bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized, active-controlled phase IIb study with trabedersen (AP 12009) in recurrent or refractory high-grade glioma patients: Basis for phase III endpoints
Authors: Bogdahn U. , Schneider T. , Oliushine V. , Parfenov V. , Mahapatra A. K. , Balasubramaniam A. , Venkataramana N. , Stockhammer G. , Heinrichs H. , Schlingensiepen K.
Published: August 2020

2037

Background: High-grade gliomas (HGG) strongly overexpress TGF-beta 2. Trabedersen (AP 12009), a TGF-beta 2-specific inhibitor, was successfully tested in 3 Phase I/II studies in recurrent or refractory HGG. Methods: The Phase IIb study AP 12009-G004 was an open-label, randomized, active-controlled dose-finding study. Main objectives: to compare response rate, survival, and safety of 2 doses of trabedersen (10 μM or 80 μM) vs. standard chemotherapy (TMZ or PCV). 145 patients with recurrent or refractory HGG (AA WHO grade III or GBM WHO grade IV) were randomized and 134 patients (AA = 39; GBM = 95) received study medication. Trabedersen was given intratumorally by convection-enhanced delivery. Results: AA and GBM patients in both trabedersen groups had long-lasting tumor responses (currently up to 4 years). AA: (10 μM trabedersen vs. control): significantly better overall response rate was noted at 14 months (CR+PR; p=0.034*) and lower tumor progression rates at 6, 12 and 14 months; difference at 14 months was statistically significant (p=0.003*). 2-year survival rate was 2-fold higher (p=0.088**). Tumor progression rate at 14 months and 2-year survival rate correlated with a median overall survival benefit of 17.4 months. GBM: 10 μM trabedersen was as efficacious as standard chemotherapy in all patients. It was clearly superior regarding 2-year survival in the pre-specified subgroup of patients younger than 55 years and the subgroup with a KPS > 80. The superior long-term survival of trabedersen-treated AA and GBM patients was the basis for extending the follow-up period of this Phase IIb study. Conclusions: Based on Phase IIb results, the pivotal Phase III study SAPPHIRE in recurrent or refractory AA patients has started. Primary efficacy endpoint is 2-year survival rate; secondary endpoints are progression rate at 14 months, time to death, quality of life, safety and tolerability. A separate study in GBM is being planned.

[Table: see text]

[Table: see text]
Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma
Authors: Supko J. G. , Grossman S. A. , Peereboom D. M. , Chowdhary S. , Lesser G. J. , Nabors L. B. , Mikkelsen T. , Desideri S. , Batchelor T. T.
Published: August 2020

2039

Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level.

[Table: see text]
Bevacizumab plus etoposide among recurrent malignant glioma patients: Phase II study final results
Authors: Reardon D. , Desjardins A. , Vredenburgh J. J. , Gururangan S. , Peters K. B. , Norfleet J. A.
Published: August 2020

2046

Background: Significant therapeutic benefit has been observed among recurrent malignant glioma (MG) patients treated with bevacizumab (BV), a neutralizing monoclonal antibody to vascular endothelial growth factor (VEGF) with or without chemotherapy. In this study, we evaluate the efficacy of BV plus etoposide (E), a topoisomerase inhibitor, among recurrent MG patients. Methods: Recurrent patients with no more than three prior episodes of recurrence are eligible, while those with prior BV treatment or prior intracranial hemorrhage are excluded. The primary outcome measure is 6 month progression-free survival (6-PFS). BV is dosed at 10 mg/kg intravenously every other week. Etoposide is orally administered daily (50 mg/m2) for days 1–21 of each 28-day cycle. Results: Fifty-nine patients (GBM, n = 27; grade 3 MG, n = 32) with a median of 2 prior progressions have enrolled. With a median follow-up of 45 weeks, median overall survival (OS) for GBM and grade 3 MG patients were 46 and 47 weeks, while the 6-PFS is 44% and 40.6%, respectively. The most common toxicities were neutropenia (41%), fatigue (22%), and infection (20%) and were grade 2 in most cases. One patient developed grade 1 intracranial hemorrhage and 1 patient had a grade 4 GI perforation. Conclusions: Combination of bevacizumab and etoposide is well tolerated in recurrent MG patients and is associated with encouraging anti-tumor benefit. Accrual is complete and an update of further treatment and follow-up will be presented.

No significant financial relationships to disclose.
Influence of expression of EGFR and PTEN on outcome in patients with primary glioblastoma treated with standard radiochemotherapy and cetuximab: Interim analysis from the GERT-Protocol
Authors: Combs S. E. , Hartmann C. , Welzel J. , von Deimling A. , Debus J. , Platten M. , Wick W. , Gaiser T.
Published: August 2020

2050

Background: The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma (GBM). Anti-EGFR treatments have shown to be associated with EGFR deletion mutant variant III (EGFRvIII) expression in presence of PTEN expression, suggesting a prognostic role of EGFRvIII expression. We determined molecular biomarkers and correlated these with outcome in the GERT trial. Methods: To date, 39 patients were treated within the GERT protocol (Combs SE et al., 2006) evaluating radiochemotherapy (RCHT) with temozolomide (TMZ) and weekly CTX. Pretreatment paraffin-embedded tumor tissue of 32 patients was available for molecular analysis. Twenty-three patients were male, 9 were female. Median age was 49 years. We analyzed amplification of EGFR, expression of EGFR, EGFRvIII, the tumor-suppressor PTEN and O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Results: Median follow-up was 12 months. Overall survival (OS) at 12 and 24 months was 89% and 42%. Progression-free survival (PFS) was 76% and 45% at 6 and 12 months, respectively. MGMT promoter hypermethylation was detected in 16/32 tumours. Methylated MGMT did not impact PFS or OS (p = 0.48 and p = 0.08). Data on EGFR copy number of 31/32 tumors showed EGFR gene amplification in 11 tumors. EGFR protein expression was found in 23/32 patients. EGFR-amplification did not impact PFS or OS (p = 0.56, p = 0.3). Patients with EGFR expression showed longer PFS (p = 0.05), but unaltered OS (p = 0.06). EGFRvIII was seen in 5/32 patients, only in tumors with EGFR amplification. Expression of EGFRvIII did not influence PFS (p = 0.26) or OS (p = 0.09). Reduced PTEN (22/32) did not influence PFS or OS (p = 0.27, p = 0.85). Outcome was not associated with coexpression of EGFRvIII and PTEN (n = 5); coexpression of EGFR and PTEN (n = 13) significantly influenced PFS (p = 0.005), but not OS (p = 0.10). Conclusions: Expression of EGFR, and coexpression of EGFR/PTEN is associated with significant increase in PFS after RCHT with TMZ and CTX. EGFR-amplification, reduction of PTEN expression and expression of EGFRvIII did not impact PFS nor OS. Randomized data in the primary treatment of GBM might help identify patients for anti-EGFR therapies.

[Table: see text]
MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma
Authors: Aldape K. D. , Jones G. , Wang M. , Hegi M. , Janzer R. C. , Stupp R. , Mehta M. P. , Gilbert M. R.
Published: August 2020

2051

Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens.

No significant financial relationships to disclose.
Effect of proton pump inhibitor co-medication on imatinib disposition: A healthy volunteer study
Authors: Beumer J. H. , Shah D. D. , Yerk M. , Komazec K. A. , Christner S. , Appleman L. J. , Redner R. R. , Miller B. M. , Egorin M. J.
Published: August 2020

2503

Background: Imatinib mesylate, a potent inhibitor of Bcr-Abl and c-kit tyrosine kinases, is widely used to treat gastrointestinal stromal tumors and Philadelphia chromosome-positive leukemias. Imatinib often causes gastric upset and is therefore frequently administered with a proton pump inhibitor (PPI). Yet, the resulting elevated gastric pH, delayed gastric emptying, and inhibition of ABC transporters in the gut could change imatinib absorption, thereby affecting the therapeutic effectiveness of imatinib. To test this hypothesis, we sought to define the effect of PPI on the plasma pharmacokinetics of imatinib. Methods: 11 healthy subjects (6 M, 5 F; 21–56 years) were enrolled in a 2-period, open-label, randomized cross-over, fixed- sequence study. In one period, they received a single 400 mg dose of imatinib p.o., in the other, 40 mg omeprazol daily for five days followed by a single 400 mg dose of imatinib p.o.. The periods were separated by a wash-out period of ≥ 14 days. Plasma samples from 0–72 h after dosing were obtained. Plasma concentrations of imatinib and its active metabolite CGP74588 were determined with an LC-MS assay and data were analyzed non-compartmentally. The study was powered to detect a 30% difference in imatinib AUC with 80% power and a 5% type I error. Results: See Table . Conclusions: This study demonstrates that the use of PPI to treat imatinib-induced gastric upset does not significantly affect imatinib plasma AUC. Support: Novartis; NIH/NCRR/CTSA Grant UL1 RR024153

[Table: see text]

[Table: see text]
Association of pharmacokinetics and germ-line mutations in EGFR and ABC transporters with erlotinib toxicity in patients with non-small cell lung cancer (NSCLC)
Authors: Hamada A. , Sasaki J. , Saeki S. , Iwamoto N. , Inaba M. , Ushijima S. , Urata M. , Kishi H. , Fujii S. , Semba H. , Saito H.
Published: August 2020

2506

Background: Erlotinib demonstrates substantial inter-individual differences in response and the development of skin rash (grade≥2) was correlated with efficacy. Erlotinib interacts with its target EGFR and the efflux transporter ABCB1 and ABCG2. EGFR CA repeat is associated with incidence of skin rash. A 421C>A SNP in ABCG2 and 1236C>T, 2677 G>(T/A), and 3435C>T SNPs in ABCB1 are associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants and pharmacokinetics of erlotinib on toxicity grade in Japanese patients treating single agent erlotinib. Methods: Twenty-two patients with NSCLC received erlotinib orally at 150 mg/day and plasma levels of erlotinib were measured on days 1(D1), 8(D8), and stable phase (>day 14) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the EGFR, ABCB1, and ABCG2 genes using direct nucleotide sequencing or TaqMan assay. Eligibility criteria included: performance status (PS) < 3, age < 75, stage IIIB-IV, and written informed consent. Results: The mean Cmax (±SD) of D1 and D8 were 1.8 ± 1.0 and 3.1 ± 1.4 μg/ml, respectively. Trough concentration (Cmin) at D1 and steady state were 0.9 and 1.7 μg/ml, respectively. Grade 1–2 skin rash or diarrhea occurred in 95% of patients. One patient (Cmax at D1, 3.0 μg/ml) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The area under curves and Cmax on D1 were correlated with the severity of skin rash (p=0.05 and 0.01), however, Cmin were not correlated. Patients with homozygous variant and heterozygous for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state (2.4 vs 1.2 μg/ml, p=0.01). EGFR CA repeat and AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT developed grade≥2 skin rash or diarrhea. Conclusions: The present study suggests that ABCB1 gene polymorphism is associated with the variable toxicity and pharmacokinetics to erlotinib treatment.

No significant financial relationships to disclose.
Rationally designed treatment for solid tumors with MAPK pathway activation
Authors: Karantza-Wadsworth V. , Stein M. , Tan A. , Mehnert J. , Poplin E. , Lin Y. , White E. , DiPaola R. S.
Published: August 2020

2532

Background: Preclinical studies shed light to the mechanism conferring paclitaxel resistance in solid tumors with active Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) pathway, and determined a molecular mechanism by which addition of the proteasome inhibitor bortezomib abrogated this resistance, enabling tumor regression in animals in vivo. Methods: A Phase I study was contacted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors were treated with weekly paclitaxel and bortezomib. Six patients had NSCLC; 4, colon cancer; 2, pancreatic; 2, melanoma; 1, breast; 1, ovarian. Patients with baseline neuropathy greater than or equal to Grade 1 were excluded. The starting dose was 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) was used for dose escalation with 3-patient cohorts treated at each dose level. The Target Toxicity Level (probability of DLT at the MTD) was set at 25%. Maximum dose escalation was no more than 75% of the previous SED level, if no Grade 3 hematologic toxicity or DLT were observed. Otherwise, the maximum dose escalation was no more than 50% of the previous SED level. The process continued until SED changes were no more than 10% for two consecutive cohorts. Results: The MTD for the combinatorial treatment was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib. Of 15 evaluable patients, 1 patient with paclitaxel-resistant NSCLC had PR and 5 patients (2, NSCLC; 1, pancreatic; 1, colon; 1, ovarian) had stable disease. Median TTP was 2.3 months (0.8 to 6 months). Three NSCLC patients achieved TTP longer than 5 months. The combination of paclitaxel and bortezomib was relatively well tolerated. Paclitaxel PK parameters are being determined, and paraffin-embedded tumor specimens are being evaluated for MAPK pathway activation by IHC for phospho-ERK. Results will be correlated with clinical response. Conclusions: The MTD for the proposed combinatorial treatment is 60 mg/m2 for paclitaxel and 1.0 mg/m2 for bortezomib, and is relatively well tolerated. Combination of paclitaxel with bortezomib is effective in taxane-resistant NSCLC, and worthy of further investigation.

No significant financial relationships to disclose.
TRAP1, a novel antiapoptotic gene responsible for multidrug resistance in human colorectal carcinoma cells
Authors: Landriscina M. , Costantino E. , Maddalena F. , Piscazzi A. , Fersini A. , Calise S. , Esposito F.
Published: August 2020

2541

Background: TRAP1 has been recently described as a component of a mitochondrial pathway selectively up- regulated in tumor cells which antagonizes the proapoptotic activity of cyclophilin D and is responsible for maintenance of mitochondria integrity, thus favoring cell survival. Interestingly, novel TRAP1 antagonists cause sudden collapse of mitochondrial function and selective tumor cell death, suggesting that this pathway may represent a novel molecular target to improve anticancer therapy. Furthermore, we recently observed that TRAP1 is significantly up-regulated in osteosarcoma cells adapted to growth in mild oxidizing conditions and this correlates with a phenotype more resistant to H2O2-induced DNA damage and apoptosis. This evidence prompted us to investigate the role of TRAP1 as being responsible for multi-drug resistance in human colorectal cancer. Methods and Results: The evaluation of TRAP1 expression by immunoblot and quantitative RT-PCR analysis in a series of 26 human colorectal carcinomas allowed us to observe up-regulation in 17/26 tumors. Accordingly, TRAP1 protein levels were increased in HT-29 colorectal carcinoma cells resistant to 5-fluorouracil, oxaliplatin and irinotecan. Interestingly, HT-29 colorectal carcinoma and Saos-2 osteosarcoma cells transfected with TRAP1 gene exhibited a phenotype resistant to 5-fluorouracil-, oxaliplatin- and irinotecan-induced apoptosis, evaluated by MTT incorporation analysis and annexin V staining. Consistently, the transfection of a dominant negative N-terminal deletion mutant of TRAP1 as well as the inhibition of TRAP1 activity by the TRAP1 ATPase antagonist, shepherdin, increased the sensitivity to apoptosis induced by 5-fluorouracil, oxaliplatin and irinotecan in wild type HT-29 colorectal carcinoma cells and in HT-29 cells resistant to the single agents. Conclusions: These results suggest that the increased expression of TRAP1 in human colorectal carcinomas could be part of a pro-survival pathway responsible for multidrug resistance. Thus, targeting TRAP1 may represent a novel strategy to improve the efficacy of anticancer agents in colorectal cancer.

No significant financial relationships to disclose.
Evaluation of renal function and carboplatin clearance in Japanese cancer patients
Authors: Shimokata T. , Yasuda Y. , Hamada A. , Kawada K. , Hasagawa Y. , Ando Y.
Published: August 2020

2556

Background: There is a close relationship between carboplatin clearance and glomerular filtration rate (GFR). Calvert developed the following formula for the dosing of carboplatin: dose (mg) = target area under the concentration versus time curve (AUC, mg ml-1 min) × [GFR (ml min-1) + 25]. However, this formula has not been evaluated in Japanese population. In this study, we prospectively evaluated renal function and carboplatin clearance in Japanese cancer patients. Methods: GFR was measured by inulin clearance before chemotherapy. The dose of carboplatin was determined by Calvert's formula using adjusted 24-h creatinine clearance (Ccr) by adding 0.2 (mg dl-1) to serum creatinine. A pharmacokinetic study was performed during the first cycle of the chemotherapy. Blood samples were obtained at 10 points within 24 hours. The observed AUC of carboplatin and the observed carboplatin clearance were calculated. Results: Inulin clearance was estimated in 28 cancer patients. Estimation of renal function with adjusted 24-h Ccr and estimated GFR equation (eGFR) were unbiased [mean prediction error (MPE) = -2.3%, 5.2% respectively] and acceptably precise [root mean squared error (RMSE) = 23.7%, 25.7% respectively], whereas non-adjusted Ccr and the Cockcroft-Gault equation overestimated GFR (MPE = 24.2%, 12.5% and RMSE = 37.2%, 32.7% respectively). Observed carboplatin clearance was proportional to GFR in range of renal function in this study (r = 0.903) and we verified the linearity. Non-renal clearance of carboplatin in Japanese cancer patients was 5.6 (ml min-1). Conclusions: 24-h Ccr adjusted by adding 0.2 (mg dl-1) to serum creatinine and eGFR were useful in assessing renal function for carboplatin dosing. It was suggested that non-renal clearance of carboplatin in Japanese cancer patients was less than 25 (ml min-1).

No significant financial relationships to disclose.
A phase I study of enzastaurin (Enz) combined with pemetrexed (Pem) in advanced non-small cell lung cancer (NSCLC)
Authors: Takahashi T. , Yamamoto N. , Murakami H. , Ohe Y. , Kunitoh H. , Nokihara H. , Koshiji M. , Tamura T.
Published: August 2020

2572

Background: Enz is an oral serine-threonine kinase inhibitor that is designed to suppress tumor growth through PKC and PI-3 kinase/AKT. Pre-clinical data shows Enz's synergistic activity with Pem in many cancer cell lines including NSCLC. This phase 1 study is to evaluate the safety, pharmacokinetics (PK), and clinical activity of two schedules of Enz combined with Pem in patients (pts) with previously treated advanced NSCLC. Methods: An oral daily dose of 500 mg Enz was given once daily (QD) in cohort 1 or twice daily (BID) in cohort 2 in combination with 500 mg/m2 Pem on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day Enz lead-in treatment that preceded Pem administration: a loading dose of 1125 mg on day 1 followed by 500 mg total daily dose on days 2–7. Blood samples for PK evaluation were collected on day 2 of cycle 1 (following loading dose) and day 1 of cycle 2 (steady- state). Samples were analyzed for Enz, Pem, and its active metabolites. Results: 12 pts (8 males, 4 females; ECOG PS 0–1) with median age of 62 (49 - 74) were enrolled into this study and completed safety evaluation for cycle 1: 8 pts with adenocarcinoma, 3 pts with squamous cell carcinoma, and one with other. All pts had received prior platinum-based chemotherapy. Total analyte concentrations (sum of Enz and its metabolites) reached steady-state by day 8 of dosing. Total analyte mean steady-state average concentrations (%CV) following QD and BID dosing were 2850 nmol/L (53.5%) and 3420 nmol/L (39.5%), respectively. Exposures following loading dose were within the range of concentrations seen at steady-state. Enz dosing regimen (QD or BID) did not alter Pem PK. One dose-limiting toxicity (Grade 3 QTc prolongation) occurred 1 day after the Enz loading dose in cohort 1. Grade 3/4 toxicities occurring in 6 pts included leukocytopenia, neutropenia (3 pts each), increased ALT, and increased AST (2 pts each). To date, 1 pt achieved PR and 6 pts achieved SD. 5 pts received more than 10 cycles of treatment without disease progression; 4 of these pts are still on therapy. Conclusions: Both schedules of Enz in combination with Pem are well tolerated and clinically active in pts with advanced NSCLC.

[Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora A kinase (AAK) inhibitor MLN8054 in patients (pts) with advanced solid tumors
Authors: Macarulla T. , Rodríguez-Braun E. , Tabernero J. , Roselló S. , Baselga J. , Lee Y. , Manfredi M. , Liu H. , Fingert H. , Cervantes A.
Published: August 2020

2578

Background: MLN8054, a first-generation, selective AAK inhibitor, induces chromosome alignment and segregation defects during mitosis, leading to cell death (Hoar et al, MolCellBio 2007;27:4513). This phase I trial examined the safety, PK, and PD of MLN8054 administered orally to adult pts with advanced solid tumors. Methods: Pts received increasing oral doses of MLN8054 until dose-limiting toxicity (DLT) in the first cycle was seen in ≥2 of 3–6 pts in a cohort. Two cohorts received 10 and 20 mg once daily (QD) on d1–5 and d8–12 of 28d cycles. Benzodiazepine-like adverse effects (somnolence) associated with chemical structure and presumably unrelated to AAK inhibition were observed with QD dosing in another Phase 1 study (Dees et al, EJC Suppl 2008;6[12]:91), so subsequent cohorts in this trial were treated with 25, 35, 45, 55, 60, 70, and 80 mg/d in four divided doses (QID) on d1–14, with the largest dose at night. To manage somnolence, methylphenidate 5–15 mg was permitted with daytime doses in the 45–80 mg cohorts. Results: 43 pts received MLN8054 (median 1 cycle [range 1–10]). Dose escalation stopped at 80 mg/d due to DLTs including G3 somnolence (n=1) and G3 transaminitis (n=1). G2 oral mucositis (n=1), which may signal target-related toxicity, was observed first at 80 mg/d, a dose considered to be above the MTD. In PK analyses, MLN8054 was absorbed rapidly (Tmax = 1–2h) and terminal half-life was 30–40h, presenting a linear exposure-dose profile. In PD analyses, MLN8054 at higher doses increased mitotic count in skin and tumor biopsies and reduced chromosome alignment and spindle bipolarity in the mitotic cells in tumor biopsies, outcomes consistent with AAK inhibition. Stable disease (range 4–9 cycles) was observed in 3 pts (colorectal, non-small cell lung, and melanoma). Conclusions: MLN8054 was absorbed rapidly with a long half-life; PD findings supported MLN8054 inhibition of AAK at higher doses. Dosing for 14d of a 28-d cycle was feasible, but off-target DLTs limited dose escalation before mechanism-based toxicity was seen. MLN8237, a second-generation AAK inhibitor designed with greater mechanistic potency and to minimize benzodiazepine effects, is now in clinical trials.

[Table: see text]
A phase I pharmacokinetic study of a liposomal formulation of paclitaxel administered weekly to Asian patients with solid malignancies
Authors: Lim W. T. , Leong S. S. , Toh C. K. , Ang C. S. , Wong N. S. , Tan E. H. , Chowbay B.
Published: August 2020

2581

Background: Genexol-PM is a sterile, lyophilized polymeric micellar formulation of paclitaxel which is devoid of Cremophor EL and hence is more tolerable and less toxic. This phase 1 study sought to determine the maximum tolerated dose and the pharmacokinetic profile of Genexol-PM in Asian cancer patients with solid malignancies. Methods: Patients (N=35) refractory to previous chemotherapy were enrolled in a phase 1, open-label, dose-escalating study to assess safety, tolerability ad pharmacokinetics of Genexol-PM administered as a 1h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80mg/m2. Cohorts of 1–6 patients were treated at 100, 120, 140, 160, 180 and the maximum administered dose was 200 mg/m2. Results: The median age was 56 years (range: 39 - 67 years) and two thirds of the enrolled patients were male (67%). Twenty-three patients (96%) had received prior chemotherapy, including eleven patients (46%) who had previously received taxane-based chemotherapy. The majority of patients had lung, nasopharyngeal and breast cancers. DLT was reached at 200 mg/m2. The MTD was 180 mg/m2. Grade 3 granulocytopenia was common in patients receiving Genexol-PM at doses of 120 mg/m2 or higher in the first cycle. The most common grade 3 non-haematologic adverse events in cycle 1 were fatigue, myalgia and neuropathy and occurred mainly at dose level 7 (200 mg/m2) in 4%, 4% and 8% of the patients. Five (21%) patients had partial response, 9 (38%) had stable disease and seven (29%) patients had disease progression. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both Cmax and AUC0-∞ values increasing by approximately 4- and 3-fold as the dose of Genexol-PM was increased from 80mg/m2 to 200mg/m2 with no significant change in clearance. The median total-body clearance of Genexol-PM for all patients was 43.9 L/hr. Conclusions: The weekly regimen of Genexol-PM was found to be well-tolerated and responses were observed in patients with refractory tumours, including patients who had failed taxane-based chemotherapy previously.

No significant financial relationships to disclose.
Comparison of the immunogenicity of Montanide ISA 51 adjuvant and cytokine-matured dendritic cells in a randomized controlled clinical trial of melanoma vaccines
Authors: O'Neill D. W. , Adams S. , Goldberg J. D. , Escalon J. B. , Rolnitzky L. M. , Cruz C. M. , Angiulli A. , Old L. , Pavlick A. C. , Bhardwaj N.
Published: August 2020

3002

Background: Dendritic cell (DC) vaccines have been widely used in clinical trials to treat cancer. However, no study has compared the immunogenicity of the most commonly used DC type (cytokine-matured, monocyte-derived DCs) to more traditional vaccine adjuvants. We performed a randomized controlled trial comparing the immunogenicity of cytokine-matured DCs loaded with 6 HLA-A2-restricted peptide antigens and a foreign protein, KLH, to a vaccine containing the same antigens emulsified in the mineral oil adjuvant Montanide ISA 51 VG. Methods: 51 HLA-A2+ patients with resected stage IIb-IIIc melanoma were randomized to receive DCs (25 patients) or Montanide (26 patients). DCs were differentiated from autologous blood monocytes with IL-4 and GM-CSF, then matured with IL- 1β, IL-6, TNFα and PGE2. 18 million DCs were given i.d. every 4 weeks x 4, and immune responses analyzed (MHC multimers, T cell proliferation, cytokine secretion, antibodies). A 3-fold increase over baseline was considered a response. Results: Both vaccines were well tolerated. Immunogenicity was significantly greater with Montanide, as demonstrated by response rates to Flu, Melan-A and NY-ESO-1 peptides by IFNγ ELISPOT. Similar results were obtained by MHC multimer staining, with higher response rates seen using pre-sensitized assays. T cell proliferation to KLH was seen in both arms (90% DC, 100% Montanide), but the magnitude of response was significantly higher for Montanide (36-fold vs. 14-fold increase over baseline, p=0.002, Wilcoxon). KLH-specific CD4+ T cells that produced IFNγ, TNFα and IL-2 were seen only with Montanide, and all Montanide patients, but only 5% of DC patients, developed antibodies to KLH (p<0.001, Fisher's). Conclusions: A water-in-oil vaccine adjuvant, Montanide ISA 51, was significantly more immunogenic than DCs. Future studies of new DC vaccines should compare DCs to standard adjuvants to determine if their added difficulty and expense are truly warranted.

[Table: see text]

[Table: see text]
Phase I study of intranodal direct injection of adenovirus encoding recombinant CD40-ligand (Ad-ISF35) in patients with chronic lymphocytic leukemia
Authors: Castro J. E. , Sandoval-Sus J. D. , Melo-Cardenas J. , Darrah D. , Urquiza M. , Pakbaz R. S. , Prussak C. E. , Kipps T. J.
Published: August 2020

3003

Background: Transduction of chronic lymphocytic leukemia (CLL) cells with replication-defective adenovirus (Ad) encoding a genetically engineered, membrane-stablized CD154 (ISF35) converts transduced, and “bystander” non-transduced, CLL cells into proficient antigen presenting cells that can induce immunity against autologous leukemia cells. Preclinical studies demonstrated that direct injection of Ad-ISF35 into lymphoma nodules can induce potent anti-lymphoma immune responses in test animals, capable of eradicating lethal tumors at distal sites and protect against recurrent disease upon subsequent re-challenge with syngeneic tumor. Methods: We conducted a phase I study on 15 patients to evaluate the safety of intranodal direct injection (IDI) of Ad-ISF35. Pts, ages 45–71 yrs, with rapidly progressive disease (median CLL doubling time of 3.7 months) each received a single ultrasound guided IDI of 1 to 30 x 1010 Ad-ISF35 viral particles in 4 different dose cohorts. Results: IDI of Ad-ISF35 was well-tolerated and effective in inducing systemic responses. Some pts had grade ≤ 2 injection-site erythema, pain and/or swelling, or flu-like symptoms. Some pts in the highest-dose cohorts had transient, asymptomatic grade 3/4 hypophosphatemia. No long-term (≥ 6 wk) adverse effects were observed. Although there was no evidence for dissemination of Ad-ISF35 beyond the injected lymph node, IDI of Ad-ISF35 induced blood CLL cells to express death receptors, pro-apoptotic proteins, and immune co-stimulatory molecules similar to those induced on “bystander” CLL cells co-cultured with Ad-ISF35 transduced cells in vitro. Importantly, IDI of Ad-ISF35 resulted in significant reductions in blood leukemia cell counts and a median reduction of 53.2% (range 25–75.4%) in the size of lymph nodes and/or spleen, which was durable (≥ 4 months) in 9 pts. Despite aggressive disease prior to treatment, the median treatment-free survival was 5.3 months and 3 pts have yet to require additional treatment after 1-year follow-up. Conclusions: Single IDI of Ad-ISF35 was safe and effective in inducing systemic biologic and clinical responses in pts with CLL. IDI of Ad-ISF35 might be effective in the treatment of CLL and related lymphomas.

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Survival update from a multicenter, randomized, phase III trial of vitespen versus observation as adjuvant therapy for renal cell carcinoma in patients at high risk of recurrence
Authors: Wood C. G. , Srivastava P. , Lacombe L. , Gorelov A. I. , Gorelov S. , Mulders P. , Zielinski H. , Teofilovici F. , Isakov L. , Escudier B.
Published: August 2020

3009

Background: Vitespen (formerly HSPPC-96) is a novel, autologous, heat shock protein (gp96)-peptide complex vaccine. The survival registry is investigating long-term efficacy of vitespen in renal cell carcinoma (RCC) patients at high risk for recurrence postnephrectomy. Methods: Eligible patients were enrolled and active in Antigenics’ C-100–12 phase III protocol, with a last survival status of alive at study end. Patients randomized in C-100–12 (1:1, vitespen vs. observation) had AJCC stage I (T1b), II (≥5 cm; Fuhrman grade 3/4), stage III, or stage IV (M0) RCC, ≥25% clear cells, ECOG performance score 0/1 and ≥7 g viable tumor tissue for vaccine production. The registry's primary objective is to assess OS. Registry patients are contacted every 6 (no recurrence) or 3 (upon recurrence) m, for a total of 3 y from final C-100–12 data cutoff. Results: Upon C-100–12 termination, 513 of 728 patients were eligible for follow-up. Currently, 306/513 (60%) patients are in the registry database; 207 patients are being contacted. The cohort of 306 patients is well balanced by C-100–12 randomization arm: (59.8% vitespen, 59.5% observation). Formal statistical analyses are in process. Descriptively, updated OS data show a favorable trend in the vitespen arm vs. observation in all analysis sets, especially among patients with earlier-stage disease (stage I/II high grade; n = 118) or at intermediate risk for recurrence (stage I/II high grade, III T1, T2, T3a, low grade; n = 184 ), with 13/125 (10.4%) vs. 21/115 (18.3%), and 18/184 (9.8%) vs. 33/178 (18.5%) deaths reported in the vitespen and observation arms, respectively. Conclusions: The registry provides an opportunity to confirm whether the emerging survival advantage demonstrated at the data cutoff for the C-100–12 trial improves with prolonged follow-up. Formal statistical analyses are ongoing; data available to date show continuing signals of clinical benefit associated with vitespen treatment in patients with better prognostic factors.

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A phase I study of the anti-natural killer inhibitory receptor (KIR) monoclonal antibody (1–7F9, IPH2101) in elderly patients with acute myeloid leukemia (AML)
Authors: Vey N. , Bourhis J. , Dombret H. , Bordessoule D. , Prebet T. , Charbonnier A. , Squiban P. , Damholt B. , Blaise D. , Olive D.
Published: August 2020

3015

Background: The outcome of the majority of patients with AML remains poor, especially in the oldest patients. Allogeneic SCT is a curative approach for AML. In some models, it has been shown that KIR mismatch is important for the anti-leukemic effect of the graft, most probably through unleashed NK cells towards AML blasts, as suggested by enhanced in vitro NK lytic activity of KIR-HLA mismatched donor NK against recipient blasts. To mimic this effect with a pharmaceutical agent, a fully human IgG4 anti-KIR mAb specific for KIR2DL1/2/3 (HLA-C specific KIRs) was generated. We present the results of the first-in-human phase I trial of this agent in patients with AML in complete remission (CR). Methods: Patients aged 60–80 years with non promyelocytic AML in first CR following induction and 1–6 cycles of consolidation chemotherapy, normal renal, and hepatic functions, KIR-expression on patient NK-cells and who signed informed consent were eligible.Dose escalation (0.0003, 0.003, 0.015, 0.075, 0.3, 1, 3 mg/kg) was studied using a 3+3 scheme. Pharmacokinetic (PK) and circulating cytokines (MIP1β, TNF) were measured by ELISA. KIR occupancy and activation markers (CD69) were monitored by flow cytometry. Results: To date, inclusion has been completed until 1mg/kg cohort. Data of the first 15 patients (end of 0.3 mg/kg cohort) are available. No dose limiting toxicity has been observed. Side effects that could be related to drug administration were mild and transient. The first dose level resulted in a transient KIR occupancy ranging from 20 to 50%. PK values were then in line with modelling data, resulting at 0.3 mg/kg in a Cmax= 6350 ± 504 ng/mL, >80% KIR saturation for one week, and desaturation in the following week. As expected for an IgG4, NK cell numbers were unaffected by the treatment. Upregulation of CD69 on NK cells and concomitant increases in TNF and MIP1b circulating cytokines were observed in some patients at the highest doses (0.075, 0.1, 0.3 mg/kg) but a dose dependency has not been reached yet. Conclusions: Anti-KIR treatment is safe and well tolerated to date. At the 0.3mg/kg dose, MTD has not been reached, but a one week receptor blockade and signs of NK activation were observed.

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Decrease of VEGF within malignant ascites during catumaxomab treatment: Results from a pivotal phase II/III study
Authors: Jäger M. , Schoberth A. , Theissen B. , Hess J. , Friccius-Quecke H. , Lindhofer H.
Published: August 2020

3029

Background: Treatment with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal cavity (Jäger et al., ASCO 2007) and led to clinically relevant prolongation of puncture-free survival (PuFS) in patients with malignant ascites (MA) in a pivotal phase II/III trial (Parsons et al., ASCO 2008). As vascular endothelial growth factor (VEGF) levels are markedly elevated in MA in comparison to cirrhotic ascites the question was addressed whether catumaxomab treatment impacts the expression or accumulation of VEGF within MA. Here we report that in addition to tumor cell depletion, VEGF protein levels in MA significantly decreased upon catumaxomab therapy. We propose that the strongly correlated tumor cell elimination and reduced VEGF protein levels are causative for the prolonged PuFS of patients suffering from MA. Methods: VEGF and total protein levels were measured by ELISA and BCA from MA supernatants before catumaxomab therapy, after the 1st infusion (10μg; day 3) and after the 4th infusion (150μg; day 11). Data were statistically analysed for the ratio of the VEGF protein concentration versus the total protein concentration for the MA treatment groups with ovarian (OC) or nonovarian cancer (NC) as underlying disease and the corresponding control groups that received paracentesis only. Results: One day after the last catumaxomab infusion 46 or 47 patients analysed in the OC or NC treatment group showed a statistically significant decrease in VEGF to total protein ratio when compared to the measurement before catumaxomab therapy (ANOVA p=0.034 for OC and p<0.001 for NC). These results are consistent with the tumor cell elimination previously assessed in these patients. In contrast, the OC control group showed a statistically significant increase of VEGF to total protein ratio (p=0.009), which is accompanied by an increase in tumor cell numbers. In the NC control group VEGF to total protein ratio remained unaffected (p=0.096). Conclusions: Catumaxomab therapy significantly reduced VEGF protein levels correlating with tumor cell elimination in MA, which in turn led to the prevention of fluid accumulation in the peritoneal cavity and finally to prolonged PuFS of patients suffering from MA.

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Increased humoral and cellular immunity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Parker S. , Berman D. , Bennett K. L. , Alaparthy S. , Tsuchihashi Z. , Chasalow S. D. , Zhan P.
Published: August 2020

3031

Background: Ipilimumab is an anti-CTLA-4 monoclonal antibody (Ab) that overcomes T-cell suppression. In this phase II study (CA184004), humoral and cellular responses were assessed in ipilimumab-treated pts with unresectable stage III/IV melanoma. Methods: Ipilimumab 3 or 10 mg/kg was given every 3 weeks x 4. Tetanus boosters were given ≤10 days pre-treatment. Influenza and pneumococcal vaccines were given 5 days after first ipilimumab dose. Tetanus, anti-influenza, and anti-pneumococcal Ab levels were assessed at pre-dose and Wk 7. Humoral response to 5 tumor antigens (Ag) and a control Ag (DHFR) were examined at baseline (BL) and at Wks 4, 8–9, and 12. DTH skin tests were given at pre-dose and Wk 4, with responses recorded 15 minutes (min) and 24–72 hours (hrs) post-test. Peripheral T-cell populations were evaluated through flow cytometry at BL, Wk 4, and Wk 12. Results: Pts received ipilimumab 3 (n = 40) or 10 mg/kg (n = 42). Increases from BL in humoral responses to pneumococcal (40–50/78 pts, depending on Ab) and tetanus (58/78 pts) vaccines were noted, even in pts who did not receive on-study pneumococcal (4–9 pts) or tetanus (7 pts) vaccines. Increased humoral response to influenza only occurred in pts receiving the influenza vaccine. Maximum increase from BL of ≥ 5-fold titer (clinically meaningful threshold) in humoral response to tumor Ag MELANA (23.2% of pts), SSX2 (20.3%), NYES01 (18.8%), MAGEA4 (10.1%), and P53 (4.3%) (DHFR, 4.3%) was noted without tumor vaccines. Tumor Ag response was not associated with clinical activity (complete or partial response, or stable disease ≥ 24 wks). Increased DTH reactions were noted for tetanus, 24–72 hrs (3 mg/kg: 5/7 pts; 10 mg/kg: 3/6 pts); tuberculin, 15 min (3 mg/kg: 7/15 pts; 10 mg/kg: 4/15 pts); Candida, 15 min (3 mg/kg: 4/6 pts; 10 mg/kg: 2/7 pts); and Trichophyton, 15 min (3 mg/kg: 3/4 pts; 10 mg/kg: 2/5 pts). Significant increases from BL in percents of HLA-DR+ CD4+ (p = 9.3x10-7), HLA-DR+ CD8+ (p = 0.018), and ICOS+ CD4+ (p = 0.0027) effector T cells were noted. Conclusions: Humoral immunity in ipilimumab-treated pts increased (± vaccination) in an Ag-dependent manner and cellular immunity was enhanced. Change in tumor Ag response was not associated with clinical activity.

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Phase I clinical experience of a targeted TCR-IL2 fusion protein in patients with metastatic malignancies
Authors: Pennock G. , Fishman M. , Gonzalez R. , Thompson J. , Huang B. , Tang S. , Rhode P. , Wong H.
Published: August 2020

3040

Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In tumor xenografts in animal models, this fusion protein demonstrated potent and targeted antitumor activity. Methods: A phase I/IIa multicenter clinical study was initiated to assess safety and clinical response of ALT-801 in patients with various metastatic malignancies. Patients screened positively for HLA-A2 and tumors expressed p53 peptide/HLA-A2 complex. In this dose escalation trial, patients received ALT-801 as a daily intravenous infusion for 4 days followed by a 10-day rest period and 4 additional daily doses. Results: Data from three dosing cohorts (0.015, 0.04, and 0.08 mg/kg/dose) indicate that ALT-801 is well-tolerated up to 0.04 mg/kg/dose. The half-life of ALT-801 is 2.5–4 hours per pharmacokinetic analysis, depending on the dose. Even at the 0.015 mg/kg level, there were sufficient concentrations of ALT-801 in the patients’ serum to fully activate cell lytic activity in vitro. Treatment with ALT-801 also led to immune activation in patients as demonstrated by elevated serum IFN-γ levels as well as an increase in IFN-γ-producing immune cells in patients’ blood. Interestingly, serum TNF-α, a major inducer of hypotension in patients receiving high-dose IL-2 treatment, was not induced in patients receiving ALT-801. Evidence of antitumor activity (i.e., stable disease, tumor shrinkage) was observed in some patients after one or two courses of ALT-801. Conclusions: At a dose of 0.04 mg/kg, ALT-801 is a well-tolerated agent that generated a vigorous immune response and demonstrated clinical efficacy in a group of patients with various metastatic malignancies. An expansion cohort of patients is in progress at 0.04 mg/kg.

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Mediator release during combined radio chemotherapy in rectal carcinoma
Authors: Matuschek C. , Bölke E. , Gripp S. , Budach W. , Hermsen D. , Peiper M.
Published: August 2020

3043

Background: Bacterial translocation is a well-documented phenomenon after polytrauma and major abdominal surgery. Today neoadjuvant chemoradiotherapy is the gold standard for uT3, N+ rectal cancer. The aim of this study was to evaluate if a gut barrier dysfunction occurred during radiotherapy and elective rectal surgery. Methods: We investigated in 45 patients (25 male, 20 female) with uT3N+ rectal carcinoma and neoadjuvante long-term radio chemotherapy with 5-FU and pelvis irridation up to 50.4 Gy on admission and weekly during radiotherapy and after surgery IL-6, LPS-binding protein, IL-8, TNF-α and procalcitonin. Results: There were no clinical complications in all patients. During radiochemotherapy we could not detect a significant increase of the acute phase response. IL-6 plasma levels showed maximal values 6 h after surgery (270 pg/ml) und CRP had its maximal values 48 h (185 mg/l). IL-8, TNF-α, LPS-BP, and procalcitonin were not elevated during an uncomplicated postoperative course. Conclusions: During an uncomplicated course of radio chemotherapy we could not detect elevated mediator releases. During surgery we could find a significant mediator liberation, which correlated with the amount of the operative trauma.

No significant financial relationships to disclose.