bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictive value of Ile105Val polymorphism of the gluthatione-S-transferase P1 in patients with metastatic colorectal cancer (m CRC) treated with the triplet combination of irinotecan, oxaliplatin, and capecitabine
Authors: Zarate R. N. , Rodriguez J. , Bandres E. , Bitarte N. , Ramirez N. , Ponz M. , Chopitea A. , Viudez A. , Garcia-Foncillas J. 
Published: August 2020

2544 Background: Several phase I/II trials have shown that the triplet combination of oxaliplatin, irinotecan and capecitabine is a feasible and active in solid tumors. We aimed to investigate whether germline polymorphisms may be predictors of clinical outcome in mCRC pts treated with this combination. Methods: The following genetic polymorphisms were analysed: glutathione S-transferase (GSTP1-Ile105Val, GSTT1 and GSTM1 deletion), TYMS (TS-5´UTR 2R/3R; TS-5´G/C; TS-3´UTR 6-bp deletion), MTHFR 1298A>C, UGT1A1, ERCC1, XPD. Polymorphisms from peripheral lymphocytes were detected using the TaqMan genotyping assays (Applied Biosystems, CA). Univariate analysis (Fisher´s exact test for response; log-rank test for TTP and OS) was performed to examine associations between polymorphisms and clinical outcome. Results: Blood samples for 63 out of 72 prospectively enrolled pts were tested for genomic analysis. Median age was 57 (32–78), median ECOG 1(0–2), median number of cycles administered 6 (1–13), median number of metastatic sites was 1 (1–4). M/F: 50/22. Risk according to Köhne classification was low (52.8% of pts), intermediate (26.4%) and high (8.3%). Overall response rate (ORR) was 62.5%. Median progression-free survival (PFS) was 9.87 months (95% CI; 7.6–12) and median overall survival was 24.6 months (95% CI; 19.5–29.7). A significant association was observed between MTHFR 1298A>C and haematological toxicity, with C/C genotype pts being at higher risk of grade 3–4 neutropenia (50% vs. 28%, p = 0.035) and leucopenia (50% vs. 15%, p = 0.04). Heterozygous and homozygous GSTP-105Val showed a significant superior response rate (80%) compared to only 40% in pts harbouring the GSTP1–105Ile/Ile genotype (p = 0.008, Fisher´s exact test). PFS was also adversely affected in pts with GSTP1–105Ile/Ile (5.2 months vs. 12.3 months in those pts with at least one GSTP1–105Val allele, p = 0.001). In the multivariate analysis, the relative risk for progression was 3.4 (95% CI; 1.3–9.1) for the GSTP1–105Ile/Ile genotype (p = 0.01). Conclusions: The GSTP1-Ile105Val polymorphism is a strong predictor of clinical outcome for XELOXIRI therapy in mCRC pts. No significant financial relationships to disclose.
Evaluation of the relationship between patient factors and the reduction in clearance of pegylated liposomal doxorubicin
Authors: La-Beck N. M. , Zamboni B. A. , Tzemach D. , Schmeeda H. , Sapir R. , Gabizon A. , Zamboni W. C. 
Published: August 2020

2548 Background: The reticuloendothelial system (RES), which includes monocytes, may have a key role in clearance (CL) of nanoparticle sized pegylated liposomes. However, the factors affecting the CL of liposomes are unclear. Age, body composition, and monocyte count have been related to CL of liposomal agents (Zamboni, ASCO '07; Maruca, ASCO '07; Sidone, AACR- NCI-EORTC '07). The CL of pegylated liposomal doxorubicin (PLD) decreases significantly from cycle 1 to 3 (Gabizon, Cancer Chemother Pharmacol 2008). The objectives of this study were to evaluate factors associated with decreases in PLD CL. Methods: Patients (pts) with various solid tumors were randomized to PLD administered IV every 28 days at 30, 60 and 45 mg/m2 (n = 6) or 60, 30 and 45 mg/m2 (n = 6) on cycles 1, 2 and 3 respectively. Serial plasma samples for PLD pharmacokinetic (PK) analysis were obtained prior to and at 1 h, 24 h, 72 to 96 h, 7 d, 14 d, 21 d, and 28 d after PLD infusion on cycles 1, 2, and 3. Samples were processed to measure sum total (encapsulated + released) doxorubicin by HPLC with fluorescence. PLD CL was calculated by noncompartmental methods. Precycle monocyte count, age, and ratio of total body weight to ideal body weight were compared to PLD CL. Results: Mean + SD PLD CL on cycles 1 and 3 were 23.7 + 7.7 mL/h and 16.4 + 5.4 mL/h, (P < 0.0001). Pts with a reduction as compared with an increase in precycle monocyte count from cycle 1 to 3 had a mean + SD change in PLD CL of -11.5 + -3.5 mL/h and -5.3 + -3.0 mL/h, respectively (P = 0.09). Median age was 61 years old (yo). Pts > 61 yo and < 61 yo had a mean + SD change in PLD CL from cycles 1 to 3 of - 8.7 + -4.3 mL/h and -5.2 + -5.4 mL/h, respectively (P = 0.16). Conclusions: PLD CL decreased significantly from cycle 1 to 3. Decreased precycle monocyte count was associated with a larger decrease in PLD CL compared to increased monocyte count. Pts > 61 yo had a larger decrease in CL compared to pts < 61 yo. These results suggest monocytes are involved in the CL of PLD and that older pts may have less RES reserve and thus may be more likely to have a larger decrease in PLD CL with subsequent treatment cycles. Statistical significance was not met due to small sample size; however, further investigation of the association between changes in PLD CL and patient age and monocyte count is warranted. [Table: see text]
Results from phase Ib studies of PX-12, a thioredoxin inhibitor in patients with advanced solid malignancies
Authors: Ramanathan R. K. , Dragovich T. , Richards D. , Stephenson J. , Pestano L. , Hiscox A. , Leos R. , Chow S. , Millard J. , Kirkpatrick L. 
Published: August 2020

2571 Background: PX-12, a small-molecule inhibitor of Thioredoxin-1 (Trx-1) stimulates apoptosis, down-regulates HIF- 1α, VEGF in animal models. High levels of Trx-1 have been linked to chemoresistance in lung cancers. The phase 2 dose of PX-12 was 226 mg/m2 given by 3-h infusion IV x 5 days, q 21d (Ramanathan RK et al. CCR 13; 2109; 2007). Two Phase 1b trials of PX-12 in patients with advanced solid tumors have been completed to determine the safety, tolerability and optimal biologic dose when delivered by prolonged infusion. Methods: PX-12 was administered as a 24-h infusion every q7- 14d starting at 150 mg/m2/day (n=18); or a 72-h infusion q 21d, starting at 300 mg/m2/day (n=14) using a portable delivery pump. Results: Both the 24- or 72-h infusion of PX-12 were well tolerated in patients at doses up to 400 mg/m2/day. Common grade 1/2 AE's included fatigue, taste alteration, and odor caused by expired drug metabolite. In the 24 h study the maximal dose evaluated was 450 mg/m2. No DLTs were observed in this study. Since no MTD was reached on 24-h infusion up to 450 mg/m2 dose level, additional higher doses were explored utilizing 72-h infusion. DLT in the 72-h study at the highest dose administered (500 mg/m2/day) included reversible hypoxia with or without pneumonitis. Best response was stable disease in 3 pts (SD): liver cancer and colon cancer (24-h infusion) and rectal cancer (72-h infusion). Pharmacodynamics (PD): PX- 12 lowered circulating Trx-1 levels in patients who had starting Trx-1 levels 3-fold greater than that of the normal population (5.4 ng/mL) including all three SD. Circulating VEGF and FGF-2 levels were also lowered over multiple courses of treatment in these patients. The pharmacokinetics of PX-12 showed a dose dependent increase of Cmax and no accumulation over multiple cycles following a 24 h infusion. Conclusions: Dosing at 400 mg/m2/day appears safe and tolerable as a 24–72-h infusion. Extending the infusion time to 72h appears to decrease the intensity of cough and odor compared to bolus 1–3 h infusion. The PD effect produced by PX-12 was apparent only in those patients with elevated plasma Trx-1 levels. Patients with elevated TRX-1 levels appear to have the best probability of having SD. Supported by ProlX Pharmaceuticals/Oncothyreon through an award from the NCI. [Table: see text]
A phase I study of the safety and pharmacokinetics (PK) of XMT-1001 given as an intravenous (IV) infusion once every three weeks to patients with advanced solid tumors
Authors: Sausville E. , Garbo L. , Weiss G. J. , Anthony S. , Shkolny D. , Yurkovetskiy A. V. , Bethune C. , Fram R. J. 
Published: August 2020

2574 Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro- drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 demonstrated an improved therapeutic window as compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT- 1001 administered as an IV infusion once every 3 weeks. The objectives of this phase I study are to determine the maximum tolerated dose and to assess safety and PK of XMT-1001. Initially 3 patients (pts) are entered at each dose level. The cohort is expanded to 6 pts if a patient experiences a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Thirty two pts with refractory solid tumors have received 82 cycles of XMT-1001 at 8 dose levels ranging from 1.0 to 20.5 mg CPT equivalents/m2. Two pts had Gr 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. After the introduction of new clinical trial material with an improved formulation, to date, no infusion reactions suggestive of hypersensitivity have occurred (11 patients, 22 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Myelosuppression was observed in 3 pts treated at 15.4 mg CPT equiv/m2 dose level. Stable disease was observed in 7 pts with the following tumor types and dose levels expressed in mg CPT equivalents/m2: NSCLC (1.0 mg/m2, 6 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), and colon (15.4 mg/m2, 6 wks). PK demonstrates dose proportional increases in plasma levels of XMT-1001 (conjugated CPT) and confirms the formation of its expected release products. To date, levels of free CPT in urine are low. Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease was observed in patients with refractory tumors. [Table: see text]
Phase I study of combination treatment with PTK 787/ZK 222584 (PTK/ZK) and cetuximab for patients with advanced solid tumors: Safety, pharmacokinetics, pharmacodynamics, and toxicity analysis
Authors: Langenberg M. H. , Witteveen P. O. , Lankheet N. , Roodhart J. M. , Rosing H. , Beijnen J. H. , Voest E. E. 
Published: August 2020

2575 Background: Based on the current knowledge of tumor biology there is a rationale to combine targeted therapies that block different growth factor pathways. Here we combined PTK/ZK, a small molecule inhibitor of all three vascular endothelial growth factor receptors, PDGFR and c-kit, with cetuximab, a monoclonal antibody against the epidermal growth factor receptor. Methods: In this phase I study patients were treated with PTK/ZK daily (cohort 1; 750 mg od, cohort 2; 1250 mg od, cohort 3; 250 mg [morning] and 500 mg [evening], cohort 4; 500 mg [morning] and 750 mg [evening]) combined with cetuximab 250mg/m2 weekly in cycles of 28 days in cohorts of 3 patients. Toxicity was evaluated conform CTCAE classification version 3.0. Pharmacokinetics and circulating endothelial (progenitor) (CE(P)) cell analysis by flow cytometry were performed. Response was assessed using RECIST criteria. Results: Safety and tolerability were evaluated in 16 out of 18 treated patients (median age 61, range 43–78) with advanced tumors of the colon (8), lung (1), chordoma (2), biliary tract (1), cervix (1), ovarian (1), breast (1) and pancreatic cancer (1). The most frequently reported adverse events (all CTCAE grades) were acne (87%), dry skin (81%), fatigue (69%), nausea (63%), ataxia/dizziness (50%), vomiting (50%), headache (38%) and diarrhea (31%). One dose limiting toxicity (DLT) occurred in cohort 3 (grade 3 transaminitis (AST)). The study was terminated after cohort 4 because the predefined maximum doses for vatalanib and cetuximab were attained. Preliminary PK analysis revealed no significant changes in PTK/ZK exposure upon coadministration with cetuximab. Biomarker analysis showed stabilized CE(P)Cs levels during treatment. 7 out of 14 patients evaluable for efficacy analysis (50%) showed SD for at least 2 months and 1 patient (colon cancer) a PR for 11.5 months. Conclusions: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has anti tumor activity. No MTD was defined; the recommended phase II dose is the predefined maximum combination dose: weekly cetuximab 250 mg/m2 combined with twice daily PTK/ZK 500/750 mg. No significant financial relationships to disclose.
Phase I study of infusion of HER2/neu (HER2) specific T cells in patients with advanced-stage HER2 overexpressing cancers who have received a HER2 vaccine
Authors: Disis M. L. , Salazar L. G. , Coveler A. , Waisman J. , Higgins D. , Childs J. , Bates N. , Dang Y. 
Published: August 2020

3000 Background: Adoptive T-cell therapy has shown promise in the treatment of advanced-stage melanoma. We have previously reported that expansion of HER2-specific T cells from peripheral blood mononuclear cells (PBMC) can be greatly facilitated by vaccine-priming. In this study, we evaluated the safety and clinical efficacy of infusion of HER2-specific T cells in patients with advanced HER2 overexpressing cancers. Methods: 10 patients with progressive HER2+ metastatic breast and ovarian cancer, not considered curable by conventional therapies, will be enrolled in this study. The patients must have been pre-immunized with a HER2-specific vaccine. Three escalating doses of T cells are given at 10-day intervals. Cyclophosphamide or denileukin diftitox is administrated before the first dose of T cells. Results: To date, 5 of 10 subjects have been enrolled. T cells were expanded with HER2-specific class II restricted peptides. After in vitro expansion cell products were >95% CD3+ with an average of 35% CD4+ and 60% CD8+ T cells. The maximal doses infused were 1x109-41x109 cells (median 10x109). Subjects tolerated the infusions well with the primary toxicity being related to the conditioning agent. Objective tumor regression has been observed in 2 of the 5 treated patients. One other patient has had stable disease after treatment. In patients with tumor regression, the magnitude of HER2-specific T cells in the infused product was 8-fold higher than that in patients without clinical responses. The total number of HER2-specific T cells infused was 43-fold higher in responding patients than in nonresponding patients. Moreover, HER2-specific CD4+ and CD8+ T cells persisted over a year and even augmented in magnitude post-infusion in responding patients. Conclusions: Adoptive transfer of autologous HER2 specific polyclonal T cells generated from PBMC after vaccine-priming is well tolerated and has shown evidence of some clinical efficacy in patients with advanced-stage HER2+ cancers. No significant financial relationships to disclose.
Persistent immunity and survival after immunization with a HER2/neu (HER2) vaccine
Authors: Salazar L. G. , Goodell V. , O'Meara M. , Knutson K. , Dang Y. , dela Rosa C. , Guthrie K. A. , Disis M. L. 
Published: August 2020

3010 Background: Our initial vaccine studies showed that optimally treated breast cancer patients can be immunized against HER2 during active immunization. The majority of patients developed T-cell immunity to HER2 peptides and protein and also epitope spreading (ES). The goal of this study was to determine if patients previously immunized with a HER2 vaccine had persistent immunity years after active immunization and to assess their clinical outcome in terms of overall survival (OS). Methods: Subjects eligible for this IRB-approved long term follow-up (LTFU) study: (1) had HER2+ breast cancer and were immunized between 1996–1999 in a phase I HER2 peptide vaccine trial, (2) were at least 1 year out from their last vaccine, and (3) if donating blood samples could not be receiving chemotherapy. 52 patients (37 stage IV, 15 stage III) were identified and 21/52 patients (12 stage IV, 9 stage III) were determined to be living. All 21 subjects were contacted by letter and sent a LTFU Questionnaire. OS was defined as the time between date of vaccine study entry and death or last follow-up and was estimated using the Kaplan-Meier method. Cox proportional hazards were used to determine associations between OS and known clinical and vaccine-related immunologic factors; analyses included all 52 subjects. Long-term T-cell immunity was evaluated using IFN-γ ELISPOT assay. Results: Median follow-up time for the 21 patients still alive was 112 months (range, 104–126 months). Blood samples were collected in 10/21 subjects and 6/8 (75%) evaluble patients had persistent T-cell immunity to immunizing HER2 peptides; and 7/8 patients (88%) had T-cell immunity specific for HER2 protein and peptides not contained in their immunizing mix (defined as ES). In multivariate analysis, number of chemotherapy regimens prior to vaccination (HR=5.7 (CI 95%, 1.5–23; p=<0.001)), and development of ES after HER2 vaccination (HR=0.34 (CI 95%, 0.12–1.0; p=0.05)) were independent predictors of OS. Median OS for 33 subjects who developed ES was 84 months vs 25 months for 16 subjects who did not develop ES. Conclusions: HER2-specific T-cell immunity elicited with active immunization is durable years after vaccination has ended and the generation of ES is an independent predictor of OS. No significant financial relationships to disclose.
Immunologic impact of anti-CTLA-4 therapy
Authors: Sharma P. , Tsavachidou D. , Kamat A. , Ng Tang D. , Chen H. , Fu T. , Troncoso P. , Wolchok J. , Logothetis C. J. , Allison J. P. 
Published: August 2020

3019 Background: Blockade of the T-cell inhibitory molecule known as cytotoxic T lymphocyte antigen-4 (CTLA-4) results in antitumor responses. To date, trials have been conducted with over 4,000 patients with various malignancies in the metastatic disease setting, which allow for correlation of therapy with clinical outcome but do not provide analyses of relevant biomarkers in the systemic circulation that reflect changes within the tumor microenvironment. Approximately 10% of treated patients respond to therapy. Why some patients respond while others do not remains unknown. The identification of intermediate biomarkers are essential for us to understand whether anti-CTLA-4 antibody has “hit its target” to affect human immune responses and whether these identified immune responses can serve as predictive markers of clinical outcomes. Methods: We conducted a presurgical clinical trial with anti-CTLA-4 antibody. Patients with localized bladder cancer (N=10) were given two doses of antibody prior to undergoing surgery. Immunological analyses were conducted on patients’ tissues and blood samples. Results: Expression of the inducible costimulator (ICOS) molecule was increased on CD4 T cells within tumor tissues and systemic circulation. ICOS-expressing T-cells have not previously been reported to have a role in anti-tumor responses. We showed that CD4+ICOShi T cells produced IFNγ and could recognize the NY-ESO-1 tumor antigen. Pre- and post-therapy CD4 T cells were analyzed by reverse-phase protein array and microRNA array, which led to the identification of signaling pathways and regulatory mechanisms that play a role in enhanced T-cell function. Furthermore, murine models confirmed our initial findings and implied a role for ICOS-expressing T-cells in antitumor responses. Finally, we extended our findings to the metastatic disease setting of melanoma patients (N=14) and our preliminary data indicate an improved survival for anti-CTLA-4 treated patients who have a sustained increase in ICOS-expressing CD4 T cells. Conclusions: Our presurgical clinical trial allowed for the correlation of data from tumor tissues with data from peripheral blood, thus identifying ICOS-expressing T-cells as a relevant biomarker that can be used to monitor patients who receive anti-CTLA-4 therapy. [Table: see text]
Phase II study of recombinant IL-21 (rIL-21) plus sorafenib as second- or third-line therapy for metastatic renal cell cancer (mRCC): Final results
Authors: Bhatia S. , Heath E. , Puzanov I. , Miller W. , Curti B. , Gordon M. , Ernstoff M. , Hausman D. , Hunder N. , Thompson J. 
Published: August 2020

3023 Background: Despite the positive impact of targeted therapies on treatment for mRCC, the efficacy of these agents appears to decrease beyond the first-line setting. There is an unmet need for novel therapies after failure of vascular endothelial growth factor (VEGF)-directed agents. rIL-21, a cytokine that enhances CD8+ T-cell and NK cell activity, has single-agent antitumor activity (J Clin Oncol. 2008;26:2034). Based on promising results of a phase I study of rIL-21 plus sorafenib, we initiated a phase II study to explore the safety and efficacy of this combination as second- or third-line treatment for mRCC. Methods: Patients with mRCC received second- or third-line therapy with sorafenib 400 mg PO BID continuously plus rIL-21 30 μg/kg IV on days 1–5 and 15–19 of each 7-week treatment course (TC). Efficacy endpoints included progression-free survival (PFS) and overall response rate (ORR) per RECIST. Response was assessed by the investigator and by independent radiologic review (IRR). Results: 33 patients were enrolled from 14 sites in the U.S. and Canada. Median age was 61 years (range, 46–75); ECOG performance status was 0 (n=15) or 1 (n=18). Patients had received 1 (n=25) or 2 (n=8) prior lines of therapy, including sunitinib (n=19), temsirolimus (n=5), bevacizumab (n=3), everolimus (n=2), IL-2 (n=11), or other (n=4). Grade ≥3 adverse events considered at least possibly related to study drug and occurring in ≥3 patients included hypophosphatemia (33%), hand-foot syndrome (24%), rash (24%), thrombocytopenia (8%), and neutropenia (8%). Twelve patients remain on study; 13 withdrew for progressive disease (PD), 6 for toxicity, and 2 for other reasons. IRR has been performed for the first 23 patients who completed at least 1 full TC, with 6 confirmed PR (26%), 1 unconfirmed PR (4%), 14 SD (61%), and 2 PD (9%). While median PFS cannot yet be determined, 14 of the first 29 patients have completed at least 3 TCs, equivalent to approximately 21 weeks, with SD or better. Conclusions: rIL-21 plus sorafenib is associated with an acceptable safety profile and promising antitumor efficacy in previously treated patients with mRCC. The observed ORR to date compares favorably with the rate previously reported for sorafenib in the first and second-line setting. [Table: see text]