bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 .