bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of bortezomib in combination with intensified CHOP-like regimen (ACVBP) in patients with previously untreated T-cell lymphoma: Results of the GELA LNH05–1T trial
Authors: Delmer A. , Fitoussi O. , Gaulard P. , Laurent G. , Bordessoule D. , Morschhauser F. , Ferme C. , Tilly H. , Gisselbrecht C. , Coiffier B.
Published: August 2020

8554

Background: Patients with peripheral T/NK cell lymphomas (PTCL) still have a dismal prognosis with 5-yr survival less than 30% in most cases. No alternative regimen has been proven superior to CHOP so far. This multicenter phase II study was carried out to assess efficacy and safety of bortezomib in combination with an intensified CHOP-like regimen. Methods: Pts aged 18 to 65 yrs with previously untreated PTCL were planned to receive 4 bi-monthly cycles of ACVBP (doxorubicine 75 mg/m2 D1, cyclophosphamide 1200 mg/m2 D1, vindesine 2 mg/m2 D1 and D5, bleomycine 10 mg D1 and D5 and prednisone D1 to D5) followed by a sequential consolidation consisting of HD methotrexate (2 courses), etoposide + ifosfamide (4 courses) and cytarabine (2 courses) at 2 weeks intervals. Bortezomib 1.5 mg/m2 was administered at D1 and D5 of each ACVBP cycle, and then at D1, D8 and D15 every 4 weeks during consolidation phase for a total of 20 injections during the whole treatment. Results: 57 eligible pts (M 38, F 19, median age 52.5 yrs) with mostly AITL and PTCL NOS subtypes were enrolled between January 2006 and November 2007; 78% had stage III-IV disease and 53% had aaIPI ≥ 2. Forty six pts (81%) have completed induction treatment with ACVBP and only 28 (49%) the consolidation phase, mainly for disease progression. The CR + CRu rate was 45% after induction and 46% after consolidation. As of November 14th, 2008, 22 pts (39%) have died, mostly from lymphoma. The median percentage of planned dose of bortezomib received was 98% during ACVBP induction where the vinca alkaloid used was vindesine, and ranged from 90 to 95% during the consolidation courses. The dose intensity of bortezomib was 84.3% during induction, similar to that of doxorubicine and cyclophosphamide. Thrombocytopenia was more pronounced than previously observed with ACVBP alone but no life-threatening hemorrhagic event occurred. Conclusions: The combination of bortezomib with ACVBP is feasible without neurological or platelet unexpected toxicities. The response rate of such a regimen in PTCL does not appear higher than previously observed with ACVBP alone in our historical cohort.

No significant financial relationships to disclose.
Salvage chemotherapy with rituximab, oxaliplatin, cytosine arabinoside, and dexamethasone (ROAD) in patients with relapsed CD20+ aggressive B-cell lymphoma
Authors: Johnston P. B. , LaPlant B. , Kurtin P. , Habermann T. , Moore D. , Nabbout N. , Nikcevich D. , Rowland K. , Witzig T.
Published: August 2020

8556

Background: In the original PARMA trial it was demonstrated that salvage chemotherapy with DHAP followed by autologous bone marrow transplant resulted in increased overall survival over salvage chemotherapy with DHAP alone in patients with aggressive lymphomas. The current study was designed to assess safety and feasibility of ROAD as a salvage chemotherapy regimen which could be administered as an inpatient or outpatient. Methods: Patients received immunochemotherapy on the following schedule: rituximab 375 mg/m2 weekly × 4, oxaliplatin 130 mg/m2 on day 2, Ara C 2000mg/m2 x 2 doses on day 2 and dexamethasone 40 mg on days 2–5, with OAD repeated at 3 week intervals (up to 6 cycles). Patients were considered for autologous stem cell transplantation after 2 cycles if eligible. Eligible histologies included diffuse large B cell lymphoma, mantle cell lymphoma and transformed lymphoma in first relapse. Results: 50 patients were accrued from Aug 2006 through Jul 2008: 5 patients were deemed ineligible after central pathology review. Baseline characteristics of eligible patients included median age 69 (range 23 - 77), 53% were male, 53% had advanced stage at relapse, LDH was elevated in 58% and all patients had an ECOG PS of 2 or less. Patients received a median of 2 cycles of therapy (range 1–6) with 39/45 receiving treatment in cycle 2, with 12 patients continuing beyond 2 cycles. 31 patients experienced grade III/IV hematologic toxicity and 22 patients had grade III/IV non-hematologic toxicity, primarily febrile neutropenia. One patient developed grade III nephrotoxicity due to disease progression. Twenty patients received their treatments exclusively as outpatients. 26 responses were seen in the 45 eligible patients (58%, 95% CI: 44–74%), with 20 responding patients proceeding to autologous SCT. Conclusions: ROAD is a safe and effective salvage chemotherapy regimen for relapsed aggressive lymphoma, including as a preparatory regimen prior to stem cell transplant. It appears to have similar response rates to R-DHAP in a similar patient population, but without the potential nephrotoxicity (data from prior published study from NCCTG). ROAD can be safely administered as an inpatient or outpatient.

No significant financial relationships to disclose.
A phase I trial evaluating the safety and biological activity of iboctadekin (rhIL-18) in combination with rituximab in patients with CD20+ B-cell non-Hodgkin's lymphoma
Authors: Robertson M. J. , Kline J. , Bauman J. , Gardner O. , Jonak Z. , Koch K. M. , Murray S. C. , Weisenbach J. , Toso J.
Published: August 2020

8566

Background: Iboctadekin (rhIL-18) is an immunostimulatory cytokine that has demonstrated anti-tumor activity in several preclinical models. When administered as monotherapy in phase I clinical studies, rhIL-18 was safe, well tolerated and induced potent biological responses (e.g. Th1 cytokine production and expression of activation markers on NK, CD8+ and CD4+ cells). These data affirm the endogenous role of IL-18 as a co-stimulatory cytokine and suggest that its optimal use would be in a combination with other immune modulators such as rituximab. Methods: Patients with CD20+ B cell non-Hodgkin's lymphoma are being given rituximab (375 mg/m2) IV weekly for 4 consecutive weeks in combination with ascending doses of intravenous rhIL-18 (1 to 100 mcg/kg in 6 cohorts of 3 patients each) IV weekly for 12 weeks to identify a dose that is safe and tolerable and gives a maximum biological effect. Eligible patients must have disease which progressed after standard therapy or for which there is no effective standard treatment. Assessments include safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity and anti-tumor activity. Results: To date, thirteen subjects have been enrolled in the first four cohorts (1, 3, 10 and 20 mcg /kg of rhIL-18). The combination is well tolerated with a safety profile similar to that observed with rituximab or rhIL-18 monotherapy. The pharmacodynamic response is as expected with a dose-dependent decrease in circulating activated (CD69+) NK cells within 4 hours after completing the rhIL-18 infusion which rebound to pre-dose levels within 2–4 days. Using the International Working Group response criteria for lymphoma, two subjects had complete responses at 10 and 20 mcg/kg, one subject had a partial response at 10 mcg/kg and three subjects had stable disease at 1, 3 and 3 mcg/kg. Conclusions: These data show that the combination of rhIL-18 and rituximab is safe, well tolerated and induces potent biological activity. This study will define the dose level to be used in a future phase II trial evaluating this combination in patients with relapsed or refractory follicular lymphoma.

[Table: see text]
Efficacy of the DAC inhibitor LBH589 in both rituximab-sensitive and rituximab-resistant lymphomas and effect on the antitumor activity of chemotherapy agents, monoclonal antibodies, and bortezomib
Authors: Maraj I. , Hernandez-Ilizaliturri F. J. , Chisti M. , Czuczman M. S.
Published: August 2020

8576

Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins [histones (class I) and non-histones (class II)], leading to regulation of gene transcription and other cellular processes. LBH589 is a novel and potent DAC class I and II Inhibitor undergoing pre-clinical and clinical testing. In order to develop therapeutic options for refractory/resistant B-cell lymphomas we studied the effects of LBH589 in the anti-tumor activity of chemotherapy agents and monoclonal antibodies in a panel of rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), and in lymphoma cells isolated from patients with treatment-naïve or refractory/relapsed B-cell lymphomas by negative selection using magnetic beads. NHL cells lines were exposed to the following chemotherapy agents or monoclonal antibodies: CDDP, doxorubicin, vincristine, bortezomib or rituximab, veltuzumab, or isotype, alone or in combination with LBH589. In dose-sequence studies the treatment with LBH589 preceded or followed in vitro exposure to the chemotherapy agent or the monoclonal antibody by 24 hrs. Changes in mitochondrial potential were determined by alamar blue reduction using a kinetic assay. Patient-derived tumor cells were exposed to either LBH589, bortezomib or both. Changes in ATP content were determined by cell titer glow assay. RNA was isolated from NHL cell lines exposed to LBH859 and changes in gene expression of the Bcl-2 family members were determined by qualitative polymerase chain reaction (PCR). LBH589 was active as a single agent against RSCL, RRCL or patient-derived tumor cells. In addition, Bcl-XL gene down-regulation was observed following exposure to LBH859. Synergistic activity was observed by combining LBH589 and chemotherapy agents, bortezomib or either of the two anti-CD20 mAbs studied. The sequence of administration impacted the degree of antitumor activity observed. Our data suggests that LBH589 is active against various RSCL, RRCL and patient-derived tumor cells. Findings suggest that LBH589 added to systemic anti-CD20 and/or chemotherapy could result in a novel and potent treatment strategy against B-cell lymphomas.

No significant financial relationships to disclose.
Prognostic significance of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFR), and vascularity in diffuse large B-cell lymphoma treated with immunochemotherapy (R-CHOP)
Authors: Gratzinger D. , Advani R. , Zhao S. , Talreja N. , Tibshirani R. J. , Horning S. J. , Levy R. , Lossos I. S. , Gascoyne R. D. , Natkunam Y.
Published: August 2020

8581

Background: Diffuse large B cell lymphoma (DLBCL) cells coexpress VEGF, VEGFR1 and VEGFR2. In patients (pts) treated with CHOP chemotherapy alone, VEGFR1 predicted improved overall survival (OS) while microvessel density (MVD) predicted poorer OS; VEGF and VEGFR2 were not predictive (Lab Invest. 2008;88:38). We now assess these factors in pts treated with R-CHOP. Methods: 162 pts with de novo DLBCL treated with R-CHOP and median followup of 44 months were evaluated retrospectively with immunohistochemistry on tissue microarrays. Scoring: VEGF, VEGFR1, VEGFR2, and phosphoVEGFR2 (pVEGFR2) in lymphoma cells (categorical variable) <5%, none; 5–30%, weak; >30%, strong. MVD (continuous variable): average CD34+ microvessels/4 hpf. Statistics: univariate Cox proportional hazards regression, and multivariate Cox regression for testing independence from the International Prognostic Index (IPI) for two endpoints, OS and progression-free survival (PFS). Pearson chi-square testing for independence of variables. Results: VEGF and MVD did not correlate with OS or PFS. Pts with higher VEGFR2 (53%) had poorer OS but not PFS independent of the IPI (z=3.15, p=0.0016; 2 yr OS 100%/84%/76%). Pts with any pVEGFR2 (13%) had worse PFS independent of IPI (z=1.98, p=0.048) and a trend toward poor OS (p=0.056). VEGFR1 did not correlate with OS or PFS in the group as a whole. Since VEGFR1 and VEGFR2 expression correlate strongly (Χ2=56, p =9.8E-12) opposing associations with outcome could be masked. On subset analysis the 39% of pts with weak VEGFR2 had better OS with higher VEGFR1 (z=-1.64, p=0.016; 2 yr OS 68%/85%/92%). Conclusions: In contrast to our prior observations in CHOP treated pts, in DLBCL treated with R-CHOP MVD was not prognostically significant. The association of VEGFR1 with better OS was previously seen with CHOP alone, whereas the correlation of VEGFR2 and phosphorylated VEGFR2 with poorer OS was only seen with R-CHOP. Independent confirmation will be important, especially because multiple comparisons were made with 5 predictors and 2 endpoints tested. It is possible that VEGFR1 and VEGFR2 oppose each other functionally; future studies are indicated to address the mechanism of this effect.

No significant financial relationships to disclose.
EPOCH-F: A salvage regimen for multiple myeloma prior to reduced intensity allogenic hematopoietic stem cell transplantation
Authors: Jamshed S. , Fowler D. , Neelapu S. , Dean R. M. , Steinberg S. M. , Snow K. , Odom J. , Gress R. E. , Bishop M.
Published: August 2020

8592

Background: Variation in baseline host immune status contributes to inconsistent donor engraftment and may impede maximal graft-versus-myeloma effects after reduced intensity allogenic hematopoietic stem cell transplantation (RIHSCT) for advanced multiple myeloma (MM). As no specific salvage regimen has been designed for MM patients being considered for RIHSCT, we evaluated EPOCH-F a novel salvage regimen designed to provide disease control and immune depletion. Methods: EPOCH-F is an infusional chemotherapeutic regimen consisting of etoposide, vincristine and adriamycin, with prednisone, cyclophosphamide and fludarabine given in 21 day cycles prior to RIHSCT. Targeting a CD4+ T cell count, 22 pts were treated <5 cycles of EPOCH-F. Pts proceeded to RIHSCT after adequate lymphodepletion or if there was disease progression during EPOCH-F, regardless of CD4 count. Results: Median age was 53 years (range 36–65); median time from initial therapy to transplant was 12 months (range 2–168). Median number of prior therapies was 2 (range 1–8), 63% had chemotherapy sensitive disease and 68% had received a novel agent. Pts received a median of 3 cycles (range 1–5), with manageable toxicities, mostly hematologic. Grade IV Neutropenia was seen in 77% of the administered cycles with only 6 episodes of neutropenic fever. Median lymphocyte count decreased from 1423/μL (range 335–2788) to 519/μL (range 102–1420); CD4 count decreased from 320/μL (range 130–1366) to 115/μL (30–309). In 21 evaluable pts, the ≥PR rate to EPOCH-F was 22% with 13% CR/nCR. 68% had SD and only 1 pt progressed. 20 pts underwent RIHSCT from HLA matched sibling. Median Day 100 chimerism was 100% (range 60–100, mean 95). 70% of patients achieved ≥VGPR and CR/nCR was seen in 40%. Acute GVHD (grade II-IV) was seen in 47% and chronic GVHD (grade III-IV) was seen in 52% of the pts. TRM at 100 days was 5% and 30% at 60 months. Median overall survival of patients after RIHSCT was 46.1 months. Conclusions: EPOCH-F is an active regimen which provides pre-transplantation lympho-depletion, disease control and allows consistent engraftment in multiple myeloma patients undergoing RIHSCT.

No significant financial relationships to disclose.
Phase II study of aflibercept (VEGF trap) in recurrent inoperable stage III or stage IV melanoma of cutaneous or ocular origin
Authors: Tarhini A. A. , Christensen S. , Frankel P. , Margolin K. , Ruel C. , Shipe-Spotloe J. , DeMark M. , Kirkwood J. M.
Published: August 2020

9028

Background: Aflibercept is a fusion protein combining the Fc portion of human IgG1with the extracellular ligand-binding domains of human VEGFR1 and VEGFR2, acting as a high-affinity soluble VEGF receptor and potent angiogenesis inhibitor. Methods: Phase II study of aflibercept in patients with inoperable stage III or IV melanoma who had received no prior chemotherapy or hormonal therapy. A 2-stage design was adopted focusing upon response rate (RECIST) and 4-month PFS rate. First stage accrual of 21 patients was specified, while final accrual of 41 is planned, with adequate response/4 month PFSR. Aflibercept was given at 4 mg/kg IV every 2 weeks. Response was assessed every 8 weeks. Results: Twenty seven patients (16 male, 11 female), age 23–83 (median 58) have been enrolled to date. All had AJCC stage IV melanoma (3M1a, 3M1b, 21M1c). Karnofsky PS: 100 (13), 90 (11) or 80 (3). Nine patients had primary ocular melanoma, 16 cutaneous and 2 unknown primary site. A total of 160 cycles have been administered (median 4; range 1–18). Grade 3/4 toxicities included cerebral ischemia (1 patient; 4%), confusion (1; 4%), thrombocytopenia (1; 4%), hypertension (7; 26%), hypotension (1; 4%), left ventricular diastolic dysfunction (1; 4%), fatigue (1; 4%), proteinuria (4; 15%), extraocular muscle paresis (1; 4%), renal failure (1; 4%), back pain (1; 4%), headache (1; 4%). Interim analysis was conducted after the first 21 patients (stage 1). Eight (1 M1a, 1M1b, 6M1c; 4 ocular, 3 cutaneous, 1 unknown primary) of the first 21 patients had at least 4 months of PFS (10 out of 27; 2 additional patients with cutaneous melanoma had SD: 1M1a and 1M1c). One patient (23rd; cutaneous, M1c) had a confirmed complete remission. Four patients were taken off study prior to response evaluation for toxicity (3) or treatment refusal (1). One patient is currently disease free who was not evaluable for response (previous surgery and radiofrequency ablation of measurable disease site). Eleven patients had progression. Conclusions: Aflibercept can be administered with acceptable toxicity, and exhibits promising antitumor efficacy against advanced melanoma. This study continues second stage accrual with anticipated closure before June 2009.

[Table: see text]
A phase I/II study of CR011-vcMMAE, an antibody-drug conjugate (ADC) targeting glycoprotein NMB (GPNMB) in patients (pts) with advanced melanoma
Authors: Hwu P. , Sznol M. , Pavlick A. , Kluger H. , Kim K. B. , Boasberg P. , Sanders D. , Simantov R. , Crowley E. , Hamid O.
Published: August 2020

9032

Background: GPNMB is expressed on melanoma cells and represents a potential target for ADCs. CR011-vcMMAE is a fully-human monoclonal antibody to GPNMB conjugated to the tubulin inhibitor monomethylauristatin E (MMAE). Dose limiting toxicity in Phase I (n=32) was rash; tumor shrinkage including one partial response (PR) was observed. We now report Phase II data at the maximum tolerated dose of 1.88 mg/kg iv q3w. Methods: Eligible pts had unresectable stage III or stage IV melanoma and had received no more than 1 prior cytotoxic regimen but any number of other therapies. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint was overall response (ORR) by RECIST using a minimax two-stage design (p0=0.5; p1=0.2, α=β=0.1) with 18 patients in the first stage and a total of 32 pts. Secondary endpoints included progression free survival (PFS) and duration of response. Results: 36 pts (median age 67 years [range 37–79]; 94% stage IV; 68% M1c) were treated for a median of 2.4 months (m)(range 0.5–7.5m). 18 pts discontinued (14 PD, 2 consent, 1 adverse event [AE], 1 stable disease [SD]) and 18 pts were ongoing. The study met the criteria for advancement to the second stage; 4 PRs (1 unconfirmed) and 19 SD (range 1.7–7.5 mo) have been observed; final ORR is pending. The unconfirmed PR was in a pt with 96% tumor reduction and PD 6 weeks later. Median PFS was 4m. The most common AEs were rash (81%), fatigue (72%), alopecia (63%) and pruritus (56%). The most common grade 3/4 AEs were neutropenia (22%) and rash (19%). Grade 2 or higher rash was associated with longer PFS. Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced melanoma. Rash may be a useful biomarker for activity. More frequent dosing is being explored.

[Table: see text]
Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials
Authors: Lutzky J. , Wolchok J. , Hamid O. , Lebbe C. , Pehamberger H. , Linette G. , de Pril V. , Ibrahim R. , Hoos A. , O'Day S.
Published: August 2020

9034

Background: The monoclonal antibody ipilimumab targets cytotoxic T-lymphocyte antigen-4. The most common AEs associated with ipilimumab are irAEs, and both antitumor and irAE responses likely reflect its immune-mediated mechanism of action. In this report, a potential association between disease control (DC) or overall survival (OS) and irAEs in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in 3 Phase II clinical trials was explored. Methods: Across 3 Phase II studies (CA184008, 022, and 007), ipilimumab (10 mg/kg) was given every 3 weeks (Q3W) x 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (wk) 24 (maintenance). In study 022, pts were randomized to 0.3, 3, and 10 mg/kg groups, whereas study 008 was a single-arm trial of ipilimumab 10 mg/kg. In study 007, ipilimumab 10 mg/kg was administered either with placebo or daily prophylactic budesonide. Disease control (CR/PR/SD) was evaluated using modified World Health Organization (mWHO) and immune- related response criteria (Hodi FS, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3008). Association between DC and grade 0/1 vs. grade ≥2 irAEs was examined (studies 007, 008, and 022). Association between OS and irAEs which developed within 12 wks of ipilimumab treatment was also explored using landmark analyses from Day 81 (studies 008 and 022). Results: Across the 3 phase II studies, the rate of DC by mWHO in pts with grade 0/1 irAEs was 20–24% and in pts with grade ≥2 irAEs was 34–43%. The number of pts with DC was higher among those who experienced an irAE compared with those who did not, but DC was not statistically significantly associated with grade 0/1 vs grade ≥2 irAEs. For pts who lived up to Day 81 in studies 008 and 022, median OS (95% CI) from Day 81 was 14.8 mo (10.0–21.7) for any irAE and 8.21 mo (5.29–13.7) for no irAE within 12 weeks; median OS was 13.6 mo (5.78-NR) for any grade ≥2 irAE and 11.3 mo (7.95–15.8) for no grade ≥2 irAE within 12 weeks. Conclusions: DC and survival benefits with ipilimumab are observed among pts that develop an irAE and among pts that do not develop an irAE. Thus, pts who do not experience an irAE may still demonstrate clinical benefit with ipilimumab.

[Table: see text]
Dendritic cell vaccination in melanoma patients: Update and subgroup analysis of clinical response to post-vaccine treatment
Authors: Ridolfi L. , Fiammenghi L. , Petrini M. , Granato A. M. , Ancarani V. , Pancisi E. , Valmorri L. , Riccobon A. , Ridolfi R.
Published: August 2020

9042

Background: Dendritic cells (DCs) play a crucial role in the interplay between innate and adaptive immune response towards cancer. The combination of immunotherapies with standard treatments for cancer could represent a further chance for advanced melanoma patients. In the literature, higher response rates than those normally obtained have been reported after second-line chemotherapy in patients with non small cell lung cancer pre-treated with vaccines and in patients with follicular B-cell lymphoma vaccinated with an anti-idiotype vaccine whilst in remission. On the basis of this data, we reviewed and updated the clinical results of our dendritic cell based vaccine clinical trial in stage IV melanoma patients. Methods: From December 2002 to 2007, 24 pre-treated metastatic melanoma patients were vaccinated with mature DCs (mDCs) pulsed with autologous tumor lysate (ATL) and keyhole limpet hemocyanin (KLH) followed by a 5-day treatment with low-dose subcutaneous Interleukin-2. Results: We observed 2 complete response (CR), 2 mixed response (MR), 5 partial response (PR), 4 stable disease (SD) and 11 progressive disease (PD) (overall response (OS) 37.5%; clinical benefit 54.1%). All 13 responders had delayed-type hypersensitivity (DTH) positivity to KLH, of whom 10 also showed positivity to the lysate. Eleven (45.8%) of the 24 patients underwent further lines of treatment (5 chemotherapy [CT], 3 surgery [S], 4 biotherapy, 2 radiotherapy [RT] and 4 biochemotherapy [BioCT]) after stopping vaccination (8 due to progression and 3, in SD, because all of their lysate had been used). Of these 11 patients, 2 obtained CR (1 RT, 1 S), 5 PR (3 BioCT, 2 S) for an OR of 63.6%, 1 SD (BioCT) and 3 showed PD as the best response to subsequent therapies, with a median OS of 30 months (range 16–52). Of the 3 SD patients who were forced to stop vaccine treatment, 1 had CR following RT and 2 progressed. Conclusions: Metastatic melanoma responds poorly to standard therapy, in particular after first-line treatment. Vaccination could enhance clinical response to subsequent third- or fourth-line therapies, thus prolonging overall survival.

No significant financial relationships to disclose.
Validation of a multimarker blood assay for postoperative assessment of stage IV melanoma patients in a prospective international phase III trial
Authors: Hoshimoto S. , Shingai T. , Wang H. , Elashhoff R. M. , Morton D. L. , Hoon D. S.
Published: August 2020

9045

Background: Currently there are no validated prognostic molecular biomarkers for assessment of outcome after complete resection of stage IV melanoma patients. To validate blood molecular biomarkers for prognostic value and monitoring of these patients, we evaluated the clinical utility of a multimarker quantitative reverse-transcription PCR (qRT-PCR) for detecting circulating tumor cells (CTC) of patients blood enrolled in a multicenter international (29 sites) phase III trial of postoperative adjuvant therapy. After complete metastasectomy, AJCC stage IV patients underwent immunotherapy with bacille Calmette-Guerin (BCG) plus placebo or BCG plus melanoma vaccine. Methods: Bleeds were taken before and during treatment in both randomized treatment arms. Pre- and during treatment bleeds from patients were assessed by an optimized qRT-PCR assay for MART1, MAGEA3, and PAX3 genes mRNA. Median clinical follow-up time was 21.8 and 24.2 mos. for disease-free survival (DFS) and overall survival (OS), respectively. Results: MART1, MAGEA3, and PAX3 were detected in 64 (26%), 56 (23%), 73 (29%) of 244 post-operative pretreatment patients, respectively. Multivariate Cox analysis showed that biomarker-negative patients had significantly higher DFS than biomarker- positive patients (risk ratio 1.56, 95% CI, 1.14 - 2.15; P=0.0062). In serial-bleeds (pretreatment, mos 1 and 3) analysis of 214 patients, biomarker-negative patients had significantly higher OS than patients with 1–2 positive- or 3 positive-biomarkers (risk ratio 2.37, 95% CI 1.14 - 4.94, P=0.021; and risk ratio 2.90, 95% CI 1.28 - 6.53, P=0.01, respectively). Multivariate analysis confirmed that 1–2 positive- and 3 positive-biomarkers were significant independent prognostic factors for poor OS (risk ratio 2.44, 95% CI 1.16 - 5.12, P=0.019; and risk ratio 3.08, 95% CI 1.36 to 6.98, P=0.007, respectively). Conclusions: This prospective multicenter blood biomarker validation study demonstrates that multimarker qRT-PCR analysis of CTC has significant clinical utility as a prognostic factor of disease outcome at pretreatment, and as a treatment monitoring prognostic factor in stage IV melanoma patients.

No significant financial relationships to disclose.
Phase II study of vincristine sulfate liposomes injection in patients with metastatic uveal melanoma
Authors: Bedikian A. Y. , Sato T. , Kim K. B. , Papadopoulos N. E. , Hwu W. , Homsi J. , Davies M. , Cheung C. , Imperiale S. M. , Prasad P. , Hwu P.
Published: August 2020

9067

Background: Preclinical and clinical studies showed that liposomal encapsulation of vincristine sulfate (VCR) results in increased drug circulation time and accumulation of VCR at the tumor site. Marqibo has been administered safely at 2.25 mg/m2, a dose exceeding that typically employed for VCR ( dose capped at 2 mg), with tolerable clinical toxicities consistent with VCR. Of the 27 previously treated patients with metastatic melanoma in the Marqibo pharmacokinetic studies, 3 patients had a tumor response, including one patient with uveal melanoma metastatic to the lung that experienced a complete response. Methods: Patients with metastatic uveal melanoma with no more than one prior systemic therapy were enrolled. Patients with controlled brain metastases were allowed. Marqibo (2.25 mg/m2 by 1-hour intravenous infusion, no dose capping) was administered every 14 days until tumor progression. Responses were assessed every 6 weeks using the Response Evaluation Criteria in Solid Tumors (RECIST). Toxicity was assessed at least as frequently as before each dose. Results: Preliminary data is available for 22 enrolled patients (73% female). Median age was 65 years (range 38–79), 23% were previously treated with systemic chemotherapy, 86% had liver metastasis and 96% had M1c disease. Baseline serum LDH levels were elevated in 73% and were more than 2 × ULN in 37% of the patients. Twenty-one patients were evaluable for response; one patient discontinued the treatment after a single dose of therapy for toxicity without tumor progression. No patients died of drug toxicity while on the study. Twelve patients (57%) had stable disease. Estimated median survival is 6.4 months. Fourteen patients are alive, 2 for more than 12 months. Treatment related side effects were mostly grade 1 or 2; peripheral neuropathy was the only grade 3 toxicity, seen in 18% of the patients. The hematologic toxicities were minor; no neutropenia or thrombocytopenia was seen. Conclusions: Marqibo is well tolerated as single agent therapy in patients with advanced stage IV uveal melanoma. Its impact on the progression-free and overall survival of these critically ill patients will be presented.

No significant financial relationships to disclose.
Impact of concomitant immunosuppression on the presentation and prognosis of patients with melanoma
Authors: Frankenthaler A. , Lee M. , Seery V. , Renzi S. , Kinnaman M. , Liu V. , Friedman E. , Atkins M. B.
Published: August 2020

9070

Background: Melanoma has been reported to be susceptible to immune control. Therefore, we hypothesized that concomitant immune suppression might impact the course of the disease. Methods: We examined the Beth Israel Deaconess Medical Center Cutaneous Oncology Program database for pts with immune suppression at the time of melanoma diagnosis. The demographics and stage of these pts were compared to those in the database as a whole. In addition, 3 controls matched for age, gender, stage and tumor location were identified for each case and disease outcome was compared between cases and controls. Results: 19 pts were identified with melanoma and concomitant immune suppression in a database of 1820 melanoma pts. Other diagnoses included renal transplant (4) inflammatory arthritis (8), Multiple Sclerosis (2), and ulcerative colitis (3). Immunosuppressive meds included methotrexate, azothioprine, cyclosporine, prednisone, infliximab, and natalizumab. Melanoma stages at diagnosis were in situ 1, IB 7, IIA 1, IIB 1, IIIB 3, IIIC 5, and IV 1. Compared to the database as a whole, cases were more likely to be female (84% vs 45%) and have a higher disease stage (42% stage IIIB/C vs 26%). In addition, more cases appeared to have an amelanotic primary (21% vs. 5.4%) or an atypical mole syndrome (21% vs 10.2%). For pts who relapsed, the cases had a shorter disease free interval (DFI) (2.1 vs 9.7 yrs) than the controls. At a median f/up of 52 mos, 37% of the cases had relapsed and all of these pts had died. At a median f/up of 76 mos, 30% of the controls had relapsed yet only 47% of these pts had died. As a consequence, cases appeared more likely to have died of their disease than controls (42% vs 23%) (p=0.10). Conclusions: Compared to the general melanoma population, pts with concomitant immune suppression appear more likely to be female, have an amelanotic primary or atypical mole syndrome and more advanced disease at presentation. Although pts with concomitant immune suppression are equally likely to relapse compared to matched controls, those that relapse appear to have a shorter DFI and to be less likely to be salvaged, suggesting more aggressive tumor behavior in this setting. Thus, diagnosis and treatment of a primary melanoma at an early stage appears especially important in an immunosuppressed population.

No significant financial relationships to disclose.
Multicenter study on prognostic factors in 692 patients with brain metastases of malignant melanoma
Authors: Eigentler T. K. , Figl A. , Krex D. , Mohr P. , Kurschat P. , Tilgen W. , Bostroem A. , Heese O. , Garbe C. , Schadendorf D.
Published: August 2020

9081

Background: This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM-MM). Methods: In a retrospective survey in nine cancer centres of the German Cancer Society 692 patients were identified with BM-MM during the period 1986–2007. Overall survival was analysed using Kaplan-Meier estimator and compared by log-rank analysis. Cox proportional hazards models were used to identify prognostic factors significant for survival. Results: The median overall survival of the entire cohort was 5.0 months (95%CI: 4–5). Prognostic factors in the univariate Kaplan- Meier analysis were: Karnofsky Performance Status (≥ 70 vs. <70; p<0.001), number of BM-MM (single vs. multiple; p<0.001), pre-treatment levels of serum LDH (normal vs. elevated; p<0.001), pre-treatment levels of S100 (normal vs. elevated; p<0.001), Prognostic groups according to Radiation Therapy Oncology Group (Class I vs. Class II vs. Class III; p=0.0485), kind of applied treatment (for the cohort with single BM-MM, only) (stereotactic radiotherapy or neurosurgical metastasectomy vs. others; p=0.036). Cox proportional hazards models revealed pre-treatment elevated level of serum LDH (HR: 1.6, 95%CI: 1.3–2.0; p=0.00013) and number of BM-MM (HR: 1.6, 95%CI: 1.3–2.0; p=0.00011) in the whole cohort of patients as independent prognostic variables, whereas in patients with single BM-MM the kind of applied treatment (stereotactic radiotherapy or neurosurgical metastasectomy vs. others; HR: 1.5, 95%CI: 1.1–1.9; p=0.0061) was identified as unique prognostic factor. Conclusions: Overall survival of patients with BM-MM mainly depends on the number of metastases and pre-treatment levels of LDH. In case of a single brain metastasis the application of stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival.

No significant financial relationships to disclose.
Ginger for chemotherapy-related nausea in cancer patients: A URCC CCOP randomized, double-blind, placebo-controlled clinical trial of 644 cancer patients
Authors: Ryan J. L. , Heckler C. , Dakhil S. R. , Kirshner J. , Flynn P. J. , Hickok J. T. , Morrow G. R.
Published: August 2020

9511

Background: Despite the widespread use of antiemetics, post-chemotherapy nausea and vomiting continue to be reported by up to 70% of patients receiving chemotherapy. Ginger (Zingiber Officinale), an ancient spice, is used by practitioners worldwide to treat nausea and vomiting. We conducted a multi-site, phase II/III randomized, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for chemotherapy-related nausea in cancer patients at the University of Rochester-affiliated Community Clinical Oncology Program (CCOP) member sites. Methods: Cancer patients who experienced nausea following any chemotherapy cycle and were scheduled to receive at least three additional cycles were eligible. Patients were randomized into four arms: 1) placebo, 2) 0.5g ginger, 3) 1.0g ginger, or 4) 1.5g ginger. All patients received 5-HT3 receptor antagonist antiemetics on Day 1 of all cycles and took three 250mg capsules of ginger or placebo twice daily for six days starting three days before the first day of the next two cycles. Patients reported the severity of nausea during the morning, afternoon, evening, and night on a 7-point semantic rating scale (‘1' = ‘Not at all Nauseated' and ‘7' = “Extremely Nauseated”) for Days 1–4 of each cycle. The goal was to determine if ginger was more effective than placebo in controlling chemotherapy-related nausea in participants given a 5-HT3 receptor antagonist antiemetic. Results: A total of 644 patients were accrued (90% female, mean age = 53). Breast (66%), alimentary (6.5%), and lung (6.1%) cancers were the most common cancer types. Analysis of covariance (ANCOVA) examined change in nausea in the four study arms on Day 1 of cycles 2 and 3. All doses of ginger significantly reduced nausea (p=0.003). The largest reduction in nausea occurred with 0.5g and 1.0g of ginger. Also, time of day had a significant effect on nausea (p<0.001) with a linear decrease over 24 hours for patients using ginger. Conclusions: Ginger supplementation at daily dose of 0.5g-1.0g significantly aids in reduction of nausea during the first day of chemotherapy. Supported by NCI PHS grants 1R25CA10618 and U10CA37420.

No significant financial relationships to disclose.
Spiritual support of patients with advanced illness and associations with end-of-life care and quality of death
Authors: Balboni T. A. , Paulk M. E. , Balboni M. J. , Trice E. D. , Wright A. A. , Phelps A. C. , Block S. D. , Prigerson H. G.
Published: August 2020

9514

Background: Little is known about whether spiritual support is associated with advanced cancer patients' medical care and quality of death (QoD) at the end of life (EoL). Methods: Coping with Cancer is an NCI/NIMH-funded, prospective, longitudinal, multi-institutional study of advanced, incurable cancer patients conducted from September 2002-August 2008. Analyses were based on 343 deceased patients who were interviewed at baseline and then followed until death a median of 117 days later. At baseline, spiritual support was assessed by (1) patient-rated support of spiritual needs by the medical system (eg, physicians, nurses, chaplains) scored from 0 (not at all) to 5 (completely supported) and (2) patient-reported receipt of hospital/clinic pastoral care services. Outcomes measured included medical care received in the last week of life (hospice; receipt of aggressive EoL care defined as ICU admission, resuscitation, ventilation or chemotherapy in the last week of life; and death in an acute care facility) and QoD. QoD assessments (possible 0–30, with increasing scores reflecting better QoD) were obtained by post-mortem interviews of a caregiver present in the patient's last week of life. Multivariable analyses examined (1) associations between spiritual support variables and EoL care outcomes, controlling for baseline confounds (eg, race, religiousness, patient EoL care preferences) and (2) associations between spiritual support variables and QoD with adjustment for confounds (eg, baseline quality of life, aggressive EoL care). Results: In adjusted analyses, greater medical system spiritual support was associated with increased receipt of hospice care [OR = 2.97 (1.24–7.11), p = .01], but not with receipt of aggressive EoL care or death in an acute care facility. Receipt of pastoral care services was not associated with any EoL care outcome. In adjusted analyses, spiritual support from the medical system and receipt of pastoral care services were significantly associated with better patient QoD (standardized β = 0.16, p = .009 and β = 0.20, p = .0005, respectively). Conclusions: Support of advanced cancer patients' spiritual needs by the medical care team is associated with increased receipt of hospice care and improved patient QoD.

No significant financial relationships to disclose.
Acute myeloid leukemia or myelodysplastic syndrome (AML/MDS) and overall mortality with chemotherapy (CT) and granulocyte colony-stimulating factor (G-CSF): A meta-analysis of randomized controlled trials (RCTs)
Authors: Lyman G. H. , Dale D. C. , Culakova E. , Poniewierski M. S. , Wolff D. , Kuderer N. M. , Lambert K. , Crawford J.
Published: August 2020

9524

Background: To evaluate the risk of AML/MDS and overall mortality in patients receiving CT ± G-CSF, a meta-analysis of RCTs were conducted. Methods: Electronic databases searched through August 2008 identified 3,794 articles for initial screening. Eligibility included RCTs of solid tumor or lymphoma patients randomized to CT ± primary G-CSF support, ≥2 years follow-up and reporting AML/MDS or all second malignancies. Pre-specified study categories included: a)same dose/schedule, b)dose-dense or c)dose-escalated CT. Primary outcomes were AML/MDS and mortality. Dual blinded data extraction was performed. Relative risk (RR) and absolute risk difference (ARD) were estimated by Mantel-Haenszel. Results: Median follow-up was 54 months. 12,642 patients were randomized to CT ± primary G-CSF support. Second malignancies were reported in 3.3% and 3.2% with and without G-CSF, respectively (P=.942). RR for AML/MDS with CT+G-CSF compared to control was 1.92 [P=.006] with ARD increase of 0.4% [P=.008]. RR for AML/MDS in study categories to receive the same, dose-dense or dose-escalated CT+G-CSF were 1.95 [P=.346], 1.20 [P=.666] and 2.47 [P=.006], respectively. RR for mortality with CT+G-CSF was 0.898 [P<.0001] with ARD decrease of 3.3% [P<.0001]. RR for mortality in study categories to receive the same, dose-dense or dose-escalated CT+G-CSF were 0.95 [P=.140], 0.84 [P<.001] and 0.91 [P=.019], respectively. Delivered relative dose intensities (RDI) were 1.18, 1.46 and 1.23 in studies planned to receive the same, dose-dense or dose-escalated CT, respectively. A significant association was observed between delivered RDI and reduced mortality [P=.013]. No differences in estimates of AML/MDS or mortality were observed between industry and non-industry-funded studies. Conclusions: Risk of AML/MDS is increased with dose escalated CT+G-CSF. Nevertheless, CT+G-CSF is associated with greater reductions in overall mortality. Dose-dense regimens are associated with the greatest RR reduction in mortality and lowest risk of AML/MDS. Further research is needed to differentiate any impact of G-CSF on the risk of AML/MDS from that due to increased CT intensity.

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The use of vitamin E for prevention of chemotherapy-induced peripheral neuropathy: A phase III double-blind, placebo controlled study—N05C31
Authors: Kottschade L. A. , Sloan J. A. , Mazurczak M. A. , Johnson D. B. , Murphy B. , Rowland K. M. , Smith D. A. , Berg A. , Stella P. J. , Loprinzi C. L.
Published: August 2020

9532

Background: Chemotherapy induced peripheral neuropathy (CIPN) continues to be a substantial problem for many cancer patients (pts). Pursuant to promising appearing pilot data, the current study evaluated the use of vitamin E for the prevention of CIPN. Methods: A phase III, randomized, double-blind, placebo controlled study was conducted in pts undergoing therapy with neurotoxic chemotherapy, utilizing twice daily dosing of vitamin E (400mg)/placebo. The primary endpoint was the incidence of grade 2+ sensory neuropathy (SN) toxicity (CTCAE v 3.0) in each treatment arm, analyzed by Chi-square testing. Major eligibility criteria included: planned curative intent adjuvant chemotherapy with neurotoxic chemotherapy, ≥ 18 years of age, ECOG PS of ≤2, no existing peripheral neuropathy or coronary artery disease, no prior treatment with neurotoxic chemotherapy, and no concurrent treatment with neuropathic or opioid pain medication. Planned sample size was 100 patients per arm, to provide 80% power to detect a difference in incidence of grade 2+ SN toxicity from 25% in the placebo group to 10% in the vitamin E group. Results: Two-hundred seven pts were enrolled between 12/01/2006 and 12/14/2007. Cytotoxic agents included taxanes (109), cisplatin (8), carboplatin (2), oxaliplatin (50) or combination (20). Eleven pts canceled prior to starting treatment and there were 7 ineligible pts on study. Thus there were 189 evaluable pts included in the current analysis. In this analysis, there was no difference in the incidence of grade 2+ SN between the 2 arms (vitamin E- 34% [95% CI- 25.0–44.8%] placebo- 29% [20.1–39.4%]; P=0.43). There, likewise, were no significant differences between treatment arms for time to onset of neuropathy (P= 0.72), for chemotherapy dose reductions due to neuropathy (P= 0.21) or patient questionnaire reported neuropathy symptoms. The treatment was well tolerated overall. Conclusions: Vitamin E did not appear to reduce the incidence of sensory neuropathy in the studied group of patients receiving neurotoxic chemotherapy but it appeared to be well tolerated.

No significant financial relationships to disclose.
Low-molecular-weight heparin for venous thromboprophylaxis in ambulatory cancer patients: A meta-analysis
Authors: Kuderer N. M. , Khorana A. A. , Francis C. W. , Lyman G. H. , Falanga A. , Ortel T. L.
Published: August 2020

9537

Background: Patients with cancer have an increased risk of venous thromboembolism (VTE). However, routine VTE prophylaxis is generally not recommended in ambulatory cancer patients. Several randomized controlled trials (RCTs) of low-molecular-weight heparin (LMWH) in ambulatory cancer patients have been reported with inconclusive results. Methods: A systematic review of RCTs of LMWH in ambulatory cancer patients without a VTE diagnosis was conducted. Included trials had to report VTE as primary or secondary outcome. An extensive electronic database search was conducted, including Medline, EMBASE, Cochrane Library along with abstracts from major meetings. Dual-blinded data extraction was performed. Meta-analysis was conducted using Mantel and Haenszel method to estimate relative risk (RR) and absolute risk difference (ARD) ± 95% CI. Primary outcomes in this analysis were all reported VTE and major bleeds. Most trials did not require VTE screening by imaging, precluding a separate analysis of asymptomatic VTE events. Results: Six RCTs were identified with a total of 2,648 patients including 1,525 receiving LMWH and 1,123 controls. No significant heterogeneity was observed across trials. Among patients receiving LMWH, the crude incidence of VTE was 2.95% compared to 5.25% among control patients. LMWH reduced the RR of VTE by 36% compared to controls (RR=0.64 [0.44 - 0.94], P=0.021), and reduced the ARD by 1.8% [0.2% - 3.4%]. Major bleeding events were reported in 1.57% LMWH patients compared to 0.98% in controls. The non-significant RR increase by LMWH for major bleeding was 1.85 [0.923 - 3.68], P=0.081, with an ARD of 0.9% [0.0% - 1.8%]. Results were comparable in the analysis limited to studies with VTE as primary outcome. Conclusions: While patients experienced a 36% relative risk reduction in VTE with LMWH, the absolute risk reduction was small, and concerns remain about the potential increase in major bleeding. Therefore, routine VTE prophylaxis in ambulatory cancer patients cannot be recommended at this time. Additional research is needed to identify cancer outpatients at high risk for VTE, in whom prophylaxis may have a more favorable risk-benefit ratio.

[Table: see text]