bluuebunny/crossref_metadata_2025 huggingface dataset:
Depatuxizumab mafodotin (Depatux-M) plus temozolomide (TMZ) in recurrent glioblastoma patients: Real-world experience from a multicenter study of Italian Association of Neuro-Oncology (AINO).
Authors: Caccese Mario , Padovan Marta , Eoli Marica , Pellerino Alessia , Rizzato Simona , Caserta Claudia , Simonelli Matteo , Michiara Maria , Zagonel Vittorina , Ruda Roberta , Lombardi Giuseppe
Published: May 2020

2544

Background: Precision medicine is a promising tool in oncology. Depatux-M is a new antibody-drug conjugate, consisting of a specific antibody against activated EGFR and a cytotoxic agent with antimicrotubule activity. The Intellance2/EORTC 1410 phase II trial, showed interesting results for Depatux-M and TMZ combination in EGFR-amplified glioblastoma (GBM) patients (PTS) at first recurrence after RT and TMZ. In our study, we investigated clinical outcome and safety of this combination used in recurrent GBM PTS as “compassionate use”. Methods: In this prospective observational study, PTS were enrolled from 7 centres of AINO. Major inclusion criteria were: histologically confirmed diagnosis of GBM, 1 or more prior systemic therapies, ECOG PS ≤ 2 and EGFR-amplified (analyzed by FISH). According to original schedule, patients received Depatux-M 1.25 mg/kg every two weeks combined with TMZ until disease progression or unacceptable toxicity. Kaplan-Meier method was used to estimate the survival curves, RANO criteria for radiological assessment, CTCAE v5.0 for drug related adverse events. Results: From October 2018 to June 2019, we enrolled 36 PTS: median age was 57, ECOG PS 0-1 in 88% of PTS, MGMTmet in 64%, 42% received the treatment as second-line therapy and 27% underwent further chemotherapy at progression. At the time of analysis, 13 PTS (36%) had died and 27 PTS (75%) had progressed. Median OS was 8.7ms (95%CI not available), 6ms OS was 68%; median PFS was 2.3ms (95% CI 1.8 – 2.8), 6ms PFS was 37%. All PTS were evaluable for response: disease control rate was 47%: stable disease was reported in 36% and partial response in 11% of PTS. Drug-related adverse events led to dose reductions of Depatux-M in 17% of PTS, in 28% was delayed and in 8% was permanently discontinued. The most frequent grade 3-4 adverse events were ocular toxicity in 67% and haematological toxicity in 17% of PTS; no death was considered drug-related. Conclusions: We report the first “real world” experience of Depatux-M plus TMZ in recurrent GBM. We showed encouraging clinical benefit, despite most patients were treated beyond the second-line of therapy. Overall the results are closed to those reported in previous phase II trial. Although toxicity was higher than expected, it was manageable and only a small group of patients discontinued the treatment due to serious adverse events
Preliminary assessment of low-intensity transcranial magnetic stimulation (TMS) during the treatment for brain glioblastomas.
Authors: Popov Ivan A. , Kit Oleg I. , Shikhlyarova Alla I. , Frantsiyants Elena M. , Rostorguev Eduard E. , Atmachidi Dmitriy P. , Timoshkina Natalya N. , Gusareva Marina A. , Potemkin Dmitrii S. , Stasov Vitaliy V. , Arapova Yulia Yu. , Protasova Tatiana P. , Zhukova Galina V. , Kavitskiy Sergey E. , Ignatov Sergey N. , Cherkiev Islam U. , Nikitin Emzari S. , Kuznetsova Natalya S.
Published: May 2020

2545

Background: The standard treatment of malignant brain gliomas, including surgical and radiation therapies, does not provide recovery and a long-time favorable prognosis. The development of technologies and international guidelines on the introduction of electric (TTF) and electromagnetic (TMS) fields in combination treatment for glioblastomas aims to improve immediate results, as shown in experiments on human glioblastoma cell culture. The TMS protocol requires further refinement in parameters of frequency, intensity, and exposure with an assessment of the immediate results of combined treatment. Methods: The study included 60 patients diagnosed with MBG receiving osteoplastic craniotomy with radical (within visible unchanged tissues) tumor removal. Starting from the second day after the surgery, patients of group 1 (n = 30) received 10 sessions of magnetotherapy in the double exposure mode. For the first morning exposure, we used an ultra-low-frequency magnetic field (ULFMF) (0.03 to 9.0 Hz) on the hypothalamus projection area to induce a general antistress reaction. After 2.5-3 hours, local (on the surgical site) TMS exposure with the Neuro-MSD system (Russia) was applied in the pulse algorithm, up to 1 GHz and 5 Hz, 15 mT, 3 min. The induction was reduced exponentially (C = 0.8). The control group 2 (n = 30) did not receive ULFMF or TMS. Magnetic resonance imaging (MRI) was used to determine the volume of tumors (Vt, cm3) and perifocal edema (Ve, cm3) calculated according to the Shrek’s formula for an ellipsoid (V = a×b×c×π/6). Results: Before surgery, Vt = 54.7±5.7cm3 in group 1, in group 2 - Vt = 60.9±8.5cm3 (no statistical differences). After surgery and the subsequent course of ULFMF and TMS, residual tumor volumes in group 1 were 2.5 times lower than in controls (p < 0.05). The difference between Ve values before and after treatment was on average 80.7 cm3 in group 1 and 41.8 cm3 in group 2 (p < 0.05). Conclusions: The inclusion of sequential ULFMF and TMS exposures into postoperative therapy for gliomas, taking into account various vectors of the influence on the projection of centers of homeostasis regulation and the surgical field, as well as the development of programmed modes of biotropic exposure parameters, improves antitumor and anti-edematous effects.
Genome-wide methylation analysis in long-term survivors of glioblastoma (GBM).
Authors: Chau Justin , Dhungana Neha , Kohlmeyer Jordan , Petronek Michael , Quelle Dawn , Sato Mariko , Darbro Benjamin , Jones Karra , Monga Varun
Published: May 2020

2552

Background: Identification of tumor characteristics that may be associated with survival in patients with glioblastoma (GBM) has been largely characterized by IDH mutations and MGMT promoter methylation status. However, these genetic changes and other currently available data are not sufficient to explain the longevity experienced by a subset of long-term survivors (LTS) - patients surviving longer than 3 years past diagnosis. Methods: The study identified GBM patients established and treated at University of Iowa Holden Comprehensive Cancer Center from 2007-2017 whose disease recurred after initial resection. Patients were categorized LTS if they survived > = 3 years beyond initial definitive resection; short-term survivors (STS) if less than 3 years. Pathologic specimens at initial and repeat resection underwent genome wide methylation analysis using the Infinium EPIC microarray system. Data were analyzed to identify genes that exhibited differentially methylated CpG regions. Results: Resection specimens from GBM survivors were compared to those of STS. A total of 29 samples were analyzed and compared (15 LTS and 14 STS samples). Multidimensional scaling plots identified significant differences in genomic constitution between LTS and STS specimens. Granular analysis yielded 89 differentially methylated regions significantly associated with long-term survival (adjusted p < 0.05). PTPRN2 (p = 0.000376), PTPN11 (p = 1.38E-05), and PAX6 (p = 0.000671) were found to exhibit numerous differentially methylated CpG sites between MGMT-methylated vs. unmethylated specimens. Further notable, higher levels of differentially methylated CpG shores and open-seas regions on chromosome 12 were associated with long-term survival (p = 1.89E-08). Conclusions: Our study identified multiple significant epigenetic differences that, functionally or consequentially, may be associated with extended survival in GBM patients. The implication that CpG shores, rather than islands, are associated with long-term survival raises further intriguing questions regarding the depth of epigenetic complexity in this disease. More immediately, the surprising association of multiple protein phosphatases with LTS in our study may hint at the class’ previously unspecified, yet integral, role in delaying disease progression and identify new, novel avenues for therapy.
Role of high-dose chemotherapy with autologous stem cell transplantation for primary central nervous system lymphoma: A systematic review.
Authors: Nabeel Shaha , Ahmed Zahoor , Farooqui Arafat Ali , Shah Zunairah , Ashraf Aqsa , Imtiaz Hassan , Ashraf Rabia , Neupane Karun , Faisal Muhammad Salman , Anwer Faiz
Published: May 2020

2562

Background: High dose chemotherapy (HDCT) followed by autologous stem cell transplant (ASCT) has shown to overcome intrinsic chemo-resistance and improve disease control in Primary Central Nervous System Lymphoma (PCNSL). Our study reviews the treatment outcome in PCNSL with sequential HDCT and ASCT. Methods: 8/34 studies were finalized after systematic search of PubMed, Cochrane, and Clinicaltrials.gov for treatment of PCNSL with HDCT followed by ASCT. Results: 251/288 patients were evaluated. Mean age was 55.5 years. 227 underwent HDCT-ASCT. 174 were newly diagnosed (ND) and 77 had relapsed refractory (R/R) PCNSL. ND patients showed superior outcomes in terms of progression free survival and overall survival. Combinations of High dose Rituximab, Busulfan and Cyclophosphamide significantly improved survival outcomes in RR patients. Significant toxicities mainly included pancytopenias and opportunistic. Conclusions: Primary CNS lymphoma treated with HDCT followed by ASCT has shown promising outcomes and has set a benchmark for future studies. [Table: see text]
Postoperative radiation therapy (PORT) impact on clinical outcomes of resected atypical meningioma: A meta-analysis.
Authors: Gallagher Kevin M. , akhtar furqan , Haddad Philip A.
Published: May 2020

2570

Background: Although meningiomas are among the most prevalent types of brain tumors, atypical meningiomas (AM) account for around 4% of all meningiomas. AMs tend to be more aggressive with relatively higher rates of recurrence and mortality. Gross total resection (GTR) has been the standard of care when possible. However, GTR itself is not always enough to prevent recurrence of AMs. The role of PORT remains controversial in AM as the comparative studies to support its use have provided conflicting results. The purpose of this meta-analysis is to evaluate the impact of PORT on clinical outcomes in resected AMs. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of (i) AM diagnosis, (ii) English language, (iii) Simpson graded resections, and (iv) comparative studies reporting recurrence rates (RcR), Progression Free Survival (PFS), and Overall Survival (OS) with hazard ratios (HR) or Kaplan-Meier curves. A meta-analysis was conducted using an inverse variance method with random-effects model. Results: Twenty-two comparative studies with a total of 5,129 patients were included and analyzed. When GTR was attained, PORT was associated with improved RcR (HR = 0.72, 95%CI:0.59-0.86) and PFS (HR = 0.77, 95%CI:0.65-0.90), but not OS (HR = 0.93, 95%CI:0.83-1.04). When subtotal resection (STR) was attained, PORT was associated with improved PFS (HR = 0.35, 95%CI:0.26-0.48) as well as OS (HR = 0.70, 95%CI:0.54-0.89). Conclusions: This is the first meta-analysis to show that PORT is associated with PFS benefit in AMs with GTR and STR. Moreover, PORT significantly improved OS of AMs that underwent STR but had no impact on OS when GTR was achieved. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of PORT in this patient population.
A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients.
Authors: Rocconi Rodney Paul , Stevens Erin E. , Bottsford-Miller Justin N. , Ghamande Sharad A. , Aaron Phylicia , Wallraven Gladice , Bognar Ernest , Manley Meghan , Horvath Staci , Manning Luisa , Nemunaitis John J. , Herzog Thomas J , Monk Bradley J. , Coleman Robert L. ,   Vigil Team
Published: May 2020

3002

Background: Recent studies have shown poor clinical outcomes and limited survival advantage to checkpoint inhibitors (CIs) in advanced stage ovarian cancer (OvC). Vigil is a personalized precision vaccine constructed from autologous tumor tissue transfected with a DNA plasmid encoding GM-CSF and bi-shRNA-furin thereby creating TGFβ expression control and enhancing immune activation. Phase 1 and 2 trials in OvC demonstrate safety, functional immune activation and clinical response benefit. Combining Vigil with CIs may broaden responsiveness of immunotherapy in OvC. Methods: This is a randomized, 3-part safety Phase 1 study of Vigil in combination with Atezolizumab in recurrent OvC patients. Part 2 is a randomized, intra-patient crossover study of Vigil first (VF) or Atezolizumab first (AF) for two cycles followed by sequence of the combination of the two agents. Vigil (1 x 106 or 1 x 107 cells/ml) or Atezolizumab (1200mg) were administered 1x every 21 days each cycle until progression or untoward adverse event. We now report the preliminary results of part 2 of the study. Results: Twenty-one patients were randomized (1:1) to VF (n = 11) or AF (n = 10), groups were similar in demographics. Grade 3/4 toxic events occurred in 17% of AF patients compared to 3% in VF patients. Median OS of VF patients (n = 11) was not reached vs. AF (n = 10) 10.8 months suggested modest advantage to VF (HR 0.33, one-sided p 0.097). However, the subset analysis of BRCA1/2 wild type (wt) demonstrated more significant overall survival benefit in VF (n = 7) median OS not reached vs. AF (n = 7) 5.2 months (HR 0.12, one-sided p 0.015). Conclusions: The combination of Vigil immunotherapy and checkpoint inhibitor atezolizumab in recurrent OvC demonstrated safety and suggest a lower toxicity profile and a significant OS advantage in recurrent BRCA1/2-wt OvC patients treated with Vigil first followed by the combination of Vigil and Atezolizumab. Clinical trial information: NCT03073525 . [Table: see text]
Durvalumab and tremelimumab in combination with FOLFOX in patients with RAS-mutated, microsatellite-stable, previously untreated metastatic colorectal cancer (MCRC): Results of the first intermediate analysis of the phase Ib/II MEDETREME trial.
Authors: Ghiringhelli François , Chibaudel Benoist , Taieb Julien , Bennouna Jaafar , Martin-Babau Jerome , Fonck Marianne , Borg Christophe , Cohen Romain , Thibaudin Marion , Limagne Emeric , Fumet Jean-David
Published: May 2020

3006

Background: Single agent PD-1/L1 inhibition are not effective in metastatic colorectal cancer (MCRC) with microsatellite stable tumors. However, signal of efficacy was shown using combo therapy of anti-PD-L1 and anti CTLA-4 in multitreated patients. FOLFOX regimen could induced immunogenic cell death and elimination of myeloid derived suppressor cells (MDSCs) thus leading to a potential positive effect on antitumor immune response. Methods: This is a single arm exploratory investigator-initiated trial planned to include 57 pts to receive mFOLFOX6 (6cycles) in combination with durvalumab (150mg/q2W) and tremelimumab (75mg/q4W). After 6 cycles of chemotherapy, patients are treated with durvalumab untils progression. Primary endpoint is 6 months’ progression-free survival rate. Secondary endpoints are response rate, tolerability and translational research evaluating tissue and blood immune parameter. Upon Simon’s design an efficacy intermediate analysis was planned after the 16th patient has passed 6 months. Results: As of 1st of January 2020 the 55/57 pts were enrolled and treated with the MEDETREME regimen at 8 French sites. The intermediate efficacy analysis was conducted on the 1st of January after a median of 13.4 months of treatment. The following adverse events were noted: asthenia (81.25%), neuropathy (87.5%), diarrhea (56.25%) and neutropenia (62.5%). Notable grade 3/4 (CTC AE 4.03) include asthenia (18.75%) diarrhea (12.5%) neutropenia (50%) and elevated blood pressure (25%). Most of adverse events were related to chemotherapy. It has been noted one cytolysis grade 3, one thyroid dysfunction grade 3 and one hypophysitis grade 3 related to immunotherapy. Median PFS was not reached. Progression free survival at 6 months was observed in 10/16 pts (62,5%) given 5 CR, 5 PR and 4 SD. Updated translational data will be presented at the meeting. Conclusions: The interim safety analysis has supported safety and efficacy of the MEDITREME regimen in first- line MCRC. Finally, results will be presented after maturation of follow up. Clinical trial information: NCT03202758 .
Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.
Authors: Brown Landon Carter , Sedhom Ramy , Schwartz Eric B , Zhu Jason , Kao Chester , Tucker Matthew D , Labriola Matthew , Gupta Rajan T. , Marin Daniele , Wu Yuan , Zhang Tian , Harrison Michael Roger , George Daniel J. , Alva Ajjai Shivaram , Antonarakis Emmanuel S. , Armstrong Andrew J.
Published: May 2020

3007

Background: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a putative tumor suppressor and one of the most frequently altered genes in cancer. Our prior single-center work suggested that LRP1B alterations may enrich for responses to immune checkpoint inhibitors (ICI) in solid tumors including prostate cancer; however, validation of these findings is needed. Methods: We conducted a multicenter, retrospective analysis of patients with LRP1B alterations (on tissue-based next-generation sequencing panels) treated with ICI at Duke, Johns Hopkins (JHU), and University of Michigan (UM). The primary objective was to assess the association between objective response rate (ORR) to ICI and pathogenic LRP1B alterations, defined as deletions or truncating alterations, when compared with LRP1B variants of undetermined significance (VUS), defined as missense mutations not predicted to be pathogenic in COSMIC. Missense changes with a COSCMIC FATHMM score of > 0.8 were categorized separately as likely pathogenic. Summary statistics, ORR, progression free survival (PFS), and overall survival (OS) were calculated. Results: 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations were treated with ICI. Median age was 61 (range 32-82). The most common tumor types by alteration (pathogenic or likely pathogenic/VUS%) were lung (33/47%), GI (17/13%), prostate (11/7%), sarcoma (2/9%), melanoma (11/0%), and others (26/24%). 93% of patients received single-agent PD-(L)1 inhibition. The ORR for patients with either pathogenic/likely pathogenic alterations, or VUS alterations was 57% and 18%, respectively. After excluding MSI-high or TMB-high ( > 10 mut/Mb) tumors, ORR was 14/25 (56%) and 6/36 (17%), respectively. Pathogenic or likely pathogenic LRP1B alterations were associated with longer PFS (HR 0.39, 95% CI 0.24-0.63) and OS (HR 0.58, 95% CI 0.36-0.95). Conclusions: This multicenter study shows impressive and durable objective response rates to ICI for patients harboring pathogenic LRP1B alterations when compared to those with LRP1B VUS, independent of TMB/MSI status. Further mechanistic insights and prospective validation studies are warranted. [Table: see text]
Early safety from a phase I, multicenter, open-label clinical trial of talimogene laherparepvec (T-VEC) injected (inj) into liver tumors in combination with pembrolizumab (pem).
Authors: Hecht J. Randolph , Pless Miklos , Cubillo Antonio , Calvo Aitana , Chon Hong Jae , Liu Chunxu , Snyder Wendy , Chan Emily , Chaney Marya F. , Chesney Jason Alan , Prat Aleix
Published: May 2020

3015

Background: T-VEC is a genetically modified, oncolytic HSV-1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immunity. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with checkpoint inhibitors (Andtbacka JCO 2015, Chesney JCO 2017, Ribas Cell 2017). T-VEC has also demonstrated tolerable safety for intrahepatic inj (Hecht JCO 2018). This phase 1b, multicenter, open-label, dose escalation study (NCT02509507) evaluates the safety of intrahepatic inj of T-VEC in combination with intravenous (IV) pem in patients (pts) with hepatocellular carcinoma (HCC) or liver metastases (mets). Methods: The primary objective is to assess the maximum tolerated concentration (MTC) of T-VEC inj into liver tumors based on the incidence of dose-limiting toxicities (DLTs). DLT rate was evaluated with the mTPI up-and-down design. Eligible pts were ≥ 18 years, had progressive HCC or breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer, or renal cell cancer liver mets, with measurable liver tumors suitable for inj. This dose escalation study comprised 2 groups: A (non-HCC) and B (HCC). T-VEC was given initially at 106 plaque-forming units (PFU)/mL followed by up to 4 mL of 107 PFU/mL (cohort 5) or 108 PFU/mL (cohort 6) every 21 (±3) days (Q21D). Inj volume was based on lesion size. Pem (200 mg) was given IV Q21D. Results: Here we report on three cohorts: A5 (107 PFU/mL T-VEC + pem), A6 (108 PFU/mL T-VEC + pem), and B5 (107 PFU/mL T-VEC + pem). Twenty-nine pts were treated: 7 in A5, 17 in A6, 5 in B5. Median age was 61 years (range: 30, 76). Median number of inj was 4 and median treatment duration was 88 days. One DLT of cholestatic hepatitis was observed out of 6 DLT evaluable pts in cohort A5. No DLTs were observed in cohort A6 and B5. MTC was 108 PFU/mL in non-HCC patients; exploration of MTC in the HCC population is ongoing. Treatment-emergent adverse events (TEAEs) were consistent across cohorts. The most common treatment-emergent treatment-related adverse events (TETRAE) were pyrexia (79.3%), chills (37.9%), and nausea (37.9%). Eight pts (27.6%) had grade 3/4 TEAEs: 2pts (6.9%) related to the combination therapy and the rest not related to treatment. No fatal AEs were observed. Conclusions: T-VEC intrahepatic inj in combination with IV pem at standard doses has thus far been demonstrated as feasible and tolerable to continue further investigation. Clinical trial information: NCT02509507 .
Phase I/II study to evaluate systemic durvalumab + intraperitoneal (IP) ONCOS-102 in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Interim phase I clinical and translational results.
Authors: Zamarin Dmitriy , Odunsi Kunle , Slomovitz Brian M. , Duska Linda R. , Nemunaitis John J. , Reilley Matthew , Bykov Yonina , Holland Aliya , Hubbard-Lucey Vanessa M. , Shohara Lisa , Schwarzenberger Paul , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Jaderberg Magnus Erik , Venhaus Ralph Rudolph
Published: May 2020

3017

Background: Metastasis to the peritoneal cavity is associated with end-stage disease in many cancers, including OC and CRC, both of which exhibit poor responses to checkpoint inhibitors. Locoregional treatment with oncolytic viruses may be used to improve the efficacy of checkpoint inhibitors at both treated and distant tumor sites. This study evaluates the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GMCSF), with systemic durvalumab, an anti PD-L1 antibody, in patients with peritoneal disease who have histologically confirmed OC or metastatic CRC and have failed prior standard therapies. Methods: This ongoing Phase 1/2, open-label study (NCT02963831) evaluates safety and antitumor/biologic activity of durvalumab (1500 mg IV, every 4 weeks x 12) + ONCOS-102 (IP, weekly x 6); cyclophosphamide is given pre first ONCOS-102 dose. Phase 1 uses a 3+3 design to evaluate the ONCOS-102 dose (1 or 3 x 1011 VP) to be given with durvalumab. Phase 2 evaluates the activity of the combination using Simon’s 2-stage MINIMAX design. Safety, response rate by RECIST 1.1, and immunological effects in tumors were evaluated for Phase 1; the current abstract reports on the phase 1 results. Results: Enrollment opened 7 Sep 2017; data cutoff, 1 Nov 2019. There were 17 patients treated in Phase 1: 8 CRC, 9 ovarian; 94% female; median age, 56 [37-77] years; ECOG PS0, 47%; ECOG PS1, 53%. There were no DLTs. Grade 3 treatment-related AEs included hypokalemia (n = 2); anemia, myocarditis, increased GGT, and influenza like illness (n = 1 each). There were 4 deaths due to PD. One patient had durable confirmed partial response and remains on treatment > 1 year; 4 patients had stable disease as best overall response. Two patients remained on treatment at data cutoff. Analysis of pre- and on-treatment tumor biopsies revealed changes in the tumor-infiltrating immune cells and PD-L1 expression, including an increase in tumor-infiltrating CD8 T cells in 5 of 11 evaluable patients. Conclusions: Combination of durvalumab and IP ONCOS-102 was safe, and no DLTs were observed. Preliminary analyses demonstrate evidence of biologic and clinical activity. Phase 2 enrollment is ongoing. Clinical trial information: NCT02963831 .
The preliminary efficacy and safety data of KN046 in patients failed on prior immune checkpoint inhibitors therapy.
Authors: Zhao Hongyun , Ma Yuxiang , Zhang Yang , Hong Shaodong , Yang Yunpeng , Fang Wenfeng , Xu June , Van Hardy , Kong Paul , Yang Fei , Li Jingying , Lu Yao , Zhang Li
Published: May 2020

3020

Background: KN046 is a bispecific antibody that blocks PD-L1 and CTLA-4 by interaction with PD1 and CD80/CD86. KN046-CHN-001 (NCT03529526) is a, dose escalation and expansion phase Ia/Ib clinical trial in China. Here we reported safety, tolerability and preliminary efficacy in patients failed on prior immune checkpoint inhibiters (ICIs) treatment. Methods: Patients progressed on ICIs (including but not limited to antibodies targeting PD-1, PD-L1, OX40, et al) with pathologically confirmed solid tumor, ECOG 0-1, measurable lesion per RECIST v1.1, no immune-related adverse events (IRAEs) led to ICIs discontinuation, were enrolled and received intravenous KN046 treatment across four dose levels including 3.0 mg/kg (n = 3) and 5.0 mg/kg (n = 20) Q2W; and 5.0 mg/kg (n = 4), 300.0 mg flat dose (n = 2) Q3W. Safety and tolerability were assessed per NCI-CTCAE v5.0. Treatment-emergent AEs (TEAEs) and IRAEs were decided by investigators. Efficacy was evaluated by investigators per RECIST 1.1 every 6 weeks. Results: Twenty-nine who progressed on prior ICIs therapy were enrolled (25anti-PD-1 antibody; 3 anti-OX40 antibody; and 1 anti-CD137 antibody) and were included in the current analysis. Among 29 patients, 19 were nasopharyngeal cancer (NPC) and 9 were non-small cell lung cancer (NSCLC). The median duration of the exposure of KN046 was 12 weeks (range 2 to 40). Eleven patients remained on the treatment and 18 discontinued due to disease progression (n = 13), AE (n = 1), death (n = 1) and others (n = 3). Twenty-six (89.7%) patients experienced TRAEs of all grades and 2 (6.9%) experienced grade≥3 TRAEs (1 grade 3 anemia and 1 grade 3 infusion-related reaction). The most common (≥10%) TRAEs were pruritus (8, 27.6%), rash (8, 27.6%), asthenia (6, 20.7%), fatigue (6, 20.7%), pyrexia (5, 17.2%), infusion related reaction (4, 13.8%), alanine aminotransferase elevation (3, 10.3%) and white blood cell count elevation (3, 10.3%). Eleven (37.9%) patients experienced irAEs (with no grade≥3). Objective responses were occurred in 3 (12.0%, 25 evaluable) patients, disease control rate was 52.0% (10 stable disease). Median progression free survival was 2.69 (95%CI 1.31,5.52) months. Median overall survival was not reached. PFS rates for 3 and 6 Months were 41.0% (95%CI 18.5, 62.5) and 21.9% (95%CI 4.6, 47.3). OS rates for 6 and 9 months were88% (95%CI 57.2, 97.1) and 58.7% (95%CI 8.3, 89.2), respectively. Conclusions: Overall, KN046 showed a favorable safety profile and promising clinical benefit in advanced solid tumor patients who failed on prior ICIs therapy. Clinical trial information: NCT03529526 .
Envafolimab (KN035) in advanced tumors with mismatch-repair deficiency.
Authors: Shen Lin , Li Jian , Deng Yanhong , Zhang Weijie , Zhou Aiping , Guo Weijian , Yang Jianwei , Yuan Ying , Zhu Liangjun , Qin Shukui , Xiang Silong , Lu Haolan , Gong John , Xu Ting , Liu David
Published: May 2020

3021

Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc formulated for subcutaneous injection. This open-label phase II study evaluated the safety and antitumor activity of KN035 in patients with advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cancer. Methods: The study included patients aged ≥18 years with previously treated MSI-H/dMMR colorectal cancer (CRC) or other advanced solid tumors. MSI-H/dMMR status was assessed centrally for CRC and gastric cancer (GC) and locally for other tumors. KN035 was administered at 150 mg once weekly until progression, unacceptable toxicity, or withdrawal. Tumor assessments were every 8 weeks. The primary endpoint was the objective response rate per RECIST v1.1 by independent radiology review. The primary efficacy population (PEP) included patients with CRC who failed fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I) plus those with advanced GC who had failed at least one prior systemic treatment. This was a planned interim analysis performed after the first 50 patients in the PEP had at least two on-study tumor assessments (PEPi). Results: As of December 17, 2019, 103 patients with MSI-H/dMMR advanced cancers were enrolled at 25 centers in China. The PEPi included 39 patients with CRC and 11 with GC, with a median follow-up of 7.5 months. The overall population included 65 patients with CRC (24 had prior therapy with F and O or I), 18 with GC, and 20 with other tumors, with a median follow-up of 6.7 months. The confirmed objective response rate was 30% (95% CI: 17.9%, 44.6%) in the PEPi, 54.2% (95% CI: 32.8%, 74.4%) in the CRC patients who had prior therapy with F and O or I, and 34.0% (95% CI: 24.9%, 44.0%) in the overall population. Of patients who had an objective response at the interim analysis, 80% of those in the PEPi, 84.6% of CRC patients who had prior therapy with F and O or I, and 85.7% of those in the overall population were still responding at the time of data cutoff. Median progression-free survival was 6.6 months in both the PEPi and the overall population. Median overall survival was not reached in either population. Fourteen (13.6%) patients had grade 3–4 treatment-related adverse events. No grade 5 treatment-related adverse events, pneumonitis, or colitis were reported. Local injection-site reactions, all grade 1 or 2, were reported in nine patients. Conclusions: Envafolimab demonstrated durable anti-tumor activity with a manageable safety profile in patients with previously treated advanced MSI-H/dMMR cancer. Clinical trial information: NCT03667170 .
First-in-human clinical trial of the autologous CD7-CART for relapsed/refractory ACUTE lymphoblastic leukemia/lymphoma.
Authors: Zhang Mingzhi , Yang Lin , Fu Xiaorui , Zhang Lei , Meng Huimin , Li Ling , Li Xin , Wang Xinhua , Sun Zhenchang , Yu Hui , Li Zhaoming , Nan Feifei , Chang Yu , Zhou Zhiyuan , Yan Jiaqin , Li Jiwei , Wang Min , You Fengtao , Chen Yu-Sheng , Zhang Bozhen
Published: May 2020

3026

Background: CD7 represents a potential target for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL). We developed CD7 nanobody derived chimeric antigen receptor T-cells (CD7-CART), and established a non-gene editing strategy by anchoring CD7 in the ER and/or Golgi to overcome the CART fratricide. Methods: This single-arm, open-label, phase I study is to investigate CD7-CART cell manufacturing feasibility without contamination of malignant T cells, and the safety and efficacy of the CART on patients with CD7 positive relapsed/refractory T-ALL/T-LBL. 3 subjects, identified as both CD4 and CD8 negative T-ALL or T-LBL were enrolled. CART cells were manufactured by using CD4+/CD8+ sorted T cells from leukapheresis. All patients (Pts) were pretreated with Flu/Cy prior to CART infusion. 1x106/kg CART cells were given to case 2 and 3, while 1.5x106/kg to case 1. Results: Case 1 was diagnosed as refractory ALL with myeloid differentiation, who had received intensive chemotherapy and allogeneic hematopoietic stem cell microtransplantation. Case 2 was diagnosed as ALL (T/B mixed type) but relapsed with CNS involvement, and received radiotherapy in addition to intensive chemotherapy. Prior to CART infusion, case 2 had no abnormal B cells but 17.69% of abnormal early T cellsfrom BM. Case 3 had stage VI of T-LBL, which recurred after multi-cycle chemotherapy of BFM-90 regimen and autologous SCT. After CART treatment, no neurotoxicity was observed in all pts. Case 1 had grade 3 CRSwhile case 2 and 3 had grade 1, although increased IL-6 was detected in all pts. Significant CART expansion and persistence were observed in case 2 and 3, and MRD negative CR was confirmed on day 28 in both pts. The number of generalized lymphadenopathy, lymph node size, and the degree of metabolism were all significantly reduced in case 3. Case 1 had only moderate CART expansion, but abnormal early T cells from BM decreased from 70.03% to 19.57% on day 30. After CART infusion, the number of peripheral abnormal T cells became either undetectable in case 2 and 3, or significantly decreased in case 1. Interestingly, CART had unsustained effect on normal T cells in all pts. As of Feb-10-2020, case 1 has 5 months of OS, including 3 months of PFS. Case 2 and 3 has reached 2 and 1 months of PFS and is still in remission. Conclusions: CD7-CART cells can be manufactured without contamination of malignant T cells. CD7-CART therapy is well-tolerated and has great therapeutic potential for relapsed/refractory CD7 positive T cell malignancies. Clinical trial information: NCT04004637 .
Efficacy of SCRI-CAR19x22 T cell product in B-ALL and persistence of anti-CD22 activity.
Authors: Gardner Rebecca Alice , Annesley Colleen , Wilson Ashley , Summers Corinne , Narayanaswamy, Prabha , Wu Vicky , Huang Wenjun , Johnson Adam , Li Amanda , Schultz Kirk R. , Lindgren Catherine , Mgebroff Stephanie , Brown Christopher , Park Julie R. , Jensen Michael C.
Published: May 2020

3035

Background: Loss of CD19 expression is a major cause of limited durable B-ALL remission following CD19 CAR T cells, which might be overcome by utilization of dual CD19xCD22 CAR T cell targeting. Methods: A Phase I trial (NCT03330691) of SCRI-CAR19x22 was developed using dual transduction of lentiviral vectors encoding for either a CD19- or CD22-specific CAR T cell construct, both with 4-1BB co-stimulation. Manufacturing was performed in a closed G-Rex system with IL-7, IL-15 and IL-21. After lymphodepletion, CAR T cells were infused at 1 or 3 X 106 CAR T cells/kg dose levels. Leukemic response and CAR T cell persistence were evaluated by flow cytometry. Results: Products were successfully manufactured in all 28 enrolled subjects with 7.92 average days in culture (range of 7-11 days) and consisted of an average CD8:CD4 ratio of 3.09 (range 0.19 to 8.9). The cellular product CAR composition was 29% CD19, 31% CD22 and 39% CD19 and CD22 targeting. 13 subjects had prior exposure to CD19 or CD22 targeting therapies with diverse expression of CD19 and CD22 on the leukemic blasts. No dose limiting toxicities occurred in the 27 infused subjects. The recommended phase 2 dose is 3 x 106 CAR+ cells/kg. CRS was present in 80% of subjects, with 85% of CRS being grade 2 or less, and a peak grade of 3 (n = 3). Mild neurotoxicity occurred in 38%, with a single grade 3 event. 84.6% obtained a CR, of which 95% were MRD negative. Of the 4 subjects who did not achieved a CR, 2 had a pre-existing CD19 negative population and one had previously received CAR T cells and rejected SCRI-CAR19x22. There have been 4 relapses with varying CD19 and CD22 expression as follows: 1 CD19-CD22-, 1 CD19+CD22+, and 2 CD19-CD22+. The in vivo engraftment of CAR T cells peaked most frequently between day +7 and +14 and was predominated by the CD19 CAR+ T cells. Conclusions: We demonstrate manufacturing feasibility and safety of SCRI-CAR19x22. While initial efficacy is demonstrated, CD22 activity is poor due to limited expansion of the CD22 CAR-containing components and subjects with pre-existing CD19 negative leukemia fared poorly. Development of a revised CD22 CAR that exhibits a reduction tonic signaling is underway, with plans to explore the new construct in the context of a dual-targeting CD19xCD22 CAR T cell product. Clinical trial information: NCT03330691 .
Neutrophil-lymphocyte score: A novel prognostic scoring system that utilized the dynamic change of neutrophil, lymphocyte, and albumin and its comparison to other indices.
Authors: Zhao Songzhu , Li Mingjia , Spakowicz Daniel , Patel Sandip H. , Johns Andrew , Grogan Madison , Miah Abdul , Husain Marium , He Kai , Bertino Erin Marie , Shields Peter G. , Wei Lai , Carbone David Paul , Otterson Gregory Alan , Presley Carolyn J , Owen Dwight Hall
Published: May 2020

3048

Background: Indications for immune checkpoint inhibitor (ICI) in cancer care are expanding rapidly. There is increasing need for accurate decision tool to better guide treatment. We have constructed a new prognostic scoring system, neutrophil-lymphocyte score (NRS), based on the nonlinear dynamic change of neutrophil to lymphocyte ratio (NLR) in relation to survival over the first cycle of ICI treatment. We compared this novel system to existing indices such as NLR, lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), Advanced Lung Cancer Inflammation Index (ALI), and Systemic Immune-inflammation Index (SII). Methods: This is a retrospective analysis of 837 patients at Ohio State University from 2011-18. Neutrophil (ANC), lymphocyte (ALC), platelet (plt), monocyte (AMC), albumin (alb), and body mass index (BMI) were collected at baseline. Repeat labs were collected at cycle 2. NLR = ANC/ALC, ALI = BMI x alb / NLR, LMR = ALC/AMC, SII = platelet x NLR, PLR = plt/ALC. NLR Ratio = baseline NLR / repeat NLR. Based on the association between NLR and the overall survival, we assigned 1 point (p) for baseline NLR < 0.7, 6p for 0.7 to < 2, 5p for 2 to < 3, 4 p for 3 to < 4, 3 for 4 to 5, 2p for 5 to < 9, and 1p for ≥9. We also assigned 1p for NLR ratio < 0.6, 2p for 0.6 to < 0.8, 3p for 0.8 to < 1.2, 5p for 1.25 to < 1.4, 3p for 1.4 to < 1.6, and 2p for ≥1.6. NLS = sum of these 2 scores . NLS_A = NLS*alb. Time-dependent receiver operator characteristic (ROC) curves with integrated time-dependent area under the curve (TD AUC) values were used to evaluate the predictive accuracy of each index for survival. Results: For baseline and repeat values, all indices were statistically significant (P < 0.001) in predicting survival. Baseline integrated TD AUC were: ALI 0.704, NLR 0.692, SII 0.663, LMR 0.645, and PLR 0.612. All of the repeat indices at cycle 2 had higher prognostic value than their baseline counterparts. Integrated TD AUC for indices at cycle 2 were: ALI 0.740 (with baseline BMI), NLR 0.729, SII 0.694, LMR 0.671, and PLR 0.652. NLS_A was a composite score based on the dynamic change of NLR from cycle 1 to 2 and the treatment alb with integrated TD-AUC at 0.754. Conclusions: Indices constructed from ANC, ALC, AMC, Plt, alb, and BMI can be obtained inexpensively and provide great prognostic value for pts on ICI. We have constructed a novel scoring system (NLS_A) and demonstrated its improvement over the current prognostic indices. Studies with a larger cohort are needed to further improve and validate this system.
Tumor methylation patterns to measure tumor fraction in cell-free DNA.
Authors: Melton Colin , Singh Pranav , Venn Oliver , Hubbell Earl , Gross Samuel , Saito Yasushi , Newman Joshua , Zhang Lily , Chang Christopher , Cann Gordon , Larson Matthew H. , Stuart Sarah , Demas Vasiliki , Aravanis Alexander , Jamshidi Arash
Published: May 2020

3052

Background: Cell-free DNA (cfDNA) tumor fraction (TF), the proportion of tumor molecules in a cfDNA sample, is a direct measurement of signal for cfDNA cancer applications. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) is a prospective, multi-center, observational, case-control study designed to support development of a methylation-based, multi-cancer detection test in which a classifier is trained to distinguish cancer from non-cancer. Here we leveraged CCGA data to examine the relationship between cfDNA containing tumor DNA methylation patterns, TF, and cancer classification performance. Methods: The CCGA classifier was trained on whole-genome bisulfite sequencing (WGBS) and targeted methylation (TM) sequencing data to detect cancer versus non-cancer. 822 samples had biopsy WGBS performed; of those, 231 also had cfDNA targeted methylation (TM) and cfDNA whole-genome sequencing (WGS). Biopsy WGBS identified somatic single nucleotide variants (SNV) and methylation variants (MV; defined as methylation patterns in sequenced DNA fragments observed commonly in biopsy but rarely [ < 1/10,000] in the cfDNA of non-cancer controls [n = 898]). Observed tumor fragment counts (SNV in WGS; MV in TM), were modeled as a Poisson process with rate dependent on TF. TF and classifier limits of detection (LOD) were each assessed using Bayesian logistic regression. Results: Across biopsy samples, a median of 2,635 MV was distributed across the genome, with a median of 86.8% shared with ≥1 participant, and a median of 69.3% targeted by the TM assay. TF LOD from MV was 0.00050 (95% credible interval [CI]: 0.00041 - 0.00061); MV and SNV estimates were concordant (Spearman’s Rho: 0.820). MV TF estimates explained classifier performance (Spearman’s Rho: 0.856) and allowed determination of the classifier LOD (0.00082 [95% CI: 0.00057 - 0.00115]). Conclusions: These data demonstrate the existence of methylation patterns in tumor-derived cfDNA fragments that are rarely found in individuals without cancer; their abundance directly measured TF, and was a major factor influencing classification performance. Finally, the low classifier LOD (~0.1%) motivates further clinical development of a methylation-based assay for cancer detection. Clinical trial information: NCT02889978 .
Results of a first-in-human phase I study of SRF231, a fully human, high-affinity anti-CD47 antibody.
Authors: Patnaik Amita , Spreafico Anna , Paterson Alison M. , Peluso Marisa , Chung Jou-Ku , Bowers Beth , Niforos Demi , O'Neill Alison M. , Beeram Muralidhar , Iafolla Marco , Lester Julia , Schram Alison M.
Published: May 2020

3064

Background: CD47 is a transmembrane protein that acts as a “Don’t Eat Me” signal to evade immune recognition. It is overexpressed in multiple cancer subtypes and is associated with poor prognosis. SRF231 is an investigational, fully human, high-affinity CD47-targeting antibody that delivers an activating signal to myeloid cells and displays favorable preclinical characteristics regarding its receptor occupancy/tumor exposure/efficacy relationship. Methods: In a Phase 1 study, SRF231-101 (NCT03512340), patients with advanced solid and hematologic malignancies who had failed standard therapy were enrolled in dose escalation cohorts (accelerated single-patient followed by standard 3+3) to establish the preliminary safety of SRF231 as a monotherapy and identify a dose and schedule suitable for expansion. In addition to collection of safety data, clinical outcomes were evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and SRF231 pharmacokinetic (PK) and pharmacodynamic (receptor occupancy) analyses were performed. Results: As of January 11, 2020, a total of 46 patients were enrolled, 25 in every-3-week intravenous (IV) dosing schedules and 21 in weekly IV dosing schedules. Weekly dosing schedules also explored the use of a 1.0 mg/kg initiation dose. Other than one patient with recurrent follicular lymphoma, all patients had recurrent/refractory solid tumors. The most common treatment emergent adverse events across dosing schedules were low-grade fatigue (43%), headache (35%), and pyrexia (30%). On every-3-week dosing schedules, 2 dose-limiting toxicities (DLTs) were observed: Grade 3 febrile neutropenia and Grade 3 hemolysis, both at a 12.0 mg/kg dose level. On weekly dosing schedules, 3 DLTs were observed: Grade 4 thrombocytopenia (6.0 mg/kg), Grade 4 amylase and lipase increased (4.0 mg/kg with initiation dose), and Grade 3 fatigue (4.0 mg/kg). The maximum tolerated dose was 9.0 mg/kg on an every-3-week and 4.0 mg/kg on a weekly schedule. Receptor occupancy was maintained at > 90% throughout the dosing period with a 4.0 mg/kg weekly dose schedule. Out of 37 patients who were response evaluable by RECIST, there were no complete or partial responders, although prolonged stable disease has been observed. Conclusions: Preliminary data from a Phase 1 study of SRF231, an anti-CD47 antibody, demonstrate that SRF231 may be administered safely and doses of 4.0 mg/kg weekly maintain > 90% receptor occupancy throughout the dosing period. Updated safety data, clinical outcomes, and PK/pharmacodynamic data will be presented. Clinical trial information: NCT03512340 .
Preliminary dose escalation results from a phase I/II, first-in-human study of MGC018 (anti-B7-H3 antibody-drug conjugate) in patients with advanced solid tumors.
Authors: Powderly John D. , Jang Sekwon , Lohr Joanna , Spira Alexander I. , Bohac Gerry C. , Sharma Manish
Published: May 2020

3071

Background: Antibody-drug conjugates (ADCs) are cancer agents that have a cytotoxic payload linked to a monoclonal antibody (mAb) that target cancer cells. ADCs offer increased cytotoxic activity while reducing normal tissue exposure. B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 mAb. It is hypothesized that MGC018 has activity against B7-H3 expressing tumors with an acceptable safety profile. Methods: This study evaluates safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of MGC018 in a dose escalation 3+3+3 design. In addition, pharmacokinetics, immunogenicity, and tumor response using RECIST v1.1 are evaluated. Cohort expansion will enroll at the MTD to assess safety and tumor response. Results: The study is enrolling Cohort 3 (6 total cohorts planned) in dose escalation. 20 patients (pts) were enrolled as of Feb 03, 2020. At least 1 treatment related adverse event (TRAE) occurred in 16 pts (80.0%). The most common TRAEs were neutropenia/decreased neutrophil count (35%); fatigue, lymphopenia/decreased lymphocyte count (30.0%); palmar plantar erythrodysaesthesia (PPE), skin hyperpigmentation (25.0%); pruritis, nausea, chills, infusion related reaction (20.0%); and vomiting, pyrexia, maculopapular rash (15.0%). Eleven pts (55.0%) experienced TRAEs ≥ Grade 3; events were decreased lymphocyte count/lymphopenia (n = 6), decreased neutrophil count/neutropenia (n = 3), PPE (n = 2), and maculopapular rash (n = 2). Three related serious adverse events occurred in 3 unique pts: pneumonitis in a pt with concurrent bacterial pneumonia, non-infectious gastroenteritis, and stasis dermatitis in a pt with chronic venous insufficiency. One DLT has occurred (Grade 4 neutropenia). No febrile neutropenia was observed. Target lesion decrease was noted in 1 pt each with small cell lung cancer (-6.3%), non-small cell lung cancer (-23.8%), and metastatic castrate-resistant prostate cancer (mCRPC) (-29.4%) with PSA change from 82.8 ng/ml to 57.1 ng/ml. One mCRPC pt with bone only disease had substantial improvement on bone scan and PSA decrease from 60 ng/ml to 4.7 ng/ml. Conclusions: Results to date demonstrate a manageable safety profile with early evidence of clinical activity. Continued dose escalation and clinical investigation of MGC018 is ongoing. Clinical trial information: NCT03729596 .