On April 12, 2021 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company developing onvansertib to treat cancers with the greatest medical need for new treatment options, including KRAS-mutated colorectal cancer, pancreatic cancer and castrate-resistant prostate cancer, reported data from its ongoing Phase 1b/2 trial that demonstrate the continued robust patient response to treatment with onvansertib and progression-free survival when combined with standard-of-care therapy in second line KRAS-mutated metastatic colorectal cancer (mCRC) (Press release, Cardiff Oncology, APR 12, 2021, https://www.prnewswire.com/news-releases/cardiff-oncology-announces-onvansertib-phase-1b2-data-that-continues-to-demonstrate-robust-response-to-treatment-and-progression-free-survival-in-kras-mutated-mcrc-301266257.html [SID1234577917]).

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Patients enrolled in the ongoing Phase 1b/2 trial receive onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). The overall response rate (ORR) in the trial is 39% to-date, and onvansertib in combination with FOLFIRI/bevacizumab has been well tolerated with no major or unexpected toxicities attributed to onvansertib. The median progression free survival (mPFS) of evaluable patients is 9.4 months. This represents an increase over the mPFS observed in a systematic literature-based analysis of second line mCRC clinical trial data from 23 randomized trials including a total of ~10,800 patients (mPFS of 4.5 months)1 and the 5.7-month mPFS observed in the pivotal trial that supported the regulatory approval of FOLFIRI plus bevacizumab in second line mCRC2.

"As we have continued to collect data from this ongoing trial, we have consistently seen an impressive and durable response to treatment, and a favorable safety and tolerability profile," said Daniel H. Ahn, D.O., lead investigator and medical oncologist, Mayo Clinic Cancer Center, Arizona. "Notably, the ORR and mPFS observed in the trial compare very favorably to what has been seen historically in second line mCRC patients. These promising results highlight the potential of onvansertib to address the unmet needs in mCRC, and I look forward to discussing them in detail during Cardiff Oncology’s upcoming key opinion leader webinar."

Mark Erlander, Ph.D., chief executive officer of Cardiff Oncology added, "We are very pleased with the results to-date from our Phase 1b/2 mCRC trial. In addition to continuing to show a consistent and robust response rate, we have also reported intriguing biomarker analyses highlighting the potential of plasma KRAS mutant allelic frequency as a tool to predict patient response to onvansertib. We look forward to providing results from the Phase 2 trial later this year."

Highlights from the updated data announcement include:

Efficacy:

7 of 18 (39%) evaluable patients achieved a partial response (PR); 4 patients had a confirmed PR with 1 patient going on to curative surgery; 1 patient with a non-confirmed PR went off study following PR prior to confirmatory scan due to a treatment-unrelated adverse event; 2 patients with non-confirmed PRs await results from confirmatory scans
Evaluable patients have a mPFS of 9.4 months (95% confidence interval: 7.85 months – not reached)
7 patients remain on treatment to-date
Biomarker:

Clinical responses were observed across different KRAS mutations, including the 3 most common in colorectal cancer (G12D, G12V, G13D)
The greatest decreases in plasma KRAS mutant allelic frequency (MAF) after 1 cycle of treatment were observed in patients achieving a PR
All 7 patients with a PR had a >75% decrease in KRAS MAF after one cycle of treatment
Safety/Tolerability

Onvansertib in combination with FOLFIRI/bevacizumab has been well tolerated with no major or unexpected toxicities attributed to onvansertib
Key Opinion Leader Webinar

The updated Phase 1b/2 mCRC trial data will be presented during a key opinion leader (KOL) webinar taking place today, April 12, 2021 at 11:00 a.m. ET. The webinar will feature KOLs Dr. Ahn (Mayo Clinic Arizona), and Dr. Sharma (START Midwest), who will also discuss the current treatment landscape and unmet medical need in KRAS-mutated mCRC and observations from the EAP evaluating onvansertib in combination with FOLFIRI/Avastin in KRAS-mutated mCRC.

During the webinar, Dr. Erlander will also present a corporate update and outlook for the year. Dr. Erlander and Drs. Sharma and Ahn will be available to answer questions following the conclusion of the formal presentations.

To register for the webinar, please click here.

References

Giessen et al, Acta Oncologica, 2015; 54:187-193
Bennouna et al., Lancet Oncol. 2013; 14(1):29-37
About the Phase 1b/2 Trial of Onvansertib in KRAS-mutated mCRC

This is a multi-center, open-label Phase 1b/2 trial of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab) to evaluate the safety and preliminary efficacy of the combination regimen in the second-line treatment of patients with KRAS-mutated mCRC. The 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, will enroll up to 44 patients with a KRAS mutation and histologically confirmed metastatic and unresectable disease. In addition, eligible patients must have failed treatment with, or be intolerant to, FOLFOX (fluoropyrimidine and oxaliplatin) with or without bevacizumab. The trial is being conducted at six cancer centers across the U.S.: USC Norris Comprehensive Cancer Center, The Mayo Clinic (Arizona, Rochester and Jacksonville), Kansas University Medical Center (KUMC), CARTI Cancer Center and Inova Schar Cancer Institute. For more information on the trial, please visit View Source

On April 12, 2021 Orion reported that it will publish Interim Report for January–March 2021 on Tuesday, 27 April 2021 approximately at 12.00 noon EEST (Press release, Orion , APR 12, 2021, View Source [SID1234577916]). The release and related presentation material will be available on the company’s website at www.orion.fi/en/investors after publishing.

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Webcast and conference call

A webcast and a conference call for analysts, investors and media will be held on Tuesday, 27 April 2021 at 13.30 EEST. The event will be held only online and by conference call.

A link to the live webcast will be available on Orion’s website at www.orion.fi/en/investors. A recording of the event will be available on the website later the same day.

On April 12, 2021 ONCURIOUS NV, a Belgium-based biotech company focused on developing innovative oncology treatments, reported that encouraging data from a Phase 1 dose escalation study of TB-403 in pediatric subjects with relapsed or refractory medulloblastoma (MB), was presented at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Oncurious, APR 12, 2021, View Source [SID1234577915]).

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The data was presented by Dr. Giselle Sholler, Director, Isabella Santos Foundation Solid and Rare Tumor Program, Chair at Beat Childhood Cancer Research Consortium, and Professor, Paediatric Oncology at the Levine Children’s Hospital in Charlotte, NC.

The Phase 1 trial (ONC-403-001) was an open–label, multi-center, dose escalation study of TB–403 in a total of 15 pediatric subjects – 11 with relapsed or refractory MB, 2 with Ewing Sarcoma (ES) and 2 with alveolar rhabdomyosarcoma (ARMS). The study was conducted in conjunction with the Beat Childhood Cancer Research Consortium, Massachusetts General Hospital and Atrium Health Levine Children’s Hospital.

The study evaluated 4 dose levels of TB-403: 20 mg/kg, 50 mg/kg, 100 mg/kg, and 175 mg/kg. The dose limiting toxicity (DLT) assessment cycle for the study was 28 days with subjects receiving 2 doses of TB-403 at Day 1 and Day 15 respectively. After the DLT period, temozolomide or etoposide could be added to the subject’s treatment regimen.

Evaluations for the response to TB-403 were made at the end of cycle 1 and every 2 cycles thereafter.

The key safety findings from the study were as follows:

TB-403 was safe and well tolerated at all dose levels: no maximum tolerated dose (MTD) was reached
TB-403 exposure of children is in accordance with the exposure of the drug in adults
TB-403 exposure and concentration increased dose-proportionally over the dose range of 20-175 mg/kg

The key response findings were as follows:

At the 3 highest dose levels of TB-403, 7 out of 8 of medulloblastoma patients had stable disease
4 medulloblastoma patients had prolonged stabilization of disease > 100 days
Exploratory biomarker analysis showed a decrease in plasma levels of free placental growth factor (PlGF) to undetectable levels at all doses of TB-403, with no apparent changes in other angiogenic or inflammatory factors.

The results of the Phase 1 study warrant further evaluation of TB-403 in pediatric subjects with relapsed or refractory medulloblastoma (MB).

Dr. Giselle Sholler, Chair at Beat Childhood Cancer Research Consortium, commented: "I am pleased that the Beat Childhood Cancer Research Consortium has been able to play a key role in this important study. The encouraging data that I presented at AACR (Free AACR Whitepaper) show that treatment with TB-403 can produce a clinically meaningful response in a significant number of children with relapsed and refractory medulloblastoma. The encouraging results, in what is a very difficult to treat patient population, warrant further clinical investigation, and we at the Beat Childhood Cancer Research Consortium would be happy to play our role in any such effort."

TB-403 is a humanized monoclonal antibody against PlGF which is expressed in several types of cancer, including medulloblastoma. A paper in Cell (Cell, 152, 1065-76, 2013), highlighted that PlGF plays a role in the growth of medulloblastoma. The paper was based on preclinical research conducted by Prof Rakesh Jain from the Massachusetts General Hospital at Harvard (Boston) and the team of Prof Dr. Peter Carmeliet from the VIB/ KU Leuven.

Prof Dr. Peter Carmeliet from the VIB/ KU Leuven, added, "I am pleased that our preclinical research showing that PlGF plays a key role in the growth of medulloblastoma has been confirmed in this Phase 1 clinical study with TB-403. I look forward to following the further clinical development of this novel PIGF inhibitor and am confident that it has the potential to benefit children suffering from this devastating brain cancer."

Dr. Patrik De Haes, Executive Chairman of Oncurious said, "I would like to thank everyone who has taken part in the execution of this successful study with TB-403, especially the patients and their families. The data that has been generated show that TB-403 could expand the treatment options for children with relapsed and refractory medulloblastoma. Meanwhile, Oncurious’ international patent application, published with a positive indication on the patentability of the combination of TB-403 with etoposide or temozolomide, and expiring as late as 2040, puts Oncurious in a good position to evaluate potential partnering options for future development and manufacturing of TB-403."

On April 12, 2021 Genprex, Inc. ("Genprex" or the "Company") (NASDAQ: GNPX), a clinical-stage gene therapy company focused on developing life-changing therapies for patients with cancer and diabetes, reported that its collaborators presented positive preclinical data for the combination of TUSC2 immunogene therapy (REQORSA) in combination with chemotherapy and immunotherapies for the treatment of non-small cell lung cancer (NSCLC) (Press release, Genprex, APR 12, 2021, View Source [SID1234577913]). Collaborators also presented positive preclinical data for the use of REQORSA in combination with targeted therapies for the treatment of NSCLC. These data were presented in two presentations at the 2021 American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting. The TUSC2 gene is a tumor suppressor gene and is the active agent in REQORSA.

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"We are pleased to have these positive data that provide further support for the therapeutic potential of REQORSA in combination with immunotherapies and targeted therapies in NSCLC presented before an audience of the world’s leading cancer researchers. These data are particularly encouraging as we look to initiate our upcoming combination Acclaim-1 and Acclaim-2 clinical trials of REQORSA in NSCLC," said Rodney Varner, President and Chief Executive Officer of Genprex. "We know that many patients inevitably develop resistance to immune checkpoint blockade therapy or EGFR-TKI therapy. These data show that REQORSA in combination with immunotherapies and targeted therapies may provide enhanced efficacy in NSCLC that has become resistant to these regimens, offering hope to a large patient population who currently has limited treatment options."

Featured Genprex-supported posters presented at AACR (Free AACR Whitepaper) 21 include:

Oral Presentation:
Session: MS.IM02.02 – Overcoming Resistance in the Tumor Microenvironment: Novel Immunomodulatory Agents

Title: "TUSC2 immunogene therapy enhances efficacy of chemo-immune combination therapy and induces robust antitumor immunity in KRAS-LKB1 mutant NSCLC in humanized mice"

Poster Number/Channel: #76/Channel 03

Presentation Date/Time: April 10, 2021 from 2:50-3:00 p.m. ET

Presenters: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Feng Meng, Min Jin Ha, Elizabeth Shpall, Jack A. Roth. University of Texas MD Anderson Cancer Center, Houston, TX

Poster Presentation:
Session: PO.ET03.01 – Drug Resistance in Molecular Targeted Therapies

Title: "Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC"

Poster Number: #1105

Presentation Date/Time: April 10, 2021 from 8:30 a.m. – 11:59 p.m. ET

Presenters: Ismail M. Meraz, Mourad Majidi, RuPing Shao, Lihui Gao, Meng Feng, Huiqin Chen, Min Jin Ha, Jack A Roth

The first presentation, entitled "TUSC2 immunogene therapy enhances efficacy of chemo-immune combination therapy and induces robust antitumor immunity in KRAS-LKB1 mutant NSCLC in humanized mice," showed that the triple combination of chemotherapy, immunotherapy (immune checkpoint blockade) and REQORSA demonstrated strong antitumor efficacy and induced robust antitumor immunity in KRAS-LKB1 (KL)-mutant NSCLC in clinically relevant humanized mice models.

In this study, researchers evaluated the antitumor immune response of a chemo-immunotherapy combination with REQORSA on highly metastatic KL-mutant human lung cancer in humanized mice. Humanized mice were first treated with REQORSA, immunotherapy nivolumab (Opdivo), or the combination. The results showed synergistic antitumor activity with the combination. Next, humanized mice were treated with REQORSA, immunotherapy pembrolizumab (Keytruda), or the combination. When REQORSA was added to the chemotherapy and immune checkpoint blockade combination, metastases regression was significantly greater than either REQORSA, REQORSA and pembrolizumab, or chemotherapy and pembrolizumab treatments.

"KRAS is a frequent genomic driver in lung adenocarcinoma,", said Michael Redman, Executive Vice President and Chief Operating Officer of Genprex. "LKB1 (also known as STK11) is a distinct subgroup of KRAS-mutants and is the most prevalent genomic driver of resistance to PD-1 blockade in KRAS-mutant lung cancer."

The second poster, entitled "Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR-mutant NSCLC," showed that REQORSA in combination with targeted therapy osimertinib (Tagrisso) demonstrated synergistic antitumor efficacy in EGFR mutant osimertinib resistant NSCLC tumors in H1975-OsiR isogenic tumors. Researchers also found that the upregulation of PDK1 was associated with osimertinib resistance.

In this study, researchers developed an osimertinib resistant H1975-OsiR isogenic cell line through continuous exposure to osimertinib. Xenograft tumors from both H1975-parental and H1975-OsiR cells were developed in NSG mice and were treated with osimertinib. Synergistic antitumor activity of REQORSA and osimertinib was found in H1975-OsiR tumors. The combinations showed a robust antitumor effect compared with single agent treatment groups. Reverse phase protein array (RPPA) data showed that PDK1 was significantly upregulated in the REQORSA and osimertinib group when compared with either control, osimertinib alone or REQORSA alone treated H1975-OsiR tumors, indicating that PDK1 may be associated with osimertinib resistance. No PDK1 inhibitor effect was found in the REQORSA treated group, implicating the specific role of PDK1 in osimertinib resistance.

On April 12, 2021 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, reported the presentation of two posters on the company’s clinical and preclinical oncology programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting I, taking place April 10-15, 2021 (Press release, Alpine Immune Sciences, APR 12, 2021, View Source [SID1234577912]).

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CT213: NEON-1: A First-in-Human Phase I Open-Label Study of ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, in Advanced Malignancies

Dr. Mark Voskoboynik from Nucleus Network and The Alfred Hospital in Melbourne, Australia, presented a Trials in Progress poster describing the ongoing first-in-human, phase 1 clinical trial involving monotherapy with ALPN-202, the company’s lead oncology program.
The trial, NEON-1, includes separate parts for dose escalation and expansion cohorts, and is enrolling patients with advanced solid tumors or lymphoma. Dose escalation continues to progress, with no dose-limiting toxicities to date.
P1740: Engineered Variant Domain Fusion Proteins Provide Checkpoint Inhibition and Tumor Antigen Dependent CD28 Costimulation Resulting in Potent Anti-Tumor Immunity

Alpine researchers demonstrated the use of directed evolution to engineer novel variant immunoglobulin domain (vIgD) Fc fusion proteins that enable tumor antigen-dependent CD28 costimulation.
The fusion proteins targeted the PD-L1 or HHLA2 tumor antigens, and demonstrated potent efficacy in antigen-positive tumor models in vitro and in vivo.
"Together, these presentations summarize the potential for an exciting, emerging CD28 costimulation portfolio," said Stanford Peng, MD, PhD, Alpine’s President and Head of Research and Development. "We look forward to the opportunity to present initial clinical data from NEON-1 at an upcoming scientific meeting and are optimistic about the potential to advance one or more of our preclinical programs toward the clinic in the near future."

Full abstracts are available on the AACR (Free AACR Whitepaper) Virtual Annual Meeting website and posters for both presentations are available on the Scientific Publications page of Alpine’s website.

About Alpine’s Directed Evolution Platform

Alpine’s directed evolution platform engineers native immune proteins, primarily of the immunoglobulin or tumor necrosis factor (receptor) superfamilies, into novel functional domains: variant immunoglobulin domains (vIgDs) and/or variant TNF domains (vTDs), respectively. These domains have acquired unique functional properties designed to benefit patients with cancer or inflammatory diseases.

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor with the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. NEON-1 (NCT04186637), a Phase 1 study of ALPN-202 in patients with advanced malignancies, is currently enrolling. Alpine is also targeting the initiation of NEON-2, a Phase 1 combination study of ALPN-202 and a PD-1 inhibitor, later this year.