G-CSF Support Research Articles

Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial

The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. The 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. ClinicalTrials.gov Identifier NCT00312208.

The adjuvant PANTHER study: A randomized comparison between dose-dense and tailored epirubicin (E), cyclophosphamide (C) and docetaxel (D) vs. standard dose 5-fluorouracil (F), epirubicin (E), cyclophosphamide (C) and docetaxel—Health-related quality of life during ongoing therapy.

1035Background: Chemotherapy is dosed per mg/m2, which results in marked differences in inter-patient pharmacokinetics and toxicities. Tailored chemotherapy is based on dose adjustments based on individually recorded toxicities. Previous studies revealed superior survival outcomes with dose dense (DD) adjuvant regimens, but docetaxel was previously not considered suitable in a DD strategy. Health related quality of life (HRQoL) was a secondary endpoint in the Panther study. Methods: Patients with node positive breast cancer (BC), or with node negative BC > 20 mm, receptor negative (Er and Pr) Elston grade III, were randomized between tailored dose dense therapy (E 38-120 mg/m 2) C 450-1200 mg/m 2) followed by four cycles D75-100 mg/m 2) every second week (three weeks pause between EC and D), G-CSF support and prophylactic antibiotics), the ddtEC-D arm, vs. the control arm (three cycles F500 E100 C500 followed by three cycles of D100 every third week). HRQoL was evaluated using EORTC QLQ-C30 + EORTC QLQ-BR...

Alemtuzumab added to CHOP for treatment of peripheral T-cell lymphoma (pTNHL) of the elderly: Final results of 116 patients treated in the international ACT-2 phase III trial.

7500Background: Standard treatment in pTNHL pts is unsatisfactory due to a high rate of early progression. Alemtuzumab (A), a monoclonal anti-CD52 antibody, has demonstrated efficacy in relapsed pTNHL pts, and phase II trials have shown feasibility of concomitant A+CHOP application. We report the final analysis of the international ACT-2 phase III randomized trial in elderly pts comparing standard CHOP to A-CHOP. Methods: Between 2007 and 2013, 116 pts from 52 centers were randomized to receive either 6 cycles of CHOP or A-CHOP at 14-day intervals with G-CSF support. Pts were to receive a total of 360 mgs A (until pt 39) or 120 mg. The protocol demanded stringent CMV / EBV monitoring and anti-infective prophylaxis. The study was powered to detect a 15% increase in EFS with the addition of A to CHOP. Results: 116 pts (median age 69 yrs, 58% male) were randomized (58/58). Histologies were 41% AITL, 39% pTNHL NOS , 6% ALCL , 14% other subtypes. Complete treatment as planned was applied in 79% (CHOP) resp 57%...

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 <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.

Abstract OT3-02-03: An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer

Abstract Background: The combination of the anthracycline, doxorubicin with cyclophosphamide (AC) is a widely used chemotherapy regimen in early stage breast cancer. Studies have shown that dose dense chemotherapy (incorporating AC) improved both disease-free survival and overall survival compared to once every 3 week treatment with daily subcutaneous G-CSF support. An important advance in the use of dose dense chemotherapy regimens was the development of pegylated forms of G-CSF, which offered the convenience of a single subcutaneous injection, rather than multiple daily injections. Lipegfilgrastim is a pegylated long-acting covalent conjugate of filgrastim (G-CSF). In a pivotal randomised phase III study in breast cancer lipegfilgrastim was shown to be non-inferior to pegfilgrastim. Although lipegfilgrastim is licensed in Europe and can facilitate every 2 week (dose dense) scheduling of chemotherapy there are a lack of prospective data about its efficacy in this setting. In this prospective, non-interventional, study we are investigating the incidence of treatment-related neutropaenia following four cycles of dose dense AC with lipegfilgrastim support. Methods: The primary end point of this prospective, single arm study is to determine the incidence of treatment-related neutropaenia, defined as an absolute neutrophil count (ANC) of <1.0 x 109/L, following four cycles of dose dense AC with lipegfilgrastim support. The secondary end points are to (1) determine the incidence of febrile neutropaenia, defined as temperature > 38°C and ANC <1.0 x 109/L, during 4 cycles of dose dense AC with lipegfilgrastim and (2) examine the incidence of treatment-related neutropaenia during subsequent intravenous chemotherapy post completion of AC. Eligibility criteria include, patients with stage I-III breast cancer, planned treatment with dose dense AC in the adjuvant or neoadjuvant setting, age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 and adequate bone marrow function. Patients with prior exposure to chemotherapy and/or G-CSF, who are pregnant, have a cardiac or other concurrent illness, which at the investigator's discretion contraindicates the use of AC will be excluded. We will enrol 40 consecutive patients who are planned to undergo dose dense AC. Based on previous clinical trials, we expect that the incidence of treatment-related neutropaenia will be <12%. However, it is likely that the current study will more closely resemble real-world practice and a higher incidence of treatment-related neutropaenia may be observed. This study has been approved by the Instituational Review Board and 9 patients have been consented to date. (registered with clinicaltrials.gov). Citation Format: Lyons T, Mallet V, Collins D, Malone E, Milewski M, Egan K, Hennessy B, Grogan L, Breathnach O, Morris P. An observational study of dose dense chemotherapy with lipegfilgrastim support in early breast cancer. [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 OT3-02-03.

A Phase II Study of Ofatumumab-High Dose Methylprednisolone Followed By Ofatumumab-Alemtuzumab in 17p Deleted or TP53 Mutated CLL

Abstract BACKGROUND: Even in the age of kinase inhibitors, the prognosis for patients (pts) with CLL with del(17p) or TP53 mutations remains poor, with the median PFS only 28 mo. for pts with relapsed/refractory del(17p) CLL treated with ibrutinib. High dose methylprednisolone (HDMP) and alemtuzumab (alem) both have activity in 17p disease and work independently of TP53. Prior work has demonstrated that giving HDMP/alem simultaneously is efficacious, but toxic. We hypothesized that giving these agents sequentially with ofatumumab (ofa) would maintain efficacy while decreasing toxicity. METHODS: This phase II study of ofa/HDMP followed by ofa/alem in CLL pts with 17p deletion or TP53 mutation employed a parallel 2-arm design (treatment-naive (TN) and relapsed/refractory (R/R)). Therapy was the same in both arms and included ofa/HDMP for 2-4 cycles (part A) followed by ofa/alem for 4-24 weeks, up to maximum response (part B). Responders could proceed to alloHSCT or a maintenance phase with ofa given q2 mo and alem given q2 wks (part C). Antimicrobial prophylaxis for PCP, HSV/VZV, and fungal infections was mandatory, as was G-CSF support. The primary objective was to estimate the ORR at the conclusion of the two-part induction therapy in both cohorts. Secondary objectives were to estimate the rate of CR, objective response by compartment, rate of MRD negativity by 4 color flow cytometry, PFS, and OS, rate at which transplant-eligible pts were able to proceed to alloHSCT, and to assess safety. Toxicity was assessed by IW-CLL and CTCAE v4.0. Response assessments by IW-CLL criteria were performed mid-way and at the end of parts A and B, and q6 mo. on part C. RESULTS: A total of 30 patients were enrolled. Baseline pt characteristics were as follows: TN (n=15): median age 64 (range 45-86), median WBC 58K, Hct 31, Plts 134, B2M 4.3, IGHV unmutated 79%, median %bone marrow (BM) involvement 80%. R/R (n=15): median age 65 (range 58-80), median WBC 31, Hct 33, Plts 114, B2M 4.5, IGHV unmutated 73%, median %BM involvement 60%, median # prior therapies 2 (range 1-4) including 9 pts with prior FCR or FR and 7 pts with prior BR. One patient in each arm had TP53 mutation without 17p deletion, and 4 pts had mut NOTCH1. The median number of copy number changes by SNP array was high, at 12.4 in the TN and 14 in the R/R cohorts. In the TN arm, 14/15 pts moved from part A->B, 5 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the TN arm was 80% (67% PR, 13% CR), with 12/15 (80%) pts achieving BM MRD negativity. The TN 2-yr PFS and OS are 70% and 85%, respectively. In the R/R arm, 8/15 pts moved from part A->B, 4 moved from part B->C, and 5 moved on to alloHSCT in remission. The best ORR for the R/R arm was 68% (all PRs), with 8/15 (54%) pts achieving BM MRD negativity. The R/R 2-yr PFS and OS are 53% and 67%, respectively. Responses in both arms were independent of TP53 and NOTCH1 mutation status. Studywide, a greater number of somatic mutations was associated with shorter PFS and OS (HR 1.13 per mutation, 95% CI 1.02-1.25, p=0.015 and HR 1.185, 95% CI 1.047-1.341, p=0.0073, respectively). The most common grade 3/4 toxicities were: neutropenia (33%), thrombocytopenia (20%), anemia (10%). Infectious complications included pneumonia (5 cases, 1 Gr2, 3 Gr3, 1 Gr4), febrile neutropenia (2 cases, both Gr3), and cellulitis (1 case, grade 3). Four pts had low-level CMV reactivation, but no CMV infections occurred. Venous thromboembolism occurred in 3 pts. With a median follow-up time among survivors of 25 mo., 21 of the total 30 pts are still alive, and causes of death included: progressive disease n=6, infection n=3. 12/18 (67%) pts who were transplant eligible were able to proceed to HSCT. Discontinuations were due to: progressive/refractory disease (n=10, including 3 Richter's transformations (R/R n=2, TN n=1)), physician decision (n=2), and unacceptable toxicity (n=1). CONCLUSION: Ofa/HDMP followed by Ofa/alem is highly active for both TN and R/R CLL pts with del(17p) and/or TP53 mutation. In addition to a robust ORR, we observed a high rate of MRD-negativity in the bone marrow, which allowed most of the transplant-eligible pts to proceed to alloHSCT. Sequential dosing appears to reduce infectious complications compared to concurrent dosing. This regimen is a feasible option for pts with ultra-high risk CLL to facilitate maximal cytoreduction prior to alloHSCT. <> Disclosures Davids: Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Single Agent Gemcitabine As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma after Autologous Stem Cell Transplantation

The aim of this study was to evaluate the efficacy and safety of gemcitabine as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma after autologous stem cell transplantation (ASCT). Fifteen patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2, had adequate organ function and had undergone ASCT. Patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 15, every 4 weeks. The median age was 26 years (range, 18-44) and 8 (53%) were female. Eight (53%) had primary refractory disease. All had previous platinum-based salvage chemotherapy (IIVP, 7; ICE, 5; DHAP, 3). All (100%) had relapsed/refractory disease following ASCT as their last treatment. Eleven (73%) had refractory/progressive disease after ASCT. None had previous brentuximab vedotin treatment. Median number of previous lines of chemotherapy was 2 (range, 2-3). Median number of gemcitabine cycles administered to the patients was 4 (range, 2-6). Treatment response was assessed with PET-CT in majority of the patients before and 2-3 cycles after gemcitabine, and those patients who demonstrated a response continued to receive a maximum of 6 courses of gemcitabine or bridged to allogeneic SCT. Of 15 patients, 1 (7%) had complete response, 5 (33%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 40%. The median time to progression for responding patients was 3 months (range, 2-7 months). Two patients were successfully bridged to allogeneic SCT. Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 8 patients: thrombocytopenia (40%), neutropenia (33%) and anemia (7%). Three patients had grade 4 thrombocytopenia and 2 had grade 4 neutropenia. Dose reduction was necessary in 3 patients and treatment cycle postponed in 2 patients because of hematological toxicity. Five patients (33%) needed G-CSF support. Two patients developed febrile neutropenia. No treatment-related deaths occurred. Gemcitabine was shown to be an active salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma after ASCT, producing an overall response rate of 40%. Although, the median PFS time was short, some patients can be bridged to allogeneic SCT. Hematological toxicity was common. DisclosuresOff Label Use: Gemcitabine in Hodgkin's Lymphoma.

Gemcitabine in Combination with Oxaliplatin (GEMOX) As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma

This study's objective was to evaluate the efficacy and safety of gemcitabine in combination with oxaliplatin (GEMOX) as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma. Twenty-five patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2 and had adequate organ function. Patients received intravenous gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) on days 1 and 15, every 4 weeks. The median age was 29 years (range, 18-64) and 16 (68%) were male. Twenty-one (84%) had primary refractory disease (n=13) or relapsed within 12 months after initial therapy (n=8). All had previous platinum-based salvage chemotherapy (ICE, 23; DHAP, 2). Ten patients (40%) had relapsed/refractory disease following autologous stem cell transplantation (SCT). None had previous brentuximab vedotin treatment. Twenty-one (84%) patients were refractory or progressive on the last treatment. Median number of previous lines of chemotherapy was 2 (range, 2-4). Median number of GEMOX cycles administered to the patients was 3 (range, 2-6). Treatment response was evaluated with PET-CT before and 2-3 cycles after treatment, and those patients who demonstrated a response continued to receive a maximum of 6 courses of GEMOX or bridged to SCT. Of 25 patients, 2 (8%) had complete response, 9 (36%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 44%. Seven of the 10 patients who had relapsed/refractory disease after autologous SCT achieved a response (CR, 2; PR, 5). The median time to progression for responding patients was 3 months (range, 1-40 months). One patient is disease free for 40 months. Three patients were successfully bridged to SCT (autologous, 2; allogeneic, 1). Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 10 patients: thrombocytopenia (36%), neutropenia (16%) and anemia (8%). Among these, 7 had previous autologous SCT. One patient had grade 4 neutropenia and thrombocytopenia. Treatment cycle postponed in 6 patients without dose reduction because of hematological toxicity. Seven patients (28%) needed G-CSF support. One patient developed febrile neutropenia. No treatment-related deaths occurred. GEMOX was shown to be an effective salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma, producing an overall response rate of 44%. It is an active regimen in patients who had relapsed/refractory disease after autologous SCT. Although, the median PFS time was short, some patients can be bridged to SCT and some can get long-term PFS. Hematological toxicity was common, especially in patients with previous autologous SCT. DisclosuresOff Label Use: Gemcitabine in Hodgkin's Lymphoma Oxaliplatin in Hodgkin's Lymphoma.

Preliminary Results of a Phase 2, Open-Label Study of Venetoclax (ABT-199/GDC-0199) Monotherapy in Patients with Chronic Lymphocytic Leukemia Relapsed after or Refractory to Ibrutinib or Idelalisib Therapy

Preliminary Results of a Phase 2, Open-Label Study of Venetoclax (ABT-199/GDC-0199) Monotherapy in Patients with Chronic Lymphocytic Leukemia Relapsed after or Refractory to Ibrutinib or Idelalisib Therapy

Incidence and Outcomes of Neutropenia in Patients with Celiac Disease- a Consecutive Analysis of 1729 Patients

▪Background: Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease.Methods: The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes.Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients.Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98).Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. DisclosuresNo relevant conflicts of interest to declare.

Discovery of N-(4-(3-(2-Aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), A Highly Selective, Orally Bioavailable Inhibitor of Aurora Kinases with Activity against Multidrug-Resistant Cancer Cell Lines

Efforts to improve upon the physical properties and metabolic stability of Aurora kinase inhibitor 14a revealed that potency against multidrug-resistant cell lines was compromised by increased polarity. Despite its high in vitro metabolic intrinsic clearance, 23r (AMG 900) showed acceptable pharmacokinetic properties and robust pharmacodynamic activity. Projecting from in vitro data to in vivo target coverage was not practical due to disjunctions between enzyme and cell data, complex and apparently contradictory indicators of binding kinetics, and unmeasurable free fraction in plasma. In contrast, it was straightforward to relate pharmacokinetics to pharmacodynamics and efficacy by following the time above a threshold concentration. On the basis of its oral route of administration, a selectivity profile that favors Aurora-driven pharmacology and its activity against multidrug-resistant cell lines, 23r was identified as a potential best-in-class Aurora kinase inhibitor. In phase 1 dose expansion studies with G-CSF support, 23r has shown promising single agent activity.

Variation in the use of granulocyte-colony stimulating factor (G-CSF) for dose dense paclitaxel: A single institution retrospective study.

561 Background: In randomized trials, administration of dose dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) with G-CSF support improved outcomes compared with every 3 w...

A phase II trial to assess the activity of gemcitabine and docetaxel as first line chemotherapy treatment in patients with unresectable leiomyosarcoma.

BackgroundGemcitabine and docetaxel have been shown to be active in pre-treated relapsed leiomyosarcoma. This study investigated the combination as first line treatment in patients with unresectable locally advanced/metastatic leiomyosarcoma.MethodsPatients received gemcitabine 900 mg/m2 days 1 and 8, and docetaxel 100 mg/m2 day 8, administered 3-weekly for up to 8 cycles, with GCSF support on days 9–15. Patients who had received previous radiotherapy were treated at 75% dose. Patients were evaluated for response by RECIST 1.0 after cycles 2, 4, 6 and 8, and 3-monthly after completing treatment.ResultsForty-four patients were evaluable for response. Eligible patients had histologically proven leiomyosarcoma of the uterus (54.5%) or other sites (45.5%). Thirty-nine patients (84.4%) had metastatic disease, and 5 (15.6%) had locally advanced disease. Six patients (13.6%) had grade 1 disease, and 23 (75%) had grade 2/3 disease. All patients had demonstrated disease progression prior to trial entry. Responses were as follows: partial response 11 (25.0%), stable disease (confirmed) 16 (36.6%), stable disease (unconfirmed) 7 (15.9%), progressive disease 10 (22.7%). Median progression-free survival and overall survival were 7.1 months (95% CI 5.7–8.3) and 17.9 months (95% CI 10.6–25.2), respectively. Progression free rates at 3 and 6 months were 70.5% (95% CI 56.7–84.2%) and 59.1% (95% CI 44.3–73.9%).ConclusionsThis study demonstrates gemcitabine and docetaxel to be active in locally advanced/metastatic leiomyosarcoma in the first line setting. Further investigation comparing with current standard therapies for leiomyosarcoma is warranted.

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.

Graft Versus Host Disease Prophylaxis with a Bortezomib-Based Regimen without G-CSF Support for Patients Undergoing MUD Transplant: Evaluation of Engraftment Kinetics and Transplant Outcomes

Graft Versus Host Disease Prophylaxis with a Bortezomib-Based Regimen without G-CSF Support for Patients Undergoing MUD Transplant: Evaluation of Engraftment Kinetics and Transplant Outcomes

FOLFIRINOX for advanced pancreatic cancer: The Princess Margaret experience.

417 Background: The FOLFIRINOX regimen has been shown to significantly increase both overall (OS) and progression free (PFS) survival in metastatic pancreas cancer (MPC), albeit with an increase in adverse events (AEs). It is not known whether initial dose reductions compromise FOLFIRINOX efficacy and there are limited data regarding treatment of locally advanced pancreatic cancer (LAPC). Methods: We conducted a retrospective review of patients (pts) treated with FOLFIRINOX for MPC or LAPC at Princess Margaret Cancer Centre, and began treatment between Dec 2011 and April 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. Results: 102 pts were identified; 66 MPC and 36 LAPC. Median age was 65 years. 72% of pts had pancreatic head tumors. At baseline 95% of pts had an ECOG performance status of 0 or 1; 95% had bilirubin &lt; 1.5 ULN and 45% had a biliary stent. 68% of pts initiated treatment with a dose reduction (93% reduction or omission of bolus 5FU, 88% reduction in Irinotecan, 68% reduction in Oxaliplatin and 66% reduction in infusional 5FU). Median number of cycles was 6 (1-31); 25% of pts received &lt;4 cycles. Median OS in metastatic pts was 12.9 months (mo) and 23 mo in LAPC; Median PFS was 8.7 mo (metastatic) and 11.1 mo in LAPC. There was no significant difference in PFS (10.9 vs. 10.3 mo; p=0.60) or OS (11.1 vs. 14.0 mo; p=0.19) between the full starting dose and reduced starting dose groups respectively. Partial response or stable disease was achieved in 57% of pts; 11% of the LAPC pts had a surgical resection. Grade 3/4 hematologic AEs were observed in 43% of pts (febrile neutropenia in 6%). Only 13% of pts received G-CSF support. Grade 3/4 non-hematologic AEs were observed in 28% of pts, including vomiting (19%), nausea (16%) and diarrhea (16%). 18% of pts had a treatment related hospitalization (5% neutropenic sepsis, 13% GI toxicity/dehydration.) There was one treatment related death. Pt wellbeing (scored on a validated questionnaire) significantly improved from baseline to cycle 4 (p=0.002). Conclusions: Modest dose reductions do not appear to compromise efficacy of FOLFIRINOX. Our median PFS, OS and AEs are comparable to other studies using FOLFIRINOX in both LAPC and metastatic disease.

A Randomized Comparison of Low-Dose Cyclophosphamide + G-CSF Versus G-CSF Alone Mobilization after Lenalidomide-Bortezomib-Dexamethasone (RVD) Induction in Multiple Myeloma

Introduction Autologous stem cell transplantation (ASCT) is the standard treatment in multiple myeloma (MM) for eligible patients below 70 years of age. The main mobilization treatment in Europe consists of combination of cyclophosphamide (CY) and G-CSF. It is questionable if CY is useful in mobilization. CY as an alkylating agent might also have some negative long-term effects. Bortezomib seems not to have negative impact on autologous stem cell harvesting, but prolonged use of lenalidomide might hamper mobilization. There are only a few studies regarding autologous stem cell mobilization after RVD induction. We designed this randomized study as a substudy of the Finnish Myeloma Group Study (NCT01790737) to compare the results of CY+G-CSF versus G-CSF mobilization in autologous stem cell harvesting. The primary endpoint is the percentage of patients reaching ≥ 3 x 106/kg CD34+ cells (or ≥ 6 x 106/kg for two transplants), with ≤ 2 apheresis after low-dose CY+G-CSF vs. G-CSF mobilization. Secondary endpoints are need for plerixafor, graft cellular composition and engraftment after ASCT. Patients and methods This phase 2 study will include 80 patients below 70 years of age with symptomatic MM and eligible for ASCT. At registration the patients are randomized equally to arm A) CY 2 g/m2 + G-CSF 5 μg/kg or arm B) G-CSF 10 μg/kg. Before mobilization three RVD induction cycles are given. Each 3-week RVD cycle includes lenalidomide 25 mg daily on days 1−14, bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, and dexamethasone 160 mg/cycle. By this schedule the first harvest is estimated to be on day +10 in CY + G-CSF and on day +5 in G-CSF group. Apheresis will start with blood CD34+ level >10 x 106/l. The target cell yields for one and two grafts are ≥ 3 and ≥ 6 x 106 CD34+ cells/kg, respectively, and the minimum for one graft ≥ 2 x 106/kg. Plerixafor is given if B-CD34+ cell count is less than 10 x 106/l on days +10 or +5, respectively, or if the first apheresis product contains 0.5 x 109/l, and unsupported platelets > 20 x 109/l. Results Fifty-six patients have been included, and the mobilization data for the first 37 patients are available for analysis. The primary endpoint was reached in 90% of the patients (18/20) in arm A and in 82% (14/17) in arm B (p=NS). The median number of apheresis to reach the goal in arms A and B is one (1-3) and two (1−3), respectively (p=0.03). The median number of harvested cells in the two arms is 6.2 (2.2−12.1) and 4.8 (2.9−7.6) x 106/kg, respectively (p The median number of CD34+ cells transplanted, was 4.1 (2.2−7.3) and 3.2 (2.3−4.7) x 106/kg in arms A and B, respectively (p=0.01). In arm A the median neutrophil engraftment was on day +14 (9−28) (16 patients) and in arm B on day +15 (11−25) (15 patients) (p=0.68). The median platelet engraftment days were +13 (8−22) and +11 (8−21) in arms A and B, respectively (p=0.67). At ASCT the response rates in arm A were ≥ VGPR 65% (13/20), PR 25% (5/20), and 10% (2/20) were progressing, and the respective rates for arm B were 70% (12/17), 18% (3/17),and 12 % (2/17). Conclusions Preliminary results of this randomized mobilization substudy with a limited number of patients show no clinically significant differences between the number of harvested CD34+ autologous stem cells. However, in CY+G-CSF group the CD34+ cell target was reached by less aphereses. After short induction course of RVD it seems possible to harvest also for two autografts with G-CSF only mobilization. However, when compared to historical data the CD34+ cell counts in blood and grafts were lower than after bortezomib + dexamethasone induction, and also neutrophil engraftment seemed to be slower after lenalidomide-based induction therapy. We conclude that CY can be omitted in the mobilization regimen for MM patients who have responded to short course of RVD. Disclosures Silvennoinen:Janssen-Cilag: Research Funding; Celgene: Research Funding; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding.

Preliminary Clinical Experience on the Efficacy and Feasibility of a New Combination Regimen Consisting of Pixantrone, Etoposide, and Bendamustine with or without the Addition of Rituximab in Patients with Relapsed/Refractory Aggressive Non-Hodgkin Lymphomas

Background: With currently available therapies, relapsed/refractory aggressive non-Hodgkin lymphoma (NHL) after high-dose therapy or, in not transplant-eligible patients, after first-line chemotherapy represents an unequivocally unmet clinical need. Aim and Methods: Therefore, we aimed at evaluating a combination chemotherapy regimen based on pixantrone (Pix), a novel aza-anthracenadione recently approved by the European Medicines Agency in adult patients with multiply relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with Pix, as well as to their documented efficacy in salvage regimens in relapsed/refractory aggressive NHL and to a well-known feasibility profile when given alone or in combination. The monoclonal anti-CD20 antibody rituximab was added if tumor cells in the relapse biopsy specimen were CD20-positive. The adopted schedule consisted of Pixantrone 50 mg/m2 i.v. day 1+8, Etoposide 100 mg i.v. day 1, Bendamustine 90 mg i.v. day 1 with or without the addition of Rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT after cycle 1 or 2. G-CSF support was administered according to local guidelines. Results: A total of 8 evaluable patients with relapsed/refractory aggressive NHL were treated according to the PREBEN/PEBEN schedule. Abstract 5435. Table 1summarizes the clinico-pathological features of the patient cohort along with selected feasibility and efficacy parameters related to the PREBEN/PEBEN regimen (PET/CT status after 1 or 2 courses):Patient characteristicsPREBEN/PEBEN-related parametersPt #DxAgeSexCS at relapseN of prior Rx linesPrior TxN coursesTox grade 3-4Best responseDoR1DLBCL (ABC)70MIV3N6thrombocytopeniaCR*6 mo2DLBCL (ABC)49MIV3Y2-PD-3DLBCL (ABC)53MIV2N2neutropenic fevergoodPR4+ mo4DLBCL (ABC)64MIV2N2neutropenic fevergoodPR3+ mo5DLBCL (GCB)69FIV3N2-CR2+ mo6tFL62MIII3Y2neutropenic feverSD-7tCLL51FIV5Y2neutropenic feverPD-8PTCL-NOS57FIV2N6diarrhoeaCR4+ moBaseline (pt#1) after 1 x PREBEN (pt#1) [Display omitted] [Display omitted] Conclusion: The PREBEN/PEBEN schedule is feasible (out-patient regimen) and in individual patients it elicits profound responses early in the course of therapy. A phase 1-2 study in relapsed/refractory DLBCL and PTCL is in preparation. Disclosuresd’Amore:Amgen: Research Funding; Sanofi Aventis: Research Funding; CTI Life Sciences: Advisory board, Advisory board Other, Speakers Bureau; Mundipharma: Advisory board, Advisory board Other, Speakers Bureau; Takeda: Advisory board, Advisory board Other, Speakers Bureau; Kyowa Kirin Pharmaceuticals: Advisory board Other, Speakers Bureau; Roche: Research Funding.

Phase I Study of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Abstract Background: Despite recent approval of 4 new drugs for relapsed PTCL, an unmet need remains for new therapies. Survival of relapsed/refractory PTCL patients is improved by stem cell transplant particularly if patients are in CR prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) is commonly used salvage regimen which produces CR rates ranging from 7% to 23% in patients with PTCL (Zelenetz 2003, Mikesch 2013). Romidepsin is a HDAC inhibitor which showed overall response rate of 25% with CR rate of 15% in a large phase II trial for relapsed/refractory PTCL (Coiffier 2012). To further improve outcomes particularly in CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with standard ICE in patients with relapsed/refractory PTCL. Methods: The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose of the romidepsin in combination with standard ICE. A statistical design of modified toxicity probability interval method was used (Ji 2010). Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2), or 12mg/m2 (level 3). All patients received G-CSF support. Patients could receive next cycle of treatment on day 14 if ANC was &gt; 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment. Results: As the time of the data cut off (August 2014), a total of 9 patients were registered (4 PTCL-NOS, 4 AITL, 1 NK/TCL) and 7 were assessable for toxicity and response (Cheson 2007). Two patients were consented but did not received treatment. Median age of patients was 60 (range 59-70) years, 5 patients had primary refractory disease and 5 patients had advanced stage disease at the time of enrollment. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT. At the time of data cut off a total of 7 patients were treated with 2, 4 and 1 patients respectively at dose level 1, 2 and 3, respectively. Median number of treatment cycles were 2 (range 1-4). The common non-hematologic toxicity of grade 3/4 was fatigue (71%), nausea (43%), shortness of breath (29%), and vomiting (14%). With a total of 15 cycles overall given, grade 3/4 thrombocytopenia and neutropenia occurred in 87% and 40% of the cycles and febrile neutropenia occurred once in 1 patient. Dose limiting toxicities occurred in a 70 year-old female treated at dose level 2 with renal failure which was considered to be associated with ifosfamide and etoposide and in 67 year-old male with bone marrow involvement who previously had a front-line consolidative ASCT 6 months earlier and was treated at dose level 3 with persistent grade 3/4 thrombocytopenia. The overall response rate was 71% (5/7, 95%CI: 22-96%) with all in CR. Two patients who received dose level 1 underwent allogeneic transplant and one patient in dose level 2 underwent autologous stem cell transplant but all patients relapsed after transplant. Median duration of response was 7.2 months and six of the 7 patients experienced further disease progression. Summary: In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of thrombocytopenia and neutropenia as anticipated than with romidepsin or ICE alone. Even though romidepsin plus ICE produces a high CR rate, early relapse despite this even when followed by transplant indicates the crucial need to develop methods to detect minimal residual disease and approaches to best address this. Enrollment continues to this trial. Disclosures Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding.

24 Androgen receptor (AR) expression in triple negative breast cancer (TNBC): results from a phase II neoadjuvant trial with carboplatin and eribulin mesylate in TNBC patients

for 57+ weeks. At the RD (n = 14): mean (SD) clearance (CL) 18.1 (7.2) L/h; AUC 318 (123) h·mg/L; Cmax 90.5 (30.7) mg/L; t1/2 30.5 (13.6) h. No apparent association between CL and DLT or magnitude of neutropenia was found. Conclusions: The RD of PM01183 is 5mg FD on D1&8 q3wk. At this RD, myelosuppression led to frequent dosing delays or omissions, but G-CSF support enabled the targeted dose intensity in some individuals. Two patients had prolonged disease stabilization lasting over a year. No signs of cumulative toxicity were observed. Interindividual variability in CL was high, but did not appear to be associated with toxicity.