On September 23, 2019 City of Hope reported that it has opened and is treating the first patients in its CAR T cell trial for prostate cancer that has spread to other parts of the body (Press release, City of Hope, SEP 23, 2019, View Source [SID1234539717]). The trial uses a CAR T cell – also developed at City of Hope – that targets the prostate stem cell antigen (PSCA) in prostate cancer.

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The trial, which can enroll up to 33 patients, aims to find the appropriate dose of PSCA CAR T cells that a patient should receive and any side effects that the treatment may cause. Researchers will also study the expansion and persistence of the CAR T cells, survival outcomes and other findings.

Patients with PSCA-positive castration-resistant prostate cancer that has metastasized to other areas in the body, and who meet other requirements, are eligible for the trial, which includes the National Cancer Institute as a collaborator.

According to the American Cancer Society (ACS), other than skin cancer, prostate cancer is the most common cancer in American men. The ACS estimates that about 174,650 men will be diagnosed with new cases of prostate cancer and about 31,620 deaths will occur due to prostate cancer.

"Patients with advanced prostate cancer are in urgent need of a therapy that could provide a more durable remission," said Tanya Dorff, M.D., City of Hope associate clinical professor in the Department of Medical Oncology & Therapeutics Research, head of the Genitourinary Cancers Program and the trial’s principal investigator. "CAR T cell therapy has cured some cancers that are difficult to treat, and we want to know if we can do that for prostate cancer. Our hope is that this CAR T cell therapy can be a game changer for these patients."

CAR T cell therapy involves taking a patient’s immune cells, known as T cells, from the bloodstream. They are then reprogrammed in a laboratory to recognize and attack a specific cancer-causing protein, such as PSCA, and reintroduced into the patient’s bloodstream, where they get to work destroying targeted tumor cells.

City of Hope will manufacture the CAR T cells using in its own facility, the Cellular Therapy Production Center. This process includes a critical step: The patient’s T cells are reprogrammed with viruses engineered in another of City of Hope’s GMP facilities, the Center for Biomedicine & Genetics. These two facilities, coupled with its Chemical GMP Synthesis Facility, make City of Hope one of the few cancer centers in the world with the ability to produce GMP cellular, genetic and drug-based therapies for its patients.

City of Hope developed the CAR design in its own laboratory with a goal of finding the most effective and long-lasting CAR T cell to target PSCA.

"Developing a CAR T cell therapy for solid tumors is particularly challenging because they need to first reach the solid tumor and then survive in a harsh microenvironment that is filled with cancer cells and other cells that make up the tumor mass," said Saul Priceman, Ph.D., assistant professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation. "This CAR design has allowed for optimal cytokine production, which are chemical messengers that help enhance the anti-tumor activity of a CAR T cell, and destruction of prostate stem cell antigen (PSCA)-positive prostate cancers by the CAR T cells."

The trial is one of the first CAR T trials for prostate cancer in the nation. Since the late 1990s, City of Hope has been a leader in advancing CAR T cell therapies across a range of blood cancers and, in recent years, it has also opened trials for solid tumors, including brain cancer (glioblastoma) for adults and children, HER2-positive breast cancer that has metastasized to the brain and this prostate cancer trial.

City of Hope patents covering the PSCA CAR have been licensed to Mustang Bio.

City of Hope received a Challenge Award in 2013 from the Prostate Cancer Foundation (PCF) to support the CAR T cell therapy’s preclinical development, and in 2016 from PCF, which was matched by City of Hope, to fund the clinical trial. Research is also supported by a generous gift from Barbara and Zach Horowitz and Gary Marsh and Jody Horowitz Marsh.

The trial is part of City of Hope’s T Cell Therapeutics Research Laboratory, which currently has 20 open CAR T and T cell clinical trials.

On September 23, 2019 Biodesix, Inc. reported updates on continued expansion of pipeline and companion diagnostic developments. Chief Development Officer Dr. Gary Pestano, Ph.D., highlighted the company’s capabilities in the development and commercialization of companion diagnostics aimed at directing the treatment of non-small cell lung cancer (NSCLC) at the 2019 Clinical Biomarkers & World CDx Conference (Press release, Biodesix, SEP 23, 2019, View Source [SID1234539715]). Director of Scientific & Medical Affairs, Dr. Yishan Chuang, Ph.D., presented real-world data on the importance of monitoring KRAS mutations in blood at the RAS-Targeted Drug Discovery meeting.

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Companion Diagnostic Developments

Dr. Pestano cited two case studies of recent projects in CDx development. The first outlined Biodesix’s worldwide agreement to develop and commercialize the hepatocyte growth factor inhibitor antibody ficlatuzumab with Aveo Oncology (AVEO), using Biodesix’s proprietary VeriStrat test as a CDx to identify NSCLC patients most likely to benefit from treatment with ficlatuzumab.

Biodesix’s recent agreement with Thermo Fisher was also presented, highlighting the ability to access a global footprint of instruments with rapid turn-around time and low-input material requirements for a liquid biopsy NGS test. The 52-gene panel is currently under dual track single-site PMA review by the FDA and CMS, with a goal of gaining approval with reimbursement in 2020. The approval will be initially focused on EGFR and NSCLC, with the ability to extend into other targets and indications as new partnerships develop.

"Our ongoing efforts in the discovery, development, and commercialization of companion diagnostic tests alongside our partners in biopharma further demonstrates Biodesix’s commitment to advancing precision medicine," said Pestano. "Companion diagnostics, in addition to Biodesix’s portfolio of proprietary blood-based tests both currently available and in development, are designed to answer critical unmet needs across the continuum of care in oncology, NSCLC, and lung disease."

Monitoring KRAS Mutations in Blood

Dr. Chuang shared data from INSIGHT, an observational study assessing real-world clinical utility of VeriStrat and GeneStrat testing in 3,000 NSCLC patients across 33 sites in the U.S. Results from the INSIGHT study demonstrate poor response to treatment with platinum doublet-based chemotherapy in patients when KRAS mutations are detected in the blood (OS 3.4 months v. 14.0 months, p<0.001). It was noted that the particularly poor prognosis observed in these groups may be linked to tumors that shed DNA into the blood having a more aggressive disease state to those that don’t, highlighting the value of blood-based testing in addition to standard tissue testing. Additionally, longitudinal monitoring of KRAS mutation clearance in the blood may be an important indicator for treatment response. Dr. Chuang also noted that by combing information from both the circulating proteome with the VeriStrat test and circulating genome with GeneStrat testing provides additional value in predicting NSCLC patient prognosis.

"With the exciting development of KRAS targeted therapy in clinical studies, there is an increasing need for swift mutation testing with liquid biopsy," said Dr. Chuang. "From Biodesix’s INSIGHT study, we also see that patient prognosis could be further elucidated when we consider both KRAS mutation information in combination with the circulating proteome in blood."

On September 23, 2019 Tarveda Therapeutics, Inc., a clinical stage biopharmaceutical company discovering and developing a new class of potent and selective precision oncology medicines for the treatment of patients with a wide range of solid tumor malignancies, reported that the company will present results from the Phase 1 portion of a Phase 1/2a study of PEN-866 in patients with advanced solid malignancies at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019, occurring September 27 – October 1, in Barcelona, Spain (Press release, Tarveda Therapeutics, SEP 23, 2019, View Source [SID1234539714]). In addition, Mark Bilodeau, Chief Scientific Officer of Tarveda, will present on payload masking in activated Heat Shock Protein 90 (HSP90) binding miniature drug conjugates at the 10th Annual World ADC, occurring October 8 – 11, in San Diego, California.

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At ESMO (Free ESMO Whitepaper), Johanna Bendell will present results from an ongoing Phase 1 study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of PEN-866 in patients with progressive, advanced solid malignancies. At the time of this reporting, a number of patients remain on the study, therefore this does not represent the final data set. PEN-866 is a miniature drug conjugate that selectively binds to the activated intracellular target HSP90 and is linked to a topoisomerase 1 inhibitor (SN-38), a potent anti-cancer payload. PEN-866 is designed to accumulate and be retained in tumors and, by way of a sustained release of SN-38, cause prolonged DNA damage and tumor regressions.

Details of the presentations are as follows:

ESMO Congress 2019
Title: First in human phase 1/2a study of PEN-866, a Heat Shock Protein 90 (HSP90) – SN38 conjugate for patients with advanced Solid Malignancies: Phase 1 results.
Date: September 28, 2019
Time: 12:00 PM CEST
Location: Poster Area (Hall 4), Fira Gran Via, Barcelona, Spain

10th Annual World ADC
Title: Payload Masking in HSP90 Targeting Miniature Drug Conjugates to Expand the Therapeutic Window
Date: October 11, 2019
Time: 12:30 PM PT
Location: Manchester Grand Hyatt, San Diego, CA

On September 23, 2019 AVEO Oncology (NASDAQ: AVEO) and EUSA Pharma reported the upcoming presentation of final results from the Phase 2 portion of the TiNivo study, a Phase 1b/2 multicenter trial of oral (PO) tivozanib (FOTIVDA), AVEO’s once-daily, potent and selective vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI), in combination with intravenous (IV) nivolumab (OPDIVO, Bristol-Myers Squibb), an immune checkpoint, or PD-1, inhibitor, for the treatment of advanced or metastatic renal cell carcinoma (RCC) (Press release, AVEO, SEP 23, 2019, View Source [SID1234539713]). The results will be presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Annual Congress, in a poster presentation titled "TiNivo: Tivozanib combined with nivolumab results in prolonged progression free survival in patients with metastatic renal cell carcinoma (mRCC). Final Results." (Presentation 947P).

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The Phase 1b/2 study enrolled a total of 28 patients. The Phase 2 portion of the study (n=22) was designed to assess the safety, tolerability, and anti-tumor activity of the full dose and schedule of PO tivozanib (1.5 mg/QD for 21 days followed by a 7-day rest period), as established in the Phase 1b portion of the study (n=6), in combination with IV nivolumab (240 mg every 2 weeks). The combination was generally well tolerated and showed additive or synergistic activity for objective response rate and progression free survival (PFS) in both treatment naïve and previously treated patients with mRCC. Overall median PFS for the 25 patients treated at the study’s full dose and schedule was 18.9 months (95% CI: 16.4; NR). Median PFS for previously untreated patients (n=12) was 18.5 months, while median PFS for previously treated patients (n=13) has not yet been reached as of the August 27, 2019 data cutoff date. An objective response rate was observed in 56% of patients (complete responses + partial responses), including one treatment naïve patient (1/12) achieving a complete response, and disease control (complete response + partial response + stable disease) was observed in 96% of patients. The most common treatment-related Grade 3/4 adverse event was hypertension.

An abstract of these data is currently available via the ESMO (Free ESMO Whitepaper) 2019 Annual Congress website. A copy of the poster will be available following the presentation at www.aveooncology.com, or further information can be obtained via EUSA Pharma Medical Information.

"Tivozanib has shown a favorable adverse event profile, thanks to its unique selectivity, that we believe has the potential to make it the ideal candidate for combination with an immunotherapy, like nivolumab, in metastatic RCC," said Doctor Bernard Escudier, MD, ex-Chairman of the Genitourinary Oncology Committee, Gustave Roussy, and lead investigator of the study. "With considerable follow up now complete in the TiNivo study, the long median PFS suggests a favorable durability of response, particularly in the second line. I look forward to seeing this potential explored in a larger outcome study in the near future."

"We are pleased with the level of antitumor activity we are seeing with this combination both in treatment naive and previously treated patients," said Michael Bailey, president and chief executive officer of AVEO. "We believe these data highlight the potentially unique benefits of a tivozanib-immunotherapy combination in a refractory patient population, a setting in which conclusive immunotherapy-TKI combination studies have yet to be conducted. We look forward to working with our partners at EUSA to determine potential next steps for the tivozanib-immunotherapy combination."

"The data arising from combination studies with checkpoint inhibitors demonstrates the considerable potential for tivozanib in metastatic RCC," said Lee Morley, chief executive officer of EUSA Pharma. "EUSA continue to seek reimbursement and launch tivozanib across the EU in line with its EMA approval as monotherapy in the first line setting where its efficacy and favorable tolerability profile continues to provide benefits to patients, and are excited by the prospect of further development of tivozanib as part of a future IO-TKI treatment option."

Presentation Details

Title: TiNivo: Tivozanib combined with nivolumab results in prolonged progression free survival in patients with metastatic renal cell carcinoma (mRCC). Final Results.
Presenter: Philippe Barthelemy, Medical Oncology Department, Hôpitaux Universitaires de Strasbourg, Strasbourg, FR
Presentation Number: 947P
Date and Time: September 30, 2019, 12:20 p.m. CEST
Location: Poster Area (Hall 4)

About Tivozanib

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) in the European Union plus Norway, New Zealand and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications.1,2 Tivozanib has been shown to significantly reduce regulatory T-cell production in preclinical models3 and has demonstrated synergy in combination with nivolumab (anti PD-1) in a Phase 2 study in RCC4. Tivozanib has been investigated in several tumor types, including renal cell, hepatocellular, colorectal, ovarian and breast cancers.

On September 23, 2019 Vedanta Biosciences, a clinical-stage company developing a new category of therapies for immune-mediated diseases based on rationally-defined consortia of human microbiome-derived bacteria, reported a $16.6 million Series C-2 financing round, bringing the total capital raised in its Series C and C-2 round to $62.1 million (Press release, Vedanta Biosciences, SEP 23, 2019, View Source [SID1234539712]). Participants include QUAD Investment Management, SV Investment Corp., Shinhan Investment-Private Equity, Shinhan Capital-Yeollim Partners, Partners Investment Co., Ltd, FC Capital, and SymBiosis LLC, who join the previously announced Series C investors, including the Bill & Melinda Gates Foundation, Bristol-Myers Squibb, Rock Springs Capital, JSR Corporation, Shumway Capital, Invesco Asset Management, Health for Life (Seventure Partners), and founder PureTech Health. The funding further supports the expansion of Vedanta’s broad clinical pipeline, including the recently launched Phase 1b/2 study of VE416 in food allergy, a planned Phase 1b/2 study of VE800 and OPDIVO (nivolumab) in advanced or metastatic cancers, and the ongoing Phase 2 study of VE303 in recurrent Clostridioides difficile infection (rCDI).

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"We welcome the support from both existing and new investors for Vedanta’s expanding activities and maturing portfolio of product candidates based on rationally-defined consortia," said Bernat Olle, Ph.D., co-founder and chief executive officer of Vedanta Biosciences.

Vedanta Biosciences is developing drug candidates based on consortia of natural non-pathogenic bacterial strains designed to effect robust and durable therapeutic changes in a person’s gut microbiota. In contrast to fecal transplants or administration of fecal fractions, Vedanta Biosciences’ consortia are defined compositions of bacteria manufactured from pure, clonal cell banks, bypassing the need to rely on direct sourcing of fecal donor material of inconsistent composition.