.5 and 70 months, there were 29 (8.8%) versus 42 (12.8%) disease relapses (p=0.102) and 11 (3.3%) versus 19 (5.8%) deaths (p=0.135), in the sequential and concurrent arms, respectively. The median DFS has not yet been reached in either arm (p=0.053) and the 5-year DFS rates were 92.6% versus 88.2% for sequential and concurrent arms, respectively. Dose reduction was required in 1.2% versus 3% (p=0.001) of the treatment cycles in the sequential and concurrent arms, respectively. Toxicity included grade 2-4 neutropenia in 54% versus 41% (p=0.001), febrile neutropenia 2.7% versus 6.1% (p=0.06), anemia 12% versus 17% (p=0.07), nausea/vomiting 18.5% versus 12.4% (p=0.03) of patients in the sequential and concurrent arms, respectively. There were no toxic deaths. Conclusion: In this interim analysis both the efficacy and the toxicity profile seem to favor the sequential over the concurrent regimen. Citation Format: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Timotheadou E, Rigas G, Varthalitis I-I, Kalbakis K, Agelaki S, Georgoulias V. Sequential versus concurrent administration of epirubicin and docetaxel as adjuvant chemotherapy in women with high-risk axillary lymph node negative early breast cancer. An interim analysis of a multicenter randomized study from the Hellenic oncology research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-12-02.

A single-arm, multicenter, open-label phase II trial of cabazitaxel as second-line treatment for patients with locally advanced or metastatic transitional cell carcinoma (TCC).

372 Background: For patients with advanced TCC who have progressed on a platinum-based regimen, no widely accepted standard second line therapy currently exists. A 2-stage phase II study was conducted to assess the activity and toxicity profile of the microtubule inhibitor cabazitaxel (Jevtana; FDA-approved in hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen) in patients with metastatic TCC after failure of prior platinum-based chemotherapy. ClinicalTrials.gov NCT01600339. Methods: Patients with one prior platinum based systemic therapy for metastatic TCC received cabazitaxel at a dose of 25 mg\m2every 21 days with prophylactic GCSF support, until disease progression or unacceptable toxicity. The primary endpoint was objective tumor response rate (ORR). Secondary endpoints included safety, time to progression (TTP), and overall survival (OS). Results: Twenty-three patients were enrolled to the study, 19 of whom received treatment. Male\female ratio was 15\4 and the median age was 67 (range, 56-81) years. Partial response (PR) was observed in 1 patient (5.3%), 10 patients (52.6%) achieved stable disease (SD), including 8 (42.1%) that had prolonged SD (≥16 weeks).Furthermore, the disease control rate (PR or prolonged SD) was 47.4%. The median TTP and OS were 4.2 (95% CI, 2.0-6.0) months and 9.9 (95% CI 5.6-13.2) months, respectively. The median number of treatment cycles was 5 (range 1-10). One patient experienced Grade 5 toxicity. Neutropenic fever occurred in 10.6% of patients. Most common toxicities were anemia and diarrhea. Conclusions: Cabazitaxel had modest efficacy in the treatment of advanced TCC, and there was no evidence of a significant response. Toxicity profile was considerable. The role of Cabazitaxel in urothelial carcinoma may need further evaluation in rational combination strategies, but not as a single agent. Clinical trial information: NCT01600339.

Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan

Uterine leiomyosarcoma (LMS) and undifferentiated endometrial sarcoma (UES) are rare, aggressive malignancies. Both are treated similarly; however, few chemotherapy agents are effective. Recently, the combination of gemcitabine (900 mg/m(2), days 1 and 8) plus docetaxel (100 mg/m(2), day 8) with granulocyte colony-stimulating factor (G-CSF, 150 μg/m(2), days 9-15) has been shown to have activity in LMS. In Japan, neither prophylactic G-CSF at a dose of 150 μg/m(2) nor docetaxel at a dose of 100 mg/m(2) are approved for use. For this reason, we evaluated the combination of 900 mg/m(2) gemcitabine plus 70 mg/m(2) docetaxel regimen without prophylactic G-CSF support in advanced or recurrent LMS and UES in Japanese patients. Eligible women with advanced or recurrent LMS and UES were treated with 900 mg/m(2) gemcitabine on days 1 and 8, plus 70 mg/m(2) docetaxel on day 8, every 3 weeks. The primary endpoint was overall response rate, defined as a complete or partial response. Of the eleven women enrolled, 10 were evaluated for a response. One complete response and 2 partial responses were observed (30 %) with an additional 4 (40 %) having stable disease. Mean progression-free survival was 5.4 months (range 1.3-24.8 months), and overall survival was 14 months (range 5.3-38.4 months). Grade 4 neutropenia was the major toxicity (50 %). The median number of cycles was 5 (range 2-18). Twenty-two cycles (44 %) employed G-CSF. The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES.

A multicenter phase I–II study of docetaxel plus epirubicin plus bevacizumab as first-line treatment in women with HER2-negative metastatic breast cancer

PurposeTo assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC). Patients and methodsWomen with previously untreated HER2-negative MBC received B (15 mg/kg), E (75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate (ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points during therapy. ResultsEighty-three women were enrolled with median age 62 years, performance status 0–1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis, complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate 66.3%; 95% CI 56.09–76.44%). The median time to progression was 20.1 months and the 1-year overall survival rate 82.3%. Grade 3–4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%, thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary embolism and another one myocardial infarction while on treatment. Although DEB administration significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before treatment initiation was significantly associated with worse progression-free survival (p = 0.001 and p = 0.004) and overall survival (p = 0.001 and p = 0.027), respectively. ConclusionsThe DEB regimen is a very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated with worse outcome. Clinicaltrials.govNCT00705315

The safety and tolerability of FE100C-D chemotherapy in a non-trial population of node positive breast cancer compared to PACS-01 trial group; Salmaniya Medical Complex experience

Introduction: In our institution, adjuvant taxanes are currently offered to fit node-positive breast cancer patients who are either Her2 positive (any ER/PR) or triple negative (ER/PR/Her2 negative). The FE 100 C-D (FE100C × 3 → docetaxel 100 mg/m 2 × 3) regime, based on the PACS 01 trial1 is used. Materials and Methods: We retrospectively audited our experience with FE 100 C-D at Salmaniya Medical Complex. Over a 2-year-period, 100 patients commenced adjuvant FE100C-D chemotherapy. Data was matched with the FE 100 C-D arm of the PACS 01 trial. Results: Median age was 54 years. Twenty-six patients (26%) had ≥1 episode of febrile neutropenia (FN), including one fatal episode; 29% patients required treatment interruption ≥1 week; 30% patients had dose reductions; and 30% patients received < 90% dose intensity of docetaxel. Conclusion: The FN rate was substantially higher and docetaxel dose intensity substantially lower in our unselected sample of patients than in the trial population, this real-life data demonstrates the problems of applying clinical trial data to the more generalised patient population. Meanwhile, the routine use of prophylactic G-CSF support with this protocol is warranted.

Phase II study of neoadjuvant high-dose ifosfamide with concurrent radiotherapy followed by surgical resection in high-risk soft tissue sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.

10052 Background: High-dose ifosfamide (HDI) has shown promising activity as single agent in first-line chemotherapy for advanced soft tissue sarcoma (STS). The purpose of this study was to assess the activity and toxicity of a preoperative doxorubicin-free regimen of HDI given concurrently with radiotherapy (RT) and followed by surgery in patients (pts) with localized high-risk STS. Methods: Pts with localized &gt; 5 cm grade 2-3 and deep STS of the extremities and trunk wall, ≤65 years, no prior chemotherapy and ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and concomitant external beam RT to a total dose of 50 Gy, followed by surgical resection. Postoperatively, pts with pathological response received 2 cycles of HDI and those with positive surgical margins 16 Gy of RT. The primary study endpoint was pathologic response (≥ 95% pathologic necrosis). A Simon 2-stage design (response rate P0=15%, P1=35%, α=0.10, β=0.10) required at least 2 responses in the first 17 pts to expand to a second cohort, and 7/32 responses to be considered of positive. Results: From March 08 to December 10, 34 pts were included. Two pts were ineligible. Median age was 54 (18-65). Tumor location was extremity (28 pts) and trunk wall (4). Preoperative planned treatment was completed in 87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 were R0 resections, of which 2 were amputations, and 4 were R1 resections. Pathologic response was ≥ 95% necrosis in 9 pts (28%) and 50%-94% necrosis in 12 pts. After a median follow-up of 21 months, estimated 2-year rates for disease-free survival and overall survival were 58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. Conclusions: Preoperative treatment with HDI given concurrently with RT in pts with high-risk STS is feasible and safe, yielding promising pathologic response rates.

First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors.

3009 Background: Aurora kinases A, B, and, C play essential roles in regulating cell division. Overexpression of aurora A and B in human tumors is associated with high proliferation rates and poor prognosis. AMG 900 is an investigational, orally administered, highly selective inhibitor of aurora A, B, and C that demonstrated activity in drug-resistant cell lines and human tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 900. Methods: Key eligibility criteria: ≥ 18 years old, advanced solid tumors, measurable disease, ECOG ≤ 2, and adequate organ function. AMG 900 was administered orally daily for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation phase, the starting dose was 1 mg and was escalated by 100% in subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation continued in a standard 3+3 design at ≤ 25% if DLT occurred or ≤ 50% if G2 related toxicity occurred. The maximum tolerated dose (MTD) was determined without prophylactic G-CSF support. Results: As of OCT 2011, 19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 mg) had received ≥ 1 dose of AMG 900. Demographics were 58% women, median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 DLTs: G4 neutropenia &gt; 7 days at 24 mg (n=1) and 30 mg (n=1); G4 neutropenia &gt; 7 days + G4 thrombocytopenia at 30 mg (n=1); and febrile neutropenia (FN) at 30 mg (n=1). MTD without G-CSF support was 24 mg. 89% of pts had treatment-related adverse events (AEs). G≥3 treatment-related AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 (11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed no obvious departures from dose-proportionality with a half-life of ~16 h. Tumor-response data were available for 17 pts: stable disease, 13 pts (range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease in CA-125 (SD &gt; 6 months). Conclusions: AMG 900 administered at 24 mg daily for 4D Q2W is the recommended dose for phase 2 trials. Dose escalation is now ongoing to determine the MTD with prophylactic G-CSF.

A single-arm phase II trial to evaluate the combination of cetuximab plus docetaxel, cisplatin, and 5-fluorouracil (TPF) as induction chemotherapy (IC) in patients (pts) with unresectable SCCHN

6015 Background: TPF combination is the new standard IC. Adding cetuximab to PF chemotherapy is superior to PF alone in metastatic disease. We incorporated cetuximab into IC with TPF and subsequent radiotherapy (RT) in unresectable SCCHN. Methods: Phase II trial conducted in 7 Spanish hospitals. Previously untreated pts aged 18–70 yrs, ECOG PS 0–1 with unresectable SCCHN were eligible. Induction comprised T 75mg/m2 day 1, P 75mg/m2 day 1, F 750mg/m2 days 1–5, and cetuximab 250mg/m2 days 1, 8, and 15 (initial dose 400mg/m2 on cycle (C) 1, day 1), repeated every 21 days x 4 C, with prophylactic antibiotics and G-CSF support. Subsequently, pts received accelerated RT with a concomitant boost (69.9Gy) and cetuximab 250mg/m2 weekly. The primary endpoint was the objective response rate (RR) to cetuximab TPF as neoadjuvant therapy. Simon's optimal two-stage design was used to calculate the sample size of 49 evaluable pts. Results: 50 pts were enrolled: median age 54 yrs (33–68); 44 male; all stage IV (T4=31, N2–3=40). Primary sites were: oropharynx, 23; hypopharynx, 16; oral cavity, 5; larynx, 4.41(82%) pts received all 4 cycles of cetuximab TPF; 47 pts received ≥2 C and were evaluable for response using RECIST. 3 pts received &lt;2 C (2 deaths from intercurrent disease and febrile neutropenia, 1 secondary neoplasm diagnosed). The table shows RR. Serious grade 3/4 adverse events (AEs) were: neutropenia 24%; neutropenic fever 20%; infection 6%; thrombocytopenia 4%; diarrhea 12%; hepatotoxicity 4%; hypomagnesemia 2%. Grade 3 AEs were: nausea/vomiting 2%; mucositis 6%; renal failure 4%; asthenia 4%; rash 4%; hypotension 4%. There were 2 AE-related deaths (febrile neutropenia and hepatic insufficiency). Conclusions: The addition of cetuximab to TPF IC in pts with unresectable SCCHN yields a high RR, mainly CR, potentially prolonging survival. Cetuximab TPF combination should be given to pts with good PS with specialized support provided. [Table: see text] [Table: see text]

Prophylactic G-CSF and antibiotics enable a significant dose-escalation of triplet-chemotherapy in non-small cell lung cancer

In advanced non-small cell lung cancer (NSCLC) the clinical benefit of a platinum-based doublet is only modest, therefore, attenuated dosed three-drug combinations are investigated. We hypothesized that with adequate support a full dosed chemotherapy triplet is feasible. The study was designed as a dose finding study of paclitaxel in chemotherapy-naive patients. Paclitaxel was given as a 3-h infusion on day 1, followed by fixed doses of teniposide (or etoposide) 100mg/m(2) days 1, 3, 5 and cisplatin 80 mg/m(2) day 1 every 3 weeks. As myelotoxicity was expected to be the dose-limiting toxicity, prophylactic G-CSF and antibiotic support was evaluated. Indeed, paclitaxel 120 mg/m(2) resulted in dose-limiting neutropenia, despite G-CSF support. Teniposide/etoposide day 1, 3, 5 was less myelotoxic compared to day 1, 2, 3. G-CSF support allowed paclitaxel dose-escalation to 250 mg/m(2). The addition of prophylactic antibiotics enabled dose-escalation to 275 mg/m(2) without reaching MTD. In conclusion, G-CSF and antibiotics prophylaxis enables the delivery of a full dosed chemotherapy triplet in previously untreated NSCLC patients.

Phase II: Concurrent cisplatin/radiotherapy followed by adjuvant cisplatin/docetaxel for locally advanced nasopharyngeal carcinoma

5573 Background: Concurrent cisplatin and radiotherapy as well as docetaxel/cisplatin combination are highly active agents for locally advanced nasopharyngeal cancer (LANPXCA).The efficacy and tolerability of concurrent cisplatin/radiotherapy followed by adjuvant docetaxel/cisplatin are explored in a phase II study Methods: From May 2001 to Feb 2003, 17 patients with LANPXCA stage III-IV were treated with 2 cycles of 3 weekly cisplatin 100mg/m2 concurrently with radiotherapy aiming at 70Gy Gy/ 35 fraction/ 7 weeks. Three weeks post radiotherapy 4 cycles of adjuvant 3 weekly docetaxel 60mg/m2 1 hour IV infusion D1 and cisplatin 60mg/m2 2 hours IV infusion D1 with prophylactic G-CSF support as 5μg/kg s.c. D3–5 were added. The median follow up was 30.2 months (15.6 - 41.1). Results: The median age was 50 years (25–70) and male to female ratio was 4.3:1. Nasal obstruction 82.4%, neck swelling 76.5%, headache 70.6% and impaired hearing 52.9% were the commonest symptoms. The most common histopathologic grade was G3 squamous cell carcinoma 94.1%. The majority of patients were stage IV 70.6% while 29.4% were stage III, (AJCC, 1997). Patients with G2 ECOG performance status were 47.1% while 52.9% were G1. The treatment was tolerable with the commonest G3 acute toxicities were dysphagia 23.5%, oral mucositis 11.3%, dermatitis 11.3%, leukopenia 5.9% and thrombocytopenia 5.9% while the commonest late toxicity was G2 mouth dryness in 88.2%. Complete remission was achieved in 15/17 patients (88.2%) while 2/17 (11.8%) were partial responders. Failure sites were locoregional; parapharyngeal space 5.9% and cervical nodes 5.9%. The Kaplan Meyer 41- month disease free survival was 88.2% while the 41- month overall survival was 100%. Conclusions: Concurrent cisplatin with radiotherapy followed by adjuvant docetaxel/cisplatin combination chemotherapy appears to be an effective and tolerable outpatient treatment for LANPXCA. No significant financial relationships to disclose.

Fourteen-Day CHOP Supported with Granulocyte Colony-Stimulating Factor in Patients with Aggressive Non-Hodgkin's Lymphoma: Results of a Phase II Study

The safety and efficacy of compressed-cycle (14-day) standard-dose CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) supported with prophylactic recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim) were evaluated in patients with aggressive non- Hodgkin's lymphoma (NHL). Patients with intermediate- or high-grade NHL (Working Formulation groups D-H and J; N = 120), accrued from 25 clinical practices, were given 6 cycles of standard-dose CHOP every 14 days. Granulocyte colony-stimulating factor 5 μg/kg was given daily subcutaneously in each cycle, starting on day 2 and continuing until the absolute neutrophil count was ≥ 10,000/μL. The overall response rate was 89%, with complete responses (CRs) in 52 of 120 patients (43%) and partial responses in 55 (46%). These results are consistent with previously reported outcomes from trials in this population. Of the 720 chemotherapy cycles planned for all patients, 615 (85%) were given on time at full dose. The median relative dose intensity (RDI) of cyclophosphamide and doxorubicin was 99%; the RDI of vincristine was 73%. In the 53 patients ≥ 60 years of age, 80% of the chemotherapy cycles were given on time at full dose, with median RDIs similar to those in the entire population. Response rates in the older patients were also similar, with CRs in 24 patients (45%) and partial responses in 21 (40%). Hematologic toxicity was significant but tolerable, with no treatment-related deaths. At a median follow-up of 20.6 months, 77% of patients were still alive. Standard-dose CHOP administered every 14 days with prophylactic G-CSF support was delivered as planned in most patients and produced response rates comparable with those with CHOP given every 3 weeks, without exceptional toxicity.

Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients

To determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of docetaxel in combination with fixed doses of epirubicin. Women with locally advanced or metastatic breast cancer were given docetaxel, 60 mg/m2 in escalated doses by steps of 10 mg/m2, in association with two fixed doses of epirubicin (90 mg/m2, and 75 mg/m2). Since neutropenia was foreseen to be the most likely DLT, a third group with prophylactic G-CSF support was planned to define the MTD of docetaxel with 90 mg/m2 of epirubicin. Selected patients underwent pharmacokinetic evaluation of docetaxel. Fifty-eight patients entered the study. At the first step (90 mg/m2 of epirubicin) the MTD was obtained at 60 mg/m2 of docetaxel. At the second step (75 mg/m2 of epirubicin) the MTD of docetaxel was 80 mg/m2. At the third step (epirubicin 90 mg/m2) G-CSF allowed a safe escalation of docetaxel up to 90 mg/m2. Neutropenia was the most common hematological adverse event. Without G-CSF, grade 4 neutropenia occurred in 69% of cycles, of which 11% was complicated by fever. In G-CSF group, grade 4 neutropenia and neutropenic fever occurred in 31% and 3%, respectively. Most frequent non-hematological adverse effects were asthenia (45%), nausea (39%) and mucositis (36%). No patient developed congestive heart failure. Two toxic deaths occurred. Overall response rate was 73% in 42 out of 58 patients, with no apparent epirubicin dose-related effect. No statistically significant effect of the two doses of epirubicin was observed in docetaxel pharmacokinetics. On the basis of the toxicity profile, the docetaxel pharmacokinetics and the response rate observed, epirubicin 75 mg/m2 combined with docetaxel 80 mg/m2 can be recommended for further studies.