On October 7, 2021 Kinnate Biopharma Inc. (Nasdaq: KNTE) ("Kinnate"), a biopharmaceutical company focused on the discovery and development of small molecule kinase inhibitors for difficult-to-treat, genomically defined cancers, reported that it will be presenting design and rationale details of a Phase 1 trial (KN-8701: NCT04913285) evaluating KIN-2787 during the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Kinnate Biopharma, OCT 7, 2021, View Source [SID1234590929]).

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KIN-2787, Kinnate’s most advanced product candidate, is an orally available small molecule pan-RAF inhibitor being developed for the treatment of patients with lung cancer, melanoma, and other solid tumors. KIN-2787 has been designed to target both monomeric and dimeric forms of the mutant BRAF kinase and minimize paradoxical activation, a liability often observed with other RAF inhibitors that can adversely impact tolerability and require addition of a MEK inhibitor to suppress pathway activation. Unlike currently available treatments that target only Class I BRAF kinase mutations, KIN-2787 targets Class II and Class III BRAF alterations, where it has the potential to be a first-line targeted therapy, in addition to covering Class I BRAF mutations. In pre-clinical studies, KIN-2787 has shown favorable pharmaceutical properties, achieves substantial systemic exposures in toxicology studies and induces regressions in human cancer xenograft models driven by BRAF Class I, II or III alterations.

"Approved BRAF inhibitors have limited clinical activity in diverse solid tumors driven by BRAF Class II or III alterations, highlighting the urgency to develop effective next-generation targeted therapies for these patients who currently have limited options," said the trial’s co-investigator and presenter Meredith McKean, MD, MPH, Associate Director, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute at Tennessee Oncology. "We are pleased to share additional details of this two-part trial with this year’s conference attendees."

KN-8701 (NCT04913285) is a first-in-human, multicenter, non-randomized, open-label, Phase 1 trial of KIN-2787 in adult patients with BRAF mutant advanced and metastatic solid tumors (AMST). KIN-2787 is given orally bid continuously in 28-day cycles until drug intolerance or disease progression. Planned sample size is approximately 115 patients in two parts: Part A is a trial of dose-escalation to maximum tolerated dose open to patients with AMST driven by BRAF Class I, Class II or Class III genomic alterations. Part B will evaluate a selected dose of KIN-2787 in three cohorts of patients with melanoma, NSCLC, or other AMST, each driven by BRAF Class II or Class III alterations. Standard Phase 1 enrollment criteria are required, and key exclusion criteria include known clinically active brain metastases from non-brain tumors, and prior receipt of BRAF-, MEK-, or MAPK-directed inhibitor therapy (except for cases in which these inhibitors were used in FDA-approved indications).

"We are pleased with the progress of this first-in-human trial of KIN-2787 and grateful to all the trial participants. With poorer prognosis observed in NSCLC and melanoma patients harboring tumors driven by BRAF Class II or III alterations, there is a dire need for more effective and better tolerated therapies," said Richard Williams, MBBS, Ph.D., Chief Medical Officer of Kinnate. "We are proud to collaborate with the Sarah Cannon Research Institute and all the other sites participating in this important trial."

The KN-8701 trial is currently recruiting across three centers in the United States. For more information, please visit www.kinnate.com/patients.

The poster (#P226), titled "Design and rationale of a first in human (FIH) Phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF mutation positive solid tumors," was presented by Dr. McKean and can be accessed online at: View Source

On October 7, 2021 -Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported positive initial results from a Phase 1 trial of its novel CBP/p300 inhibitor, the oral small molecule FT-7051, in men with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Forma Therapeutics, OCT 7, 2021, View Source [SID1234590945]). Initial clinical data from the Courage Study, an ongoing first-in-human Phase 1 trial presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), showed an encouraging safety profile of FT-7051, as well as high specificity to the CBP/p300 pathway.

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"Preliminary data from the Courage Study are promising," said Andrew J. Armstrong, M.D., principal investigator of the Courage Study, and Professor of Medicine, Pharmacology and Cancer Biology, and Director of Research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. "Managing the balance between safety, tolerability and efficacy is a key element of targeting this pathway, and thus far the doses studied are achieving pharmacodynamic target engagement with acceptable tolerability."

Preliminary results reported today include data as of Sept. 1, 2021, from eight men enrolled in the trial. FT-7051 was administered in 28-day cycles, with 21 days of dosing followed by seven days of no dosing. Three patients remain on study; five patients left the study (four due to disease progression and one withdrawal of consent). The adaptive trial design is intended to efficiently explore safe and efficacious doses of FT-7051. Prior to enrollment, all of the men had received diagnoses of mCRPC, castration-levels of serum testosterone and rising levels of the biomarker prostate specific antigen (PSA) after the failure of at least two lines of therapy with an approved androgen-receptor pathway inhibitor.

The initial pharmacokinetic (PK) analysis of FT-7051 documented rapid absorption, which produced maximum blood concentrations within two hours. The 150 mg dose achieved drug concentrations that approached the predicted efficacious dose based on modeling with preclinical results. Skin biopsies of the men participating in the study demonstrated a reduction in H3K27AC, a marker of activity in the CBP/p300 pathway, the target of FT-7051.

The majority of the treatment-emergent adverse events (TEAEs) were mild or moderate, at Grade 2 or lower, with no events leading to treatment discontinuation. One patient experienced Grade 3 hyperglycemia, which was medically managed. Following a dose reduction, this patient remained on treatment and experienced an ongoing PSA decline of greater than 50% at 12 weeks and greater than 80% at 16 weeks. Based upon these safety results, dose escalation is ongoing. The trial is continuing according to its adaptive design to further understand the safety and tolerability of FT-7051, gather data on clinical response including PSA and radiographic tumor response, as well as the assessment of secondary endpoints of clinical response.

"There is substantial need for new therapies to treat those with mCRPC as they progress while on existing lines of anti-androgen or chemotherapy," said David N. Cook, Ph.D., senior vice president, Forma Therapeutics’ chief scientific officer. "Thanks to the eight patients who participated in the Courage Study to date, we have made progress in understanding the potential of CBP/p300 inhibition in prostate cancer and look forward to continuing our dose escalation study."

Presentation Details

Abstract P202: Initial Findings from an Ongoing First-in-human Phase 1 Study of the CBP/p300 Inhibitor FT-7051 in Men with Metastatic Castration-Resistant Prostate Cancer (Link)
Abstract P204: Targeting the p300/CBP Epigenetic Pathway to Overcome Hormone Therapy Resistance in Advanced Prostate Cancer
Forma continues to enroll men into the Courage Study. For more information, please visit View Source or View Source

About CBP/p300

Tumor resistance to anti-androgen therapies can arise due to mutations and other changes within the androgen receptor (AR). Androgen binds to two paired proteins in ARs, CBP and p300, in a location that is highly resistant to mutations known as the bromodomain. FT-7051 is designed to attach to the CBP/p300 bromodomain potently and selectively, which then blocks androgen binding and reduces AR activation. In preclinical studies, FT-7501 demonstrated activity in both prostate cancer models that were sensitive or resistant to the approved androgen-inhibitor medicine enzalutamide.

About Prostate Cancer

Prostate cancer is the second most frequent cancer in men globally, accounting for more than 1.4 million new diagnoses and 6.8 percent of all male cancer deaths in 2020.1 In the United States, more than 248,000 men will be diagnosed with prostate cancer in 2021, and the disease will account for more than 34,000 deaths.2 When cancer has spread beyond the prostate and surgery or radiation are not an option, first-line treatment suppresses the male hormone androgen because it can stimulate prostate cancer cell growth.3,4 This treatment, called medical castration, slows progression for about two years, but most men will develop resistance and their cancer will progress.5,6 The five-year survival rate of men with metastatic prostate cancer is 30 percent.7

On October 7, 2021 PierianDx, the global leader in clinical genomics knowledge, reported that it will partner with Florida Cancer Specialists & Research Institute (FCS) to support expanded access to the highest quality genomic testing on solid tumors and hematologic malignancies and lymph nodes leveraging NGS technology (Press release, PierianDx, OCT 7, 2021, View Source [SID1234590914]). Under the partnership, FCS will locally analyze and interpret sequencing data generated with the Illumina TruSight Oncology 500 Research Use Only assay and the Invitae VariantPlex, LiquidPlex, and FusionPlex panels using PierianDx Clinical Genomic Workspace (CGW) to rapidly and accurately detect mutations and offer the best therapeutic options for patients.

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Historical approaches to precision medicine testing include centralized testing performed at large national laboratories where the laboratory typically has little-to-no interaction with the patient and limited treating physician interaction. By localizing genomic testing, FCS patients will benefit from more direct access to testing within the context of care. Offering these tests in the FCS laboratory will also enable improved collaboration between the diagnostic team who interpret the test results and the treating physicians, which drives alignment across the care team and increases confidence in the clinical utility of genomic testing.

The genomic test results at Florida Cancer Specialists will be delivered via a customizable report generated by the PierianDx CGW. Powered by a comprehensive knowledgebase and secure and scalable data analysis platform, the PierianDx CGW will enable Florida Cancer Specialists to quickly and accurately classify and interpret variants to inform treatment or match patients to the right trial within the practice’s large network of participating clinical trials.

According to Florida Cancer Specialists CEO Nathan H. Walcker, "We see tremendous clinical and strategic value to performing this very important testing in-house. By offering in-house genomic testing, we will continue to seek the best options for care for our patient population by quickly and efficiently providing existing treatments as well as optimizing clinical trial matching opportunities. We look forward to partnering with PierianDx to provide even greater tools to our physician partners at FCS and enabling wider access to high complexity testing to the patients we are privileged to serve."

"We are thrilled to provide our best-in-class bioinformatics and knowledge platform to support personalized, community-based cancer care," states Mark McDonough, CEO of PierianDx. "Partnering with leading-edge institutions like Florida Cancer Specialists aligns perfectly with our mission to democratize clinical genomics and to optimally serve physicians and the patients they treat."

On October 7, 2021 Y-mAbs Therapeutics, Inc. ("Y-mAbs" or the "Company"), NASDAQ: YMAB), a commercial-stage biopharmaceutical company focused on the development and commercialization of novel, antibody-based therapeutic products for the treatment of cancer, reported that the U.S. Food and Drug Administration ("FDA") has granted Rare Pediatric Disease Designation ("RPDD") for the Company’s lutetium labelled omburtamab antibody program for the treatment of medulloblastoma (Press release, Y-mAbs Therapeutics, OCT 7, 2021, View Source [SID1234590930]).

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177Lu-omburtamab-DTPA, a monoclonal B7-H3 antibody that has been radiolabeled with lutetium-177, is currently in a multicenter Phase 1 clinical trial in pediatric patients with refractory medulloblastoma, and in a multicenter Phase 1 clinical trial targeting B7-H3 positive CNS/LM tumors in adults. We believe that both indications address clear unmet medical needs.

"The RPDD makes us eligible for a Priority Review Voucher ("PRV") upon potential approval of the biologics license application for this rare pediatric cancer. Among our leading compounds under development, four now have RPDDs, and this designation for 177Lu-omburtamab-DTPA further increase our chances of ultimately receiving multiple PRVs," said Thomas Gad, founder, Chairman and President.

Dr. Claus Moller, Chief Executive Officer further notes, "We are dedicated to bring 177Lu-omburtamab-DTPA to patients who desperately need alternative methods of treatment. We are very pleased by this recognition by the FDA and look forward to expanding the ongoing Phase 1 studies with 177Lu-omburtamab-DTPA into separate Phase 2 arms."

Researchers at Memorial Sloan Kettering Cancer Center ("MSK") developed omburtamab, which is exclusively licensed by MSK to Y-mAbs. As a result of this licensing arrangement, MSK has institutional financial interests in the product.

On October 7, 2021 Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA in aggressive cancers, reported that it will present a poster at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Boundless Bio, OCT 7, 2021, View Source [SID1234590946]). The poster, LBA005: Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors, is available to registered attendees starting at 9AM EST today.

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"Over the past decade, targeted therapies have delivered significant health improvement to patients with oncogene-driven cancers, with KRASG12C inhibitors being the most recent example," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "Despite the use of potent inhibitors against oncodrivers like KRAS, resistance inevitably emerges. ecDNA driven oncogene copy number amplifications, a mechanism that is distinct from second site mutations, is a frequent cause of resistance in cancer cells. Boundless Bio, in collaboration with the Dana-Farber Cancer Institute and Mirati Therapeutics, has shown that, in colorectal patients treated with KRASG12C inhibitors, ecDNA based amplification played an important role in resistance to KRASG12C inhibitor therapy. These results further substantiate our mission to develop novel therapeutic strategies that can address ecDNA-enabled cancers."

"We are pleased to collaborate with Boundless Bio on this important work to identify mechanisms of acquired resistance to KRASG12C inhibitors," said Dr. Mark Awad, M.D., Ph.D., Assistant Professor of Medicine at Harvard Medical School and Clinical Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute. "There is mounting evidence that cancers rely on oncogene amplification to drive tumor growth and resistance, and some of this copy number amplification may be occurring on extrachromosomal DNA. The development of innovative therapies for ecDNA-driven cancers will hopefully provide new treatment options for our patients in the future."

Study Summary

We first confirmed the presence of ecDNA in tumor biopsy samples collected by the Dana-Farber Cancer Institute from clinical trial patients treated with the KRASG12C inhibitor, adagrasib. Analysis of next-generation sequencing (NGS) data using proprietary Boundless Bio software enabled detection of circular DNA structures encompassing the KRAS locus. Consistent with this finding, fluorescence in situ hybridization (FISH) analysis by Boundless Bio scientists confirmed the presence of KRAS amplifications on ecDNA.

Next, an in vivo study was performed to investigate whether resistance to KRASG12C inhibitor monotherapy is mediated through an ecDNA mechanism. We used a genetically modified CT26 murine colorectal cancer model expressing KRASG12C alleles. In line with recent clinical data, both adagrasib and sotorasib induced transient tumor regressions in the CT26 model that subsequently resumed tumor growth following several weeks of continuous therapy. Strikingly, in both adagrasib and sotorasib resistant tumors, bioinformatic analysis of whole-genome sequencing data and FISH analysis from isolated recurrent tumors identified high levels of ecDNA mediated amplification of KRASG12C compared to vehicle-treated samples. The kinetics of KRAS amplification on ecDNA was also determined, showing increased KRAS copy number within two weeks after initiation of KRASG12C inhibitor treatment. Such rapid onset of resistance after tumor regression is consistent with previous in vivo studies with other ecDNA enabled tumor models. Cultures from ex vivo experiments also maintain resistance due to KRAS amplified ecDNA. Collectively, these observations implicate ecDNA as an important mediator of resistance to KRASG12C inhibitor monotherapy.

This study, along with previously published studies, confirm the evasive dynamics of ecDNA-driven oncogene copy number amplification upon therapeutic pressure on oncodrivers such as EGFR, FGFR, and now mutant KRAS. Because ecDNA can be distributed heterogeneously throughout tumors, resistance to targeted therapies can be rapid, aggressive, and difficult to treat. Here we confirm the critical need for novel therapeutic strategies directed to the function of ecDNA within cancer cells and the urgency to bring these therapies to patients with oncogene amplified cancers.

About ecDNA

Extrachromosomal DNA ("ecDNA") are circular units of nuclear DNA found within cancer cells, and which contain highly transcriptionally active genes, including oncogenes, but are physically distinct from chromosomes and lack centromeres. ecDNA replicate within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells have the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including targeted therapy, immunotherapy, chemotherapy, or radiation, thereby making ecDNA one of cancer cells’ primary mechanisms of growth, recurrence, and treatment resistance. ecDNA are not found in healthy cells but are present in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.