On June 4, 2018 Rgenix, Inc., a clinical stage biopharmaceutical company developing first-in-class small molecule and antibody cancer therapeutics, reported it is presenting data on the safety, pharmacodynamics, and clinical activity from the dose escalation stage of the ongoing Phase Ia/b trial of RGX-104, an oral small molecule immunotherapy that targets the liver X receptor (LXR) (Press release, Rgenix, JUN 4, 2018, View Source [SID1234527164]).

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In a poster presentation of an abstract accepted for the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), "Pharmacodynamic and clinical activity of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies", Rgenix showed the first-in-class compound to be capable of generating immunologic and anti-tumor activity.

RGX-104 is a small-molecule LXR agonist that modulates innate immunity by activating the ApoE gene. In murine models, the small molecule depletes myeloid derived suppressor cells (MDSCs) and stimulates dendritic cells (DCs), activating anti-tumor immunity as a single agent as well as in combination with adoptive T cell therapy or checkpoint inhibitors. The Phase 1a/b trial in progress is studying the therapy with regards to safety, efficacy, pharmacokinetics and pharmacodynamics. A total of 26 patients with a broad array of tumors have received RGX-104 at a range of dose levels and frequency as part of the dose escalation stage of the study.

RGX-104 was well tolerated across dose cohorts, with hyperlipidemia – an on target effect of LXR agonism – representing the most common adverse event. Robust ApoE target gene engagement was observed in patients, along with substantial MDSC depletion and DC stimulation in 12 of 17 evaluable patients. Activation of circulating PD-1+ T cells was observed in 11 of the 12 patients that experienced MDSC depletion.

One patient with a high-grade neuroendocrine malignancy with small cell features had a confirmed radiographic partial response with a 53% reduction in index hepatic metastases at the 160 mg BID dose. This response was associated with a greater than 12-fold increase in activated PD-1+ T cells. Additionally, seven patients had stable disease for durations of 8-16 weeks. The dose of 160 mg BID was chosen as the Recommended Phase 2 Dose, with robust pharmacodynamic effects on ApoE expression and relevant immune cell populations.

Masoud Tavazoie, MD, PhD, and Chief Executive Officer of Rgenix, said, "Today’s presentation illustrates the promise of our lead clinical candidate RGX-104. It enables us to move forward with our plans to study the compound in expansion cohorts as a single agent as well as in combination with a PD-1 inhibitor in patients with both checkpoint-inhibitor refractory and naïve tumors." Escalation and Expansion cohorts in the Phase 1b stage of the clinical trial are currently enrolling patients with epithelial ovarian carcinoma (EOC), melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell cancer (RCC), bladder cancer (BLC), and triple negative breast cancer (TNBC).

On June 4, 2018 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapies against cancers and infectious diseases, and University of Leeds, reported that new clinical data1 obtained with Pexa-Vec further demonstrate anti-tumor activity after intravenous (i. v.) infusion (Press release, Transgene, JUN 4, 2018, View Source [SID1234621826]). These data were presented by Dr. Alan Anthoney (University of Leeds) in a poster presentation at the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 4, in Chicago .

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These first clinical results confirm Pexa-Vec’s activation of anti-tumor immunity and targeted oncolytic activity. The key findings of the trial show:

selective expression and replication of Pexa-Vec in the tumor tissues;
induction of a robust anti-tumor immune response:
with the stimulation of an adaptive response (T cells) targeted to tumor specific antigens,
the activation of innate immune response (NK cells), and
an elevation of cytokines associated with immune stimulation;
one partial and one complete necrosis of tumors among the patients with colorectal cancer and liver metastases (pathological responses);
upregulation of PD-L1 and PD-1 signaling molecules, a finding that strongly supports the rationale for combining Pexa-Vec with anti-PD-1 inhibitors.
Dr Alan Anthoney, Consultant in Medical Oncology at Leeds Teaching Hospitals, Senior Lecturer in the Institute of Cancer & Pathology at the University of Leeds and principal investigator of the trial, said: "We are very encouraged to report that a single IV administration of Pexa-Vec displayed cytolytic activity at tumor sites, where it elicited a robust activation of tumor-antigen specific immune cells. In one patient with colorectal cancer liver metastasis a complete pathological response has been observed. These data clearly support the anti-tumor activity of Pexa-Vec. The final data from this trial will be published in an upcoming paper. Our decision to lead this clinical trial, investigating the potential of new weapons against cancers, testifies to our commitment at Leeds University and Leeds Teaching Hospitals NHS Trust to evaluate new innovative options that might improve the lives of our patients with cancer."

Maud Brandely, Chief Medical Officer of Transgene, added: "These very positive translational data confirm the targeted oncolytic activity and the potential of Pexa-Vec in advanced stages cancers. The observed upregulation of PD-1 and PD-L1 positive pathways strongly supports the rationale for combining Pexa-Vec with anti-PD-1 immunotherapies, which is the focus of an ongoing Phase 1/2 trial in the first-line treatment of liver cancer (HCC). These data are also crucial for our next generation of multifunctional oncolytic viruses based on our Invir.IOTM platform: this trial clearly shows that Vaccinia virus based immunotherapeutics can reach the tumor sites after i. v. administration, and selectively replicate within cancer cells. This neoadjuvant trial is the first clinical trial led by Transgene to readout this year. We look forward to announcing additional clinical results this year, not only with Pexa-Vec, but also on our four other clinical-stage immunotherapeutics."

About the Pexa-Vec "neo-adjuvant" trial:
This clinical study is aimed at evaluating the biological effects of pre-operative intravenous administration of Pexa-Vec prior to planned surgical resection of locally advanced/poor prognosis or metastatic cancers. This single center, open label, non-randomized trial recruited 9 patients including 8 evaluable patients (3 with metastatic melanoma and 5 with colorectal cancer metastases to the liver). They received a single intravenous dose of 1×109 pfu of Pexa-Vec, 14 days prior to planned surgery. Up to 6 blood samples were collected pre- and post- injection for each patient. Imaging was performed prior at baseline and within 7 days prior to surgery. Tumor tissue was collected at surgery for histologic and translational assessments.
University of Leeds is the sponsor of the trial that was supported by Transgene and run through the NIHR Clinical Research Facility at St James’ Hospital, Leeds.

The poster is available on Transgene’s website.

About Pexa-Vec
Pexa-Vec (JX594) is an oncolytic immunotherapeutic based on an oncolytic vaccinia virus armed with a GM-CSF gene that promotes an anti-tumor immune response. Pexa-Vec is designed to selectively target and destroy cancer cells through three different mechanisms of action: selectively destroy cancer cells through the direct lysis (breakdown) of cancer cells through viral replication, reduce the blood supply to tumors through vascular disruption, and stimulate the body’s immune response against cancer cells.
Pexa-Vec is currently being evaluated in a Phase 3 trial in hepatocellular carcinoma (HCC, liver cancer) in combination with sorafenib (current standard of care). Other trials evaluating the oncolytic virus in solid tumors are underway and expected to readout in 2018, including a Phase 2 trial in combination with nivolumab (HCC).
Transgene has exclusive rights to develop and commercialize Pexa-Vec for the treatment of solid tumors in Europe. Its partner SillaJen, Inc. is focused on developing Pexa-Vec for the North American market and has also granted exclusive development and commercial rights to Pexa-Vec in Hong Kong and The People’s Republic of China to Lee’s Pharmaceutical.

On June 4, 2018 ERYTECH Pharma (Euronext:ERYP) (Nasdaq:ERYP), a clinical-stage biopharmaceutical company developing innovative therapies by encapsulating therapeutic drug substances inside red blood cells, reported that it will present pharmacodynamic characterization data from its Phase 2/3 trial of eryaspase (GRASPA) in combination with chemotherapy for the treatment of relapsed acute lymphoblastic leukemia (ALL) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held June 1-5, 2018 in Chicago, Illinois (Press release, ERYtech Pharma, JUN 4, 2018, View Source;p=RssLanding&cat=news&id=2352888 [SID1234527117]).

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The European Phase 2/3 trial pharmacodynamic data will be presented during the poster session of the Hematologic Malignancies by Dr. Iman El-Hariry, Chief Medical Officer of ERYTECH and Dr. Philip Lorenzi,
Co-Director of the proteomics and metabolomics core facility at MD Andersen Cancer Center.

Poster Session: Pharmacodynamic Characterization of eryaspase (L-asparaginase Encapsulated in Red Blood Cells) in Combination with Chemotherapy in a Phase 2/3 Trial in Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517).

Poster: 7049
Lead Author: Dr. Iman El Hariry
Poster Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
Location: Hall A
Date: Monday, June 4
Time: 8:00 a.m. – 11:30 a.m.
This randomized Phase 2/3 study enrolled patients with relapsed ALL (n=80, age: 1-55 years), randomized to eryaspase or native ASNase in combination with chemotherapy. The study demonstrated prolonged asparaginase activity and marked reduction in allergic reactions with eryaspase, when compared with control native asparaginase. In addition, the study demonstrated an overall favorable safety profile as well as a higher complete remission (CR) rate with eryaspase.

The duration of asparagine (ASN) depletion was also evaluated in the study, and was inferior in the eryaspase arm, compared to control. These results are largely confounded by the lack of a reliable assay to measure ASN due to ex vivo depletion of ASN before the enzyme can be quenched. This can lead to over-estimation of ASN depletion with a free asparaginase enzyme, less so with an encapsulated enzyme. Importantly, ASN depletion ≤2 μM was maintained for approximately 7 days in 70% and 75% of patients, in the eryaspase and control arms, respectively. Of interest, correlation with complete remission rate suggests ASN depletion ≤2 μM may not be needed with eryaspase; rather, a level ≤7.55 μM at Day 6 may be sufficient.

On June 4, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported data, which showed clinical improvement in median radiologic progression-free survival (rPFS) with Lynparza (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, JUN 4, 2018, View Source [SID1234527133]). Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.

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The results of Study 08, a randomised, double-blinded, multi-centre Phase II trial, comparing Lynparza in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, 1-5 June 2018 as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in the Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

Noel Clarke, Professor of Urological Oncology, Christie NHS Foundation Trust, Manchester, UK, said: "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "A previous trial demonstrated improvements in response rates with Lynparza monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggests that regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from Lynparza in combination with abiraterone."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. Lynparza is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of Lynparza."

Median rPFS was 13.8 months with Lynparza and abiraterone compared to 8.2 months with abiraterone alone (HR 0.65; 95% CI 0.44-0.97; p=0.034). Median PFS2 was 23.3 months vs 18.5 months (HR 0.79; 95% CI 0.51–1.21). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR 0.91; 95% CI 0.60–1.38). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients, regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS.

The safety profile of Lynparza and abiraterone was generally manageable, with no detrimental effect on quality of life compared to abiraterone alone. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% and 28%; 34% and 18%; 30% and 10%, respectively). The most common grade ≥3 AEs in the combination arm were anaemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group.

In addition to Study 08, other studies are underway to explore the potential of Lynparza as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing Lynparza monotherapy vs. enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore Lynparza in combination for the treatment of mCRPC regardless of HRR status. Lynparza was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ATM-gene-mutated mCRPC.

Lynparza is a first-in-class PARP inhibitor approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients. Lynparza has the broadest and most-advanced clinical trial development programme and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

NOTES TO EDITORS
About Study 08

Study 08 was a global, randomised, double-blinded, multi-centre Phase II trial of 142 patients, assessing the efficacy and safety of Lynparza tablets (300mg twice daily) and abiraterone tablets (4 x 250mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250mg once daily) (n=71) in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of HRR status. Prednisone/prednisolone (5mg BID) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrolment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomisation to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on the disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death, overall survival and health-related quality of life.

About metastatic castration-resistant prostate cancer (mCRPC)

Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate.[i] Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.[ii] mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.ii Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.[iii] Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.iii Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28%.iii

About Lynparza

Lynparza (olaparib) was the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza, which has the broadest clinical development programme of any PARP inhibitor, is being tested in a range of DDR-deficient tumour types, and is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On June 4, 2018 OncoSec Medical Incorporated (OncoSec) (NASDAQ:ONCS), a company developing intratumoral cancer immunotherapies, reported the presentation of a Trials in Progress poster at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2018 Annual Meeting taking place in Chicago, IL (Press release, OncoSec Medical, JUN 4, 2018, View Source [SID1234527149]).

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Titled, Trial in Progress, A Phase 2 Study of Intratumoral pIL-12 Plus Electroporation In Combination With Intravenous Pembrolizumab In Patients With Stage III/IV Melanoma Progressing on Either Pembrolizumab or Nivolumab Treatments (PISCES/KEYNOTE-695), the poster provides an update on OncoSec’s global, multi-center, registration-directed open-label Phase 2b clinical trial, assessing the Company’s investigational therapy, (intratumoral pIL-12 [tavokinogene telseplasmid] delivered with electroporation) ("tavo" or "ImmunoPulse IL-12"), and the approved anti-PD-1 therapy pembrolizumab, in patients with unresectable metastatic melanoma who have progressed or are progressing on an anti-PD-1 therapy.

PISCES/KEYNOTE-695, a phase 2b, Simon 2-stage multicenter study of tavo in combination with intravenous KEYTRUDA, will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. Stage 1 of the study will enroll 23 patients. The primary endpoint will be the Best Overall Response Rate (BORR).

Numerous sites in the U.S., Australia, and Canada are open and enrolling patients. The Company anticipates that enrollment in stage 1 will be completed by the third quarter 2018.

"Despite the addition of immunotherapy and targeted therapies, disease progression continues to occur in a significant percentage of advanced melanoma patients," said OncoSec Chief Clinical and Regulatory Officer, Sharron Gargosky, Ph.D. "We are pleased with our progress as we continue to enroll patients in the KEYNOTE-695 trial, which is evaluating the tolerability and efficacy of pembrolizumab plus tavo in Stage III/IV melanoma patients who have progressed or are progressing on approved checkpoint inhibitors."

The Company’s prior Phase 2 combination study of tavo and pembrolizumab (OMS-102) in 22 patients unlikely to respond to anti-PD-1 therapy demonstrated a 50% best overall response rate and a 41% complete response rate. In addition, the trial showed a 57% progression free survival (PFS) rate at 15 months (median PFS not yet reached) and 100% (11/11) duration of response. In clinical studies to date, tavo has demonstrated a favorable safety profile and has been well tolerated.

PISCES/KEYNOTE-695 is the second combination study conducted with tavo and pembrolizumab and, if successful, could form the basis for a BLA under the accelerated approval pathway.

Tavo has received both Orphan Drug and Fast-Track Designation by the U.S. Food & Drug Administration.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

ImmunoPulse is a registered trademark of OncoSec Medical Incorporated.

To learn more about the trial, visit www.oncosec.com. Additional details can also be found at www.clinicaltrials.gov via NCT03132675.

About PISCES/KEYNOTE-695 (Anti-PD-1 IL-12 Stage III/IV Combination Electroporation Study)
PISCES/KEYNOTE-695 is a global, multicenter phase 2b, open-label trial of intratumoral plasma encoded IL-12 (tavokinogene telseplasmid or "tavo") delivered by electroporation in combination with intravenous pembrolizumab in patients with stage III/IV melanoma who have progressed or are progressing on either pembrolizumab or nivolumab treatment. The Simon 2-stage study of intratumoral tavo plus electroporation in combination with pembrolizumab will enroll approximately 48 patients with histological diagnosis of melanoma with progressive locally advanced or metastatic disease defined as Stage III or Stage IV. The primary endpoint will be the Best Overall Response Rate (BORR).

About Metastatic Melanoma1
Melanoma is a type of skin cancer that begins in skin cells called melanocytes. As the cancer progresses, melanoma becomes more difficult to treat once it spreads beyond the skin, such as the lymphatic system (metastatic disease). Given its occurrence young individuals, the potential years of life lost to melanoma can be higher when compared with other cancers. Although melanoma is a rare form of skin cancer, it accounts for over 75% of skin cancer deaths. The American Cancer Society estimates that approximately 87,000 new melanoma cases and 10,000 deaths from the disease will occur in the United States in 2017. Additionally, the World Health Organization estimates that approximately 132,000 new cases of melanoma are diagnosed around the world every year.