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Onvasertib Demonstrates Effectiveness as Pan-KRAS Inhibitor with Confirmed Tumor Regression and Clinical Benefit Achieved in KRAS-Mutated mCRC Patients

On January 27, 2020 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, oncology therapeutics company targeting cancers that are both highly prevalent and in need of new effective treatment options including colorectal, prostate and acute myeloid leukemia, reported positive data from an ongoing Phase 1b/2 clinical trial of onvansertib plus FOLFIRI and Avastin (bevacizumab) for second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC) (Press release, Trovagene, JAN 27, 2020, View Source [SID1234553577]).
The data demonstrate the pan-KRAS inhibitory effect of onvansertib. All five patients evaluable for efficacy assessment have shown a significant reduction in their KRAS mutational burden as measured by a simple blood test, which was subsequently confirmed by tumor regression visible on radiographic scans. Three patients had a >25% tumor shrinkage and one patient is now eligible for curative surgery, a clinically meaningful achievement, which is considered to be unprecedented in this patient population with only a 5% response to standard-of-care. The data was featured in a poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO-GI) in San Francisco on Saturday, January 25th, 2020.
Onvansertib is an oral and highly-selective Polo-like Kinase 1 (PLK1) inhibitor and may provide an answer to effectively "drugging" the once thought-to-be "undruggable" KRAS mutation. PLK1 has been identified as having synthetic lethality, which means that KRAS-mutated tumors have a higher sensitivity to PLK1 inhibition compared with KRAS wild-type cells.

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"Early results from the onvansertib Phase 1b/2 trial are very exciting and encouraging," said Dr. Daniel Ahn, the principal investigator at the Mayo Clinic Cancer Center. "Regardless of the specific KRAS mutation, we are seeing decreases in the mutational burden and tumor regression in all of our patients. This is indicative of onvansertib’s effect as a pan-KRAS inhibitor."
"Successfully treating patients in the second-line setting has been quite challenging to-date, with a relatively low response rate and poor prognosis," said another of the trial’s investigators, Dr. Tanios Bekaii-Saab, leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center. "The combination of onvansertib plus standard-of-care FOLFIRI/bevacizumab offers promise as being both safe and effective."

Trovagene Inc. | 11055 Flintkote Avenue | San Diego | CA 92121 | Tel.: USA [+1] 888-391-7992

KRAS, which controls cell proliferation, has long been recognized as a major oncogene, responsible for many cancer types. Approximately 50% of mCRC patients have the KRAS mutation. The efficacy of current second-line therapy in terms of survival prolongation and response remains very limited, especially in this population, where there is only a 5% response rate. The other KRAS contenders including Amgen and Mirati, have produced some potentially promising early clinical results in non-small cell lung cancer (NSCLC); however, their drug candidates have shown limited activity in CRC as they only address one specific KRAS mutation, G12C, which accounts for only 8% of CRC, leaving room for drug developer, Trovagene, and its drug candidate onvansertib.

Onvansertib KRAS-Mutated mCRC Trial Data Highlights:

In the Phase 1b dose escalation, the 1st dose level (onvansertib 12 mg/m2) was cleared for safety; the 2nd dose level (onvansertib 15 mg/m2) is fully enrolled with no DLTs reported in the two patients treated to-date

Radiographic scans performed at 8 weeks showed tumor decrease and clinical benefit in 100% (n=5) of evaluable patients treated with onvansertib 12 mg/m2 (n=5); 1 patient achieved PR, 4 patients achieved SD

Radiographic responses were confirmed at 16 weeks with further tumor shrinkage in all patients; 3 patients had a >25% decrease; 1 patient is proceeding to curative surgery

Five different KRAS mutant variants were detected in 6 patients, which represents >90% of KRAS mutations in CRC; all five KRAS variants decreased within the 1st cycle of treatment (onvansertib dose levels 12 and 15 mg/m2)

At dose level 1 (onvansertib 12 mg/m2), 4 patients had detectable KRAS mutant ctDNA at baseline; in all 4 patients KRAS was undetectable within the 1st cycle of treatment; this preceded subsequent tumor shrinkage observed with radiographic scans, supporting the predictive value of liquid biopsy

At dose level 2 (onvansertib 15 mg/m2), the 2 patients treated to-date had detectable KRAS mutant ctDNA at baseline; in 1 patient KRAS was undetectable within the 1st cycle of treatment; radiographic scans will be performed at 8 weeks
About the Phase 1b/2 Clinical Trial of Onvansertib in KRAS-Mutated mCRC
The ongoing trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second‑Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation (NCT03829410) is evaluating the safety and efficacy of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). Up to 44 patients, with a confirmed KRAS mutation, metastatic and unresectable disease, who have failed or are intolerant of treatment with FOLFOX (fluoropyrimidine and oxaliplatin) with or without Avastin (bevacizumab), will be enrolled. The trial is being conducted at two prestigious cancer centers: USC Norris Comprehensive Cancer Center and the Mayo Clinic Cancer Center.
About Onvansertib
Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a

24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along
with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.
Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.
Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410; and a Phase 2 clinical trial of onvansertib in combination with decitabine in patients with relapsed or refractory AML (NCT03303339).
Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.

Surface Oncology Announces FDA Clearance of SRF617 and SRF388 INDs to Initiate Phase 1 Clinical Trials

On January 27, 2020 Surface Oncology (NASDAQ:SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, reported the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) applications for its antibody candidates, SRF617 (targeting CD39) and SRF388 (targeting IL-27), and the Company is executing on plans to initiate clinical trials to advance both programs (Press release, Surface Oncology, JAN 27, 2020, View Source [SID1234553576]).

"Since Surface’s founding approximately five years ago, we have brought four novel, internally developed programs to the IND stage," said Jeff Goater, chief executive officer. "The entire team is very proud of this impressive accomplishment. As we strive to have a positive impact on the treatment of people who are diagnosed with cancer, we have decided it is in the best interest of our overall mission to focus our resources on the SRF617 and SRF388 programs. Restructuring was a difficult decision because of the effect it has on our dedicated and talented people. I am extremely grateful for the efforts of our employees and their tremendous contributions to Surface’s rapid progress and strong culture. We are committed to supporting all of our employees during this transition."

The active INDs for both SRF617 and SRF388 enable Surface Oncology to initiate phase 1 clinical trials for each product candidate. The Company anticipates providing initial clinical updates for both SRF617 and SRF388 by the end of 2020.

SRF617 is a fully human anti-CD39 antibody designed to promote anti-tumor immunity through a dual mechanism of reducing immunosuppressive adenosine and driving the extracellular accumulation of immunostimulatory ATP within the tumor microenvironment. Due to this dual mechanism, Surface Oncology believes CD39 is the most promising therapeutic target on the adenosine axis, a notable immunosuppressive pathway. The Company’s phase 1/1b trial will evaluate SRF617 in patients with advanced solid tumors both as a monotherapy and in combination with other cancer therapies.

SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this highly immunosuppressive cytokine. Surface Oncology has identified particular tumor types, including hepatocellular and renal cell carcinoma, where IL-27 appears to play an important role in the immunosuppressive tumor microenvironment and may contribute to resistance to treatment with checkpoint inhibitors. Furthermore, the Company has identified a potential biomarker associated with IL-27 that may be useful in helping identify patients most likely to respond to SRF388.
The Company also remains encouraged by the promise and progress of its wholly-owned, earlier-stage programs, SRF813 (targeting CD112R) and a regulatory T cell program, and will seek to partner these programs.

The strategic restructuring will reduce the Company’s workforce by approximately 35%. With these steps to focus resources, Surface Oncology’s current cash and cash equivalents are now projected to fund the Company into 2022. Anticipated milestones under the NZV930 (targeting CD73) collaboration with Novartis and additional capital potentially available under the K2 HealthVentures debt financing, in aggregate, would extend Surface Oncology’s cash runway into the second half of 2022.

Data from OncoSec’s Visceral Lesion Applicator (VLA) to be Presented at the Society of Interventional Oncology Annual Meeting

On January 27, 2020 OncoSec Medical Incorporated ("OncoSec") (Nasdaq: ONCS), a company developing late-stage intratumoral cancer immunotherapies, reported data from initial feasibility studies of its novel visceral lesion applicator (VLA) have been accepted to be presented at the Annual Meeting of the Society of Interventional Oncology in New Orleans from January 30 – February 3, 2020 (Press release, OncoSec Medical, JAN 27, 2020, View Source [SID1234553575]).

The Company’s visceral lesion applicator (VLA) technology is designed to treat non-cutaneous, internal tumors through the direct delivery of OncoSec’s lead product candidate, TAVO (plasmid-based interleukin-12), or other immunologically relevant genes. Visceral lesions are typically difficult to treat, and include gastrointestinal tumors, pancreatic tumors, and hepatocellular carcinomas.

The study, titled, "Novel Controlled Delivery of Potent Anti-Cancer Immunotherapy Directly to Deep Visceral Lesions," will be featured in a poster displayed throughout the Society of Interventional Oncology’s annual meeting from January 30 – February 3, 2020 at the New Orleans Marriott.

About the Society of Interventional Oncology
The SIO Annual Scientific Meeting offers sessions on medical technology and how to implement new technology in oncologic practice. The conference provides a multi-disciplinary approach to cancer care. The annual meeting brings together international health care providers for international sharing of ideas. The conference leverages a combination of state-of-the-art lectures, panel discussions, invited papers, and selected abstracts of basic, translational, and clinical research to promote meaningful dialogue.

Oncolytics Biotech® Announces Statistically Significant Data Identifying CEACAM6
as a Prospective Prognostic Biomarker for Pelareorep in the Treatment of Pancreatic Adenocarcinoma

On January 27, 2020 Oncolytics Biotech Inc. (NASDAQ: ONCY) (TSX: ONC), currently developing pelareorep, an intravenously delivered immuno-oncolytic virus, reported that a poster presentation highlighting statistically significant data identifying CEACAM6 as a prospective biomarker for pelareorep in the treatment of pancreatic cancer (Press release, Oncolytics Biotech, JAN 27, 2020, View Source [SID1234553574]). The presentation was delivered at the 2020 Gastrointestinal Cancers Symposium sponsored by ASCO (Free ASCO Whitepaper) in San Francisco.

"We have identified another biomarker candidate for pelareorep," said Dr. Rita Laeufle, Chief Medical Officer of Oncolytics Biotech. "These results correlate CEACAM6 levels with long term benefit in patients with pancreatic cancer. We are working with industry and academic colleagues to verify this important finding not only in pancreatic cancer but potentially in other GI indications where this biomarker is linked to clinical outcomes"

The poster, CEACAM6 is a candidate biomarker for Reolysin (pelareorep) sensitivity in pancreatic adenocarcinoma (PDAC), highlights data from the randomized study NCI 8601: Carboplatin and Paclitaxel With or Without Viral Therapy in Treating Patients With Recurrent or Metastatic Pancreatic Cancer. Data in the presentation associate low levels of the gene CEACAM6 with prolonged progression free survival (PFS) in pelareorep-treated patients with pancreatic cancer. PFS increased over 80%, from 5.72 months to 10.32 months (p=0.05).

"I am very encouraged to see additional data come from this important study by the Ohio State University Comprehensive Cancer Center," said Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech. "This statistically significant result highlights the potential for CEACAM6 to become an additional prognostic biomarker for pelareorep and could provide considerable clinical value as we investigate its potential in pancreatic and other GI cancers."

CEACAM6 is differentially expressed in pancreatic adenocarcinoma cells. High levels of CEACAM6 are known to block viral trafficking in virally infected cells, thereby decreasing viral replication. Study investigators speculated that altered CEACAM6 levels may be predictive for pelareorep sensitivity and may serve as a biomarker.

Key data and conclusions:

CEACAM6 was the most differentially expressed gene, with an eight-fold decrease in levels of mRNA, in long-term responders compared to early progressors in patients receiving pelareorep.

Low levels of CEACAM6 mRNA expression were associated with prolonged PFS in pelareorep-treated patients (p=0.05). This treatment effect was not seen in patients that were not treated with pelareorep (p=0.35).

In pelareorep treated patients, CEACAM6 mRNA expression level was very influential with a hazard ratio of 1.54 (p=0.01), suggesting that one unit increase in CEACAM6, corresponds to an increase in the risk of progression and/or death by 54% in this arm. There was no significant relationship seen in patients that were not treated with pelareorep

CEACAM6 may be included as a candidate biomarker of resistance to pelareorep and, in theory, could inhibit viral trafficking in tumor cells

The poster presentation was co-authored by Dr. Anne Noonan, Department of Medical Oncology, Ohio State University Wexner Medical Center, Richard Solove Research Institute and James Cancer Hospital, and Dr. Tanios Bekaii-Saab Senior Associate Consultant, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona. It can be found on the Posters & Publications page of the company’s website: View Source

About Pelareorep
Pelareorep is a non-pathogenic, proprietary isolate of the unmodified reovirus: a first-in-class intravenously delivered immuno-oncolytic virus for the treatment of solid tumors and hematological malignancies. The compound induces selective tumor lysis and promotes an inflamed tumor phenotype through innate and adaptive immune responses to treat a variety of cancers and has been demonstrated to be able to escape neutralizing antibodies found in patients.

NuCana Announces First Patients Dosed in Both US and Europe in Phase III Study of Acelarin (NUC-1031) for the First-Line Treatment of Patients with Biliary Tract Cancer

On January 27, 2020 NuCana plc (NASDAQ: NCNA) reported that the first patients have been dosed in its Phase III study of Acelarin (NUC-1031) plus cisplatin for the first-line treatment of patients with biliary tract cancer and that the study design is being presented at the ASCO (Free ASCO Whitepaper)-GI Conference in San Francisco (Press release, Nucana BioPharmaceuticals, JAN 27, 2020, View Source [SID1234553573]). The enrollment of patients in NuTide:121 follows U.S. Food and Drug Administration (FDA) clearance of the company’s investigational new drug application (IND) for Acelarin.

"We are pleased to have commenced dosing the first patients in our Phase III NuTide:121 study," said Hugh Griffith, NuCana’s Chief Executive Officer. "Acelarin in combination with cisplatin has been shown in early clinical studies to achieve higher response rates compared to the current standard of care in patients with advanced biliary tract cancer, a devastating disease for which there is a significant need for more effective medicines."

NuTide:121 is a global, multi-center, randomized Phase III study that is enrolling up to 828 patients in approximately 120 sites across North America, Europe, Asia and Australia. Patients are being randomized 1:1 and treated with either a combination of Acelarin (725 mg/m2) plus cisplatin (25 mg/m2) or the current standard of care regimen, gemcitabine (1,000 mg/m2) plus cisplatin (25 mg/m2).

NuCana also announced the presentation of a poster "NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121)" at the ASCO (Free ASCO Whitepaper)-GI Conference being held in San Francisco, CA. The poster details the study design of NuTide:121 and reviews the encouraging results previously reported in the Phase Ib ABC-08 Study. The poster may be found here.

The primary objectives of NuTide:121 are Overall Survival (OS) and Objective Response Rate (ORR). Three interim analyses, including two designed to support accelerated approval, are planned as part of the Phase III study protocol, in addition to the final analysis. Based on discussions with the FDA and subject to any further regulatory guidance, the Company believes that a statistically significant improvement in ORR at either of the first two interim analyses, supported by positive trends in other endpoints, could potentially allow for an accelerated approval of a new drug application (NDA) for Acelarin. Accelerated approval requires a confirmatory clinical study to verify the drug’s clinical benefit. If accelerated approval were to occur, NuTide:121 would continue and the Company anticipates that data from subsequent analyses could provide the confirmatory data to support full (regular) approval.

More information about this study may be found here.

About Biliary Tract Cancer

Biliary tract cancer, including cholangiocarcinoma, gallbladder and ampullary carcinoma, is cancer originating in the bile duct, a vessel that transports bile from the liver to the gallbladder and small intestine. Approximately 178,000 new cases of biliary tract cancer are diagnosed each year worldwide, with more than 18,000 of those diagnoses in the United States. There are currently no agents approved for the treatment of biliary tract cancer; however, the worldwide standard of care in biliary tract cancer patients with locally advanced or metastatic disease is the combination of gemcitabine and cisplatin. Patients receiving this regimen have a median overall survival of 11.7 months.