bluuebunny/crossref_metadata_2025 huggingface dataset:
Temozolomide-induced hypermutation is associated with high-grade transformation, distant recurrence, and reduced survival after transformation in initially low-grade IDH-mutant diffuse gliomas.
Authors: Oberheim Bush Nancy Ann , Yu Yao , Villanueva-Meyer Javier , Grimmer Matthew , Hilz Stephanie , Solomon David , Choi Serah , Mazor Tali , Hong Chibo , Shai Anny , Phillips Joanna J. , McDermott Mike , Haas-Kogan Daphne A. , Taylor Jennie , Butowski Nicholas A. , Clarke Jennifer , Berger Mitchel , Molinaro Annette , Chang Susan Marina , Costello Joseph
Published: May 2020

2506

Background: Temozolomide, a commonly used alkylating agent to treat gliomas, can induce somatic hypermutation. The prevalence and clinical implications of this phenomenon are not well characterized. Methods: We used targeted and whole exome sequencing from a cohort of 82 patients with recurrent IDH-mutant low grade gliomas undergoing re-operation to evaluate the prevalence as well as the clinical implications of hypermutation. Results: Hypermutation was identified at transformation in 57% of recurrent gliomas exposed to Temozolomide, 94% of which were transformed to higher WHO grades. All patients who developed hypermutation were exposed to Temozolomide. Hypermutation was associated with transformation to higher WHO grade (OR 12.0 95% CI 2.5 – 115.5, p = 0.002) and shorter survival after transformation (HR 2.1, 95% CI 1.1-4.0, p = 0.018) compared with non-hypermutated transformed tumors, controlling for grade, molecular subtype, age, and prior radiotherapy. Patients with transformation to glioblastoma had poor survival regardless of hypermutation (p = 0.78). Hypermutated tumors were associated with development of discontiguous disease at a significantly higher frequency (p = 0.003), including four cases with spinal dissemination. Conclusions: TMZ-induced hypermutation is associated with high grade transformation, unique patterns of dissemination and shortened survival after transformation. Next generation sequencing should be considered in this patient population. These data have important implications for the management of newly diagnosed and recurrent IDH-mutant low grade gliomas.
A pediatric and young adult phase I dose escalation study of BXQ-350 for solid and central nervous system tumors.
Authors: Abdelbaki Mohamed , Setty Bhuvana , DeWire Mariko Dawn , Cripe Timothy P. , Curry Richard
Published: May 2020

2541

Background: BXQ-350 is a novel agent composed of the multifunctional, lysosomal activator protein Saposin C (SapC) and dioleoyl- phosphatidylserine (DOPS) and has demonstrated antitumor effects in both in vitro and in vivo preclinical models. Many tumors, including high-grade glioma and diffuse intrinsic pontine glioma (DIPG), and cells of tumor vasculature have aberrantly exposed phosphatidylserine (PS)-rich domains on the cell surface. BXQ-350 is an anti-tumor agent in development from Bexion Pharmaceuticals, Inc. that selectively targets tumor cell PS, particularly those translocated to the outer leaflet of the plasma membrane in tumor cells. BXQ-350 activates and participates in various cellular processes, including apoptosis and necrosis, and may also exhibit novel mechanisms leading to cell death that require further investigation. Methods: Nine refractory solid (2) and central nervous system (7) tumor patients (5F:4M, age 4-23 years of age) were enrolled in a 2-site dose escalation phase I first-in-pediatric trial ( NCT03967093 ) which completed in 2019. All patients received at least one dose of BXQ-350 which was administered as an intravenous infusion. Dosing began at 1.8 mg/kg and escalated to the highest planned dose level of 3.2mg/kg. Results: There were no BXQ-350-related serious adverse events, dose limiting toxicities, or withdrawals. The highest planned dose of 3.2 mg/kg was achieved safely but a maximum tolerated dose was not established. One osteosarcoma patient had progressive disease prior to completing cycle one of treatment and was removed from trial. Eight patients (DIPG-3, HGG-1, GBM-1, Pineoblasotoma-1, Ependymoma-1, Osteosarcoma-1) completed at least one cycle, with one DIPG patient completing cycle five. Conclusions: BXQ-350 was well tolerated with no significant dose-limiting toxicities at the highest planed dose level. A pediatric phase I trial in newly diagnosed patients is planned for 2nd quarter 2020. Clinical trial information: NCT03967093 .
Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen.
Authors: Nagpal Seema , Thomas Reena Parada , Bertrand Sophie , Yerraballa Hari Priya , Iv Michael , Li Gordon , Klotz Alison , Kiebish Michael A. , Narain Niven R. , Sarangarajan Rangaprasad , Granger Elder , Recht Lawrence David
Published: May 2020

2543

Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]
Impact of lymphopenia on survival for elderly patients with glioblastoma: A secondary analysis of the CCTG CE.6 (EORTC 26062-22061, TROG03.01) randomized clinical trial.
Authors: Song Andrew Jehyun , Ding Keyue , Laperriere Normand , Perry James R. , Mason Warren P. , Winch Chad , O'Callaghan Christopher J. , Menten Johan , Brandes Alba Ariela , Phillips Claire , Fay Michael F. , Nishikawa Ryo , Osoba David , Cairncross Gregory , Roa Wilson , Wick Wolfgang , Shi Wenyin
Published: May 2020

2547

Background: Lymphopenia (LMP) may lead to worse outcomes for patients with glioblastoma (GBM). This study is a secondary analysis of the CCTG CE.6 trial evaluating the impact of chemotherapy and radiation on LMP, as well as the association of LMP with overall survival. Methods: CCTG clinical trial CE.6 randomized elderly GBM patients (≥ 65 yrs) to short course radiation alone (RT) or short course radiation with temozolomide (RT + TMZ). In this study LMP (mild-mod: grade 1-2; severe: grade 3-4) was defined per CTCAE v3.0 criteria, and measured at baseline, 1 wk and 4 wks post-RT. Pre-selected key factors for the analysis included age, sex, ECOG, extent of resection, MGMT methylation, MMSE, and steroid use. Multinomial logistic regression models were used to identify factors associated with LMP and multivariable Cox regression models were used to study effect of LMP on survival. Results: A total of 562 patients were included for analysis (281 RT vs 281 RT+TMZ). At baseline, both arms (RT vs RT+TMZ) had similar rates of mild-mod (21.4% vs 21.4%) and severe (3.2% vs 2.9%) LMP. The 1 wk post-RT LMP rates were also similar (p = 0.25). However, RT+TMZ pts were more likely to develop both mild-mod LMP (18.2% vs 27.9%) and severe LMP (1.8% vs 9.3%) [p < 0.001] at 4 wks post-RT. Developing mild-mod and severe LMP post-RT were both associated with baseline LMP (p < 0.001) and RT+TMZ (p < 0.001). Severe LMP at 4 wks post-RT was also associated with biopsy only (p < 0.02). After adjusting for confounding factors, 4 wks post-RT LMP was not significantly associated with PFS or OS regardless of severity. However, baseline LMP (HR 1.3) was significantly associated with worse OS (HR: 1.30, 95% C.I.: 1.05-1.62, p = 0.02), regardless of MGMT status. Other factors significantly associated with worse outcome included: males (HR 1.41), biopsy only (HR 1.59), and lower MMSE (HR 1.03). Conclusions: Short course RT alone does not lead to LMP after treatment. Development of LMP post-RT is associated with addition of TMZ and baseline LMP. However, only baseline LMP is associated with worse OS regardless of MGMT status. This may be considered as a prognostic biomarker for elderly GBM patients and warrants further validation. Clinical trial information: NCT00482677 .
Escalation portion of phase II study to evaluate the safety, pharmacokinetics, and clinical activity of the PI3K/mTOR inhibitor paxalisib (GDC-0084) in glioblastoma (GBM) with unmethylated O6-methylguanine-methyltransferase (MGMT) promotor status.
Authors: Wen Patrick Y. , De Groot John Frederick , Battiste James D. , Goldlust Samuel Aaron , Garner James Stuart , Simpson Jeremy Andrew , Kijlstra Jelle , Olivero Alan , Cloughesy Timothy Francis
Published: May 2020

2550

Background: Paxalisib (previously GDC-0084) is a potent, oral, selective, brain-penetrant, small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin. The PI3K pathway is upregulated in ~85% of GBM cases and paxalisib has shown efficacy in preclinical models. A phase I study (NCT01547546) investigated paxalisib dosed once daily in 47 patients with recurrent high-grade gliomas and established a maximum tolerated dose (MTD) of 45mg once daily. The current phase Il study aims to explore the safety, tolerability, and clinical activity of paxalisib in newly diagnosed GBM and an unmethylated MGMT promotor following surgery and temozolomide chemoradiation per Stupp regimen. Methods: Part 1 of this study is an open-label, dose-escalation phase to assess the safety, tolerability and MTD. Dose-escalation started at 60mg and progressed in 15mg increments using a 3+3 design. Part 2 is an expansion cohort recruiting 20 patients randomized to administration in fed or fasted states at the MTD. Results: Part 1 is complete and reported here. Nine patients were recruited and an MTD of 60mg was determined. DLTs were hyperglycemia and oral mucositis. AEs were generally reversible and consistent with the PI3K inhibitor class with the most common events were rash, oral mucositis, and fatigue. PK at the MTD was broadly consistent with the data published for the phase 1 study. For eight response-evaluable patients in Part I the median progression-free survival (PFS) was 8.4 months, and 25% of patients remained progression free after 15 months of follow-up. Part 2 is ongoing. Conclusions: A higher MTD of 60mg was identified in newly diagnosed GBM with unmethylated MGMT promotor status than the 45mg MTD previously identified in recurrent high-grade glioma. An encouraging PFS signal is described in this poor-prognosis, unmethylated MGMT patient population. Clinical trial information: NCT03522298 .
Evaluation of glioblastoma tumor microenvironment after treatment with pembrolizumab.
Authors: Majd Nazanin , Lin Heather Y. , Yuan Ying , Alfaro-Munoz Kristin , Hunter Kathy , Heimberger Amy B. , De Groot John Frederick
Published: May 2020

2559

Background: Neoadjuvant pembrolizumab improved outcome of patients with recurrent Glioblastoma (GBM) in two early phase clinical trials. However, several large phase II/III studies in patients with newly diagnosed and recurrent GBM failed to demonstrate a therapeutic benefit of anti-PD-1 therapy. Therefore, identification of biomarkers of response is crucial for appropriate patient selection and further clinical development of anti-PD-1 therapy. We reported the outcome of our window-of-opportunity clinical trial of neoadjuvant pembrolizumab in 15 patients with recurrent GBM, demonstrating rare CD8+ T cells and abundant of CD68+ macrophages in GBM tissue after 3 weeks of anti-PD-1 treatment (NCT02337686). In the current study, we compared tumor infiltrating lymphocyte (TIL) and PD-L1 scores, known biomarkers of response to anti-PD-1 therapy in other cancers, in pre-trial vs. on-trial tumor tissue and associated these markers with survival. Methods: We determined TIL score (morphological assessment of the presence or absence of TILs, 0-3) and PD-L1 H score (defined as [1*1+ %]+[2*2+ %]+[3*3+ %], 0-200) and correlated these with survival. The Wilcoxon signed rank test was used to compare levels of PD-L1 H or TIL scores between pre-trial and on-trial specimens. The Cox proportional hazards models were used to assess associations between correlative markers and progression free survival or overall survival (OS). Results: The on-trial TIL level (median: 3) was significantly higher than the pre-trial TIL level (median: 1) (p = 0.031). However the difference between pre-trial and on-trial PD-L1 levels was not statistically significant (p > 0.9). Patients whose on-trial PD-L1 H score was ≥ 3 trended toward a longer OS than those with a PD-L1 H score < 3 (HR [95% CI] = 0.225 [0.043, 1.183]) (p = 0.0782). Conclusions: Although GBM tissue lacks abundant T cells, treatment with pembrolizumab increases trafficking of T cells to the tumor microenvironment, which is necessary but not sufficient to induce an effector T-cell response. Elevated PD-L1 expression may be a biomarker of response to anti-PD1 therapy in GBM, which needs confirmation in larger studies. Further genomic, transcriptomic, and methylation profiling of the pre-trial and on-trial tissues is ongoing. Clinical trial information: NCT02337686 .
Phase I trial of D2C7 immunotoxin (D2C7-IT) administered intratumorally via convection-enhanced delivery (CED) for recurrent malignant glioma (MG).
Authors: Desjardins Annick , Randazzo Dina , Chandramohan Vidyalakshmi , Peters Katherine B. , Johnson Margaret O , Threatt Stevie , Bullock Chevelle A , Herndon James Emmett , Healy Patrick , Lipp Eric S , Sampson John H. , Friedman Allan H. , Friedman Henry S. , Ashley David M. , Bigner Darell D.
Published: May 2020

2566

Background: D2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report the results of a phase I trial evaluating D2C7-IT delivered intratumorally by CED. Methods: Eligible patients were adults with recurrent supratentorial WHO grade III or IV MG; solitary tumor; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS>70%. Two patients per dose level (DL) were to enroll in the dose escalation portion (dose range: 40ng/mL to 23,354ng/mL). Results: From May 2015 to May 2018, 43 patients enrolled on study. Observed dose limiting toxicities include: grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17. Grade 3 or higher adverse events possibly related to D2C7-IT include: seizure (grade 4, n=2; grade 3, n=3), cerebral edema (grade 4, n=1), hydrocephalus (grade 3, n=5), headache (grade 3, n=4), hemiparesis (grade 3, n=4), dysphasia (grade 3, n=3), lymphopenia (grade 3, n=4), thromboembolic event (grade 3, n=3); and one each of grade 3 elevated ALT, urinary tract infection, fall, wound complication, generalized muscle weakness, confusion, encephalopathy, and somnolence. As of February 2020, four patients remain alive, with three patients demonstrating persistent radiographic partial response more than 54, 34 and 28 months after a single infusion of D2C7-IT. Conclusions: Dose level 13 (6,920ng/mL) was selected as the optimal phase II dose. Accrual in a dose expansion phase II trial is ongoing, and we are initiating a combination trial of D2C7-IT with checkpoint inhibitior. Clinical trial information: NCT02303678 .
Intratumoral drug distribution of adavosertib in patients with glioblastoma: Interim results of phase I study.
Authors: Romo Carlos G , Alexander Brian Michael , Agar Nathalie , Ahluwalia Manmeet Singh , Desai Arati Suvas , Dietrich Jorg , Kaley Thomas Joseph , Peereboom David M. , Takebe Naoko , Desideri Serena , Fisher Joy D. , Sims Megan , Ye Xiaobu , Ligon Keith L. , Nabors Louis B. , Wen Patrick Y. , Grossman Stuart A. , Supko Jeffrey G. , Lee Eudocia Quant
Published: May 2020

2568

Background: Wee1 is a key regulator of the G2/M checkpoint and is frequently overexpressed in glioblastoma (GB). Adavosertib is a first-in-class oral, small molecule inhibitor of Wee1 that acts primarily as a DNA damage sensitizer. A phase I clinical trial was conducted to evaluate its safety and establish the recommended phase II dosing. Studies were undertaken to evaluate whether potentially therapeutic concentrations of the drug are achieved in recurrent tumor and adjacent non-enhancing brain regions with presumed intact blood-brain barrier (BBB). Methods: Twelve patients received five daily doses of adavosertib pre-operatively at either the maximum tolerated dose (MTD) for concurrent radiation or adjuvant temozolomide. Tissue from contrast enhancing (CE) and non-enhancing (NE) brain regions was obtained for analysis during surgical resection. A second stage is being conducted using microdialysis (MD) to facilitate continuous sampling of extracellular fluid (ECF) and measuring free drug concentrations in: normal-appearing brain, contrast enhancing tumor, and a peritumoral T2 hyperintense area. The concentration of total adavosertib in plasma and tissue homogenates and free drug in ECF were determined by validated LC/MS/MS methods. Results: Geometric mean concentrations of adavosertib after a 200 mg dose were 644 ng/mL and 119 ng/mL in CE and NE tissue specimens, respectively (6 patients). At the 425 mg dose, the mean concentrations were 3,576 ng/mL in CE tissue and 885 ng/mL in NE tissue (6 patients). MD was performed in 2 patients. Samples from functional MD catheters were collected from NE brain in patient no. 1 and from two NE areas and a FLAIR hyperintense region in patient no. 2, with the following results in the table. Conclusions: The total drug concentration in tissue samples was notably lower in regions of the brain with a relatively intact BBB as compared to contrast enhancing tissue. Concentrations of adavosertib measured by MD vary markedly depending on catheter location. Free drug levels in ECF within brain with a functional BBB, although considerably lower than total drug levels in tissue, were 2-10 times below the previously reported IC50 for antiproliferative activity against sensitive GB cell lines (127 ng/mL). Whether or not the target of the drug is effectively inhibited at these concentrations remains to be demonstrated. Clinical trial information: NCT01849146 . [Table: see text]
Pilot study on outcome and antitumor efficacy of an autologous cancer cell vaccine applied in patients with advanced solid tumors.
Authors: Gonzalez Marcano Eglys , Kröhle Leona , Ahlers Joachim , Drevs Joachim
Published: May 2020

3000

Background: In the last decade cancer immunotherapy has emerged as the most promising anti-tumor approach. The most commonly used immunotherapies are vaccines and checkpoint inhibitors. An autologous cell vaccine is made with the patient's own tumor cells processed in vitro, which may elicit a cytotoxic T-lymphocytic immune response against tumor cells antigens, resulting in tumor cell death. We performed a pilot study to evaluate the clinical relevance and general outcome of an autologous vaccine as a treatment in different types of cancer. Methods: A total of 31 patients (n=31) with advanced solid tumors and the lack of standard treatments were treated with an immunotherapy protocol consisting of 6 intradermal doses of the vaccine, given the first two doses at day 1 and 2, and the rest every two weeks. All patients signed an informed consent form. Response evaluation was assessed by PET/CT identified as metric (iRECIST) response and in some cases tumor markers where available. Results: Out of 31 patients treated, 2 patients suffered from pancreatic cancer, 2 from sarcoma, 1 from lung cancer, 13 from breast cancer, 2 from ovarian cancer, 1 from prostate cancer, 1 from cholangiocarcinoma, 4 from colorectal cancer, 1 from non-Hodgkin lymphoma, 1 from gastric cancer, 1 from laryngeal and hypopharyngeal cancer, 1 from fallopian tube cancer, 1 from peritoneal cancer. Side effects related to the therapy were rare including light redness in the area of injection and in one case inflammation of the tumor area. 26 patients were evaluated for metric response and 5 for tumor marker response assessment. For tumor marker follow up 9.6 % had a SD of > 3 month and 6.5 % a PD. For metric follow up 12.9 % had a CR, 6.5 % a PR, 25.8 % a SD of > 3 month and 38.7 % a PD. Conclusions: This study have confirmed an anti-tumor response in the majority of patients treated, with none to very low side effects and a good quality of life during the treatment. To obtain more detailed and significant data on the efficacy of this therapy, a further controlled clinical phase study should be performed.
Safety and tolerability of MEDI0562 in combination with durvalumab or tremelimumab in patients with advanced solid tumors.
Authors: Goldman Jonathan Wade , Piha-Paul Sarina Anne , Curti Brendan D. , Pedersen Katrina , Bauer Todd Michael , Groenland Stefanie L. , Carvajal Richard D. , Chhaya Vaishali , Hammond Scott A , Streicher Katie , Townsley Danielle Michelle , Chae Young Kwang , Voortman Jens , Marabelle Aurelien , Powderly John D.
Published: May 2020

3003

Background: We report safety and tolerability of MEDI0562, a humanized IgG1κ OX40 monoclonal antibody (mAb), in combination with durvalumab (durva; anti-PD-L1 mAb) or tremelimumab (treme; anti-CTLA-4 mAb) in patients (pts) with previously treated advanced solid tumors. Methods: In this phase 1, open-label study (NCT02705482), adult pts received escalating doses of MEDI0562 (2.25, 7.5 or 22.5 mg/kg) every 2 wks (Q2W) in combination with durva (1500 mg/kg) or treme (75 or 225 mg/kg) Q4W, until confirmed disease progression or unacceptable toxicity. Tumor assessments were performed Q8W with immune-related Response Evaluation Criteria in Solid Tumors. Results: In total, 27 and 31 pts received MEDI0562 + durva or treme, across 5 dose combination cohorts (3 + 3 design), with a maximum tolerated dose of 7.5 mg MEDI0652 + 1500 mg durva and maximum administered dose of 10 mg MEDI0562 + 225 mg treme. Median duration of exposure was 12.0 (range 2.0–80.9) and 8.0 (range 2.0–42.0) wks, respectively. Two (22.5 mg MEDI10562 + durva) and 3 (2.25 mg MEDI0652 + 225 mg treme, 22.5 mg MEDI0562 + 75 and 225 mg treme) dose limiting toxicities were observed. For MEDI0562 + durva and MEDI0562 + treme groups respectively, treatment-emergent adverse events (TEAEs) were reported in 96.3% and 100% of pts; most common TEAEs were fatigue (55.6%) and pruritus (45.2%), Gr 3/4 TEAEs occurred in 74.1% and 67.7%; and MEDI0562-related AEs were reported in 20 (74.1%) and 24 (77.4%) pts. Six TEAEs in each group led to MEDI0562 discontinuation (22.2% and 19.4%, respectively), 2 led to death (renal failure [7.5 mg MEDI0562 + durva], multiple organ dysfunction syndrome [22.5 mg MEDI0562 + 225 mg treme]). Three response evaluable pts had PR (11.5% [7.5 and 22.5 mg MEDI0562 + durva, n = 26]). Median overall survival was 17.4 and 11.9 mos for MEDI0562 + durva and MEDI0562 + treme, with stable disease seen in 9 pts from each group, 34.6% vs 29.0%, respectively. Serum exposure of MEDI0562 increased dose proportionally. Post treatment serum antidrug antibody (ADA) was detected in 20 pts from MEDI0562 + durva and MEDI0562 + treme (74.1% and 71.4%, respectively). The impact of ADA on MEDI0562 pharmacokinetics was seen at all doses. Mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased, while mean percentage of OX40+CD4+ memory T cells decreased following the first dose of MEDI0562 + durva or treme. Conclusions: The safety profile of MEDI0562 in combination with durva or treme was similar between groups. Clinical activity was observed with MEDI0562 + durva in pts with advanced solid tumors. Clinical trial information: NCT02705482 .
Combined PD-1 inhibition (Pembrolizumab) and CCR5 inhibition (Maraviroc) for the treatment of refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC): First results of the PICCASSO phase I trial.
Authors: Haag Georg Martin , Halama Niels , Springfeld Christoph , Grün Barbara , Apostolidis Leonidas , Zschaebitz Stefanie , Dietrich Mareike , Berger Anne-Katrin , Weber Tim Frederik , Zoernig Inka , Waberer Lisa , Mueller Daniel Wilhelm , Al-Batran Salah-Eddin , Jaeger Dirk
Published: May 2020

3010

Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .
Long-term follow-up of anti-CD19 CAR T-cell therapy for B-cell lymphoma and chronic lymphocytic leukemia.
Authors: Cappell Kathryn , Sherry Richard Mark , Yang James C. , Goff Stephanie L. , Vanasse Danielle , McIntyre Lori , Rosenberg Steven A. , Kochenderfer James N.
Published: May 2020

3012

Background: T cells expressing anti-CD19 chimeric antigen receptors (CARs) can cause complete remissions of relapsed lymphoma. We conducted the first clinical trial of anti-CD19 CAR T cells to show responses against lymphoma. This CAR was later developed as axicabtagene ciloleucel. Here, we aimed to assess the long-term durability of remissions and the long-term adverse effects after anti-CD19 CAR T-cell therapy. Methods: Between 2009 and 2015, we treated 43 patients with anti-CD19 CAR T cells preceded by conditioning chemotherapy of cyclophosphamide plus fludarabine (NCT00924326). Three patients were re-treated for a total of 46 CAR T-cell treatments. Twenty-eight patients had aggressive lymphoma (diffuse large B-cell lymphoma or primary mediastinal B cell lymphoma), eight patients had low-grade lymphoma (five with follicular lymphoma and 1 each with splenic marginal zone lymphoma, mantle cell lymphoma, and unspecified low-grade non-Hodgkin lymphoma), and seven patients had chronic lymphocytic leukemia (CLL). Patients were treated in three cohorts that differed in the CAR T-cell production process and conditioning chemotherapy dose. Results: Of the 43 treated patients, 63% had chemotherapy-refractory lymphoma. Patients had received a median of 4 previous lines of therapy. The median CAR+ T cell dose per kilogram was 2X10^6. The overall remission rate was 76% with 54% complete remissions (CR) and 22% partial remissions (PR). Patients with CR had higher median peak blood CAR levels (86 CAR+ cells/µL) than those who did not have CR (16 CAR+ cells/µL, P= 0.0041). Long-term adverse effects were rare except for B-cell depletion and hypogammaglobulinemia, which both improved over time. Conclusions: This is the longest follow-up study of patients who received anti-CD19 CAR T cells. Anti-CD19 CAR T cells cause highly durable remissions of relapsed B-cell lymphoma and CLL, and long-term adverse effects of anti-CD19 CAR T cells were rare and usually mild. Clinical trial information: NCT00924326 . [Table: see text]
Feasibility and preliminary safety and efficacy of first-in-human intraperitoneal delivery of MCY-M11, anti-human-mesothelin CAR mRNA transfected into peripheral blood mononuclear cells, for ovarian cancer and malignant peritoneal mesothelioma.
Authors: Annunziata Christina M. , Ghobadi Armin , Pennella Eduardo J. , Vanas Julie , Powell Charles , Pavelova Mira , Wagner Cathy , Kuo Michael , Dansky Ullmann Claudio , Hassan Raffit , Thaker Premal H.
Published: May 2020

3014

Background: MCY-M11 is a mesothelin-targeting chimeric antigen receptor (CAR) therapy made by a non-viral, mRNA-based platform, for rapid ( < 1 day) CAR manufacturing. We are conducting a phase I dose escalation trial in ovarian cancer and malignant peritoneal mesothelioma (MPM) (NCT03608618). Methods: MCY-M11 are fresh, non-expanded, autologous peripheral blood mononuclear cells (PBMCs) transfected by flow electroporation with mRNA encoding a human anti-mesothelin CAR. Following a 3+3 design, patients are treated in dose level (DL) escalating cohorts (DL1 1.0 x 107, DL2 5.0 x 107, DL3 1.0 x 108, DL4 5.0 x 108 cells/dose), in one cycle of weekly x 3 doses, intraperitoneal (ip) without preconditioning chemotherapy. Results: By January 2020, CP-M11-101 study successfully completed DL1 and DL2 without safety concerns. Based on 11 patients treated in DL1, DL2 and DL3, ip infusion of MCY-M11 is safe and well tolerated. No infusion-related adverse events and no dose limiting toxicities (DLTs) have occurred. No neurotoxicity has been observed. Most reported treatment-related adverse events have been Grades 1-2 per NCI CTCAE. One patient in DL3 presented with G2 pericarditis, fever and transient neutropenia clinically assessed as related SAEs, that resolved without further complications. These events were assessed as on-target off-tumor effects and possibly G1 cytokine release syndrome (CRS). Two unrelated SAEs (G2 confusion in a patient in DL2; G3 enterocutaneous fistula in a patient in DL3) were reported. These 2 patients have been replaced as they did not complete the evaluation period (3 weekly infusions and the DLT 43 day follow up). There have been no treatment-related discontinuations or deaths. Three patients in DL2 showed stable disease (SD) by RECIST 1.1 at the end of the DLT period. Of them, 1 completed the study and did not participate in additional follow up, 1 remained in SD 6 months, and 1 remained in SD 2 months. In DL3, 1 patient remains in SD at 2 months, and evaluation is pending for the other 2 patients. Enrollment is ongoing. Conclusions: Feasibility of 1-day manufacturing of MCY-M11 for ip delivery is demonstrated. Treatment has been safe. Initial SD observed in DL2 and DL3 with one-cycle infusions is encouraging and supports exploration of additional strategies such as the addition of preconditioning chemotherapy and multiple cycles to increase efficacy. Clinical trial information: NCT03608618 .
Pharmacodynamic, safety, and efficacy results of a phase I/II trial of intratumoral INT230-6 alone (IT-01) or in combination with pembrolizumab (PEM) (Keynote A10) in patients with advanced solid tumors.
Authors: Thomas Jacob Stephen , El-Khoueiry Anthony B. , Walters Ian B. , Azad Nilofer Saba , Bender Lewis H. , Hanna Diana L. , Whalen Giles Francis , Olszanski Anthony J. , Siu Lillian L.
Published: May 2020

3016

Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells when given IT. Preclinical experiments show strong synergy with a PD1 antibody. Methods: Solid tumors pts that progressed on standard treatment were enrolled. INT230-6 dose was set by tumor volume, injected Q2weeks x 5. Escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. In another arm, PEM (200mg IV Q3weeks) was combined with INT230-6. Patients were monitored for safety weekly while on INT230-6. Blood and tumors were assessed for PK and PD. Results: 46 pts (17 unique cancer types) were enrolled in the monotherapy arm and 4 pts in the PEM combo arm with a median of 3 prior treatments. Doses from 0.3 ml up to-160 ml of INT230-6 (80 mg CIS and 16mg of VIN) were injected. PK results indicate 95% of the drugs are retained in the tumor when compared to historical IV dosing. No dose limiting toxicity was reported. Two pts experienced drug-related SAE’s of tumor pain. The most frequent treatment-related AEs were: pain at injected site (48%), fatigue (40%) and nausea (33%). Most AE’s were grade 1 and 2, 17% were grade 3, and none ≥ grade 4. Several injected and non-injected tumors had > 30% decreases in diameter. Assessments revealed substantial reductions in tumor volume ( > 50%). Stable pts had a median increase of 50% in circulating CD4 and CD8 T-cells, while PD subjects showed decreases in circulating T-cells (p < 0.05). Dose-response suggests that monotherapy subjects receiving > 50% of tumors injected at dose/tumor volume ratio of > 1:4 (target dosing), predicts for prolonged SD with 88%(7/8) having SD ≥ 4mo, correlating with reduced tumor viability on IHC, and increase in tumor-infiltrating lymphocytes (TIL’s). Conclusions: Proof of concept was demonstrated that INT230-6 delivers high drug doses into the tumor without systemic exposure and typical cytotoxic AEs. Systemic and local immune activation was observed. INT230-6 was safe and well tolerated in > 175 deep tumor injections with tumor burden reduction in injected and non-injected tumors (an abscopal effect). Patients who received target dosing often had prolonged disease control post treatment. Updated safety, response and biomarker data from the monotherapy and PEM combo arm will be presented. Clinical trial information: 03058289 .
Assessing readmission after axicabtagene ciloleucel immunotherapy.
Authors: Perkins Paula , Cearley Aisling , Kirk Angela , Mullane Erin , Shadman Mazyar , Maloney David G.
Published: May 2020

3024

Background: Axicabtagene ciloleucel (axi-cel) is an FDA approved CD19 targeted CAR-T for patients (pts) with diffuse-large-B cell lymphoma (DLBCL) after 2 lines of treatment. Pts are monitored inpatient for minimum 7 days after CAR-T infusion but remain at risk of complications after discharge that can lead to readmission. We report our institutional experience on the rate and etiology of readmissions after initial discharge. Methods: In this retrospective study, readmission was defined as an inpatient stay greater than 48 hours while under the auspice of the Immunotherapy service. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded based on the Lee and CTC v.4 criteria, respectively. Logistic regression models were used to study the association between clinical factors and readmission. Results: 44 pts received axi-cel. Median age was 62 (25-79). 33 pts (75%) had primary refractory disease and 14 (30%) had prior transplant. Pts had median 3 lines (2 -9) of treatment before axi-cel. Median time from most recent treatment to leukapheresis was 10 weeks (0.5-109). 22 pts (48%) received bridging therapy between leukapheresis and lymphodepletion (LD). Median duration of initial planned admission was 7.5 days (6-16). Incidence of CRS was 88% (all grades) and 12% (grade 3/4). Median time to start of CRS was 3 days (0-13). Incidence of NT was 61% (all grades) and 16% (grade 3/4) and median time to NT was 6 days (3-14). 6 pts (14%) were readmitted after initial hospitalization (1 had 2 readmissions). Median day of readmission was 13 (9-25). Median duration of subsequent hospitalization was 5 days (2-31). Reasons for readmission were: infection (2), CRS (2), GI bleed (1), progressive disease (PD) (1) and NT (1). 4 of 6 pts had no CRS or NT before readmission. 2 of the 4 were readmitted on days 9 and 13 for NT. The other 2 pts were readmitted for infection and GI bleed. 1 pt had grade 2 CRS and grade 2 NT during first admission and was readmitted on day 25 for PD. Last pt had grade 2 CRS and grade 3 NT during first admission with discharge day 13, readmission day 14 through day 17 with recurrent NT and second readmission day 30 for infection. 3 of 6 pts had ICU admissions during second admissions. There was no association between pre- and post- CAR-T variables and risk of readmission in multivariable models. Conclusions: Readmissions after discharge from initial planned hospitalization for axi-cel are not uncommon. This data supports our current policy of close monitoring until at least a month after CAR-T therapy and supports the requirement of a full-time caregiver until discharge from the Immunotherapy service.
Association of lymphocyte to monocyte ratio with clinical response and survival in patients with relapsed, aggressive non-Hodgkin lymphoma treated with axicabtagene ciloleucel CAR-T.
Authors: Al Saleh Abdullah S. , Gandhi Sangeetha , Truong Tuan , Khurana Arushi , Brandes Eva , Estby Breanna , Lange Gina , Ansell Stephen M. , Bennani N. Nora , Johnston Patrick B. , Paludo Jonas , Villasboas Jose Caetano , Porrata Luis F. , Lin Yi
Published: May 2020

3028

Background: Chimeric antigen receptor T-cell (CAR-T) therapy induces complete remission (CR) in 30-40% of patients with non-Hodgkin lymphoma (NHL). However, for patients who do not achieve CR as their first response, predictors for achieving CR as best response can guide management between careful observation or early intervention. Increased absolute lymphocyte count to absolute monocyte count ratio (ALC/AMC) predicts better response rates and survival in NHL patients receiving chemotherapy and/or autologous stem cell transplant. We evaluated the prognostic impact of ALC/AMC in CAR-T therapy for NHL. Methods: This was a retrospective review of patients who received CAR-T for NHL from June 2016-August 2019. ALC/AMC was assessed at the start of lymphodepletion (LD) chemotherapy. The receiver operator curve (ROC) was used to determine the best cutoff for ALC/AMC in predicting CR at 3 months. Event-free survival (EFS) was defined from time of CAR-T infusion to relapse or death, whichever occurred first. Overall survival (OS) was defined from time of infusion to death of any cause. Results: Forty-seven patients received axicabtagene ciloleucel, with a median follow-up of 14 months. By ROC, ALC/AMC > 0.8 before LD chemotherapy was predictive of achieving CR at 3 months. Baseline characteristics were similar between the high (n = 30) and low (n = 17) ALC/AMC groups. Patients with an ALC/AMC > 0.8 at the time of LD chemotherapy were more likely to achieve CR at 3 months (46% vs. 12%, p = 0.01), 6 months (52% vs. 0%, p < 0.0005), and 12 months (42% vs. 0%, p = 0.01). Correspondingly, the EFS and OS were significantly shorter in patients with ALC/AMC≤0.8 vs. those > 0.8 (median EFS: 2 vs. 13 months, P < 0.0001) and (median OS: 15 months vs. not reached, P = 0.03), respectively. Association between ALC/AMC ratio and EFS and OS remained consistent in multivariate Cox models after adjusting for other prognostic variables, including abnormal lactate dehydrogenase and increased ferritin level at infusion day. Conclusions: ALC/AMC > 0.8 before lymphodepletion chemotherapy is a strong predictor for complete remission as well as improved event-free and overall survival for axicabtagene ciloleucel in NHL.
Safety and efficacy of optimized tandem CD19/CD20 CAR-engineered T cells in patients with relapsed/refractory non-Hodgkin lymphoma.
Authors: Zhang Yajing
Published: May 2020

3034

Background: Chimeric antigen receptor T (CAR T) cells targeting CD19 have been used to achieve breakthroughs in the treatment of hematological malignancies, however, a high recurrence rate is the main obstacle to durable remission following CAR T cell therapy. Methods: As an open-label and single-arm phase I/IIa trial (ClinicalTrials.gov number, NCT03097770), we screened 99 patients with r/r B-NHL—including DLBCL, PMBCL, CLL/SLL, MCL, TFL and FL—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue, and a total of 87 patients received an infusion of one dose tandem CD19/CD20 CAR-engineered T cells on day 0 in the range of 0.5×106-10×106 cells per kilogram of body weight after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of CAR T cells. Efficacy, progression-free survival (PFS) and overall survival (OS) were evaluated as secondary objectives. Our clinical trials is registered with ClinicalTrials.gov, NCT03097770. Safety was assessed by CTCAE Version 5.0, and clinical response by PET-CT referred to standard international criteria. The trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Results: Between May 11, 2017, and Jan 31, 2020, 99 patients were enrolled and 87 received tandem CD19/CD20 CAR-engineered T cells across phases I/IIa. As of the cutoff date, 74 assessable patients were followed up for a median of 13.5 months (IQR 33.2 - 3.3), 62 (84%) had an objective response, and 55 (74%) had a complete response. The median progression-free survival and overall survival were all not reached. Cytokine release syndrome (CRS) occurred in 62 patients (71%), with 61% grade 1 or 2 and 10% grade 3 or more. CAR-T-cell-related encephalopathy syndrome (CRES) of grade 3 occurred in 2 patients (2%) . Three treatment-related deaths (2 in pulmonary infection and 1 in deposition of CART cells in pulmonary alveoli). Conclusions: In this study, optimized tandem CD19/CD20 CAR-engineered T cells induced a potent and durable anti-tumour response with controllable CRS and CRES. Clinical trial information: NCT03097770 .
Selective targeting of HER2-overexpressing solid tumors with a next-generation CAR-T cell therapy.
Authors: Mu Jenny , Edwards Justin , Zaritskaya Liubov , Swers Jeffrey , Gupta Ankit , LaFleur David , Hilbert David , Richman Laura
Published: May 2020

3041

Background: Conventional chimeric antigen receptor T cell (CAR-T) therapies have achieved limited clinical success in the treatment of solid tumors, in part due to the challenges of identifying tumor antigen(s) that are uniquely expressed on tumor cells. The dearth of such targets requires that current CAR-T therapies be re-engineered to preferentially target tumor cells thereby mitigating potential on-target off-tumor toxicity to normal cells. Herein we describe a novel cell therapy platform comprising Antigen Receptor Complex T (ARC-T) cells that are readily activated, silenced, and reprogrammed in vivo by administration of a novel tumor-targeting soluble protein antigen-receptor X-linker (sparX). The formation of the ARC-T, sparX, and tumor complex is required for the ARC-T to kill the tumor. Because ARC-T activity is entirely dependent on the dose of sparX administered, therapeutic doses of sparX may be defined that preferentially target cells over-expressing a target antigen and thus limit coincident kill of normal cells expressing lower levels of target antigen. Methods: We have created a library of sparX that bind different cell surface antigens, including HER2. The HER2 sparX was tested as both monovalent and bivalent constructs in vitro by assessing ARC-T cell activation, cytokine release and target cell cytotoxicity. In vivo efficacy models utilized NSG mice and incorporated tumor volume measurements and histopathologic assessments to evaluate tumor clearance. Results: In vitro studies demonstrate that co-culture of ARC-T cells, sparX-HER2 and HER2-expressing target cells drives T cell activation, expansion, cytokine secretion and cytotoxicity of target cells in a dose-dependent manner. Furthermore, by affinity tuning the HER2 binding domain and bivalent formatting of sparX-HER2, we achieved selective killing of HER2-overexpressing breast cancer cells with minimal effect on cells expressing HER2 levels representative of normal tissues. In vivo proof-of-principal studies with ARC-T/sparX-HER2 similarly demonstrate complete eradication of HER2-overexpressing solid tumor cells. Conclusions: These results demonstrate that a single intravenous dose of ARC-T cells can traffic to a solid tumor site and induce tumor eradication upon systemic administration and co-localization of tumor-targeting sparX in a mouse model. Bivalent formatting of sparX-HER2 further enabled ARC-T sensitivity to target antigen density to avoid the on-target off-tumor toxicity that has hindered conventional monovalent CAR-T treatments.