bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical and pathological response to taxanes (T) and anthracycline (AC) based neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC): A retrospective analysis from a single institution in North India
Authors: Gupta S. , Vaid A. K. , Prakash N. , Talwar V. , Doval D. C. , Prakash P. , Patole K. D. , Dewan A. K. , Chaturvedi H. K. , Kumar K. , Sharma J. B.
Published: March 2020

11107

Background: In India LABC remains a common presentation of breast cancer (BC). Pathological complete response (pCR) achievement is crucial for increasing survival in LABC. Taxanes and anthracyclines are amongst agents with highest activity in BC. We retrospectively evaluated clinical and pathological responses in LABC patients (pts) treated with T and AC based chemotherapy. Methods: 32 LABC pts with clinical stage IIB, IIIA, IIIB, IIIC who had received T & AC based NAC between October 2002 and October 2006 were evaluated. Patients received doxorubicin 60mg/m2 (21 pts) or epirubicin 75 mg/m2 (11 pts) and docetaxel 75 mg/m2 (all pts) 3 weekly for 3–4 cycles followed by surgery. Most pts received same chemotherapy as adjuvant and also radiation therapy and hormonal treatment depending upon ER, PgR status. Results: Baseline characteristics of 32 pts: median age 50 years (range 26–65); all female; performance status 0–1; clinical stage IIB (3 pts), IIIA (9 pts), IIIB (16 pts), IIIC (4 pts); node positive (25 pts), hormone receptor positive (17 pts), unknown (1 pt); 29 pts received 3 cycles of NAC, 3 pts received 4 cycles of NAC. Growth factor was used in all patients. 31 pts underwent MRM; 5 pts had clinically complete response (16%), 22 pts had partial response (69%), 4 pts had stable disease (12%), 1 pt had progressive disease (3%); pathological complete response was seen in 4 pts (12 %). There were 2 events of febrile neutropenia; grade 3 or 4 neutropenia was seen in 26 pts (81%). There was no significant thrombocytopenia, cardiovascular event and hypersensitivity reaction. Conclusions: Our analysis indicates that T and AC based chemotherapy is well tolerated and effective in Indian pts with LABC with response rates similar to international studies.

No significant financial relationships to disclose.
Doxorubicin (Dox), cyclophosphamide (Cyc) and weekly docetaxel (Doc) as first-line treatment of advanced breast cancer (ABC)
Authors: Ibrahim T. , Serra P. , Vertogen B. , Marangolo M. , Amadori D.
Published: March 2020

11516

Background: The breast is one of the leading cancer sites in women. ABC is essentially incurable with standard therapy and have a median survival of approximately 2 years. Dox, Cyc and Doc showed better efficacy results but also an increased rate of neutropenia and febrile neutropenia with respect to FAC (which is considered one of the most used standard option). The substitution of 5- fluorouracil with docetaxel resulted in an increase in the efficacy parameters but showed a higher hematological toxicity. One possible approach to reduce the rate of neutropenia is the administration of weekly docetaxel wich demostrated efficacy in ABC. Methods: ABC patients (pts) were enrolled in an open, single arm, non-randomized phase I escalation trial in 3 to 6 pts/cohorts. MTD dose was identified on the basis of DLT defined according to WHO grade classification of toxicity.*The treatment schedule was: Doc 20 mg/m2 (or 25, depending on dose level assignment) on day 1, 8, 15; Dox 40 mg/m2 (or 50, depending on dose level assignment) and Cyc 500 mg/m2 on day 1, every four weeks. Results: Eleven pts, median age 56 yrs, were enrolled. Five pts were allocated to dose level 20/50 (Doc/Dox) and six pts to dose level 20/40. At the dose level 20/50 febrile neutropenia (DLT) occurred in 2 pts. Other 3 pts experienced neutropenia WHO grade 4 (not DLT). Six patients were allocated at previous dose level and MTD was defined at Doc 20 mg/m2 in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 Conclusions: We didn’t observe toxic deaths and all the toxicity was limited and resolved. The accrual was stopped and we are waiting for one patient to end the treatment in order to analyse the final data and to design the phase II study a the dose Doc 20 mg/m2 (days 1, 8 and 15) in combination with Dox 40 mg/m2 and Cyc 500 mg/m2 (day 1) every 4 weeks.

No significant financial relationships to disclose.
A simple technique for cranio-spinal irradiation in young pediatric patients
Authors: Prabhakar R. V. , Julka P.
Published: March 2020

12501

Background: Craniospinal irradiation (CSI) is a complex radiotherapy technique. The implementation of craniospinal radiation makes atleast one junction between orthogonal cranial and spinal radiation fields. The traditional problem with CSI has been the concern over the dose delivered to the junctional area. We are presenting a simple technique of CSI which is easy to plan, treat and delivers a uniform dose to the entire cord. Methods: Ten patients of medulloblastoma suitable for CSI were taken in this study. All patients underwent CT based treatment planning. The patients were immobilized in prone position using the combination of uniframe and vacloc. CT scanning was performed for all the patients with 5 mm slice thickness. The cranium was treated with a dose of 36 Gy in 20# over 4 weeks and the spine with a dose of 30Gy in 20# over 4 weeks. Subsequently, the cranium was boosted to a dose of 20 Gy in 10 fractions over 2 weeks. For the cranial region, parallel opposed fields were used with half beam block provided by asymmetric jaws with the central axis in the caudal edge of the field. Subsequently, the gantry was brought to head top position and the couch was brought vertically down. The field length was opened to desired position to treat the spine by asymmetric jaws. In treatment planning system, doses were prescribed to the reference point placed in the cranial and spinal field. The maximum, minimum and mean dose to each anatomical structure was computed from dose volume histogram by summing the cranial and the spinal treatment plans. The junctional dose was calculated with special emphasis on field junction. Results: The results showed that the junction between the cranial and the spinal fields received relatively uniform dose. The hot spots in the cranial field were reduced by applying field in field technique. The daily setup time required for the treatment was considerably reduced with this technique. Patient with spinal field less than 30 cm from C2-C3 junction to the S1-S2 junction are ideally suited for this technique. Conclusions: Our technique of craniospinal irradiation is simple and technically sound. This technique can be applied for young pediatric patients undergoing CSI. The technique effectively deals with craniospinal irradiation

No significant financial relationships to disclose.
CNS atypical teratoid/rhabdoid tumor registry: An update
Authors: Tekautz T. M. , Weng C. , Peterson R. S. , Worley S. , Hilden J. M.
Published: March 2020

12507

Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system (CNS) in childhood, comprising up to 20% of malignant CNS tumors in patients < 3 years old. Although aggressive approaches including surgery, chemotherapy, intrathecal chemotherapy, high dose chemotherapy with hematopoietic stem cell transplant (HD-HSCT) and/or radiation have resulted in prolonged survival, overall survival remains poor. Methods: We reviewed pediatric patients with AT/RT on an IRB- approved registry formed in 1995 with new insight based on updated outcomes and additional patient enrollment. Upon patient entry, the managing physician submitted pertinent medical records for data abstraction. Physicians were contacted in accordance with privacy regulations for updated records. The Kaplan-Meier method was used to estimate survival time (from diagnosis to death or most recent status update) and groups were compared using the log-rank test at a significance level of p<0.05 with SAS® software version 9.1. Results: Analysis was conducted on 73 patients with a 4:3 male to female ratio. Age at diagnosis ranged from 5 days to 234 months, median = 19 months. Twenty-five patients have no evidence of disease, median 59 months from diagnosis (range 10–140). Forty-three patients (59%) developed recurrent or progressive disease; 6 of these patients are alive at a median of 28 months from recurrence (range 4–38). Forty-four patients (60%) are dead of disease; median time to death was 7 months from diagnosis (range 0–62). Factors correlating with survival are: primary tumor site not in spinal cord (p=0.029), lack of metastatic disease (p=0.024), gross total resection (p<0.001), and upfront radiation particularly in children < 3 years old (p<0.001). HD-HSCT appears to result in improved survival in children < 3 years of age who do not receive radiation, though the small sample size does not yield a statistically significant survival advantage. Conclusions: In treatment of AT/RT, extent of surgical resection and upfront radiation are beneficial for overall survival, particularly in young children. Early information regarding upfront HD-HSCT in lieu of radiation for children < 3 years of age with AT/RT suggests it may be effective. Prospective studies are warranted to further investigate this treatment.

No significant financial relationships to disclose.
Reirradiation and chemotherapy with ifosfamide, carboplatin and etoposide (ICE) for recurrent multiforme glioblastoma
Authors: Rodica Maricela A. , Minea L. N. , Oprea L. , Georgescu T. , Isacu I. , Tarlea A. , Bacinschi X.
Published: March 2020

12508

Background: Despite different treatment options no standard treatment regimen is yet available for patient with recurrent glioblastoma, and the prognosis remain poor. In our study our aim was to assess the efficacy of a schedule consisted in Ifosfamide plus Carboplatine plus Etoposide in recurrent multiform glioblastoma patients. Methods: Between January 2002 - December 2006 32 patients have been treated for recurrent glioblastoma multiforme. They were 18 male and 14 female, with median age 44.6 years old (range 22–65 years old). The ECOG was 0–1-2 , 12/14/6 patients respectively. 15 of them received chronic corticotherapy. All patients were previously irradiated and they have inoperable recurrences. After the confirmation of recurrence 30 of them could be reirradiated with 30 Gy using conformal beam radiotherapy on the tumor bed. Three weeks after completion of radiotherapy they receive six cycles of chemotherapy consisted in Ifosfamide 1000 mg/sqm day 1–3 + Carboplatin 75 mg/sqm day 1–3 + Etoposide 75 mg/sqm day 1–3 every 4 weeks, according to hematological tolerance. Results: Reirradiation associated with ICE chemotherapy resulted in one complete remission, three partial remission, and 8 stable disease. All responders were 37.5%. 26 patients survived at least six month and 22 of them received all six cycles. One year survival rate was 21.8%. Progression-free survival at six month was 31.25%. The regimen was well tolerated with mild toxicities. Haematological toxicity gr.I-II 8 pts, gr.III-IV 3 pt; nonhaematological toxicity: fatigability gr.I-II 12 pts., gr.III-IV 2 pt, gr.III-IV 1 pt, nausea gr.I-II 9 pts, gr.III-IV 4 pt, renal toxicity grade I-II 3 patients, Neurological toxicity grade I-II 5 patients. Conclusions: The treatment scheme has been well tolerated. Results are similar with PCV regimen, even slightly better. This regimen should be reconsider for concomitant radiochemotherapy.

No significant financial relationships to disclose.
The role of stereotactic conformal radiation boost in the temozolomide-based chemoradiation for glioblastoma multiforme: Preliminary analysis
Authors: Balducci M. , Manfrida S. , D’Agostino G. R. , Anile C. , Azario L. , Mangiola A. , Dinapoli N. , Apicella G. , Vitucci P. , Valentini V. , Cellini N.
Published: March 2020

12513

Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Aim of this analysis was to evaluate tolerance and outcome of the dose intensification by stereotactic conformal radiotherapy (SCRT) and concomitant chemotherapy with temozolomide Methods: From October 2003 to April 2006, 58 patients (34 males, 58.6%, 24 females, 41.4%) with histological diagnosis of glioblastoma multiforme received postoperative radiochemotherapy with SCRT boost. Median age was 58 yrs. ( range 25–80 yrs.). Twenty-nine out of 58 patients (50%) received a total dose of 70 Gy by conformal radiotherapy and SCRT boost delivered as concomitant and sequential, or sequential alone. The remainig 29 patients (50%) received a standard of 5940 cGy (180 cGy/day; CTV3: tumor bed + residual tumor if present + oedema; CTV2: tumor bed + residual tumor if present + 1.5 cm margins. CTV1: tumor bed + residual tumor if present + 0.5 cm margins only for the SCRT group). All patients received concomitant Temozolomide, 75 mg/m2 for a median duration of 28 days (range 14–45, depending on the chemoradiation schedule), and adjuvant chemotherapy with temozolomide for 6 cycles or until disease progression. Toxicity was recorded according to RTOG criteria; Survival analysis was calculated by the Kaplan-Mayer method and log-rank testing was used for groups comparison. Results: A 100% compliance was observed in both the groups of patients. A grade 3–4 acute neurological toxicity was registered in two patients treated with SCRT compared to one patient in the group which did not receive SCRT. One case of radionecrosis was observed in the SCRT group; in no case of either group neurological worsening nor corticosteroidal dependence were registered. At a median follow-up of 19 months (range 4–39), a trend towards a better outcome was observed in patients treated with SCRT, since the 1-year OS was 85.9% for SCRT patients (median not achieved) compared to 68.7% for the remaining patients (p=0.07). Conclusion: Our preliminary analysis suggests that a higher dose of RT delivered by conformal stereotactic boost did not increase acute or late toxicity and could achieve a better outcome in patients affected by GBM

No significant financial relationships to disclose.
Results of a phase IIb study in recurrent or refractory glioblastoma patients with the TGF-beta-2 inhibitor AP 12009
Authors: Hau P. , Bogdahn U. , Olyushin V. E. , Mahapatra A. , Parfenov V. E. , Venkataramana K. , Ludwig S. , Jachimczak P. , Heinrichs H. , Schlingensiepen K.
Published: March 2020

12521

Background: The antisense phosphorothioate oligonucleotide compound AP 12009 targets TGF-beta2. Since TMZ is now used in the adjuvant setting in GBM there is a high need for new treatment options in recurrence. In three Phase I/II dose escalation trials with AP 12009 in high-grade glioma (HGG) patients complete and long lasting tumor responses had been observed. Methods: The study G004 is an international open-label, randomized, active controlled, dose-finding Phase IIb study. Objective is a comparison of two doses of AP 12009 and standard chemotherapy. A total of 145 patients with histopathologically confirmed recurrent or refractory HGG (WHO Grades III and IV) were randomized into three treatment arms. Patients received treatment with low dose AP 12009 (10 μM), high dose AP 12009 (80 μMM), or standard chemotherapy TMZ or PCV. AP 12009 was applied by convection-enhanced delivery during using 7-day-on, 7-day-off cycles. Maximum number of cycles was 11. Results: Here we report on patients with recurrent or refractory glioblastoma (GBM, WHO Grade IV; AA patients see separate abstract). Out of 95 GBM patients treated, 28 pts received 10 μM AP 12009, 34 pts AP 12009 80 μM, and 33 pts standard chemotherapy (28 TMZ, 5 PCV). Median age differed between treatment groups (see table ). Dose finding was achieved, as efficacy and safety results for the AP-10 group were superior to those of the AP-80 group (see table ). Comparable hazard ratios for survival were seen in the three treatment groups (see table ). Long lasting responses were observed in both AP 12009 groups. Conclusions: The safety profile of AP 12009 in GBM patients was good. The durable responses in both AP 12009 groups and the survival data confirm the proof of concept obtained in Phase I/II trials for treatment of recurrent GBM patients with AP 12009.

[Table: see text]

No significant financial relationships to disclose.
Modeling and simulation of neutropenia to support dosing regimens for liposome-encapsulated paclitaxel easy-to-use (LEP- ETU)
Authors: Grasela T. H. , Fetterly G. J. , Dul J. L. , LeComte D. , Grahn A. Y. , Fiedler-Kelly J. B. , Sherman J. W. , Damjanov N. , Fishman M. N. , Tan A. R.
Published: March 2020

13011

Background: LEP-ETU is a liposomal formulation of paclitaxel designed to reduce toxicities while maintaining or enhancing the efficacy of the drug. A PKPD model was used to characterize the time course of neutrophils in relation to blood exposure of LEP-ETU in patients with solid tumors. Simulations were performed to provide justification for dosing schedule in Phase 3 trials. Methods: Data from 63 patients in two phase I studies with advanced malignancies were utilized. LEP-ETU was infused intravenously over 90 min. at 135, 175, 225, 275, 325, and 375 mg/m2 every 21 days (Q3W). A separate cohort received 175 mg/m2 of LEP-ETU infused over 3 hours following a Q3W regimen. Population PKPD modeling and simulations were performed to assess the influence of dose and schedule (275 - 325 mg/m2 Q3W vs. 90 - 110 mg/m2 QW) on neutropenia. Results: The temporal relationship between circulating neutrophils and paclitaxel concentrations was adequately characterized using a model representative of progenitor cells undergoing differentiation and maturation into neutrophils. Mean predicted (%SEM) baseline ANC was 4.3 (6) x 109/L, representative of a normal neutrophil count. Mean transit time (%SEM) was 80 (8) hr, representing a post-mitotic time delay to neutrophil maturation. The neutrophil T1/2 was 14 hr, comparable to published values. The drug effect (Slope·Cp) on the proliferation rate constant is decreased by 9- and 91-fold when 10 or 100 units of drug is present, indicative of paclitaxel’s inhibition of progenitor cell production in bone marrow. Simulations suggest a higher risk of neutropenia with the Q3W regimen and dose-dependent severity for both the Q3W and QW regimens. The predicted incidence of grade 4 toxicity increased from 33% - 42% across the dose range of 275 - 325 mg/m2 Q3W. For a dose of 110 mg/m2 given QW, the incidence of grade 4 neutropenia was 16% compared to 42% for the same total dose of 325 mg/m2 given Q3W. Conclusions: Modeling and simulation predict that a Q3W regimen of 325 mg/m2 LEP- ETU (MTD) provides acceptable neutropenia outcomes comparable to 175 mg/m2 paclitaxel Q3W, while minimizing the Cremophor- associated adverse events. Future consideration of QW regimens may be explored.

No significant financial relationships to disclose.
Phase I dose escalation trial of biweekly pemetrexed in combination with docetaxel in advanced solid tumors
Authors: Garland L. L. , Cranmer L. , Gerstner G. , Walker R. , Obregon Y. , Ebbinghaus S.
Published: March 2020

13019

Background: Pemetrexed (PEM) and docetaxel (DOC) are cytotoxic agents with a broad range of activity in solid tumors and relatively non-overlapping toxicities. We are conducting a single site dose escalation trial of biweekly dosing of PEM + DOC in advanced solid tumor patients (pts) to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and preliminary antitumor activity for the combination. Eligible pts have had 0–1 prior therapies, a performance status of 0–1, and creatinine clearance of =45 ml/min. Methods: Escalating doses of PEM (10 min infusion, d1 and 15) and DOC (1 hr infusion, d1 and 15) are administered q 28 days. Pretreatment vitamin supplementation consists of 1 mg IM vitamin B12 repeated q 9 weeks and daily oral folate 350–1,000 mcg. DLT is defined as grade 4 neutropenia =5 days, febrile neutropenia, grade 4 thrombocytopenia, or grade 3–4 non-hematological toxicity in cycle 1. Results: To date, 12 pts ages 40–70 have been enrolled at 3 dose levels. Tumor types (N pts) include leiomyosarcoma (3); schwannoma (1); synovial sarcoma (1); transitional cell carcinoma of the bladder (1) and non-small cell lung carcinoma (NSCLC) (6). One patient was withdrawn for early progressive disease. Grade 3/4 treatment-emergent toxicities for 11 pts include neutropenia (3), anemia (1), mucositis (1), hyperglycemia (1), anorexia (1), weight loss (1), hyponatremia (1), pain (1), dehydration (1), fatigue (1), and thromboembolism (1). In addition, one pt had grade 5 pneumonitis during cycle 3. Dose level 3 has been expanded due to DLT in 1 pt. Antitumor activity for 11 evaluable pts includes 2 confirmed partial responses (by RECIST) in uterine leiomyosarcoma after adjuvant AIM therapy and pretreated NSCLC; stable disease in 5 pts; and progressive disease in 4 pts. Conclusion: Biweekly dosing of PEM + DOC is feasible and shows activity in a number of advanced solid tumors. The MTD has not been reached. *Pt with early progression replaced

[Table: see text]

No significant financial relationships to disclose.
Prostate cancer: Vaccine Sentinel Immunized Node (SIN) target for adjuvant locoregional chemotherapy in autologous vaccine
Authors: Lasalvia-Prisco E. M. , Garcia-Giralt E. , Cucchi S. , Vazquez J. , Brent M. , Walton D.
Published: March 2020

13500

Background: In cancer patients, the systemic immune response elicited by Tumor Associated Antigens is started by a locoregional immune response at the microenvironment constituted by the antigen source (the tumor) and the draining sentinel lymph node (SLN). The locoregional immune response is decisional because it starts a systemic immune response configured as the SLN response: tolerogenic or protective (AJ Cochran, Nat Rev Immunol, 2006). Cancer vaccines reproduce this locoregional immune response: the vaccination site as the tumor antigen source and the draining SIN as the SLN (ML Disis, Blood, 1996). In experimental models, several chemotherapy drugs, especially Etoposide, injected in the vaccination site switch the locoregional immune response from tolerogenic to protective (RJ Scheper, Invest New Drugs, 1984). This study explores Etoposide as a locoregional adjuvant of the previously described Autologous Thermostable Hemoderivative-Cancer Vaccine ATH-CV (E Lasalvia-Prisco, ASCO, 2006). Methods: Thirty three M1 prostate cancer patients, hormone and chemotherapy resistant, performance status = 2, and PSA rising level, were included in this prospective, IRB-approved phase I/II trial. Patients were 3-group (G) randomized (11 each), submitted to different treatments: G1, no additional oncology treatment; G2, ATH-CV; G3, ATH-CV plus Etoposide 200 μg at vaccination site days 1–4 after vaccine. Statistic assessment (Student’s t-test) was performed at the 30-day end point: ATH sensitization by Delayed Type Hypersensibility test (DTH) and Lymphocyte Proliferative Assay (LPA); PSA serum level and cells immunophenotyping in biopsies of SIN scintigraphy-localized. Results: Statistical significant (p<0.05): DTH test > 5 mm: G1, 0/11; G2, 4/11 and G3, 8/11. LPA > 2.0: G1, 0/11; G2, 5/11 and G3, 9/11. Immunophenotyping: CD4+ CD25+ (Treg): G1>G2>G3. 30 days PSA increase: G1>G2>G3. No relevant toxicity was evidenced. Conclusions: In advanced prostate cancer, when all other treatments are exhausted, the sensitization and tumor antiprogressive effect of ATH-CV were potentiated by Etoposide as local adjuvant. SIN depletion of tolerogenic cells is suggested as mechanism of action.

No significant financial relationships to disclose.
Specific immune responses against hepatocellular carcinoma induced by dendritic cell- HepG2 fusion cells derived- exosomes
Authors: Zhang H. , Zhang L. W. , Liu W. C.
Published: March 2020

13511

Background: To assess the properties of exosomes secreted by fusion cells of hepatoma patient-derived dendritic cells(DCs)and hepatoma cell line (HepG2) and to evaluate the function of these exosomes to trigger efficient T cell responses against HepG2 cells in vitro. Methods: Peripheral blood mononuclear cells (PBMC) from hepatoma patients were isolated and in the presence of GM-CSF and IL-4, PBMC were cultured in vitro for one week to induce dendritic cells (DC). Fusion cells of DC with HepG2 cells (DC- HepG2) were achieved by PEG and were isolated by magnetic device with HLA Class II Dynabeads. Exosomes were then prepared from the supernatants of the fusion cells by ultra filtration centrifugation and sucrose gradient ultracentrifugation. T lymphocytes were pulsed with exosomes directly in the presence of IL-2. After co-cultured with target cells, the stimulated lymphocytes were tested by IFN-? release assay and cytotoxicity capacity assay. Results: After fusion, DC-HepG2 expressed expressed high level of DC surface molecules, including CD83 87.4%, CD80 94.9%, CD86 90.13% and HLA-DR 98.62%. Application of the isolation procedure to fusion cells also revealed exosome vesicles by transmission electron microscopy. Protein analysis by FCM was performed and revealed that the costimulatory molecule CD86 and AFP protein was detectable. The fusion cell- derived exosomes could directly activate T lymphocytes which lysed HepG2 target cells much more effectively than T cells alone did (P<0.05). To determine whether the lysis was HepG2 tumor cell-specific, SMMC7721 and K562 cells were used as target cells and nearly no lysis of these cells was observed. Furthermore, IFN-? in the culture supernatants of exosomes- activated T cells was significantly higher than that in normal control T cells (P<0.05). Conclusions: Exosomes could be purified from the supernatants of fusion cells. These exosomes could activate T cells directly and could induce effective HepG2 secific CTL responses. DC- HepG2 fusion cells-derived exosomes may represent as a promising approach of immunotherapy for HCC.

No significant financial relationships to disclose.
Clearance of monoclonal antibody (mAb) CP-675,206 by therapeutic plasma exchange (TPE) or plasmapheresis
Authors: Sharma A. , Bumerts P. , Gomez-Navarro J. , Pavlov D. , Ribas A.
Published: March 2020

13515

Background: CP-675,206 is a fully human, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blocking mAb with immune stimulating properties under development for the treatment of metastatic melanoma. The pharmacokinetics of CP-675,206 is similar to endogenous IgG, with a long plasma half-life (22 days). We explored the use of TPE in two patients (pts) receiving CP-675,206, postulating that TPE could be used to remove mAb in cases where toxicities are thought to result from persistence of mAb in circulation. Methods: For both pts, five TPEs were performed over 7 days using a Cobe Spectra blood cell separator (TPE daily x 3, 2 days rest, and TPE daily x 2). One plasma volume was processed per TPE and replaced with a 60%/40% albumin/saline solution. Plasma CP-675,206 concentration was measured at baseline and after the 3rd and 5th TPE. Results: Patient 1 was a 62 year-old with metastatic melanoma who received 8 monthly doses of CP-675,206 (10 mg/kg). Six days after the last dose, the pt was found to have elevated ALT and bilirubin and detectable anti- smooth muscle and anti-microsomal antibodies. Based on a suspicion of therapy-related autoimmune hepatitis, the pt underwent TPE. Plasma CP-675,206 concentration declined by 96% following the 5th TPE, and ALT and bilirubin normalized over the 4 weeks following TPE with no other evidence of clinical hepatitis. Patient 2 was a 78 year-old with in-transit melanoma who received 3 monthly doses of CP-675,206 (10 mg/kg) and was responding to therapy. Two weeks after the last dose the pt developed diffuse bilateral arthralgias. The pt was diagnosed with rheumatoid factor-negative rheumatoid arthritis, presumably related to therapy with CP-675,206, and underwent TPE. Pre- and post-TPE plasma CP-675,206 concentrations are pending. The arthralgias persisted, and the pt subsequently received oral methotrexate with slow improvement in symptoms over the next 6 months. Conclusions: TPE is highly effective for reducing the plasma concentration of CP-675,206 and may be useful to avert the progression of drug-related adverse events. Clinical benefit from TPE may vary depending on the interval from dosing and may be limited by slow reversibility of T-cell immunostimulation.

[Table: see text]
Interactions of breast cancer cells and tumorantigen-reactive T-cells derived from bone marrow
Authors: Schuetz F. , Sachsenweger C. , Rom J. , Schneeweiss A. , Schirrmacher V. , Beckhove P. , Sohn C.
Published: March 2020

13517

Breast cancer is an immunogenic tumor which is usually recognized by the cellular immunosystem via tumor-associated antigens (TAA) presented by antigen-presenting cells like dendritic cells. Although we were able to find tumorantigen-reactive CD8+CD45R0+ T-memory cells (TMC) in the bone marrow of 67% of primary breast cancer patients by using interferon-?-ELISPOT-analysis there seem to be a minority of non-responers. In comparison to classic tumor characteristics non-responders can be find more often in non-differentiated, hormone-receptor negative tumors. In a phase-1 trial of a cellular immunotherapy with reactivated tumorantigen-reactive autologous TMC derived from bone marrow we measured CD4+ T-cell (TC) responses in stimulation cultures ex vivo to examine whether there are other immunological answers in non-responder. TC were activated by dendritic cells pulsed with TAA from MCF-7 lysate under IL-2 co-stimulation. We were able to show that next to a classic TH1-response with high levels of IFN-a there seems to exist TH2-responses mediated by high levels of TGF-β1 and low levels of IFN-a. The relation of both cytokines was directly related to the detection of tumorantigen-reactive TC and to tumor grading. Multiplex-cytokine analysis was able to confirm these findings. Additionally there seems to be an important impact of regulatory TC in responders as well as in non-responders. In patients with tumorantigen-reactive TC a combined active and passive vaccination therapy was done. These results may play an important role in further active and passive vaccination strategies.

No significant financial relationships to disclose.
Correlation between the EGFR intron 1 CA dinucleotide repeat and skin toxicity in lung cancer patients treated with erlotinib
Authors: Garcia-Donas J. , Leskelä S. , Sanchez J. M. , Camara J. C. , Rodriguez N. , Dhimes P. , Pinedo F. , Lopez J. L. , Jara C. , Rodriguez-Antona C.
Published: March 2020

14001

Background: Acneiform rash is the main toxicity of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. The length of the CA dinucleotide repeat in EGFR intron 1 has been suggested to predict the biological effects of tyrosin kinase inhibitors. Thus, we compared this polymorphism with the rash severity in non-small cell lung cancer (NSCLC) patients treated with erlotinib. Methods: Toxicity was evaluated in 18 metastatic or locally advanced unresectable NSCLC patients treated orally with 150 mg/d of erlotinib: 7 retrospectively and 11 prospectively. Rash was graded according to a modified scale based on the Common Toxicity Criteria v.3.0, which subclassified grade II rash into IIA (topic intervention indicated) and IIB (oral intervention indicated). Genomic DNA was isolated from each patient; the length of the EGFR intron 1 CA dinucleotide repeat was measured by PCR amplification and analyzed on a capillary sequencer. Results: The most common EGFR genotypes were: 16, 20, 17 and 18 CA repeats (with 50, 25, 8 and 8% frequency, respectively). 33% of the subjects with a total amount of CA repeats <34 had grade IIB-III rash vs 11% of the subjects with =34 CA repeats. In addition, all patients with 0 grade toxicity belonged to the =34 CA group. When the only patient with a previous dermatological disease (psoriasis) was excluded from the analysis, the difference between both groups increased, reaching statistical significance (p=0.047). Conclusions: This data suggests that NSCLC patients with long EGFR intron 1 CA alleles present lower grades of skin toxicity when treated with erlotinib than patients with short CA alleles. Further studies are required to confirm this data.

[Table: see text]

No significant financial relationships to disclose.
A phase Ib study to assess the safety of lexatumumab, a human monoclonal antibody that activates TRAIL-R2, in combination with gemcitabine, pemetrexed, doxorubicin or FOLFIRI
Authors: Sikic B. I. , Wakelee H. A. , von Mehren M. , Lewis N. , Calvert A. H. , Plummer E. R. , Fox N. L. , Howard T. , Jones S. F. , Burris H. A.
Published: March 2020

14006

Background: Lexatumumab (HGS-ETR2) is a fully-human agonistic monoclonal antibody that targets and activates the Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor 2 (TRAIL-R2). TRAIL-R2 is a member of the Tumor Necrosis Factor Receptor (TNFR) superfamily that, when activated, induces apoptosis via the extrinsic pathway. Lexatumumab shows promising anti-tumor activity in preclinical models, particularly in combination with chemotherapeutic agents. Single-agent lexatumumab was well-tolerated in phase I trials. This is the first study of the safety of a TRAIL-R2 agonist in combination with chemotherapy. Methods: Patients for whom gemcitabine, pemetrexed, doxorubicin or FOLFIRI was considered an appropriate treatment received one of the full-dose chemotherapy regimens plus lexatumumab every 2 weeks (for gemcitabine and FOLFIRI) or 3 weeks (for pemetrexed and doxorubicin). Four to 6 patients were treated with 5 mg/kg lexatumumab in each chemotherapy cohort prior to dose escalation to 10 mg/kg. Results: To date, 41 patients with a wide range of cancer types have received 164 courses of lexatumumab over the 2 dose levels. The majority (33/41) received at least 2 courses (range 1 to 19). Lexatumumab was well-tolerated; no dose reductions of lexatumumab were required. Severe adverse events considered at least possibly related to lexatumumab included anemia, fatigue and dehydration. Tumor shrinkage has been observed, including confirmed partial responses (PRs) in the FOLFIRI and doxorubicin arms. Eight patients continue on study. Conclusions: Lexatumumab can be safely administered in combination with a wide range of chemotherapeutic agents. Evaluation of the efficacy of lexatumumab in combination with chemotherapy in Phase 2 trials is warranted.

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A phase I and pharmacokinetic/pharmacodynamic study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in Japanese patients with solid tumor
Authors: Fujiwara Y. , Yamamoto N. , Yamada K. , Yamada Y. , Shimoyama T. , Koizmi F. , Nishio K. , Otsuki T. , Frankel S. R. , Tamura T.
Published: March 2020

14015

Background: Vorinostat (Zolinza™), a potent inhibitor of histone deacetylase (HDAC), induces tumor growth inhibition, differentiation, and apoptosis in vitro. Increasing evidence has revealed clinical activity of vorinostat in patients (pts) with various types of cancer including cutaneous T-cell lymphoma. Methods: Japanese pts with solid tumor who failed standard therapy were enrolled in a single institution, National Cancer Center hospital, Phase I study. Pts were dosed with vorinostat BID for 14 consecutive days followed by 7 day-rest starting at 100 mg and escalated by 100 mg BID until MTD was established. Subsequently single daily dosing was tested at 400 and 500 mg. PK was measured at total of 41 timepoints. Response was also evaluated according to the international workshop criteria. Results: MTD was established as 200 mg BID and 500 mg QD for 14 consecutive days followed by a 7 day-rest. All 18 enrolled pts were assessed for safety and PK. Median age was 58 yrs [25–72]. Ten of 18 pts had lung cancer. Two of 6 pts receiving 200 mg BID experienced DLTs: Grade 4 thrombocytopenia, and Grade 4 thrombocytopenia and Grade 3 anorexia. None of 3 pts receiving 400 mg QD experienced DLT. One of 6 pts receiving 500 mg QD experienced Grade 3 anorexia and fatigue. AUC of vorinostat increased generally proportional to dose in the range of 100–500 mg. PK was not greatly affected by multiple doses. Intact drug was hardly excreted in urine (<1% of dose). PK profile is similar to that established in US pts. As of Dec 2006, 1 pt with invasive thymoma received 200 mg BID for 1 yr. Nine pts achieved SD as best response. Conclusions: This study demonstrates the safety of vorinostat 200 mg BID and 500 mg QD for 14 consecutive days followed by 7 day-rest. These would be the RD for Phase II studies on this schedule.

No significant financial relationships to disclose.
A phase I study of BMS-582664 (brivanib alaninate), an oral dual inhibitor of VEGFR and FGFR tyrosine kinases, in combination with full-dose cetuximab in patients (pts) with advanced gastrointestinal malignancies (AGM) who failed prior therapy
Authors: Garrett C. R. , Siu L. L. , Giaccone G. , El-Khoueiry A. , Marshall J. , LoRusso P. , Velasquez L. , Kollia G. , He P. , Feltquate D.
Published: March 2020

14018

Background: Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Prior studies have validated both VEGF and EGF signaling pathways as targets in AGM. The MTD of single-agent brivanib is 800 mg qd (ASCO #3051, 2006). Methods: An open-label Phase I dose-escalation study of brivanib in combination with cetuximab was conducted in pts with AGM who failed prior therapy. Brivanib was given po Day 1 and qd from Day 8, starting at 320 mg. Cetuximab was given IV Day 8 (400 mg/m2) then weekly (250 mg/m2). Dose escalation of brivanib continued to 800 mg qd, when an expansion cohort for pts with colorectal cancer (CRC) was opened for additional safety and efficacy. Fresh tissue and blood sampling for biomarker and pharmacokinetic (PK) analysis was performed. FDG-PET was obtained at Baseline X 2, Days 15 and 56. Tumor response (modified WHO) was evaluated q 8 weeks. Results: 18 pts (15 CRC, 2 esophageal, 1 other) were treated with 320, 600 or 800 mg qd of brivanib in combination with cetuximab for a median of 8 weeks (range 1 - 20+). A single DLT, bilateral pulmonary emboli, occurred at 320 mg qd. Few treatment-related AEs occurred across the 3 cohorts (Table). PK/biomarker data is pending. Available FDG-PET results from measurements in 8 pts with 2–3 target lesions showed good baseline reproducibility in SUVpeak, SUVmean and SUVmax, with intra-subject CV of 3.6%, 7.2% and 9.3%, respectively. Conclusions: Brivanib in combination with full-dose cetuximab was well tolerated at ≤800 mg qd and did not result in enhancement of cetuximab associated AEs. Pre-treatment FDG-PET is a highly reproducible imaging modality.

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Clinical response to targeted radionuclide therapy with multiple 500 mCi doses of 111In-pentetreotide in patients with progressive neuroendocrine tumors
Authors: Delpassand E. S. , Sims-Mourtada J. , Azhdarinia A. , Ashoori F. , Sureshbabu W. , Hernandez J. , Torabi F. , Espenan G. , Woltering E. A. , Anthony L. B.
Published: March 2020

14027

Background: Patients with advanced stage neuroendocrine tumors have limited therapeutic options. Previous treatments with doses up to 360 mCi per fraction have shown promising results in stabilizing progressive disease. The intent of this study was to evaluate the efficacy and safety of 2 consecutive 500 mCi doses of 111In-pentetreotide in patients with progressive neuroendocrine tumors. This study was performed according to an FDA approved IND application. Methods: In a non-randomized study, 18 patients (13 men, 5 women) with an average age of 59 (ranging from 41–83 yr.) received 2 cycles of 500 mCi 111In-pentetreotide infused over 3 to 6 hours (avg. cumulative dose range: 955–1006.1 mCi). All patients had progressive neuroendocrine tumors and failed first line therapy. All patients had grade 3 to 5 uptake in the tumors in the pre-therapy diagnostic 111In-pentetreotide scan. The primary endpoint was clinical, metabolic and imaging response using RECIST criteria. Early and long term hematological, renal and hepatic toxicities during the average follow up period of 9.87 months (range 3.93 to 17.23 months) was performed using NCI Common Toxicities criteria. Results: Sixteen out of 18 patients with previously progressive disseminated neuroendocrine disease achieved stable disease by imaging criteria. Metabolic response defined as 25% or more decline in Chromogranin or other markers was achieved in 72% of the patients. Clinical response defined by Functional Living Index (FLI) questionnaire and physical exam was achieved in 84% of the patients. Ten patients (55%) had grade I or II hematological toxicities, one patient had grade III thrombocytopenia, with nadir mean of 5 weeks after therapy. None of the patients required supportive therapy. Duration of hematological toxicities ranged from 1–6 weeks). One patient had grade II liver toxicity which appeared 4 weeks after therapy and resolved on week 5. No renal toxicity was observed during the follow-up period. Conclusions: Multiple 500 mCi doses of 111In-pentetreotide therapy are effective in patients with progressive disseminated neuroendocrine tumors. Safety profile of this regimen suggests the opportunity for non-myeloablative dose escalation.

No significant financial relationships to disclose.
A phase I dose-escalation study of the safety and pharmacokinetics (PK) of XL184, a VEGFR and MET kinase inhibitor, administered orally to patients (pts) with advanced malignancies
Authors: Salgia R. , Hong D. S. , Camacho L. H. , Ng C. S. , Janisch L. , Ratain M. J. , Kurzrock R.
Published: March 2020

14031

Background: XL184 is a potent orally available small molecule inhibitor of MET and VEGFR2/KDR, and also inhibits KIT, RET, FLT3, and Tie-2. Methods: This is a ph 1 cohort dose escalation study. Pts with advanced malignancies are treated with 2 cycles of XL184 orally daily for 5 consecutive days every 2 weeks. Response is assessed every 8 wks by RECIST criteria and pts with SD or better receive maintenance therapy. Plasma markers of angiogenesis VEGF-A, sVEGFR2 and Ang2 are being analyzed. Results: A total of 25 pts with advanced malignancies have been treated across 7 dose levels: 0.08 to 5.12 mg/kg. A total of 10 pts have had SD lasting > 3 months. Three pts with medullary thyroid carcinoma (one of whom had a documented RET mutation) had substantial reductions in plasma calcitonin. Three pts have had stable disease for over 6 months, including 1 pt with carcinoid (20% decrease in liver metastases) and 1 pt with T- cell lymphoma (on treatment for >12 mos). One pt with papillary renal cell cancer, a disease that sometimes bears activating MET mutations, demonstrated 9% tumor reduction at first restaging. There have been no DLTs to date. Preliminary PK analysis (0.08–1.28 mg/kg) suggests linear PK with average Cmax values 34.2, 70, 198, 322 and 603 ng/mL following the fifth dose at 0.08, 0.16, 0.32, 0.64 and 1.28 mg/kg, respectively. The terminal half-life is 80–90 hrs, resulting in concentrations exceeding 200 ng/mL for 96 hours following the fifth dose at 1.28 mg/kg. Conclusions: XL184 appears generally well tolerated at doses tested to date. XL184 has a long terminal half-life. Early signs of antitumor activity have been observed, at doses not associated with toxicity, in patients with various cancers, including but not limited to those that may have RET (medullary thyroid) or MET (papillary renal) mutations.

No significant financial relationships to disclose.
Clinical evaluation of nitric oxide responses to anti-VEGF therapy with bevacizumab
Authors: Nixon A. , Allen J. , Miller E. , Savage S. , Kaplan N. , Starr M. , Bendell J. , Uronis H. , Fernando N. , Hurwitz H.
Published: March 2020

14039

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has been linked to hypertension (HTN) and arterial thrombo-embolic events that may involve changes in nitric oxide (NO) bioavailability. Methods: 25 patients (pts) with advanced cancer, normal renal function and blood pressure (BP), no increased risks for anti-VEGF toxicities, and not on medications known to confound biomarker studies (including anti-hypertensives) were treated with bevacizumab (BV) 15mg/kg d1, then 10mg/kg q2 week. Prior to biomarker assessment, all patients were placed on a calorie-, nitrate-, and salt-restricted diet for 72 hr. All measures were taken pre-treatment (preRx) and on day 28 of treatment (onRx). Dependant variables included; a) Brachial artery reactivity (BAR) following hyperemic flow stimulus (endothelium-dependent) and sub-lingual nitroglycerine (NTG; endothelium-independent); b) exhaled and plasma/urine total NO2/NO3 using chemiluminescence (Sievers 280NOA) with either KI or VCl3 in HCl as the reductants; c) blood pressure. Additionally, we measured multiple regulators of vascular tone and injury. Comparisons were analyzed using Spearman signed rank tests. Results: Of 25 pts (16 F, 9 M) treated, 21 patients were fully evaluable. Significant changes or strong trends were observed upon comparing preRx vs. onRx for BP (SBP +12.4, DBP +5.6, MAP +7.9 mm Hg), and flow-mediated BAR (-2.0%) with no changes in hyperemic flow/shear stimulus or smooth muscle function (BAR NTG), indicating a decrease in brachial artery endothelial responsiveness. Exhaled NO decreased (-0.8% d1vs d28 and -0.6% pre/post infusion day1). Measurement and data analysis of urinary/plasma NO2/NO3, as well as angiogenic markers, are almost complete and will be reported. Conclusions: After one month of treatment, BV increased BP and decreased endothelium- dependent BAR and exhaled NO, suggesting potentially broad, mechanism-based effects on NO bioavailability in patients.

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Effectiveness of the dual specific Src/Abl kinase inhibitor AZD0530 in combination with tamoxifen in preventing acquired anti-estrogen resistance in breast cancer cells
Authors: Hiscox S. , Green T. P. , Smith C. , Jordan N. , James M. , Nicholson R.
Published: March 2020

14054

Background: AZD0530 is a novel, orally potent, once-daily, highly selective and dual-specific Src/Abl kinase inhibitor with potential for activity in a wide range of tumors. In the context of breast cancer, where tamoxifen resistance presents a major problem, Src inhibition may be a particularly valuable therapeutic strategy since we have previously observed that elevated Src kinase activity accompanies anti-estrogen resistance in vitro, promoting an aggressive cell phenotype. Here, we have explored the potential therapeutic effects of Src inhibition with AZD0530, alone and in combination with tamoxifen, on the acquisition of endocrine resistance in breast cancer cells. Methods: MCF7 and T47D breast cancer cells were exposed to tamoxifen (10–7 M), AZD0530 (1 μM), or both agents in combination for a minimum of 10 months with passaging as necessary, or until total cell death occurred. Cells were assayed at monthly intervals for intracellular signaling pathway activity (Western Blotting) and in vitro invasive capacity (Matrigel invasion assays). Apoptosis and proliferation were assessed by ELISA and Ki67 staining, respectively. Changes in c-Myc and cyclin-D1 were measured with RT-PCR. Results: Treatment of cells with tamoxifen alone ultimately resulted in acquired resistance, elevated Src kinase activity, and a Src- dependent increase in invasive capacity. Chronic exposure to AZD0530 alone resulted in outgrowth of AZD0530 resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasiveness. Treatment of MCF7 and T47D cells with AZD0530 and tamoxifen combined resulted in a reduction of Src, FAK, and Akt activity, inhibition of c-Myc gene expression, and complete abrogation of their in vitro invasive behavior. Furthermore, combination treatment completely prevented cell proliferation and the subsequent emergence of a resistant phenotype, with a total loss of cells by 12 weeks. Conclusions: Inhibition of Src kinase with AZD0530, when used in conjunction with anti-estrogen therapies, effectively prevents acquired resistance in breast cancer cells in vitro suggesting a potential novel therapeutic benefit of Src kinase inhibitors clinically.

No significant financial relationships to disclose.