On July 1, 2020 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported the first patient with triple negative breast cancer (TNBC) has been dosed in the ongoing phase 1 study assessing DS-1062, a TROP2 directed DXd antibody drug conjugate (ADC) (Press release, Daiichi Sankyo, JUL 1, 2020, View Source [SID1234561622]).

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Patients with TNBC, an aggressive subtype of breast cancer, have limited treatment options beyond standard chemotherapy.[1] High TROP2 expression has been reported in up to 80 percent of patients with TNBC.[2],[3]

"Following the promising preliminary results reported with DS-1062 in patients with non-small cell lung cancer, we have expanded the study to include patients with triple negative breast cancer," said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. "We continue to follow the science to determine whether DS-1062, designed with our proprietary DXd ADC technology, could serve as a new TROP2 directed therapy option for patients with TNBC and other cancers."

About the Phase 1 Study

The first-in-human, open-label, two-part, multi-center phase 1 study is designed to evaluate the safety, tolerability and preliminary efficacy of DS-1062 in patients with TROP2 unselected advanced solid tumors, which are refractory to or relapsed from standard treatment or for whom no standard treatment is available.

The first part of the study (dose escalation) assessed the safety and tolerability of increasing doses of DS-1062 to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) in patients with unresectable advanced NSCLC. The second part of the study (dose expansion) is further assessing the safety and tolerability of DS-1062 at selected dose levels for NSCLC. A cohort of patients with unresectable/advanced or metastatic TNBC has been added.

The study is currently enrolling approximately 180 patients in the U.S. and Japan with advanced unresectable NSCLC to receive DS-1062 at doses of 4, 6, and 8 mg/kg, and approximately 40 patients with advanced/unresectable or metastatic TNBC will receive DS-1062 at the 8 mg/kg dose. Patient enrollment in the dose expansion part of the study may be further expanded to include additional tumor types.

Safety endpoints include dose limiting toxicities and serious adverse events. Efficacy endpoints include objective response rate, duration of response, disease control rate, time to response, progression-free survival and overall survival. Pharmacokinetic, biomarker and immunogenicity endpoints also will be evaluated.

Updated data from this study in patients with heavily pre-treated advanced non-small cell lung cancer (NSCLC) were recently presented at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (#ASCO20).

About TROP2

TROP2 (trophoblast cell-surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers including up to 80 percent of patients with triple negative breast cancer.2,3 High TROP2 expression also has been identified in a majority of NSCLCs.[4] Research indicates that high TROP2 expression is associated with cancer cell growth and proliferation and poor patient survival.[5] TROP2 is recognized as a promising molecular target for therapeutic development in various cancers.5

About Triple Negative Breast Cancer

Approximately 10 to 20 percent of breast cancers are considered triple negative because the tumors test negative for estrogen and progesterone hormone receptors (HRs) and for human epidermal growth factor 2 receptor (HER2).[6] Patients with TNBC have limited treatment options beyond standard chemotherapy.6 An aggressive breast cancer subtype, TNBC is more likely to recur following initial chemotherapy compared to other breast cancers.[7] Overall, prognosis for patients with metastatic TNBC is worse than for the other breast cancer subtypes, and more effective therapeutic options are needed.6

About DS-1062

DS-1062 is one of three lead DXd antibody drug conjugates (ADCs) in the oncology pipeline of Daiichi Sankyo. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Designed using Daiichi Sankyo’s proprietary DXd ADC technology, DS-1062 is comprised of a humanized anti-TROP2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker with a customized drug-to-antibody ratio (DAR) of four to optimize the benefit-risk ratio for the intended patient population.

Preclinical studies have demonstrated that DS-1062 selectively binds to the TROP2 receptor on the surface of a tumor cell. It is proposed that DS-1062 is then internalized into the cancer cell where lysosomal enzymes break down the tetrapeptide-based linker and release the DXd payload.

DS-1062 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

On July 1, 2020 Xenetic Biosciences, Inc. (NASDAQ:XBIO) ("Xenetic" or the "Company"), a biopharmaceutical company focused on advancing XCART, a personalized CAR T platform technology engineered to target patient- and tumor-specific neoantigens, reported a development update for its XCART technology platform (Press release, Xenetic Biosciences, JUL 1, 2020, View Source [SID1234561619]).

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The Company entered into agreements with Scripps Research on May 19, 2020 and with PJSC Pharmsynthez on June 16, 2020 to advance the development of the XCART technology for B-cell malignancies. Both Scripps Research as well as Pharmsynthez and its collaborators have extensive experience with XCART, having co-invented the technology, and will have integral roles in the preclinical development activities.

"Our recently announced collaborations with Scripps Research, Pharmsynthez and multiple academic institutions in Russia and Belarus are critical components of our overall development plan for XCART. These agreements provide us access to partners that have the capability and capacity to expeditiously and cost-effectively advance XCART through preclinical development. We will also have access to patients and CART T clinical manufacturing suites which will potentially allow us to enter into a Phase 1 dosing study," commented Jeffrey Eisenberg, Chief Executive Officer of Xenetic.

The agreement with Scripps Research provides access to a team with extensive expertise in the CAR T space who will assist in the design and implementation of the preclinical development program for XCART. Xenetic will work with personnel in Dr. Richard Lerner’s lab, where the XCART technology was invented and where the preclinical proof of mechanism work was done. The agreement with Pharmsynthez provides access to the team that invented XCART in collaboration with Scripps Research, and also will involve institutions with extensive expertise in anti-idiotype approaches to lymphoma as well as CAR T development and manufacturing.

In collaboration with Pharmsynthez and multiple academic institutions in Russia and Belarus, the Company will conduct an exploratory trial to define and evaluate the XCART front-end process of target identification, screening and lead characterization in a real-world clinical setting. This exploratory stage entails enrollment of NHL patients, obtaining tumor biopsies and then refining the XCART front-end methods. Subsequently, the collaboration may be expanded to include development and qualification of manufacturing processes for producing autologous XCART T-cells. If successful, the Company has the potential to expand the clinical study component to dose a number of NHL patients in a Phase 1 dosing study. The data generated under the Belarus collaboration is expected to support an Investigational New Drug (IND) filing in the United States.

Curtis Lockshin, Ph.D., Chief Scientific Officer of Xenetic added, "As we move forward with these key partners, our team is focused on process development for autologous T cell manufacturing and generation of preclinical data covering the overall XCART workflow. These strategic collaborations provide us with highly cost-effective access to CAR T manufacturing and development suites, as well as clinical expertise and capabilities in the treatment of B-cell lymphomas. By augmenting preclinical data with insights gained from conduct of the XCART workflow in a human exploratory setting, we believe that we can strengthen the data sets with which we approach discussions with the United States Food and Drug Administration and, importantly, support our IND filing to advance our U.S. development strategy for XCART."

On July 1, 2020 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, reported that a peer-reviewed article published in Clinical Cancer Research (Clin Cancer Res June 30 2020 DOI:10.1158/1078-0432.CCR-19-4092) reported findings that Moleculin’s STAT3 inhibitor, WP1066, used in combination with traditional whole brain radiation therapy (WBRT) resulted in long-term survivors and enhanced median survival time relative to monotherapy in mice with implanted human brain tumors (Press release, Moleculin, JUL 1, 2020, View Source [SID1234561618]).

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The study was performed by lead author Martina Ott, Ph.D., Instructor of Neurosurgery, senior author Amy Heimberger, M.D., professor of Neurosurgery, and a team of researchers at The University of Texas MD Anderson Cancer Center. Heimberger also is the Principle Investigator of the current investigator-initiated clinical trial of WP1066 for brain tumors.

In the current study, C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and nanostring gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment.

The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control p<0.0001). Immunological memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune incompetent animals. Nanostring analysis and immunofluorescence revealed immunological reprograming in the brain tumor microenvironment specifically affecting dendritic-cell antigen presentation and T cell effector functions. The study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic-cell and T cell interactions in the brain tumor, which seems to be a requirement for a fully functional immune response
"This impressive study confirms preliminary data we announced last year," commented Walter Klemp, Chairman and CEO of Moleculin. "Importantly, the study indicated that the combination of STAT3 inhibition with whole brain radiotherapy had the capacity to enhance the therapeutic effect against established tumors as well as developing immune memory that appears to prevent recurrence."

The research was supported by the Cancer Prevention & Research Institute of Texas (IIRA-RP160482), the National Institutes of Health (CA1208113, P50 CA093459, P50 CA127001 and P30 CA016672), the Ben and Catherine Ivy Foundation, MD Anderson’s Glioblastoma Moon Shot, and the Brockman Foundation.

On July 1, 2020 Ipsen (Euronext: IPN; ADR: IPSEY), reported the primary analysis of the Phase I/II study evaluating the investigational use of irinotecan liposome injection (Onivyde) in combination with 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) together, known as NALIRIFOX in study patients with previously untreated, unresectable, locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC) during a late-breaking oral presentation at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer (WCGI), 1–5 July 2020 (Press release, Ipsen, JUL 1, 2020, View Source [SID1234561617]). The results include safety and efficacy analyses from the multicenter, open-label, study consisting of dose-exploration safety run-in (traditional 3+3 design) to confirm the maximum tolerated dose and appropriate dose regimen for NALIRIFOX in the dose-expansion phase.1

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No new safety signals were observed in the 32 patients evaluated from the recommended NALIRIFOX 50/60 mg/m2 dose (primary endpoint). Study patients achieved median progression-free survival of 9.2 months and median overall survival of 12.6 months (secondary endpoints).1

These data, in addition to promising anti-tumor activity highlighted by secondary endpoints, have led to the initiation of patient enrollment for the international Phase III NAPOLI-3 clinical study investigating the safety and efficacy of NALIRIFOX versus gemcitabine + nab-paclitaxel in the first-line setting.2 On 5 June 2020, Ipsen was granted Fast Track designation from the U.S. Food and Drug Administration (FDA) to facilitate the development and potentially expedite the review of NALIRIFOX in this indication. Programs with Fast Track designation may benefit from early and frequent interactions with the FDA over the course of drug development. In addition, the Fast Track designation program allows for the eligibility for accelerated approval and priority review if relevant study criteria are met and enables a company to submit individual sections of a New Drug Application (NDA) for review on a rolling-submission basis.

"Pancreatic cancer is aggressive, and we continue to investigate opportunities to improve outcomes for more patients that can extend survival. Unfortunately, current treatments, including immunotherapies that are transforming outcomes for patients with other solid tumors, have not demonstrated similar success in pancreatic cancer." said Zev Wainberg, M.D., lead investigator and associate professor of medicine, University of California Los Angeles. "The initial median progression-free and overall survival data from our Phase I/II trial are promising and we look forward to seeing how this investigational first-line treatment compares to gemcitabine + nab-paclitaxel in the Phase III trial now underway."

"A year following the read out of the preliminary Phase I/II study, we remain encouraged by the data, which demonstrated no new safety signals and continued to show anti-tumor activity," said Howard Mayer, M.D., Executive Vice President, Head of Research and Development at Ipsen. "Ipsen is committed to patients with pancreatic cancer. We are currently enrolling patients in our NAPOLI-3 Phase III clinical study across the U.S. and in other countries to gain a better understanding of the role of liposomal irinotecan as a potential first-line combination treatment for locally advanced and metastatic pancreatic cancer."

The Phase I/II, open-label trial (NCT02551991) was designed to assess the safety, tolerability and dose-limiting toxicities (DLTs) of NALIRIFOX for the first-line dosing of study participants with locally advanced and metastatic pancreatic cancer. Secondary objectives were to assess clinical efficacy, defined by median progression-free survival (PFS) and median overall survival (OS), best overall response rate, overall response rate (ORR), disease control rate at 16 weeks (DCR) and duration of response (DoR).1

The final analysis as of the data cut off on 26 February 2020 included all study participants from the pooled population (n=32: Part 1A-cohort B dose exploration phase n=7; Part 1B-dose expansion phase n=25) who received the maximum tolerated dose of liposomal irinotecan 50 mg/m2 [free-base], LV 400 mg/m2, 5-FU 2400 mg/m2, and OX 60 mg/m2). Patients were aged ≥ 18 years with an Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 1 and adequate organ function.1 The preliminary results from this study were presented at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer in July 2019.

Phase I/II Safety Results1:

No reported Grade 3 or higher fatigue or peripheral neuropathy.
Treatment emergent adverse events (TEAEs) Grade 3 or higher were reported by 22 of 32 study patients and included: neutropenia (31.3%), febrile neutropenia (12.5%), hypokalemia (12.5%), anemia (12.5%), diarrhea (9.4%), nausea (9.4%) and decreased neutrophil count (9.4%); vomiting occurred in 6.3% of patients.
8 patients reported TEAEs leading to discontinuation of oxaliplatin alone or all four study drugs (n=8/32), with 26 study patients requiring dose adjustment due to AEs.

Phase I/II Efficacy Results1:

Study patients saw a median PFS (95% CI) of 9.2 months (7.69, 11.96) and median OS of 12.6 months (8.74, 18.69).
BOR (Best Overall Response) included: one complete response (CR; study participant diagnosed with locally advanced Stage III disease) in 3% (1/32), 10 partial responses (PR) in 31.3% (10/32) and 15 stable diseases (SD) in 46.9% (15/32) (sum of CR+PR+SD = 81.3%).
Disease control achieved by 71.9% (23/32) of study patients at 16 weeks.

ABOUT ONIVYDE (irinotecan liposome injection)

Ipsen has exclusive commercialization rights for the current and potential future indications for Onivyde in the U.S. Servier is responsible for the commercialization of Onivyde outside of the U.S. and Taiwan under an exclusive licensing agreement with Ipsen. PharmaEngine has commercial rights to Onivyde in Taiwan.

INDICATION – UNITED STATES

Onivyde is approved by the U.S. FDA in combination with fluorouracil (5-FU) and leucovorin (LV) for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: Onivyde is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

Please see full U.S. Prescribing Information and Boxed WARNING for ONIVYDE.

About the Phase I/II Study

The Phase I/II, open-label, comparative trial is designed to assess the safety, tolerability and dose-limiting toxicities of investigational irinotecan liposomal injection (Onivyde) in combination with 5-fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) as a potential first-line treatment for metastatic pancreatic ductal adenocarcinoma cancer patients. The study has enrolled 56 patients at 15 sites across the United States, Spain and Australia. It is being conducted in two parts:

Part 1a: a safety run-in as initial dose exploration
Part 1b: dose expansion of the liposomal irinotecan + 5-FU/LV + oxaliplatin regimen
The study’s primary endpoint is safety and tolerability. Secondary assessments of clinical efficacy include overall response rate, disease control rate and best overall response. For more information visit clinicaltrials.gov and use identifier NCT02551991.3

About the NAPOLI-3 Phase III Study

The NAPOLI-3 clinical trial is an open-label, randomized, multicenter, Phase III study of irinotecan liposome injection (Onivyde) in combination with oxaliplatin (OX) and 5-fluorouracil/leucovorin (5-FU/LV) versus nab-paclitaxel plus gemcitabine in subjects who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas. The purpose of this study is to look at the efficacy and safety of investigational irinotecan liposome injection in combination with other FDA-approved drugs used for cancer therapy compared to nab-paclitaxel + gemcitabine treatment in improving the overall survival of patients not previously treated for metastatic pancreatic cancer. The study’s primary endpoint is Overall survival (OS), with secondary outcome measures defined as Progression free survival (PFS) and Overall Response Rate (ORR).

On July 1, 2020 Evelo Biosciences, Inc. (Nasdaq:EVLO), a clinical stage biotechnology company developing a new modality of orally delivered, systemically acting biologics, reported that clinical data from the Phase 1/2 open-label study of EDP1503, in combination with pembrolizumab, in patients with advanced metastatic microsatellite stable colorectal carcinoma (MSS CRC), triple-negative breast cancer (TNBC), and checkpoint inhibitor relapsed tumors, will be presented at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer Virtual Meeting being held July 1 – 4, 2020 (Press release, Evelo Biosciences, JUL 1, 2020, View Source [SID1234561615]).

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In addition to data in MSS CRC patients, the poster reported preliminary data on 11 TNBC patients (8 on high dose and 3 on low dose EDP1503). An overall response rate (ORR) of 25% (2/8) and a disease control rate of 37.5% (3/8) were observed across all TNBC subjects receiving high dose EDP1503. ORR was 33% (2/6) amongst response-evaluable patients on the high dose, with 2 patients awaiting first response assessment. Historic studies of anti-PD-1 monotherapy in heavily pretreated TNBC patients have yielded an ORR of 5-10%. The study continues enrollment in TNBC, and further data from this cohort will be available in 4Q 2020.

Details of the poster are as follows:

Title: EDP1503 induces antitumor responses via gut-mediated activation of both innate and adaptive immunity
Poster Session Date: July 1-4, 2020
Abstract ID: P-325
Category: Clinical Colon Cancer
Authors: Loise Francisco-Anderson, PhD; Shamira Shariffudin; Humphrey Gardner, MD; Michael Goldberg, PhD; Shubhra Kashyap, MS; Mary Abdou; Chris Davitt, PhD; Shannon Argueta, PhD; Pooja Parameswaran, MS; Peter Sandy, PhD; Holly Ponichtera, PhD; Mark Carlson; Maria Sizova, PhD; Valeria Kravitz; Erin Troy, PhD; Sam Andrewes, MS; Johanna C. Bendell, MD; Judy S. Wang, MD; Susanna V. Ulahannan, MD; Michael Chisamore, PhD; Mark Bodmer, PhD; and Duncan McHale, MD

The poster is available online on the ESMO (Free ESMO Whitepaper) conference website, as well as on the Evelo website, under the "publications" tab.