bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of a novel, pharmacokinetically derived schedule of flavopiridol in acute leukemias: Clinical efficacy including hyperacute tumor lysis, pharmacokinetics, and pharmacodynamics
Authors: Blum W. , Klisovic R. B. , Kefauver C. , Johnson A. , Phelps M. , Dalton J. T. , Lucas D. , Colevas A. D. , Grever M. R. , Marcucci G. , Byrd J. C.
Published: March 2020

6568

Background: Flavopiridol is a cyclin dependent kinase inhibitor with in vitro activity in many cancer cell lines. However, phase I/II studies of either 24 or 72-hour continuous infusion schedules demonstrated no significant clinical activity. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling studies which suggested that optimal dosing would be a 30 min IV bolus followed by 4 hr IV infusion. With this schedule, our group has observed impressive clinical activity in refractory CLL. Methods: We intensified this schedule for relapsed or refractory adult AML and ALL patients (pts) to administer an IV bolus over 30 min followed by an infusion over 4 hrs on 3 consecutive days in a phase I trial. Results: To date, 10 pts have been treated at 2 dose levels. Pts had relapsed/refractory AML (N=6) or ALL (N=4) and were 25–77 yrs old. 4 pts received flavopiridol at 20 mg/m2 IV bolus and 30 mg/m2 infusion; 6 received 30 mg/m2 bolus followed by 35 mg/m2 infusion. The most significant toxicity was tumor lysis; treatment was well tolerated, and toxicities were similar to those previously reported by our group with the single day dosing schedule used in CLL. Plasma levels were 1–2 μM during the infusion (N=7) and declined with a terminal half life comparable to that previously reported with a 72 hr infusion. Significant anti-leukemic activity was seen in 5/7 evaluable pts at both dose levels. Tumor lysis was seen in both ALL and AML (see table ). Downregulation of Mcl-1 protein by immunoblotting was seen in 2/3 pts tested to date. Conclusions: Single agent flavopiridol given with this novel, pharmacologically modeled schedule has clinical activity in pts with relapsed/refractory ALL and AML. Further study in acute leukemia using this schedule is warranted; dose escalation to the current trial is ongoing. (NCI U01 CA 76576–05)

[Table: see text]

No significant financial relationships to disclose.
Comparison of 2 doses of daunorubicin(45mg/m2 vs 60mg/m2) in induction therapy of patients of de novo acute myeloid leukemia
Authors: Khattry N. , Kumar L. , Kumar R. , Patel C. , Raina V. , Sharma A. , Chandra P. , Bhutani M. , Sengar M. , Kochupillai V.
Published: March 2020

6581

Background: Standard induction regimen for the management of acute myeloid leukemia (AML) includes 45 mg/m2 of daunorubicin (DNR) × 3 days and 100 mg/m2 of ara-c × 7 days. Recent studies suggest that higher doses of DNR may have better outcome. Randomized studies to objectively authenticate these observations to the best of our knowledge are not available. This study was undertaken as a preliminary trial to compare the induction remission rates and toxicity of 60 mg/m2 of DNR with standard dose of 45 mg/m2. Methods: Sixty newly diagnosed AML patients, except AML—M3, from January 2003—May 2005 were randomized to either 45mg/m2 (group A ) or 60 mg/m2 (group B) of DNR for three days. The dose of ara-c was 100mg/m2 for 7 days in both groups. All denovo AML patients with 0–2 performance status (ECOG) were included in the study. Results: Fifty six patients were evaluable, 30 in group A and 26 in group B. The baseline demographic and clinical characteristics were comparable. Twenty (67%) patients in group A and 23 (88%) in group B (p=0.05) achieved complete remission (CR). Fifteen (50%) patients in group A and 22 (84.6%) in group B (p=0.006) achieved remission after single course of induction chemotherapy. Nine patients (30%) in group A and 3 (11.5%) in group B died due to uncontrolled sepsis (p=0.09). Five patients, all belonging to Group A, had persistent disease at the time of death. Though there was no significant difference with respect to major organ toxicities in both the groups, duration of grade 4 thrombocytopenia and duration of admission were significantly greater in group A (P=0.02 and P=0.005 respectively). Conclusions: This study indicates that daunorubicin in the dose of 60 mg/m2 is superior to 45mg/m2 as a remission induction therapy for AML patients with good performance status. Further follow up is required to ascertain whether higher remission rate leads to higher disease free and over all survival.

No significant financial relationships to disclose.
Preliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP)
Authors: Jabbour E. , Giles F. , Cortes J. , O’Brien S. , Ravandi F. , Borthakur G. , Garcia-Manero G. , Letvak L. , Salvado A. , Kantarjian H.
Published: March 2020

6591

Background: AMN107 is a novel, highly selective oral Bcr-Abl inhibitor which is 20–50-fold more potent than imatinib. High response rates with AMN107 were observed in all CML phases post imatinib failure. Methods: Study Aims: Evaluate the efficacy of AMN107in newly diagnosed Ph-positive CML-CP. Study Group and Therapy: Patients with newly diagnosed Ph-positive CML-CP were treated with AMN107 400 mg orally twice daily. Results: So far, 13 patients have been treated; median age 49 (range 24 to 72). Sokal risk at pretreatment: low - 10, intermediate - 2, high - 1. Five have reached the 3 month evaluation: all 5 (100%) had a complete cytogenetic response [CGCR] (Ph 0%). This is compared with a CGCR at 3 months of 36% with imatinib 400 mg/d and 55% with imatinib 800 mg/d in historical data of newly diagnosed patients treated at M. D. Anderson. The median QPCR with AMN at 3 months was 0.67% (range 0.3 to 3.0), compared with a median QPCR of 8% with imatinib 800 mg daily. Grade 3–4 myelosuppression was observed in 3/13 and other grade 3–4 side effects in 1/13 requiring temporary AMN107 interruption for < 2 weeks and resumption at same dose level in the 3 patients with myelosuppression, and for 6 weeks+ in the patient with grade 3 elevation of liver enzymes which were reduced to grade 1 on last follow-up. One patient had a transient elevation of total bilirubin > 3 mg/L which was self limited with continued therapy. Conclusions: Early results with AMN107 400 mg orally twice daily are encouraging in newly diagnosed CML.

[Table: see text]
Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) for patients with relapsed chronic lymphocytic leukemia (CLL)
Authors: O’Brien S. , Byrd J. C. , Kipps T. J. , Forero-Torres A. , Flinn I. W. , Wynne D. I. , Molina A.
Published: March 2020

6597

Background: Lumiliximab, an anti-CD23 monoclonal antibody, had pharmacologic activity and an outstanding safety profile in a recently completed phase 1, single-agent study. Based on evidence of clinical activity, favorable safety profile, and preclinical data suggesting synergy with both fludarabine and rituximab, we initiated a combination study of lumiliximab with FCR in previously treated patients. Methods: Patients ≥18 years of age with relapsed CD23+ B-cell CLL were eligible for this open-label, dose-escalation, phase 1/2 study. Sample size was planned for ≤37 patients. Patients received either 375 mg/m2 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR for 6 cycles. Primary objectives were to determine the safety profile, recommended phase 2 dose, and clinical activity of lumiliximab with FCR. Results: Accrual began in June 2004; 30 of the 31 patients were enrolled by December 2005; data are available for 28 patients. No dose-limiting toxicity was noted in the phase 1 component (375 mg/m2 dose, n=3, and 500 mg/m2 dose, n=6) and 500 mg/m2 was chosen for the phase 2 dose. All enrolled patients had progressive, symptomatic CLL as defined by NCI criteria, median 2 prior treatments (range, 1 to 9), median age 58, 64% males, 96% WHO performance status of ≤1. Seventeen patients experienced CTC Grade 3 or 4 adverse events (hematologic toxicity typically associated with FCR). Sixteen patients completed ≥3 cycles of treatment and were evaluated for response using NCI-WG criteria: 7 (44%) patients with confirmed complete responses (CRs); 1 with unconfirmed CR (pending marrow confirmation), 3 with partial responses (PRs), 4 with PRs awaiting confirmation, and 1 with disease progression. Twelve patients are not yet evaluable for response. Conclusions: Lumiliximab in combination with FCR is well tolerated and may enhance the activity of FCR for treatment of patients with progressive CLL after prior therapy.

[Table: see text]
Phase II study of talabostat and rituximab in fludarabine/rituximab-resistant or refractory patients with CLL
Authors: Khan K. D. , O’Brien S. , Rai K. R. , Brown J. R. , Abboud C. , Hurd D. D. , Conkling P. , Yang Z. , Haltom E. J. , Uprichard M. J.
Published: March 2020

6598

Background: Talabostat (TAL) is an orally administered small molecule inhibitor of dipeptidyl peptidases such as CD26 and fibroblast activation protein (FAP) in bone marrow, lymph nodes, and stroma of solid tumors, and TAL induces cytokine and chemokines in lymph nodes and spleen. TAL enhances the activity of rituximab (RTX) in a mouse model of lymphoma. This study evaluates the efficacy of TAL + RTX in patients with advanced CLL who failed fludarabine (FLU) and/or RTX. Methods: Single-arm, open-label study of RTX 375mg/m2 weekly × 4 weeks, and TAL-300mcg BID for 6 days following each RTX infusion for a tx course of 28 days. Additional courses permitted depending on tolerability. Eligibility criteria include ECOG PS 0–2, CD20+ B-CLL, Rai Stage III/IV or Rai I/II with marked lymphadenopathy, no CNS metastases, and primary resistance or PD following FLU and/or RTX. Primary endpoint is response rate per NCI-WG criteria. Secondary endpoints include response duration, PFS, and survival. Results: 40 patients (32 men, 8 women), median age 64.0 (range 42–83) have entered the study. Most (85%) are caucasian, and 78% of patients are Rai Stage IV. Mean serum B2 microglobulin is 6.5mg/L. The median number of prior regimens is 4 (range 1 to 10); 78% of patients received prior RTX and 33% prior alemtuzumab. Partial response (PR) has been reported in 8/36 evaluable patients (22%), 6 of whom had failed RTX; 3 of these patients had also failed alemtuzumab. Response duration currently ranges from 2 to 10 months (median 5.0 months). Most toxicities are Grade 1 or 2, and include nausea, fever (28% each), and edema (25%). Fever with associated Grade 3 or 4 neutropenia is reported in 2 and 1 patient, respectively. Other Grade 3 AEs include dyspnea (n=3), fatigue (n=2), and aspergillus pneumonia and a dermal fungal infection in 1 patient each. Grade 4 AEs are thrombocytopenia, hypoglycemia, and pulmonary embolism in 1 patient each. 4 patients died due to CLL (2 due to PD) or related complications (PE or MRSA pneumonia, 1 each). Conclusions: TAL + RTX shows promising activity in CLL patients with advanced disease who failed FLU and/or RTX. AEs are similar to those seen with RTX, with the exception of edema in 25% of patients. Updated results, including median PFS and survival will be presented at the annual meeting.

[Table: see text]
Immune anemias in patients with chronic lymphocytic leukemia treated with chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab as initial therapy
Authors: Borthakur G. , O’Brien S. , Wierda W. G. , Thomas D. A. , Cortes J. E. , Kantarjian H. , Lerner S. , Keating M. J.
Published: March 2020

6604

Background: Auto-immune hemolytic anemia (AIHA) has been reported with the use of fludarabine in the treatment of chronic lymphocytic leukemia (CLL). Since rituximab has been used to treat AIHA, it was anicipated that rituximab might reduce the incidence of AIHA when combined with fludarabine to treat CLL. We analyzed the incidence of immune anemias in 300 patients (pts) with CLL treated with fludarabine, cyclophosphamide and rituximab (FCR) as initial therapy. Methods: Diagnosis of AIHA was based on clinical evidence of hemolysis (elevated indirect bilirubin, reticulocyte count, lactate dehydrogenase) combined with positive Coomb’s test and/or low haptoglobin level. Pure red cell aplasia (PRCA) was diagnosed based on absence of erythroid precursors in bone marrow aspirate and/or biopsy. Results: 29 of 300 (9.5%) pts with CLL treated on a single-arm study of FCR showed evidence of immune anemias (age range18 to 86 years,median 62 years; 24 male and 5 female). 24 pts had AIHA, 3 had PRCA and 2 pts had positive Coomb’s test only (hemoglobin>10 gm/dL). Higher beta2-microglobin and bone marrow lymphocyte percentage were associated with higher risk of developing AIHA in multivariate analysis. Immune anemia was present in 9 pts prior to FCR treatment, developed in 15 on FCR and in 5 after completion of FCR (1 month to 4 years later). AIHA was detected after a median of 4 cycles (range 1 to 6) in pts who developed it while on therapy. Coomb’s test was positive in 14 pts and negative in 15. Haptoglobin levels were low in 16, normal in 10 and not measured in 3 pts. Coomb’s test was negative in 14 of 16 pts with AIHA and low haptoglobin levels. 9 pts were treated with oral prednisone. Others treatments included cyclosporine, intravenous immunoglobulin, rituximab and splenectomy. 3 of 9 pts who had AIHA prior to starting FCR had sustained correction of anemia with FCR treatment alone. 2 pts had inadequate response to treatment of immune anemia; 1 of them developed myelodysplastic syndrome. Conclusions: The incidence of immune anemias in pts treated with FCR is comparable to other series. Low haptoglobin levels in appropriate clinical context can help to establish the diagnosis of AIHA in the face of negative Coomb’s test.

[Table: see text]
SPC2996—A Bcl-2 RNA antagonist being studied in chronic lymphocytic leukemia
Authors: Hansen B. J. , Westergaard M. , Frieden M. , Hansen H. F. , Kjaerulff L. S. , Thrue C. A. , Wissenbach M. H. , Dalby L. W. , Kearney P. , Oerum H.
Published: March 2020

6610

Background: Bcl-2 protein is a critical regulator of programmed cell death and contributes to apoptosis resistance in many cancers, including chronic lymphocytic leukemia (CLL). The novel RNA antagonist, SPC2996, is a 16-mer oligonucleotide incorporating Locked Nucleic Acid (LNA) with unique high-affinity binding to Bcl-2 mRNA and enhanced resistance to nuclease digestion. We report the pharmacological properties of this new investigational drug and are currently evaluating clinical safety and initial efficacy in CLL patients. Methods: In vitro, the effects of SPC2996 on Bcl-2 mRNA and protein levels and phenotypic responses were evaluated in human cancer cell lines by quantitative polymerase chain reaction, Western blotting and biochemical assays. In vivo bio-distribution in rodents was assessed with tritium-labelled SPC2996 given intravenously. Anti-tumour efficacy was assessed in human prostate (PC3) and melanoma (518A2 and 607B) tumour cell line xenografts in immunodeficient mice. Preclinical toxicology and safety pharmacology were evaluated after intravenous treatment in rats and primates and tissue uptake measured by HPLC. Results: In vitro, low nanomolar concentrations of SPC2996 substantially reduced intracellular levels of Bcl-2 mRNA and protein and induced apoptosis in a dose-dependant manner. In vivo, systemically administered SPC2996 accumulated in liver, kidney, bone marrow, and lymph nodes. Repeated dosing at 10mg/kg inhibited growth of human xenografts in mice. Substantial down-regulation of Bcl-2 mRNA was observed in primate tissues after intravenous administration of SPC2996 at 3 and 6mg/kg. No acute toxicity was encountered on systemic bolus dosing of substantially higher doses in primates. An international phase I/II dose-escalating study in 42 patients with relapsed or refractory CLL is currently recruiting in the USA, UK, Denmark and France. Conclusions: SPC2996 is the first member of a new generation of specific RNA antagonising oligonucleotides with enhanced properties derived from LNA. SPC2996 has the potential to lower Bcl-2 levels in CLL cells without significant toxicity and with less frequent dosing than required with previous drugs.

[Table: see text]
High efficiency transduction of chronic lymphocytic leukemia with adenovirus type 35
Authors: Hedjran F. , Whitacre D. , Kipps T. , Reid T. R.
Published: March 2020

6612

Background: Adenovirus (Ad) vectors have been used extensively in genetic manipulation of cultured cells and gene therapy, with the group C Ad serotypes 2 and 5 being most widely used. The group C viruses have been shown to infect target cells in a two-step process. There is an initial high-affinity step in which Ad fiber protein binds to the the coxsackie/adenovirus receptor (CAR), increasing the local concentration of the virus at the cell surface. In the second step, the Ad penton base protein binds to integrins on the target cell surface and the virus is internalized. CLL cells to not express CAR and so require a very high concentration of Ad5 for transduction. Group B adenoviruses differ from other groups, having been shown to require CD46 (the measles virus receptor) to infect target cells. We are investigating Ad35 for use as a gene therapy vector and a laboratory tool for manipulating CLL cells ex vivo. Methods: We used a modified viral vector (Shayakhmetov et al., 2000 J Virol (74) pp 2567–83) with first 64 amino acids from the Ad5 fiber fused to the last 279 amino acids from the Ad35 fiber substituted into the Ad5 fiber ORF. This vector was used to assess the relative efficiency of the chimeric Ad5/35 vector compared to wild-type Ad5. Results: Primary CLL cells were transduced by the standard Ad5 and chimeric Ad5F35 vectors. Ad5F35 vector is about 100-fold more potent at transducing CLL cells compared to an Ad5 vector. Twelve CLL, PBMC and HeLa samples were tested for CD46 expression by flow cytometry. Each CLL population was 90–99% bright for CD46. Primary CLL cells and normal PBMCs were transduced by Ad5F35-GFP at an MOI of 10. The CLL cells are more transducible than normal PBMCs (p<0.05). This difference in transducibility is not a result of low CD46 expression. Conclusions: Adenovirus Type 35 is a promising vector for use in delivering gene therapy agents to CLL cells at significantly lower viral doses and more favorable therapeutic index compared with traditional Ad5 vectors.

No significant financial relationships to disclose.
Cardiovascular risk profile of breast cancer patients treated with anthracycline-taxane containing adjuvant chemotherapy and/or trastuzumab
Authors: Jones L. W. , Haykowsky M. , Peddle C. J. , Joy A. A. , Pituskin E. N. , Tkachuk L. M. , Courneya K. S. , Slamon D. J. , Mackey J. R.
Published: March 2020

666

Background: With improving longevity, post-treatment cardiovascular disorders will become an increasingly important indicator of competing mortality in early-stage breast cancer. As such, we conducted a pilot study to comprehensively evaluate the CVD profile of a subset of early-stage breast cancer patients treated with adjuvant taxane-anthracycline containing chemotherapy and/or trastuzumab. Methods: Twenty-six breast cancer patients (mean 20 months post chemotherapy) who participated in Breast Cancer International Research Group 006 clinical trial and 10 healthy age-matched women were studied. We measured 14 metabolic and vascular established CVD risk factors, BMI, VO2peak and left ventricular systolic function. All assessments were performed within a 14-day period. Results: Cardiac abnormalities were suggested by LVEF <50% in 10% of patients, LVEF remained >10% below pre-treatment values in 38% while 50% presented with resting sinus tachycardia. BNP was significantly elevated in 40% and was correlated with LVEF (r = -0.72, p=<.001). For the majority of CVD risk factors, similar proportions of patients and controls (35% to 60%) were classified as ‘undesirable.’ A significantly higher proportion of patients were classified with low VO2peak (46% vs. 0%, p<0.01), being overweight/obese (72% vs. 50%, p<0.05), and having resting sinus tachycardia (50% vs. 0%, p<0.01) compared with controls. VO2peak and BMI were correlated with CV risk factors (r = -0.64 to 0.63, p<0.05; r = -0.63 to 0.67, p<0.05, respectively). Exploratory analyses revealed several differences between CVD risk factors based on chemotherapy regimen. Conclusions: Breast cancer survivors treated with adjuvant chemotherapy are at a higher risk of developing late-occurring CVD than age matched controls due to direct and indirect treatment-related toxicity.

No significant financial relationships to disclose.
10-year follow-up of the efficacy of clodronate on bone mineral density (BMD) in early stage breast cancer
Authors: Saarto T. , Vehmanen L. , Blomqvist C. , Elomaa I.
Published: March 2020

676

Background: We have previously reported that clodronate prevents bone loss in breast cancer patients (JCO 1997;15:1341, BJC 1997;75(4):602 and EJC 2001;37:2373). Here we report the 10-year follow-up data. Methods: 268 pre- (PRE) and postmenopausal (POST) node positive breast cancer patients were randomized to clodronate (CL), orally 1.6 g daily, or control groups for 3 years. PRE were treated with adjuvant chemotherapy and POST with antiestrogens (AE), tamoxifen 20 mg or toremifene 60 mg, for 3 years. The BMD of the lumbar vertebrae L1–4 (BMDLS) and femoral neck (BMDFN) was measured before the treatment and at 1, 2, 3, 5 and 10 years. 93 patients were eligible for 10-year analyses: 53 PRE and 40 POST. 132 patients had metastatic disease or died and 39 were either lost to follow-up or had to be excluded because having diseases or medications that influences bone metabolism. Results: PRE: BMDLS decreased -12.4% in the control and −8.7% in the CL group in 10 years: from 0 to 3 years −6.9 % vs. −4.2% and from 3 to 10 years −5.5% and −4.5%, respectively. BMDFN decreased −8.8% and −7.2%: from 0 to 3 years −2.9% vs. −2.6% and from 3 to 10 years −5.9% vs. −4.6%, respectively. POST: BMDLS decreased −3.0% in the AE and −1.7% in the AE+CL group in 10 years: from 0 to 3 years −1.5% vs. + 1.2% and from 3 to 10 years −1.5% vs. −2.9%, respectively. BMDFN decreased −7.7% and −6.0%: from 0 to 3 years −0.1% vs. +1.9% and from 3 to 10 years −7.6% vs. −7.9%, respectively. These differences do not reach statistical significance. At 10-years 18 patients had osteoporosis in LS and 15 in FN. Only 4 patients who had osteoporosis at 10 years had normal BMD before the therapy. Conclusions: As reported previously, clodronate prevents the bone loss during treatment in pre- and postmenopausal women. This beneficial effect seems to be maintained at least for 7 years after treatment termination in premenopausal. In postmenopausal women the effect seems to diminish within time. Due to small numbers of patients these differences are no longer statistically significant. Patients at risk of developing osteoporosis are among those who has pretreatment osteopenia i.e. baseline BMD measurement has predictive value.

No significant financial relationships to disclose.
Alternative measures predicting clinical benefit in advanced non-small cell lung cancer (NSCLC) from Southwest Oncology Group (SWOG) randomized trials: Implications for clinical trial design
Authors: Lara P. N. , Redman M. W. , Kelly K. , Edelman M. J. , Williamson S. K. , Crowley J. J. , Gandara D. R.
Published: March 2020

7006

Background: Although objective response (CR/PR) & overall survival (OS) are typical efficacy measures for new treatments in advanced stage NSCLC, each has its limitations; e.g., some patients (pts) have no measurable disease or achieve only disease stabilization (SD) while OS is influenced by effective salvage therapies. Alternative methods of determining “clinical benefit” are needed. Methods: Pooled data from 984 pts entered onto 3 randomized SWOG trials of platinum-based chemotherapy (S9509: carbo/paclitaxel (CP) vs. cisplatin/vinorelbine; S9806: carbo/gemcitabine ->P or cisplatin/vinorelbine -> docetaxel; & S0003: CP ± tirapazamine) were analyzed for survival using the Landmark method. Results: Pt characteristics: median age = 62 years; male sex = 647 pts (66%); stage IV = 826 pts (84%); weight loss ≥ 5% = 404 pts (42%); performance status (PS) 0/≥1 = 340 (36%)/606 (64%). Tumor response was seen in 260 pts (26%). Median time to response (TTR), time to progression (TTP) & OS were 1.9, 4.3 and 8.9 months. PS > 0 & weight loss were associated with worse survival (hazard ratio [HR] 1.38 and 1.28; p 0 (HR 0.75, p=0.03) and weight loss (HR 0.74, p = 0.03). Shorter TTP was associated with PS>0, stage IV, & weight loss (HR 1.34, 1.08, 1.34 and p = 0.0001, 0.01, < 0.00001). Of 886 pts alive at month 2 (time of initial response assessment following 2 treatment cycles), 62% had SD while19% had CR/PR for a disease control rate (CR+PR+SD, aka DCR) of 81%; 18% had progressive disease (PD). Although CR/PR at month 2 was associated with longer survival (HR 0.62, p<0.001), DCR had a much stronger association (HR 0.38, p<0.0001). Inclusion of DCR in the regression model improved its fit (p<0.00001), reducing the significance of CR/PR as an independent variable. Median survival among pts with CR/PR, SD, & PD were 13.5, 8.4, & 3.1 months. Conclusions: 1)DCR at month 2 is a more powerful predictor of subsequent survival than the CR/PR rate. 2) If validated, this “early look” statistical measure could enhance efficacy assessment. 3) These findings may have broad implications for the design of future trials in advanced NSCLC & will be prospectively tested in SWOG.

No significant financial relationships to disclose.
Adjuvant chemotherapy in elderly patients: An analysis of National Cancer Institute of Canada Clinical Trials Group and Intergroup BR.10
Authors: Pepe C. , Hasan B. , Winton T. , Seymour L. , Pater J. , Livingston R. , Johnson D. , Rigas J. , Ding K. , Shepherd F.
Published: March 2020

7009

Background: Recent trials have shown significant survival benefit from adjuvant chemotherapy after resection of NSCLC. Whether elderly patients tolerate platinum-based adjuvant chemotherapy and derive the same survival advantage is unknown. This retrospective study evaluated the influence of age on survival, chemotherapy delivery and toxicity in NCIC CTG BR.10. Methods: Pretreatment characteristics and survival benefit from treatment were compared for patients ≤65 & >65. Chemotherapy delivery and toxicity were compared for 213 treated patients. Results: There were 327 young and 155 elderly patients. Baseline prognostic factors by age were similar with the exception of histology (adeno 58% young, 43% elderly; squamous 32% young, 49% elderly; p=0.001) and PS (PS 0 53% young, 41% elderly; p=0.01). Overall survival by age showed a trend favoring the young in univariate (HR 0.77, CI 0.58–1.04, p=0.084) and multivariate analyses (HR 0.75, CI 0.56–1.01, p=0.059). Patients >75 years had significantly shorter survival than those aged 66–74 (HR 1.95, CI 1.11–3.41, p=0.02). Overall survival for patients >65 was significantly better with chemotherapy v observation (HR 0.61, CI 0.38–0.98, p=0.04). Chemotherapy administration and toxicity were evaluated in 63 elderly and 150 young patients. Mean dose intensities of vinorelbine (V) and cisplatin (C) were 13.2 and 18.0 in the young and 9.9 and 14.1 in the elderly (V p=0.0004; C p=0.001). The elderly received significantly fewer doses of V (p=0.014) and C (p=0.006). Fewer elderly patients completed treatment and more refused treatment compared to the young (p=0.03). There were no significant differences in toxicities, G-CSF use or hospitalization by age group, except for myalgias and mood alteration (more frequent among the young). Six of 126 deaths (4.8%) in the young were from non-malignant causes v 12 of 71 (16.9%) in the elderly (p=0.008). Conclusions: In spite of receiving less chemotherapy than young patients, adjuvant chemotherapy improves overall survival in patients aged >65 with acceptable toxicity. Adjuvant chemotherapy should not be withheld from elderly patients, although patients >75 years of age require further study.

No significant financial relationships to disclose.
Concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in advanced non-small cell lung cancer (NSCLC): A randomized phase II selectional trial SWOG 0342
Authors: Kelly K. , Herbst R. S. , Crowley J. J. , McCoy J. , Atkins J. N. , Lara P. N. , Dakhil S. R. , Albain K. S. , Kim E. S. , Gandara D. R.
Published: March 2020

7015

Background: Randomized clinical trials have failed to show a survival benefit for small molecule EGFR tyrosine kinase inhibitors plus chemotherapy in patients with advanced NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This large randomized phase II trial was designed to select a cetuximab -chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with stage IIIB (by pleural effusion) or IV (without brain metastases) NSCLC, with a performance status of 0–1 and adequate organ function were randomized to received paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or the same doses of PCb for 4 cycles followed by C. C was continued until disease progression or 1 year of therapy. The primary endpoint was overall survival; the statistical design required a median survival of ≥ 10 months for a regimen to be selected for subsequent phase III trial evaluation. The probability of correctly choosing the superior arm is 91% when the true hazard ratio is 1.3. Results: From July 2004 to June 2005, 225 eligible pts were enrolled into the study. Preliminary results are described below: Conclusions: At the time of this analysis, efficacy and toxicity were similar in the two treatment arms; both regimens were well tolerated. Assuming these results are sustained, the concurrent regimen of PCb + cetuximab has met the criteria for continued evaluation. A phase II trial of PCb + cetuximab + bevacizumab (B) is in development in anticipation of a phase III trial testing PCbB ± cetuximab. Molecular correlative studies of the EGFR signaling pathway are ongoing.

[Table: see text]

[Table: see text]
Phase II study of a TGF-β2 antisense gene modified allogeneic tumor cell vaccine (Lucanix) in advanced NSCLC
Authors: Nemunaitis J. J. , Dillman R. O. , Schwarzenberger P. , Senzer N. , Tong A. , Devol E. , Chamberlin T. , Shawler D. , Fakhrai H.
Published: March 2020

7018

Background: Lucanix (L) is a non-viral gene based allogeneic tumor cell vaccine which demonstrates enhancement of tumor antigen recognition as a result of Transforming Growth Factor (TGF-β2) inhibition. Methods: We performed a randomized dose variable phase II trial involving stage IIIB/IV non small cell lung cancer (NSCLC). Each patient received one of 3 doses (1.25, 2.5, 5.0x107 cells/injection) of L, given intradermally, to a maximum of 16 injections either monthly or every other month. Immune function, safety and anticancer activity were monitored. Results: Sixty-one patients (15 IIIB/ 46 IV; 51/61 (84%) ≥ prior cytotoxic therapy), received a total of 417 vaccinations. No significant (≥ grade 3) adverse events probably or definitely associated with administration of the vaccine were observed. A dose-related survival difference was demonstrated in patients who received ≥ 2.5 × 107 cells/injection versus those who received <2.5 × 107 cells/injection (p=0.0151). The percent of patients surviving 1 and 2 years was 61% and 52% for the high dose group and 40% and 13% for the low dose group. Fifteen percent of patients achieved a partial response. Cytokine production (IFN-γ, p=0.006; IL-6, p=0.004; IL4, p=0.007) was induced, antibody mediated response to vaccine HLA antigen was observed (p=0.014) and cell mediated response showed a correlation trend (p=0.086) in patients achieving stable disease or partial response (15%) compared to those with progressive disease. Conclusions: In conclusion, L is safe and well tolerated. A survival advantage is suggested in patients who receive ≥ 2.5x107 cells/injection thereby supporting the justification for further phase III evaluation. Phase III investigation is recommended.

[Table: see text]
Routine positron emission tomography (PET) and selective mediastinoscopy is as good as routine mediastinoscopy to rule out N2 disease in non-small cell lung cancer (NSCLC)
Authors: Serra M. , Cirera L. , Rami-Porta R. , Bastus R. , Gonzalez S. , Simó M. , Domenech M. , Barbeta E. , Soler J. M. , Belda J.
Published: March 2020

7031

Background: To evaluate the presence of mediastinal lymph node spread of NSCLC after changing the clinical staging protocol from routine to selective surgical mediastinal exploration (SME) based on PET. Methods: From 1994 to 2003, routine SME (mediastinoscopy, parasternal mediastinotomy or extended cervical mediastinoscopy) was performed to 655 patients (pts) with NSCLC as the last clinical staging procedure prior to thoracotomy. Those with no mediastinal involvement underwent thoracotomy with lung resection (T) and systematic nodal dissection (SND). From 2004, PET was routinely done in 90 pts and SME was reserved for those with positive mediastinal or hiliar uptake on PET, mediastinal lymph node diameter greater than 1cm in shorter axis on computerized tomography, and in tumors contacting with the mediastinum. All other pts and those with negative SME underwent T and SND. Results: Among 655 pts studied between 1994 and 2003, 236 (36%) had positive SME; 419 underwent T and SND and 40 (6.1%) were classsified as pN2. Of the 90 evaluable pts with PET, 27 had increased uptake in the mediastinum an 17 had positive SME; the remaining 10 ptes with negative SME underwent T and SND and 7 of them were found to have no nodal disease (false positive PET), but three of them were found to have nodal disease. Of the 63 pts with no uptake in the mediastinum, 29 underwent SME for reasons stated above: 5 SME was positive; in 24 SME was negative and the patients underwent T and SND: 21 were pN0 and 3 were pN2. Only 1 tumor of the remaining 34 pts with negative PET who underwent T and SND without SME was classified pN2. Additionally, in 1 pt PET detected N2 disease but not N3. 4 (4.5%) pts with pN2 disease were clinically understaged (negative PET and negative SME) and underwent thoracotomy. 3 pts with positive PET who underwent SME were classified pN0, but they were pN2 (false negative SME). In total, 7 (7.8%) pts with pN2 disease were clinically understaged and underwent T. This rate is not statisticallly different from the 6.1% pN2 tumor found after routine SME. Conclusions: In this preliminary study, this new clinical staging protocol with routine PET and selective SME saves up to 35% of SME and yields a similar rate of pN2 disease compared to routine SME.

No significant financial relationships to disclose.
ECOG 4599 phase III trial of carboplatin and paclitaxel ±bevacizumab: Subset analysis of survival by gender
Authors: Brahmer J. R. , Gray R. , Schiller J. H. , Perry M. , Sandler A. , Johnson D.
Published: March 2020

7036

Background: E4599 compared carboplatin and paclitaxel (PC) versus carboplatin, paclitaxel, and bevacizumab (PCB) in patients with advanced stage non-small cell lung cancer. Survival was superior with PCB. However, an unplanned subset analysis did not show a survival benefit for women in the PCB arm. Methods: Patients (pts) in the E4599 database were divided into male (M) and female (F) cohorts by assigned treatment. Survival was calculated separately for each cohort. Known prognostic factors and toxicities were compared by gender. Proportional hazards models (PHM) of survival with multiple factor combinations were fit to adjust for treatment effect for sex, performance status, stage, liver, bone and adrenal involvement, measurable disease, prior radiation therapy, weight loss ≤ 5% and to examine the difference in treatment effect by sex. Results: The analysis includes 850 patients. The median survival for M is 8.7 months (mo) (PC) versus (vs) 11.7 mo (PCB) (p=0.001). The median survival for F is 13.1 mo (PC) vs 13.3 mo (PCB) (p=0.87). On PCB, progression free survival (PFS) for M and F is 6.3 mo and 6.2 mo respectively. Response rate (RR) is 23.6% for M and 38.5% for F. Duration of response is 6.8 mo for both. No demographic differences exist between the two arms for M. A higher proportion of F on the PCB arm have liver metastasis (PCB 23.2% vs PC 11.7%, p=0.003). On the PC arm, the febrile neutropenia rate is higher for M (M 3.1% vs F 0%, p=0.02). On the PCB arm, the adverse events with a gender difference are severe hypertension (M 4.2%, F 9.9%, p=0.02), constipation (M 1.4%, F 4.7%, p=0.05), and abdominal pain (M 0.9%, F 5.2%, p=0.01). The test for a treatment by sex interaction in a PHM for survival has p = 0.04. In the PHM adjusting for the other factors, the estimated treatment hazard ratios are 0.73 for M and 0.97 for F and the test for a sex by treatment interaction has p=0.09. Conclusions: Women on the PCB arm vs the PC arm appear not to have a survival advantage. Reasons for this remain unclear. However, the addition of bevacizumab does result in significant improvements in RR and PFS, arguing in favor of an overall treatment benefit. Further analysis of other demographic information (tumor type and second-line therapy) is ongoing.

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Chemoradiotherapy (CRT) and gefitinib (G) in stage III non-small cell lung cancer (NSCLC): A CALGB stratified phase II trial
Authors: Ready N. , Janne P. , Herndon J. , Bogart J. , Crawford J. , Edelman M. , Wang X. , Gu L. , Green M. R. , Vokes E. E.
Published: March 2020

7046

Background: G is a small molecule inhibitor of EGFR with activity in advanced NSCLC and preclinical evidence of being a radiosenitizer. Methods: Patients with stage III NSCLC were assigned to stratum 1 (PS 0–1>5% weight loss and/or PS 2) or stratum 2 (PS 0–1weight loss < 5%). Both strata received induction paclitaxel (P) 200 mg/m2 and carboplatin (C) AUC of 6 IV every three weeks for 2 cycles plus G 250 mg PO/day. G was removed 4/05 from induction therapy as stage IV studies showed no benefit from adding G to P and C. Stratum 1 then received RT 200 cGy for 33 fractions (total dose 6,600 cGy) and G 250 mg PO /day. Stratum 2 received the same RT with concurrent G 250 mg/day, and P 50 mg/m2 plus C AUC of 2 weekly for 7 doses. Maintenance G was started after all toxicities were grade ≤2. Results: Activation was 5/02 and administrative closure 5/04 due to results from SWOG S0023. 64 patients were accrued and 59 (20 stratum 1, 39 stratum 2) were eligible and analyzed: median age 67, male 74%, adeno 30%, squamous 45%, other 25%, IIIA 51%, IIIB 49%. There was no clear increase for acute high-grade infield toxicities compared to CRT alone (reported PASCO 2004). Best response for stratum 1 was PR 29% for induction (RR 29%, 95% CI 10%-56%) and CR 5%, PR 45% full treatment (RR 50%, 95% CI 27%-73%); for stratum 2 PR 13% for induction (RR 13%, 95% CI 3%-34%) and CR 5%, PR 76% full treatment (RR 81%, 95% CI 65%-92%). Stratum 1 “poor risk” median failure free survival (FFS) was 11.5 months (95% CI 5.6–21.2), one year survival 60% (95% CI 33%-79%) and median overall survival (OS) 19.0 months (95% CI 7.2–21.2). Stratum 2 “good risk” median FFS was 9.2 months (95% CI 6.7–12.0), one year survival 47% (95% CI 30%–63%) and median OS was 12.0 months (95% CI 8.5–18.6). EGFR and Ras mutation analysis on tumor biopsies (n = 50) will be presented. Conclusions: Small sample size prevented planned data analysis. Survival of “good risk” patients on stratum 2 (CRT + G) was disappointing. The promising survival of the small number of “poor risk” patients on stratum 1 (RT + G) justifies a follow-up phase II trial of induction chemotherapy followed by RT with a concurrent small molecule EGFR inhibitor.

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The quantification of the catalytic subunit of telomerase in plasma is a prognostic factor in advanced non-small cell lung cancer (NSCLC) patients
Authors: Sirera R. , Camps C. , Llobat L. , Berrocal A. , Bremnes R. M. , Blasco A. , Juarez A. , Taron M. , Sanchez J. J. , Rosell R.
Published: March 2020

7052

Background: Qualitative and quantitative analysis of circulating DNA in blood is a promising non-invasive diagnostic and prognostic tool. Our aim was to study the association between the free amount in plasma of the catalytic subunit of telomerase (hTERT) and several clinical variables in advanced NSCLC patients. Methods: We examined 451 NSCLC patients in stage IIIB and IV, treated with cisplatin and docetaxel. Blood samples were collected before chemotherapy, and circulating DNA was extracted from the serum using commercial adsorption columns. The amount of free hTERT in plasma was quantified by using RT-PCR. Results: Median age was 61 years [35–82] and 84% were males. 99% had performance status 0–1. 84% were in stage IV and 16% in stage IIIB. The histological subtypes were: 32% squamous cell carcinoma, 50% adenocarcinoma, 14% anaplastic large cell, and 4% undifferentiated. 41% of the patients received second line chemotherapy. 1% achieved complete response (CR), 36% partial response (PR), 35% had stable disease (SD) and 28% progressive disease (PD). Median hTERT value was 4856 ng/ml; for patients in IIIB was 4847 ng/ml [263–964826] and 4886 ng/ml [67–4373520] in stage IV (p = 0.75). There was not association between hTERT values and response to therapy, 20588 ng/ml [122–317251] in the CR+PR group vs 50204 ng/ml [67–4373520] in the SD+PD group (p = 0.09). hTERT values were not related with the localization of the metastasis. Dividing the cohort in two sets according to hTERT median we found two significantly different groups in terms of Overall Survival (OS) and Time To Progression (TTP). Patients with hTERT <4856 ng/ml had a median TTP of 5.3 months (m) [4.4–6.1] while for hTERT >4856 ng/ml was 4.1 m [3.5–4.6], (p = 0.0009). OS when hTERT <4856 ng/ml was 10.1m [4.9–11.3] and for hTERT >4856 ng/ml was 8.4 m [7.2–9.5], (p = 0.01). In the multivariate analysis, hTERT was an independent predictive variable for TTP (HR 1.39, CI 95% 1.1–1.7, p = 0.002) and OS (HR 1.27, CI 95% 1.1–1.6, p = 0.04). Conclusions: In advanced NSCLC patients, the quantification of free circulating hTERT in plasma is an affordable and valuable prognostic marker. High plasma hTERT levels are a poor prognostic indicator for TTP and OS.

No significant financial relationships to disclose.
Clinical outcome of gemcitabine (gem)/cisplatin (cis)- vs docetaxel (doc)/cis-treated stage IV non-small cell lung cancer (NSCLC) patients (p) according to X-ray repair cross-complementing group 3 (XRCC3) polymorphism and age
Authors: Rosell-Costa R. , Alberola V. , Camps C. , Lopez-Vivanco G. , Moran T. , Etxaniz O. , De Las Peñas R. , Gupta J. , Taron M. , Sanchez J.
Published: March 2020

7055

Background: Significant interaction between XRCC1 genotype and age has been reported, with younger subjects having a greater risk of developing lung cancer. Carriers of XRCC3 241 MetMet have higher levels of DNA adducts, leading us to hypothesize that they would be more chemosensitive, especially younger patients. Methods: Real-time PCR assay was used to determine XRCC3 genotype from DNA isolated from baseline blood samples of 878 stage IV NSCLC p (162 treated with gem/cis; 716 with doc/cis). Median age, 60; 266 p (30%) <55; 239 p (39%) 55–66; 273 p (31%) >66. Adenocarcinoma: 459 p (53%). Homozygous variant XRCC3 241 MetMet was found in 124 p (14%), with the same frequency in each of the three age groups. Results: After a median follow-up of 7.6 months (m) (95% CI, 1–47 m), overall median survival (MS) was 9.5 m (95% CI, 8.8–10.2 m), with no differences between the 2 regimens. In all p with XRCC3 241 MetMet, MS was 12.9 m for p treated with gem/cis and 8.4 m for p treated with doc/cis (P = 0.06) (hazard ratio at 2 y = 0.23). In p with XRCC3 241 MetMet <55 y, MS was not reached for p treated with gem/cis and 9.2 m for p treated with doc/cis (P = 0.02), which translated into a 60% difference in survival at 2 y. This difference diminished in p with XRCC3 241 MetMet 55–66 y (MS 12.9 m with gem/cis, 6.9 m with doc/cis [P = 0.09]; 28% difference in survival at 2 y) and disappeared in p >66 y (MS 5.8 m with gem/cis, 7.8 m with doc/cis [P = 0.55]. For the other XRCC3 241 genotypes (ThrThr and ThrMet), no differences in MS were found either overall or broken down by age. Conclusions: XRCC3 241 MetMet is both an easily assessable and robust predictive marker for survival in younger gem/cis-treated NSCLC p. The survival benefit dwindles with increasing age, possibly related to the enhanced DNA repair capacity of older p.

No significant financial relationships to disclose.
Phase I study of irinotecan (Ir) and cisplatin (DDP) in combination with thoracic radiotherapy (RT), either twice daily (45 Gy) or once daily (70 Gy), in patients with limited (Ltd) small cell lung carcinoma (SCLC): Early analysis of RTOG 0241
Authors: Langer C. J. , Swann S. , Werner-Wasik M. , Lilenbaum R. , Curran W. , Sandler A. , Scidmore N. , Samuels M. , Choy H.
Published: March 2020

7058

Background: Ir in combination with DDP has proven superior to DDP & VP-16 in extensive stage SCLC (Noda et al NEJM 1/02), with marked increase in 2 yr survival (19.5%, vs 5.2%). Hence, it is critical to determine if Ir can be safely & effectively integrated with concurrent RT and DDP in earlier stage, Ltd SCLC. Methods: 1° endpoint: Determine maximum tolerated dose (MTD) of Ir d 1 & 8 plus DDP 60 mg/m2 q 3 wks & either BID RT (45 Gy) or QD RT (70 Gy). Eligibility stipulated Tx-naïve patients (pts) with Ltd SCLC, PS 0–1, adequate heme (ANC ≤ 1500/mL; plts ≥ 120,000/mL) hepatic (bili ≤ 1.5/dL) & renal (creat ≤ 1.5gr/dL) function, & baseline FEV1 of ≥ 1 liter. Ir was escalated in sequential (seq) cohorts from 40 mg/m2 (level 1) to 50 mg/m2 (level 2) & then to 60 mg/m2 (level 3) d 1 & 8 q 3 wks during each cycle of treatment. Ir & DDP were given concurrently with RT for cycle 1 in seq A (45 Gy) & during cycles 1 & 2 in seq B (70 Gy). 36 pts were targeted for accrual. DLT was defined as gr 4 esophagitis, pneumonitis, or diarrhea; gr 4 neutropenic fever, or any attributable gr 5 toxicity Results: As of 12/05, 36 pts were accrued, (21 - seq A; 15 - seq B). Median age was 64 (range 49–79) Of 33 eval pts, 18 (55%) were female; 24 (73%) PS 0; 67% had ≤ 5% wt loss. Attributable DLT was not seen in seq A, but was observed in seq B (70 Gy) at 50 mg/m2 with 1 episode each of gr 4 diarrhea & esophagitis, necessitating hospitalization. In addition, 1 pt in seq B had non-attributable gr 4 cardiovascular AEs. There has been no acute gr 5 toxicity. 1 pt experienced late gr 3 pulm toxicity, another gr 3 constitutional toxicity, including wt loss. The overall incidence of gr 3 esophagitis was 34%. Conclusions: In Ltd SCLC, I at 60 mg/m2 d 1 & 8 is safe & feasible in combination with DDP 60 mg/m2 q 3 wks & BID RT (45 Gy). The MTD for I in combination with RT (70 Gy) & DDP 60 mg/m2 is 40 mg/m2 d 1 and 8. Response, progression, survival data remain immature.

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