Prior Cytotoxic Treatment Research Articles

LGG-10. TREATMENT-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING CHEMOTHERAPY FOR PEDIATRIC LOW-GRADE GLIOMA

Abstract Treatment-related myeloid neoplasms are rare though well-defined secondary malignancies associated with prior cytotoxic treatment, (particularly alkylating agents and topoisomerase inhibitors). They are rarely associated with primary central nervous system tumours and have historically carried a very poor prognosis. Pediatric low-grade gliomas (pLGG) are the most common CNS tumours of childhood, and up to 50% of patients will require adjuvant therapy. This has traditionally consisted of low-dose metronomic chemotherapy, although the advent of genomic profiling and identification of molecular drivers of pLGG means novel targeted therapies are changing this paradigm. There has only been a single reported case of treatment-related myeloid leukaemia secondary to pLGG treatment. We present a novel case of a 17-year-old girl with treatment-related myelodysplastic syndrome following chemotherapeutic treatment for pLGG. The patient was initially diagnosed at age 4 with a metastatic pilomyxoid astrocytoma (primary suprasellar lesion with spinal metastases) and received first-line treatment with a vincristine and carboplatin regimen. She had disease progression at age 7 and received second-line treatment with thioguanine, procarbazine, lomustine and vincristine. Following further progression at age 16, a biopsy of the suprasellar mass showed a pilocytic astrocytoma with a KIAA1549-BRAF fusion. Prior to commencing a targeted treatment as third-line therapy, she was noted to have a macrocytic anaemia, which subsequently evolved to a bicytopenia. Bone marrow analysis showed a hypocellular marrow with an abnormal myeloid clone with a chromosomal 1q gain, consistent with a diagnosis of treatment-related myelodysplastic syndrome. Germline analysis was negative for bone marrow failure predisposition gene abnormalities. She is currently undergoing workup for bone marrow transplant. Given the poor prognosis of treatment-related myeloid neoplasms, this case represents an important note of caution when choosing appropriate therapy for pLGG, especially given the evolving role for targeted treatments in this disease with otherwise very favourable long-term survival.

Abstract P1-14-05: Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients with Chest Wall Breast Cancer (PERICLES): an immune-biomarker analysis of tumor infiltrating lymphocytes (TILs) and programmed cell death ligand protein 1 (PD-L1)

Abstract Background: Breast cancer (BC) with lymphangitic spread to the chest wall is a rare clinical entity affecting about 2% of pts, with poorer survival outcomes. A brisk immune infiltrate is typically reported, with up-regulation of inflammation and immune-tolerogenic genes. PERICLES clinical trial is testing the administration of pembrolizumab 200 mg Q3w plus cyclophosphamide 50 mg daily for BC with chest wall disease. In this exploratory biomarker analysis, we assessed the prevalence of the TILs score and the PD-L1 combined positive score (CPS) obtained from skin biopsies performed at screening. Methods: PERICLES (NCT03971045) is a single-center, single-arm, interventional phase 2 trial. Main inclusion criteria: histologically confirmed, inoperable, locally recurrent and/or metastatic BC with lymphangitic spread to the chest wall (including and not limited to inflammatory BC); PD-L1 positive (CPS≥1; 22C3 pharmDx®) and/or TILs positive (≥1% of CD3 or CD20-positive cells) disease on skin biopsy obtained at screening; progression to at least one prior cytotoxic treatment; no prior immune checkpoint inhibitors. The primary endpoint is objective response rate as per immune-related RECIST criteria. 46 pts will be required for the study to power for the primary hypothesis. In this analysis, we describe the baseline immune-biomarker status, in the overall population enrolled based on hormone receptor status and HER2. Correlative analyses were provided (significance at p-value< 0.05). Results: 37 pts were screened with skin biopsy of the chest wall disease (June 2020-June 2022). Biopsy and biomarker analysis were successful in 35 pts. Median age was 58 years (range: 35-79). Among the 35 pts included in the biomarker analysis, 25 (71%) pts had visceral disease and 20 (57%) had skin metastases at the diagnosis of metastatic disease; median number of previous lines of therapies was 4 (range: 1-12) and of chemotherapies was 4 (range: 1-10). 2 (6%) pts had HER2-positive disease, 13 (37%) HR-positive/HER2-negative disease, and 20 (20%) had triple-negative breast cancer (TNBC). TILs and PD-L1 CPS were < 1 in 15 (43%) pts; 20 pts (57%) were eligible for CPS and/or TILs criteria: 16 (43%) were both PD-L1 positive and TILs positive, 4 only PD-L1 positive. Median PD-L1 CPS score was 5 (range: 0-80%) in the overall population and 17 (range: 2-80%) in eligible patients; 16/35 pts (43%) had CPS≥10. Median TILs score was 0% (range: 0-55%) in the overall population, 0% (range: 0-40%) in the HER2-negative (n=16), 0% (range 0-20%) in the HER2-low (n=18), and 37.5% (range 20-55%) in the HER2-positive (n=2). No significant differences in baseline characteristics were found between positive and negative biopsies (Table). Considering only the TILs, a statistically significant correlation between HER2-positive status and TILs score was demonstrated (p< 0.001); no other correlations between receptor status (estrogen receptor, progesterone receptor, HER2) and PD-L1 CPS or TILs emerged. Conclusions: 57% of patients with chest wall BC have skin metastases positive for PD-L1 CPS and/or TILs score ≥1%. To our knowledge, these are the first prospective data on the prevalence of PD-L1 and TILs in metastatic BC with lymphangitic spread to the chest wall, highlighting potential actionability through therapeutic strategies with new immune-oncology agents in this setting. Table: Characteristics of patients included in the biomarker analysis (n=35) *Calculated with T test or Fisher’s exact test, as appropriate. Keys: BC, breast cancer; CPS, combined positive score; CT, chemotherapy; HR; hormone receptor; n, number; NA; not available; PD-L1, Programmed cell death ligand protein 1; TILs, tumor infiltrating lymphocytes; TNBC, triple negative breast cancer. Citation Format: Carmine Valenza, Pier Paolo Maria Berton Giachetti, Paola Zagami, Eleonora Nicolò, Dario Trapani, Laura Boldrini, Beatrice Taurelli Salimbeni, Liliana Ascione, Gabriele Antonarelli, Chiara Corti, Angela Esposito, Carmen Criscitiello, Nicola Fusco, Giuseppe Curigliano. Pembrolizumab and Oral Metronomic Cyclophosphamide in Patients with Chest Wall Breast Cancer (PERICLES): an immune-biomarker analysis of tumor infiltrating lymphocytes (TILs) and programmed cell death ligand protein 1 (PD-L1) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-14-05.

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study

BackgroundBrivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. MethodsEligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response. ResultsOf 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1–20). Seven (25%) patients had PFS >6months (90% CI: 7.3%–33.9%). Two (7%) (90% CI: 1.3%–20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1–4.4). The median overall survival was 7.9months (90% CI: 6.1–11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. ConclusionsBased on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.

Abstract P3-05-04: Impact of androgen receptor expression in fluoxymesterone-treated, estrogen receptor–positive metastatic breast cancer exposed to contemporary hormonal therapy

Abstract Background: The use of the nonselective androgen fluoxymesterone in patients with metastatic breast cancer (MBC) diminished after the 1960s because of its adverse events and a limited understanding of its biological effects. Although fluoxymesterone has had efficacy against tamoxifen-resistant disease in clinical studies, its role in the era of contemporary hormonal therapy is unclear. Recent studies have shown that the androgen–androgen receptor (AR) complex acts as a suppressor of estrogen receptor (ER)+ breast cancer. We hypothesized that fluoxymesterone is effective against MBC that progresses despite contemporary hormonal therapy and that the drug has more clinical benefit in patients with ER+AR+ disease than in patients with ER+AR- disease. We evaluated the survival outcomes of patients with MBC who received fluoxymesterone after contemporary hormonal therapy failed and evaluated the association between ER/AR status and survival outcomes in these patients. Methods and Materials: We included 103 patients treated with fluoxymesterone who had already received at least one prior hormonal or cytotoxic treatment for MBC between January 1, 2000, and December 31, 2014, at a single institution. A pathologist reviewed these patients' tumors' ER and AR expression levels by immunohistochemical staining. Progression-free survival (PFS) was defined from the start of fluoxymesterone treatment to the date of disease progression or last follow-up. We used Cox regression analysis to examine univariate and multivariate correlates of PFS. Results: Patients received a median of 3 (range: 0-10) prior hormonal therapies (aromatase inhibitors, tamoxifen, and/or fulvestrant) before fluoxymesterone. Of the 103 patients, 33 (32%) discontinued fluoxymesterone because of physician decision or adverse events, which included toxicity in 14 patients, and 70 (68%) were eligible for tumor response assessment by Response Evaluation Criteria in Solid Tumors. Of these 70 patients, 2 (3%) had a complete response, 7 (10%) had a partial response, and 21 (30%) had stable disease for at least 6 months, yielding a clinical benefit rate of 43%. The median PFS was 3.9 months (95% confidence interval: 3.2–5.3 months). The multivariate analysis revealed no significant association between PFS and the type or number of prior treatments. Thirty-nine patients (38%) had archived tumor slides available for AR staining. All 39 patients had ER+ disease; 5 had ≤1%, 5 had >1% but <10%, 18 had ≥10%, and 11 had no AR nuclear expression. AR positivity defined by the presence of any AR+ cells, ≥1% AR+ cells, or ≥10% AR+ cells was not significantly associated with survival outcome. Conclusions: Fluoxymesterone showed objective tumor response and prolonged control of ER+ MBC refractory to contemporary endocrine therapy. The number and type of prior treatments did not impact the drug's clinical benefit, and AR+ status did not influence the clinical outcome. Fluoxymesterone should be considered for patients whose ER+ MBC progresses despite contemporary hormonal therapy, regardless of their AR status. Citation Format: Kono M, Fujii T, Lyons GR, Huo L, Bassett R, Gong Y, Karuturi MS, Tripathy D, Ueno NT. Impact of androgen receptor expression in fluoxymesterone-treated, estrogen receptor–positive metastatic breast cancer exposed to contemporary hormonal therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-04.

Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated with CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial

Introduction Intensive induction chemotherapy for acute myeloid leukemia (AML) in patients aged 60 years or older has lower remission rates with increased induction mortality compared with younger patients. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio. Previously reported results from a phase III, randomized, open-label study of CPX-351 versus 7+3 (cytarabine and daunorubicin) in newly diagnosed older patients with secondary AML suggested superior survival in those randomized to CPX-351. We conducted an exploratory analysis of patients who received allogeneic hematopoietic cell transplantation (HCT) after induction treatment, to determine the effect of HCT on outcome by arm, as few patients in this age range can be cured with chemotherapy alone. Methods This phase III trial was a randomized, open-label, parallel-arm, standard therapy-controlled study. Eligible patients were aged 60 to 75 years with newly diagnosed secondary AML defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) (± prior treatment with hypomethylating agents), or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). The distribution of overall survival (OS) after HCT in each treatment arm was estimated using the Kaplan-Meier method, and Cox regression hazard ratio and OS rates, along with corresponding confidence intervals, are reported. Results Three hundred and nine (309) patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Patients in either arm responding to induction with a complete response (CR) or a CR with incomplete platelet or neutrophil recovery (n=125) were considered for allogeneic HCT when possible. In total, 91 patients were transplanted: 52 (34%) from the CPX-351 arm and 39 (25%) from the 7+3 arm. Patient and AML characteristics were similar according to randomized arm, including percentage of patients in each arm that underwent transplant in CR/CRi status (Table); however, the CPX-351 arm contained a higher percentage of older patients (age ≥ 70) who were transplanted (CPX-351, 31%; 7+3, 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% in the 7+3 arm patients. Causes of death Conclusions An exploratory analysis from this phase III study demonstrated that CPX-351, compared with standard cytarabine and daunorubicin, resulted in better outcomes after allogeneic HCT in older patients with high-risk AML, including 53% fewer deaths within 100 days of transplant. These results suggest that CPX-351 may provide an effective bridge to successful transplant for a very poor-risk subgroup of AML patients. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Uy:Boehringer Ingelheim: Consultancy; Glycomimetics: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Astellas Pharma: Research Funding; Ariad: Speakers Bureau; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; NS Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding. Stuart:Celator: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Medeiros:MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; ARIAD: Consultancy; Celator: Other: Travel, Accomodations, Expenses, Research Funding; Roche/Genentech: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy.

Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML.

7000Background: Older patients with secondary AML have poor outcomes following first-line cytarabine and anthracycline-based treatment. CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio with enhanced efficacy among poor risk AML patients. We report final results from a randomized open-label study of first-line CPX-351 in patients with high-risk sAML (NCT01696084). Methods: Patients 60-75 years of age with untreated AML with a history of prior cytotoxic treatment, antecedent MDS or CMML (+/- prior hypomethylator treatment), or AML with WHO-defined MDS-related cytogenetic abnormalities were eligible. 300 patients were to be randomized 1:1 to CPX-351 (100 units/m2, days 1, 3, 5) or 7+3 (cytarabine 100 mg/m2/day x 7 days, daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy. Endpoints included: overall (OS, 1o) and event free survival (EFS) assessed by stratified log rank analysis, independent blinded assessment of CR+CRi, and 60-day mortality. Patient enroll...

CPX-351 Is Effective in Newly Diagnosed Older Patients with AML and with Multiple Risk Factors

AbstractAbstract 3626 Background:CPX-351 is a liposomal formulation of cytarabine (Ara-C) and daunorubicin (DNR) in a 5:1 molar ratio designed to maximize anti-tumor synergy. CPX-351 accumulates within bone marrow with preferential uptake of liposomes by leukemia cells followed by intracellular release of encapsulated drug. A Phase 2b study randomized untreated older patients with AML 2:1 to CPX-351 or standard 7+3. At entry patients were stratified by age, cytogenetics, and presence or absence of antecedent hematologic disorder (AHD)/prior cytotoxic treatment that evolved into AML (sAML) into a high-risk group (age ≥70 or adverse cytogenetics or sAML) or standard-risk group (age 60–69 and non-adverse cytogenetics and de novo AML). The standard-risk group was relatively homogeneous, while the high-risk group gathered together patients with one, two or all three risk factors. Response after CPX-351 was increased in all patients (66.7% vs. 51.2%). Patients with secondary AML had coherent improvement in survival (HR=0.40, p=0.01), EFS (HR=0.51, p=0.04), and CR + CRi rate (57.6% vs. 31.6%). This report presents the results of uni/multivariate analyses for survival and event free survival. Methods:Untreated de novo or sAML patients, aged 60–75, PS= 0–2, serum creatinine < 2.0 mg/dL, total bilirubin < 2.0 mg/dL, ALT/AST < 3 × ULN, and LVEF ≥50% were eligible. Patients with history of treatment for their AHD were eligible. Patients received up to 2 induction and 2 consolidation courses of CPX-351 (100 u/m2; D 1, 3, 5) or 7+3 (Ara-C= 100 mg/m2/d and DNR= 60 mg/m2). Consolidation with hematopoietic stem cell transplantation (HSCT) was permitted. The primary endpoint was CR + CRi rate. Event free survival was calculated from randomization to the date of documentation of persistent leukemia after induction, relapse after achievement of response, or death, whichever occurred first. Allogeneic transplants were permitted for post remission treatment. The association between baseline characteristics and survival was assessed by univariate and multivariate Cox regression analyses. Response was included as a time-dependent variable. The multivariate model used stepwise selection to identify prognostic factors after accounting for potential treatment effects. Results:Significant factors affecting overall survival (OS) in the univariate analysis included: response (p=0.01), ≥2 risk factors (p=0.013), secondary AML (p=0.021), and adverse cytogenetics (p=0.038). After accounting for treatment, response (p=0.003) and ≥2 risk factors (p=0.005) were strongly associated with OS in the multivariate model.Table:Comparison of Response, 60-day Mortality, Median EFS, and Median OS Among Patients with 2 or more of Risk Factors2 or 3 Risk FactorsCPX-3517+3n2615No. w/Risk Factor (%)223 (88.5)12 (80.0)33 (11.5)3 (20.0)CR Rate (%)11 (42.3)4 (26.7)CRi Rate (%)7 (26.9)0CR + CRi Rate (%)18 (69.2)4 (26.7)60-day Mortality Rate (%)1 (3.8)6 (40.0)Median EFS (mos.)9.11.1Median OS (mos.)10.76.1Response and 60-day deaths were similar in both study arms for patients with 0 or 1 risk factor. Patients with 2 or 3 risk factors treated with CPX-351 had rates of response and 60-day death rates that were similar to those with only 0 or 1 risk factor. Control arm patients with multiple risk factors did much worse, with fewer CRs, no CRi's, and a substantially higher rate of early deaths. Conclusions:CPX-351 is highly active in every subgroup of older patients with newly diagnosed AML. This analysis demonstrates that CPX-351 minimizes the loss of response and increase in 60-day mortality that occurs with 7+3 treatment among patients with secondary AML and adverse cytogenetics. The relative benefit of CPX-351 is greatest among patients with ≥ 2 risk factors. Disclosures:Lancet:Celator Pharmaceuticals: Research Funding. Cortes:Celator Pharmaceuticals: Research Funding. Kovacsovics:Celator Pharmaceuticals: Research Funding. Hogge:Celator Pharmaceuticals: Research Funding. Kolitz:Celator Pharmaceuticals: Research Funding. Hoering:Celator Pharmaceuticals: Consultancy. Chiarella:Celator Pharmaceuticals: Employment. Louie:Celator Pharmaceuticals: Employment. Feldman:Celator Pharmaceuticals: Research Funding.

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

RIBBON-2: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial Evaluating the Efficacy and Safety of Bevacizumab In Combination with Chemotherapy for Second-Line Treatment of HER2-Negative Metastatic Breast Cancer.

Abstract Background: Three prior Phase III trials (E2100, AVADO, and RIBBON-1) established the clinical benefit of adding bevacizumab (BV) to various chemotherapies (chemos) as first-line treatment for metastatic breast cancer (MBC). A previous Phase III study (AVF2119g) in patients with predominantly heavily pre-treated MBC, in which BV was added to capecitabine (Cape), resulted in a significant increase in objective response rate (ORR), but did not meet the primary endpoint for progression-free survival (PFS). The current study, RIBBON-2, was designed to evaluate the efficacy and safety of the addition of BV to chemotherapies used as second-line treatment for MBC.Methods: Patients were randomized in a 2:1 ratio to chemo+BV or chemo+placebo (PL). Key eligibility criteria included one prior cytotoxic treatment for MBC, ECOG performance status of 0 to 1, and HER2-negative or unknown status. Prior to randomization, investigators chose one of the following chemo agents: taxane (T; paclitaxel 90 mg/m2/wk for 3 of the 4 weeks; paclitaxel 175 mg/m2, nab-paclitaxel 260 mg/m2, docetaxel 75–100 mg/m2, all given q3wk), gemcitabine (G; 1250 mg/m2 on Days 1 and 8 q3wk), Cape (2000 mg/m2 Days 1–14 q3wk), or vinorelbine (V; 30 mg/m2/wk). BV or PL was administered at 10 mg/kg q2wk or 15 mg/kg q3wk, depending on the chemo regimen. The primary endpoint of the study was investigator-assessed PFS pooled across the chemo cohorts. Key secondary endpoints included overall survival (OS), PFS within individual chemo cohorts, ORR, and safety.Results: 684 patients (T, 304; G, 160; Cape, 144; and V, 76) at 211 sites in 19 countries were randomized between February 2006 and June 2008. Overall, the two study arms were balanced for patient characteristics at baseline. The study met its primary endpoint of PFS pooled across chemo cohorts and also demonstrated a 10% increase in ORR when BV was added to chemo. At the interim analysis for OS, the median durations were 18 mo for chemo+BV and 16.4 mo for chemo+PL (see table).Across all chemo cohorts the incidence of BV-related AEs was consistent with data from previous studies. Hypertension was the only BV-related AE consistently increased in the chemo+BV arm across all chemo cohorts.Conclusions: The addition of BV to chemotherapies used for second-line treatment of MBC led to a significant improvement in PFS. The AE profile of BV in the overall study population and across the chemotherapy cohorts was consistent with that previously observed. Additional analyses, including PFS for the individual chemo cohorts, will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 42.

RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC)

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

Chromosome 5q deletion: Specific diagnoses and cytogenetic details among 358 consecutive cases from a single institution

The purpose of this study was to define the spectrum of hematologic neoplasms and chromosomal breakpoints associated with del(5q); separate analyses were performed to account for prior cytotoxic treatment. A total of 358 consecutive del(5q) cases were identified; specific diagnoses included myelodysplastic syndrome (MDS; 53%), acute myeloid leukemia (AML; 22%), plasma cell proliferative disorder (PCPD; 9%), myeloproliferative disorder (MPD; 7%), acute lymphoblastic leukemia (ALL; 2%), PCPD with MDS (2%), MDS/MPD (2%), and malignant lymphoma (ML; 2%). The corresponding figures in the absence/presence of prior cytotoxic treatment ( n = 250/108) were 61%/34% for MDS, 24%/19% for AML, 4%/20% for PCPD, 6%/8% for MPD, 1%/4% for ALL, and 2%/4% for ML. del(5q) occurred as the sole cytogenetic abnormality in 88 cases (25%) including 76 without prior cytotoxic therapy. Among the latter, 82% had MDS, 8% AML, 5% MPD, 4% PCPD, and 1% ML. Chromosome 5 breakpoints included q13q33 in 49% of the cases, q15q33 in 22%, q22q33 in 8%, and q13 in 3% and their distribution was not affected by specific diagnosis or treatment history. del(5q)-associated lymphoid disorders featured a higher prevalence of previous cytotoxic therapy and smaller number del(5q)-positive metaphases, when compared to their counterparts with myeloid neoplasms. We conclude that del(5q), although most prevalent in MDS, is seen across the spectrum of myeloid disorders including MPD and its occurrence in lymphoid disorders might signify, for the most part, an occult myeloid clone.

Tumor response rate as a function of number of prior therapies in phase II and III trials of topotecan (T) and eniluracil/5FU (EU)

2501 Background: Patients with 2 or more prior cytotoxic treatment regimens are often excluded from clinical trials because of expectations for greater tumor resistance to treatment. This retrospective cross-study analysis evaluated the relationship between tumor response rate (RR) and the number of prior therapies received. Methods: Phase II and III studies in the GSK database of topotecan (T, n=18) in patients with ovarian or small cell lung carcinoma (SCLC) and of eniluracil/5FU (EU, n=5) in patients with colorectal (CRC) or breast cancer were analyzed. This provided a total 4,220 patients consisting of 1,898 receiving T, 465 receiving various T comparator chemotherapy (paclitaxel, cyclophosphamide, doxorubicin or vincristine), 1,036 receiving EU, and 821 receiving EU comparator (5FU + leucovorin). Number of prior treatments was defined as the sum of all cytotoxic treatment regimens received. Best response was defined according to standard tumor response criteria with missing data or inevaluable assessments considered as progressive disease. Experimental (T or EU) vs. respective comparator arms were combined and an overall RR (CR + PR) in the analysis populations was assessed as a function of the number of prior treatments. Results: The overall RR for ovarian and SCLC patients receiving first-line treatment was 47%. RR declined to 17% for second-line therapy but was unchanged at 18% for those receiving third-line treatment. For all (CRC + breast cancer) patients in EU studies, there were no significant differences between first-, second-, or third-line treatment (RR=12%, 10% and 10% respectively). However, within the limited subset of breast cancer patients (n=145) in EU studies, RR was 54%, 14%, and 11% for first-, second-, and third-line treatments, respectively, suggesting no difference in RR once second-line treatment was administered. Conclusions: The presumption that a higher number of prior regimens always equates with greater treatment resistance may be incorrect. Patients in this analysis with 1 vs. 2 prior therapies exhibit equivalent RR to a broad range of cytotoxic therapies. Exclusion from clinical trials of patients with &gt;1 prior treatment regimen who otherwise meet study eligibility criteria may not be warranted. No significant financial relationships to disclose.

CLORETAZINE™ (VNP40101M) Is Active in Elderly Untreated Poor Risk Patients with Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS).

Background: The majority of patients (pts) with AML and high risk MDS are ≥ 60 years of age at diagnosis (median age 70), and have a poor prognosis due to age-related risk factors and disease biology. Commonly accepted risk factors in this population include age ≥ 60 yrs, ECOG PS ≥2, secondary AML, unfavorable cytogenetics, and organ dysfunction. The response rate with induction treatment for these pts is lower than that of their younger counterparts, and additional risk factors worsen prognosis. Hepatic, pulmonary, and/or cardiac compromise is likely to determine both selection and tolerance of the induction regimen, and these pts are often not considered for aggressive chemotherapy such as “3+7”. In the US, up to 70% of elderly AML/MDS pts do not receive induction treatment (Menzin, et al; Arch Int Med ; 2002; 162:1597). CLORETAZINE, a novel sulfonylhydrazine alkylating agent, has significant activity in AML/MDS with a favorable safety profile. In an ongoing Phase II trial, pts with AML or high risk MDS, age ≥60 years, and no prior cytotoxic treatment, receive CLORETAZINE 600mg/m2 for remission induction, re-induction, and consolidation.Methods: This elderly pt population was analyzed for the presence of risk factors and underlying organ dysfunction. Pts were assessed according to the commonly accepted risk factors described above and categorized by number of factors present. Organ dysfunction was defined as hepatic abnormalities (elevated liver function tests), moderate/severe pulmonary compromise (grade 2–4 dyspnea by NCI-CTC Version 3.0 or dependence on oxygen), and/or a history of significant cardiac disease. Data was obtained from case report forms of baseline demographics, medical history, physical exam, and concomitant medications.Results: 105 pts with age ≥60 were enrolled as of April 21, 2005. Specific risk factors were as follows: 31 pts (30%) were PS 2; 36 pts (34%) had unfavorable cytogenetics; 43 pts (41%) had secondary AML. Forty-eight pts (46%) had cardiac dysfunction; 26 pts (25%) had hepatic disease; and 19 pts (18%) had pulmonary dysfunction. The response rate (CR+CRp) for the group as a whole was 31% (N=33). Non-hematologic toxicity was minimal, and the early death rate of 18% is within the range expected for cytotoxic induction regimens in the elderly AML population. The table below describes the risk categories for all patients, early deaths, and responders:# Risk FactorsN [%]# CR/CRp (%)# Early Deaths (%)Age + 012 (11)7 (58)2Age + 124 (23)9 (38)4Age + 239 (37)8 (21)7Age ≥3+30 (29)9 (30)6Total10533 (31)19 (18)Conclusions: According to risk assessment on the basis of age-related risk factors, the majority of the study pt population had multiple risk factors and represents a group for whom standard AML induction therapy may not be an option. In this elderly patient population with limited therapeutic options, CLORETAZINE is tolerable and results in a response rate of 31%.

A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.

Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR > 50%) and 5 responses (R > 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.

Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study

Objectives. To estimate the objective response rate and toxicity associated with alternating megestrol acetate (MA) and tamoxifen citrate (T) in women with endometrial carcinoma. Methods. Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment. MA 80 mg BID × 3 weeks alternating with T 20 mg BID × 3 weeks orally was given. Results. Of 61 patients entered, 56 eligible patients were evaluable for toxicity and response. Fifteen patients responded (12 complete, 3 partial) for an overall response rate of 27% (90% Confidence Interval: 17–38%). In 8 of 15 (53%) responders, response duration exceeded 20 months. The response rate was 38% in patients with histologic grade 1 tumors ( n = 16), 24% in those with grade 2 disease ( n = 17), and 22% among patients with grade 3 disease ( n = 23). Women less than or equal to 60 years ( n = 16) appear to have a better response rate than those >60 years ( n = 40), 44% versus 20%. The response rate in patients with extra pelvic disease ( n = 42) was 31% as compared to 14% in those with strictly pelvic and/or vaginal disease ( n = 14). The median progression-free survival (PFS) was 2.7 months and median overall survival was 14.0 months. Two patients experienced a grade 4 thromboembolic event. Additional toxicities included one of each grade 3 gastrointestinal, grade 3 neurologic, and grade 3 genitourinary. Conclusion. A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response (CR) in some patients.

Rituximab for Treatment of Advanced Extranodal Marginal Zone B Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue Lymphoma

Background: Extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) is a relatively common type of lymphoma. Owing to its B cell lineage, it appears to be a potential target for treatment with the CD20 antibody rituximab. We present an analysis of our experience with rituximab for treatment of patients with advanced MALT lymphoma. Patients and Methods: A retrospective analysis of patients with histologically verified MALT lymphoma undergoing treatment with rituximab was done. After reassessment of histological samples for the presence of MALT lymphoma, patients were evaluated as regards date of diagnosis, prior therapy for MALT lymphoma, sites of involvement upon treatment with rituximab, clinical response in terms of complete remission (CR), partial response (PR), stable disease (SD) and progressive disease as well as symptomatic response, duration of response and survival. Results: A total of 9 patients with advanced MALT lymphoma undergoing therapy with single-agent rituximab were identified. All patients received treatment at a dose of 375 mg/m² once weekly ×4. One patient each had relapsed after chemotherapy and radiation, respectively, while none of the other 7 patients had received prior cytotoxic treatment or radiation. Three patients achieved a CR, 2 patients had PR for 6 and 14 months, while the remaining patients had SD between 8 and 18+ months. One patient died of progressive disease in spite of the initiation of chemotherapy and 1 patient succumbed to a cardiovascular event while having been in ongoing PR for 11 months. The other 7 patients are currently alive with disease 10–27 months after initiation of therapy. Follow-up biopsies for histological assessment were available in 5 patients with gastric lymphoma. In 1 patient with SD, however, persistence of CD20-positive cells within lymphoepithelial lesions was noted in spite of almost complete depletion of B lymphocytes from the normal gastric mucosa, suggesting either recirculation of MALT lymphoma cells to these lesions or defining lymphoepithelial lesions as a sanctuary site from rituximab penetration. Conclusion: Rituximab had only moderate activity in terms of inducing objective responses in our unselected and heterogeneous cohort of patients with disseminated MALT lymphoma. Long-term disease stabilization, however, along with a symptomatic benefit was seen in all patients. Our data nevertheless indicate that rituximab might not optimally penetrate into the gastric mucosa in all patients.

A Novel Snake Venom Disintegrin That Inhibits Human Ovarian Cancer Dissemination and Angiogenesis in an Orthotopic Nude Mouse Model

OVCAR-5 is a human epithelial carcinoma cell line of the ovary, established from the ascitic fluid of a patient with progressive ovarian adenocarcinoma without prior cytotoxic treatment. The unique growth pattern of ovarian carcinoma makes it an ideal model for examining the anticancer activity of contortrostatin (CN), a homodimeric disintegrin from southern copperhead venom. FACS analysis revealed that OVCAR-5 is integrin αvβ3 negative, but αvβ5 positive. CN effectively blocks the adhesion of OVCAR-5 cells to several extracellular matrix proteins and inhibits tumor cell invasion through an artificial basement membrane. In a xenograft nude mouse model with intraperitoneal introduction of OVCAR-5 cells, intraperitoneal injection of CN was used for therapy. Tumor dissemination in CN-treated versus control groups was studied by gross examination, and antiangiogenic potential was examined by factor VIII immunohistochemistry and image analysis. CN not only significantly inhibited ovarian cancer dissemination in the nude mouse model, but it also dramatically prevented the recruitment of blood vessels to tumors at secondary sites.

Dose-finding and pharmacological study of ifosfamide in combination with paclitaxel and carboplatin in resistant small-cell lung cancer

To find the maximum tolerated dose for ifosfamide in combination with paclitaxel and carboplatin in small-cell lung cancer patients (SCLC), who are resistant to cyclophosphamide, doxorubicin and etoposide (CDE). Different dose schedules of ifosfamide were combined with fixed doses of paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min. Included were 30 patients, with a median age of 60 years, and median time off prior cytotoxic treatment of 8 weeks. All patients were previously treated with CDE and 11 had received re-induction CDE. Dose limiting toxicity of our schedule was persistent thrombocytopenia. None of the patients developed neutropenic fever. Non-haematological toxicity was mild, although two treatment-related deaths occurred. Fifty-four percent of patients had a partial response and median survival time was twenty-five weeks. The maximum tolerated dose of this combination for patients with resistant SCLC is ifosfamide 2000 mg/m2 in combination with paclitaxel 175 mg/m2 and carboplatin AUC 6 mg/ml min administered on the first day of a 21-day cycle.

Phase II evaluation of paclitaxel, ?-interferon, andcis-retinoic acid in advanced renal cell carcinoma

Interferon and 13-cis-retinoic acid (13-CRA) therapy showed clinical response rates of 30% in advanced renal cell carcinoma (RCC). This combination also enhanced sensitivity to paclitaxel in a bcl-2 and mutant p53 expressing renal carcinoma cell line. Based on this, the authors conducted a Phase II clinical trial of the combination of interferon, 13-CRA, and weekly paclitaxel, in advanced RCC.The eligibility criteria consisted of unresectable or metastatic RCC, measurable disease, a Southwest Oncology Group performance status of 0-2, and adequate bone marrow, hepatic, and renal function. Prior cytotoxic or immunologic treatment including interferon was permitted. Paclitaxel was administered at a dose of 80 mg/m(2) as a 1-hour intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. Interferon was administered at a dose of 3 million units subcutaneously daily and 13-CRA at 1 mg/kg/day orally in 2 divided doses for the first 21 days of each cycle.Twenty-one patients were enrolled with a median age of 52 years, 16 males and 5 females, 10 patients with no prior therapy, 5 each with prior interleukin-2 or interferon therapy, and 1 patient with both. Four patients had also received prior investigational chemotherapy. A total of 61 cycles were administered with a median of 2 per patient. Grade 3 and 4 toxicities were neutropenia in three patients, anemia in four patients, and asthenia, skin rash, and hypersensitivity reaction in one case each. Of the 20 evaluable patients, one objective partial response was observed for a duration of 7+ months. Seven patients had disease stabilization. The median survival of the entire population was 9.5 months (range, 4-18+ months).The combination of 13-CRA, interferon, and weekly paclitaxel was well tolerated and had minimal efficacy in advanced RCC.

Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation.

Tumor necrosis factor-alpha (TNF-alpha) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6-->B6D2F1). Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-alpha to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survival relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-alpha and interleukin-1beta 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-alpha and interleukin-1beta production by host macrophages after cyclophosphamide pretreatment. These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.