On April 18, 2016 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that the Company’s collaborators from the University of Texas MD Anderson Cancer Center (MD Anderson) presented new pre-clinical data supporting the promising potential of its lead anti-cancer product candidate, VAL-083 (dianhydrogalactitol), in the treatment of non-small cell lung cancer (NSCLC) and ovarian cancer (Press release, DelMar Pharmaceuticals, APR 18, 2016, View Source [SID:1234510970]).

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Abstract (#2157): "Enhanced in vitro activity of dianhydrogalactitol (VAL-083) in combination with platinum drugs: Impact of p53 and platinum-resistance," was presented at AACR (Free AACR Whitepaper) during the "New Drugs, Therapeutic Targets, and Treatment Approaches" session.

In summary, MD Anderson researchers presented new in vitro data from their studies with VAL-083 indicating that:

VAL-083 induces apoptosis independent of p53 status, and appears to have a distinct mode of action from platinum-based chemotherapies widely used in the treatment of NSCLC and ovarian cancer;

VAL-083 demonstrated ability to circumvent cisplatin-resistance in all ovarian cell lines tested;

VAL-083 was active against NSCLC tumors harboring T790M, p53 and/or KRAS mutations, known to confer resistance to currently available therapies; and

VAL-083 demonstrated super-additivity or synergy in combination with platinum-based chemotherapy.

"These results support VAL-083 as a viable treatment option for refractory NSCLC and ovarian cancer patients failing platinum-based therapy as well as the potential benefit of a VAL-083-platinum combination," said Jeffrey Bacha, DelMar’s chairman & CEO.

Dr. Dennis Brown, DelMar’s Chief Scientific Officer, added, "The activity of VAL-083 observed in tumors harboring mutations known to be correlated with resistant phenotypes and poor treatment outcomes provides clarity and direction as we advance toward planned clinical trials in NSCLC. We can use these biomarkers for patient selection in a personalized-medicine approach to establish clinical proof-of-concept in specific tumor sub-types representing significant unmet needs within the cancer treatment market."

DelMar previously announced plans to initiate clinical trials with VAL-083 in the treatment of NSCLC in cooperation with Guangxi Wuzhou Pharmaceutical (Group) Co., Ltd., who is to provide funding for the trial in accordance with the terms of a collaboration agreement.

About VAL-083

VAL-083 is a "first-in-class," small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia (CML) and lung cancer, and has received orphan drug designation in Europe and the U.S. for the treatment of malignant gliomas. DelMar recently announced that the FDA’s Office of Orphan Products had also granted an orphan designation to VAL-083 for the treatment of medulloblastoma.

DelMar has demonstrated that VAL-083’s anti-tumor activity is unaffected by the expression of MGMT, a DNA repair enzyme that is implicated in chemotherapy resistance and poor outcomes in GBM patients following standard front-line treatment with Temodar (temozolomide).

DelMar has been conducting a Phase I/II clinical trial in GBM patients whose tumors have progressed following standard treatment with temozolomide, radiotherapy, bevacizumab and a range of salvage therapies.

Data from the Phase I dose-escalation of the study suggest that VAL-083 is well tolerated using a regimen of 40mg/m2 daily x 3 every 21 days. Dose limiting toxicity (DLT) defined by thrombocytopenia (low platelet counts) was observed at doses above 40 mg/m2. Generally, DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment.

Sub-group analysis of Phase I data suggests a dose-dependent and clinically meaningful survival benefit following treatment with VAL-083. Patients in a low dose (≤5mg/m2) sub-group had a median survival of approximately five (5) months versus median survival of approximately nine (9) months for patients in the therapeutic dose (30mg/m2 & 40mg/m2) sub-group following initiation of VAL-083 treatment. DelMar also reported increased survival at 6, 9 and 12 months following initiation of treatment with VAL-083 in the therapeutic dose sub-group compared to the low dose sub-group.

Based on these data, DelMar initiated a Phase II expansion cohort utilizing the 40mg/m2 dosing regimen in June 2015 at five clinical centers in the United States: Mayo Clinic (Rochester, MN); UCSF (San Francisco, CA) and three centers associated with the Sarah Cannon Cancer Research Institute (Nashville, TN, Sarasota, FL and Denver, CO). DelMar announced the completion of enrollment in a Phase II expansion cohort in September, 2015.

Updated interim data from this ongoing study will be presented on Tuesday April 19, 2016 at the AACR (Free AACR Whitepaper) Annual Meeting in the Phase II/III Clinical Trials in Progress" session (Abstract #CT074).

Further details can be found at View Source

About NSCLC

Lung cancer is a leading cause of cancer-related mortality around the world and effective treatment for lung cancer remains a significant global unmet need despite advances in therapy. In general, prognosis for lung cancer patients remains poor, with 5-year relative survival less than 14% among males and less than 18% among females in most countries. Globally, the market for lung cancer treatment may exceed $7 billion by 2019 according to a report published by Transparency Market research.

Non-small cell lung cancer ("NSCLC") is the most common type of lung cancer. There are three common forms of NSCLC: adenocarcinomas are often found in an outer area of the lung; squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus); and large cell carcinomas, which can occur in any part of the lung and tend to grow and spread faster than adenocarcinoma. NSCLC accounts for 85% of all lung cancer cases in the United States and approximately 90% of lung cancer cases diagnosed in China.

The current standard of care for newly diagnosed NSCLC is platinum-based combination therapy or tyrosine kinase inhibitor (TKI) therapy for patients whose cancer exhibits over expression of epidermal growth factor receptor ("EGFR") mutations. Patients exhibiting an over expression of EGFR mutations have shown an initial response rate to TKIs which exceeds the response rate for conventional chemotherapy. However, resistance to TKI therapy has emerged as an important unmet medical need commonly linked to the emergence of specific mutations such as T790M.

About Ovarian Cancer

The American Cancer Society estimates for 2015 about 21,290 women will receive a new diagnosis of ovarian cancer and approximately 14,180 women will die from ovarian cancer in the United States. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. A woman’s risk of getting ovarian cancer during her lifetime is about 1 in 75. Her lifetime chance of dying from ovarian cancer is about 1 in 100. Although initially responsive to standard-of-care chemotherapy based on platinum-taxane combinations, most tumors recur and median survival for recurrent ovarian cancer is 12 to 24 months. According to The Cancer Genome Atlas, there is a major clinical need for treatment with alternatives that can circumvent resistance to currently available chemotherapies.

On April 18, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported new safety and immune response data from the Phase 1 portion of a Phase 1/2 dose escalation and cohort expansion study examining the investigational combination of varlilumab, Celldex’s CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s anti-PD-1 immunotherapy Opdivo (nivolumab) (Press release, Celldex Therapeutics, APR 18, 2016, View Source [SID:1234510993]). The data were presented today in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans. The Phase 1 portion of the study, conducted in patients with solid tumors, has completed enrollment (n=36) and primarily enrolled patients with colorectal (n=20) and ovarian cancer (n=8). The primary objective of the Phase 1 portion of the study was to evaluate the safety and tolerability of the combination. The Phase 2 portion of the study is open to enrollment.

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Key Highlights:

Combining the potent immune activator, varlilumab, with the PD-1 inhibitor, nivolumab, showed acceptable tolerability and safety across all dose levels without any evidence of increased autoimmunity or inappropriate immune activation.
Combination therapy led to marked changes in the tumor microenvironment including increased infiltrating CD8+ T cells and increased PD-L1 expression, which have been shown to correlate with a greater magnitude of treatment effect from checkpoint inhibitors in other clinical studies.
Additional favorable immune biomarkers, such as increase in inflammatory chemokines and decrease in T regulatory cells, were also noted.
In a subset of patients (n=17) on study who had both pre- and post-tumor biopsies available, preliminary evidence suggest a correlation between biomarker data and stable disease or better in seven of these patients (4 ovarian cancer, 2 colorectal cancer, 1 squamous cell carcinoma of the head and neck).
"The combination of varlilumab and nivolumab demonstrated acceptable tolerability across all dose levels of varlilumab, showing that immune stimulation through CD27 was safely combined with PD-1 blockade," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "In addition, we observed favorable changes in intratumoral immune biomarkers, most notably an increase in tumor infiltrating lymphocytes, which is recognized to correlate with improved clinical outcome. Based on the strong preclinical data, scientific rationale and these recent results, we are very excited for the Phase 2 portion of the trial, which is now open to enrollment across six different indications."

The Phase 2 portion of the study includes cohorts in advanced non-small cell lung cancer (n=35), colorectal cancer (n=18), ovarian cancer (n=18), head and neck squamous cell carcinoma (n=18), renal cell carcinoma (n=25) and glioblastoma (n=20). The primary objective of the Phase 2 study is overall response rate for all cohorts except glioblastoma, where the primary objective is the rate of 12-month overall survival. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with nivolumab and further assessing the anti-tumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival. The study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb Company. The companies are sharing development costs.

Celldex and its collaborating investigators are presenting seven posters at the AACR (Free AACR Whitepaper) Annual Meeting. As of Monday, April 18, four of these posters have been presented and summaries of these, including the Phase 1/2 varlilumab/nivolumab combination study, can be found below.

Title: Phase 1 results from the combination of an immune activating anti-CD27 antibody (varlilumab) in combination with PD-1 blockade (nivolumab): activation across multiple immune pathways without untoward immune-related adverse events

The Phase 1, dose-escalation portion of the study assessed the safety and tolerability of varlilumab at doses ranging from 0.1 to 10 mg/kg when administered with nivolumab (3 mg/kg). Enrollment to the Phase 1 study portion is complete with a total of 36 patients treated. Data for 35 patients are included in the poster: colorectal cancer (n=20), ovarian cancer (n=8), metastatic melanoma (n=4) and head and neck squamous cell carcinoma (n=3). 69% of patients had three or more prior therapies.

All dose levels of the combination therapy showed acceptable tolerability and safety, without identification of a maximum tolerated dose. In the Phase 2 portion of the study, varlilumab will be administered at 3 mg/kg, which is based upon cumulative data across multiple studies.

The safety profile of the varlilumab and nivolumab combination has been consistent with that of each agent individually, and no unexpected toxicities have been observed. The most frequent treatment related adverse events, occurring in more than 10% of patients, were fatigue (25.7%), lymphopenia (20%), nausea (20%), chills (17.1%), arthralgia (14.3%), pruritus (14.3%) and rash (11.4%), the majority of which were grade 1 or 2. Two patients experienced drug-related serious adverse events. In the 10 mg/kg cohort, grade 4 hepatitis and grade 3 renal insufficiency was observed in a patient with ovarian cancer. Also in the 10 mg/kg cohort, grade 2 paresthesia (tingling/numbness) was observed in a patient with colorectal cancer.

Biomarker data from all varlilumab dose levels indicate increases in inflammatory chemokines and decreases in circulating T regulatory cells, which is generally consistent with varlilumab monotherapy. Importantly, in tissue biopsies from patients, the authors noted, where pre-treatment and on-study specimens were available (n=17), a marked increase of tumor infiltrating lymphocytes and an increase in PD-L1 expression. Although the Phase 1 portion of the study was focused on immune response and safety, a correlation between this biomarker readout and stable disease or better (n=7) was observed in this preliminary dataset.

The poster is available on the "Publications" page of the "Science" section of the Celldex website.

Title: In situ Vaccine for Low-Grade Lymphoma: Combination of Intratumoral Flt3L and Poly-ICLC With Low-Dose Radiotherapy

The potential activity of CDX-301 (recombinant human Flt3 ligand) is being explored in an investigator-sponsored, Phase 1/2 study of CDX-301 and poly-ICLC in combination with low-dose radiotherapy in patients with low-grade B-cell lymphomas conducted by the Icahn School of Medicine at Mount Sinai. CDX-301 is a potent hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells. To date, the study has enrolled 12 patients with indolent non-Hodgkin lymphoma. The authors presented flow cytometry and mass cytometry data from selected patients, which demonstrate the ability of CDX-301 to induce dendritic cell mobilization.

The poster is available on the "Publications" page of the "Science" section of the Celldex website.

Title: IHC and RT-PCR Assays for Detection of Cancer Antigen NY-ESO-1 in Human Tissues

The Company presented data from the development of diagnostic assays for NY-ESO-1, the target of CDX-1401, an antibody-based NY-ESO-1-specific therapeutic vaccine for multiple solid tumors. Samples from 75 solid tumor types and 38 normal adjacent tissue samples were analyzed by immunohistochemistry (IHC) and quantitative RT-PCR assays, which were developed to determine NY-ESO-1 expression. The validated diagnostic tests for use in the clinical development of CDX-1401 and preliminary screening suggest that several cancers, including non-small cell lung cancer (NSCLC), melanoma and ovarian cancer, express NY-ESO-1, which is consistent with published literature.

The poster is available on the "Publications" page of the "Science" section of the Celldex website.

Title: Targeting the melanosome: overcoming MAPK-inhibitor resistance in melanoma
Abstract: 296

Research collaborators examined the role of MiTF-regulated melanosomal differentiation antigens (MDAs), such as gpNMB, as potential therapeutic targets that could potentially overcome MAPK inhibitor resistance in melanoma. MiTF is a transcription factor that has been identified as an indicator of melanoma resistance, and through the interrogation of the TCGA melanoma database, the authors found it to be strongly correlated with MDAs, including gpNMB. In a preclinical study investigating resistance mechanisms in melanoma, glembatumumab vedotin, an antibody-drug conjugate that targets gpNMB, demonstrated synergies with therapies for BRAF mutated melanoma and overcame phenotypes associated with resistance, suggesting use of glembatumumab vedotin may be particularly effective as a single-agent or in combination in this refractory patient population.

About Varlilumab
Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a single-agent Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs.

About CDX-301
CDX-301 (Flt3L) is a potent hematopoietic cytokine that has demonstrated a unique capacity to increase the number of circulating dendritic cells in both laboratory and clinical studies. In addition, CDX-301 has shown impressive results in models of cancer, infectious diseases and inflammatory/autoimmune diseases. Celldex believes this ligand may hold significant opportunity for synergistic development in combination with other proprietary molecules in the Company’s portfolio.

About CDX-1401
CDX-1401 is a next-generation, off-the-shelf cancer vaccine designed to activate the patient’s immune system against cancers that express the tumor marker, NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 genetically linked to the NY-ESO-1 tumor antigen. Celldex has accessed NY-ESO-1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.

About Glembatumumab Vedotin
Glembatumumab vedotin is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, uveal melanoma and osteosarcoma.

Opdivo is a registered trademark of Bristol-Myers Squibb Company.

On April 18, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported new data from more than 1,200 pediatric tumors across 51 cancer subtypes that were analyzed using the company’s comprehensive genomic profiling assays, FoundationOne and FoundationOne Heme (Press release, Foundation Medicine, APR 18, 2016, View Source [SID:1234511021]). The dataset reveals novel and potentially targetable genomic alterations identified during pediatric cancer clinical care that offer the possibility for new research towards novel therapeutics. In a separate but related announcement at the White House Precision Medicine Initiative Summit in February, Foundation Medicine made this data set publically available for research to motivate and accelerate development of new therapies to fight pediatric cancer.

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These findings were presented in a late-breaking poster titled "Genomic profiling of 1239 diverse pediatric cancers identifies novel discoveries across tumors" by Juliann Chmielecki, Ph.D., associate director, cancer genomics at Foundation Medicine, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 taking place April 16-20 in New Orleans.

The poster presentation details genomic profiles from 1,239 pediatric tumors (ages 0-18). Multiple studies are actively investigating clinically relevant genomic alterations in common tumor subtypes for therapeutic exploitation. As demonstrated by the identification of novel fusions and mutations, this data set offers significant discovery potential and can be used to generate hypotheses, validate rare findings, and investigate the genomic landscape of rare tumors in a pediatric population for which only small studies currently exist. Key findings include:

Genomic profiles from 51 disease subtypes representing sarcomas (26.6 percent), other blastomas (22.4 percent), brain tumors (20.4 percent), hematological malignancies (19.5 percent), carcinomas (9.8 percent) and gonadal tumors (1.4 percent).

Alterations with proven clinical actionability in pediatric cancers (BRAF V600E and ALK, NTRK1 and ABL1 fusions) were found in 3.9 percent of samples across brain, sarcoma and hematologic cases.

Three novel ALK fusions were identified in a neuroblastoma (BEND5-ALK), a soft tissue sarcoma (IGFBP5-ALK) and an astrocytoma (PPP1CB-ALK), respectively. Two novel BRAF fusions were also found in an astrocytoma (BCAS1-BRAF) and a ganglioglioma (TMEM106B-BRAF).

This large data set also challenges the paradigm of "disease-specific" alterations as previously characterized fusions involving ALK, NTRK1 and PAX3 were observed in novel diseases from which they were originally reported.

Pediatric cancers are a rare and diverse collection of diseases. Childhood cancer rates have been rising slightly for the past few decades, with The American Cancer Society estimated 10,380 children in the U.S. were diagnosed with cancer in 2015. Pediatric cancer remains the leading cause of death by disease among children. Despite advances in detection and treatment of childhood cancer, over 1,900 pediatric patients in the United States succumb to disease each year.1

On April 18, 2016 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported a new set of preclinical data further validating the potential of its first-in-class anti-MICA/B antibody IPH4301 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans, Louisiana, USA (Press release, Innate Pharma, APR 18, 2016, View Source [SID:1234511087]).

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Poster #1491 reports that IPH4301, a humanized antibody, binds with high affinity to MICA/B and is a potent cytotoxic antibody, inducing direct tumor cell killing by ADCC. Moreover, an additional mode-of-action of the same antibody was revealed, whereby the antibody has the potential to overcome immunosuppression in tumors.

Among the highly immune-suppressive cell types in cancer are tumor-associated macrophages or myeloid-derived suppressor cells (MDSC), which can reduce NK and T cell activities. In vitro, IPH4301 could overcome immunosuppression by macrophages, restoring NK cell antibody-mediated killing to levels seen in the absence of suppressor macrophages. In addition, IPH4301 blocked MICA/B-induced down-modulation of NKG2D receptors on NK and CD8 T cells, thus disrupting a second immuno-suppressive mechanism. Finally, treatment with IPH4301 restored NK cell infiltration, prevented tumor growth and improved survival in different in vivo tumor models.

Nicolai Wagtmann, CSO of Innate Pharma, said: "We are enthusiastic about IPH4301 as a therapeutic candidate because of its dual mode of action, combining potent ADCC-mediated tumor killing with interesting immuno-modulating properties. The ability of IPH4301 to interfere with these immune-suppressive pathways, while at the same time retaining high direct ADCC potency, makes for a novel, unique proposition in the immune-oncology landscape. IND-enabling studies will start in 2016".

Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in HCC, interacts with CD16/ FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied versus placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy.
Patients with advanced HCC who had failed prior systemic therapy, ⩾18 years, ECOG 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600 mg versus placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival (PFS). Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics (PK), and an exploratory endpoint in biomarkers analysis.
185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median PFS and OS in the codrituzumab versus placebo groups in months were: 2.6 versus 1.5 (HR 0.97, P=0.87), and 8.7 versus 10 (HR 0.96, P=0.82). Projected Ctrough at cycle 3 day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged PFS and OS.
Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions.
Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome.
Copyright © 2016. Published by Elsevier B.V.

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