On November 9, 2020, Sierra Oncology, Inc. (the "Company") reported that it entered into an amendment (the "Amendment") to the License Agreement with CRT Pioneer Fund LP ("CPF"), dated September 27, 2016 (the "CRT License Agreement") (Filing, 8-K, Sierra Oncology, NOV 9, 2020, View Source [SID1234570762]).

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Pursuant to the CRT License Agreement, the Company made a one-time upfront payment of $7.0 million to CPF in October 2016 and paid $2.0 million to CPF in January 2017 for the successful transfer of two ongoing Phase 1 clinical trials. Pursuant to the terms of the original CRT License Agreement, additional milestone payments of up to an aggregate of $319.5 million was payable to CPF upon the achievement of certain developmental, regulatory and commercial milestones, including a milestone payment of $7.5 million upon the dosing of the first patient in the first Phase 1 trial of SRA737 in the United States, and a payment of $12.0 million upon the dosing of the first patient of a randomized Phase 2 trial of SRA737.

Pursuant to the terms of the Amendment, the Company has agreed to decreased additional milestone payments of up to an aggregate of $290.0 million that may be payable to CPF upon the achievement of certain developmental, regulatory and commercial milestones, including a milestone payment of $2.0 million upon the dosing of the first patient of the first trial of SRA737 following the effective date of the Amendment.

In the event that the milestone payment for Milestone Event, as defined in the CRT License Agreement, but no milestone payment for an earlier Milestone Event has been paid, then the milestone payment attached to the earlier Milestone Event will become due and payable contemporaneously with the payment for the later Milestone Event. These milestones will be accrued once they are considered probable of occurring.

In addition, the Company remains required to pay CPF, on a product-by-product and country-by-country basis, tiered high single-digit to low double-digit royalties on the net sales of any product successfully developed.

The foregoing summary of the Amendment is not complete and is qualified in its entirety by reference to the complete text of the Amendment, which the Company intends to file as an exhibit to its Annual Report on Form 10-K for the year ending December 31, 2020.

On November 9, 2020 Menarini Silicon Biosystems, the pioneer of liquid biopsy technology, reported the publication of a research study providing support for the reliability of using circulating tumor cell (CTC) count to guide frontline therapy choice for patients with estrogen receptor-positive (ER+), HER2-negative (HER2) metastatic breast cancer. Published in the November issue of JAMA Oncology, this is the first study to support clinical utility of CTC count in a ra (Press release, Menarini Silicon Biosystems, NOV 9, 2020, View Source [SID1234570666])ndomized clinical trial.

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"Based on our research, the use of the CTC count represents the first objective and reproducible decision tool to help physicians choose between hormone therapy or chemotherapy for this particular group of patients," said lead author Francois-Clement Bidard, MD, PhD, Professor of Medical Oncology at Institut Curie and University of Versailles. "Furthermore, our results indicate that the CTC count complements but does not duplicate the physician’s opinion on which treatment to choose and should be included in the decision algorithm. This CTC test may help customizing treatment decisions for all women suffering from ER+ HER2- metastatic breast cancer".

The randomized Phase III trial, known as the STIC CTC study, included 778 women with Stage 4 ER+, HER2- breast cancer and compared the outcomes of treatment decisions based on physician assessment vs. CTC count. Half of the patients were randomly assigned to the clinically driven treatment group, where treatment was selected by a physician based on clinical factors. The other half were assigned to a CTC-driven treatment group, in which patients with 5 or more CTCs in 7.5 mL of blood received chemotherapy, and those with less than 5 CTCs in 7.5 mL received hormone therapy. Menarini Silicon Biosystems’ CELLSEARCH CTC System was used to capture and isolate tumor cells circulating in the blood in all patients.

The results supported the reliability and clinical utility of using the CTC count to guide front line therapy choice. For most patients in the clinically driven arm, the CTC count correlated with the physician’s choice of treatment. In the CTC-driven group, escalation of treatment to frontline chemotherapy for patients with high CTC count significantly improved progression free survival (PFS), while de-escalation to hormone therapy for patients with low CTC count did not have a detrimental impact on PFS or overall survival (OS).

"The results of the STIC CTC study provide evidence that the CTC count can support physicians when making effective treatment decisions," said Fabio Piazzalunga, President and CEO of Menarini Silicon Biosystems. "As a company, we will continue to support research aimed at demonstrating the clinical utility of CTC and we maintain our commitment to improve patient management".

Since the trial began, the introduction of CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) in combination with endocrine therapy as a frontline option has changed the treatment algorithm for patients with ER+ HER2- metastatic breast cancer. As a result, Menarini Silicon Biosystems has now been asked to support the analysis of CTC count in an ongoing phase III study known as AMBRE, promoted by Unicancer, the only French hospital network entirely devoted to fighting cancer, and conducted within the French breast cancer intergroup (UCBG) network. The study (NCT04158362) compares chemotherapy and a combination of endocrine therapy with one of the new CDK4/6 inhibitors (abemaciclib) as the initial treatment for metastatic ER+/HER2- breast cancer with high tumor burdend.

About CELLSEARCH
CELLSEARCH is the first and only clinically validated blood test cleared by the U.S. Food & Drug Administration (FDA) for detecting and counting CTCs to aid physicians in managing patients with metastatic breast, prostate, and colorectal cancers when used in conjunction with other clinical methods of monitoring. The test is also approved by the China National Medical Products Administration (NMPA) for use in monitoring patients with Metastatic Breast Cancer. The CELLSEARCH System is the most extensively studied CTC technology, with research published in more than 650 peer-reviewed publications.

CELLSEARCH Circulating Tumor Cell Kit is not cleared or approved for use as a clinical utility test for guiding treatment decisions. For more information on the full intended use and limitations of CELLSEARCH system, please refer to the Instructions for Use at View Source

On November 9, 2020 DNAtrix, a biotech company advancing virus-driven immunotherapies for cancer, reported that four abstracts on the company’s platform technology have been accepted for presentation at the 25th Annual Scientific Meeting and Education Day of the Society for Neuro-oncology (SNO) to be held November 19-21, 2020 (Press release, DNAtrix, NOV 9, 2020, View Source [SID1234570665]). Updated data from the Phase 2 CAPTIVE study in recurrent glioblastoma (GBM) have been selected as a late-breaking abstract for oral presentation on Friday, November 20, 2020 at 11:45 a.m. ET.

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The Phase 2 multicenter CAPTIVE study is evaluating DNX-2401 (tasadenoturev), DNAtrix’s adenovirus-based immunotherapy, in combination with pembrolizumab for the treatment of GBM at first or second recurrence. Data from 49 patients will be presented.

Additionally, presentations will include data on DNX-2401 as a potential treatment for diffuse intrinsic pontine glioma (DIPG), a highly aggressive pediatric cancer of the brainstem.

The live and on-demand sessions can be found on the SNO event website at View Source

DNAtrix Late-Breaking Presentation:

Title:

Phase 2 multicenter study of the oncolytic adenovirus DNX-2401 (tasadenoturev) in combination with pembrolizumab for recurrent glioblastoma; CAPTIVE Study (KEYNOTE-192)

Abstract Number:

LTBK-04

Presenter:

Gelareh Zadeh, M.D., Ph.D., Princess Margaret Cancer Center

Date/Time:

November 20, 11:45 a.m. ET

Presentations:

Title:

Oncolytic virus for DIPG: The clinical experience with DNX-2401

Abstract Number:

CTIM-25

Presenter:

Marta M. Alonso, Ph.D., Clinica Universidad de Navarra

Date/Time:

On Demand – Pediatric (Clinical) Session I

Title:

Delta-24-RGDOX (DNX-2440) activation of the IDO-Kyn-AhR cascade in glioblastoma: old targets for a new therapy

Abstract Number:

EXTH-45

Presenter:

Teresa Nguyen, MD Anderson Cancer Center

Date/Time:

On Demand – Experimental and Translational Sciences Session IV

Title:

Characterization of the oncolytic adenovirus Delta-24-RGD (DNX-2401) as therapeutic agent for the treatment of the pediatric embryonal brain tumors AT/RT and CNS-PNET

Abstract Number:

EXTH-60

Presenter:

Marc Garcia-Moure, Ph.D., Clinica Universidad de Navarra

Date/Time:

On Demand – Pediatric (Basic Science) Session I

About DNX-2401 (Tasadenoturev)
DNX-2401 is an oncolytic adenovirus engineered specifically to infect, replicate in, and directly kill cancer cells, as well as elicit a broader anti-tumor immune response. DNX-2401 is currently being evaluated as a potential treatment for highly aggressive brain tumors, including recurrent glioblastoma in adults and newly-diagnosed diffuse intrinsic pontine glioma (DIPG) in children. Clinical studies have demonstrated that DNX-2401 was well tolerated and extended survival for patients with recurrent glioblastoma. DNX-2401 has been granted Fast Track and Orphan designation by the FDA and PRIME and Orphan designation by the EMA.

About DNX-2440
DNX-2440 is an oncolytic adenovirus expressing the immune modulator OX40 ligand, a powerful costimulatory molecule known to enhance T cell responses directed to tumors. DNX-2440 is in Phase 1 clinical testing following the demonstration of anti-cancer activity in preclinical studies, including tumor reductions, immune memory, and abscopal effect.

On November 9, 2020 Cygnal Therapeutics, the first company to build a platform to develop drugs in the new field of exoneural biology, reported that it will present a poster this week at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 35th Anniversary Annual Meeting (Press release, Cygnal Therapeutics, NOV 9, 2020, View Source [SID1234570664]). The conference will be held online as a virtual event . Cygnal’s poster will discuss research on the development and use of novel monoclonal antibodies to block tumor-promoting interactions with Neuropilin-1, leading to significant tumor growth inhibition in vivo.

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Title: A novel mechanism of Neuropilin-1 inhibition results in improved tumor growth inhibition in vivo
Number: 683
Presenters: Daniel Blom, Ph.D., Shalini Sethumadhavan, Ph.D., Eric Zhu, Ph.D.
Date and Time: Available virtually on Monday, November 9 from 8:00 a.m. ET onward

Registered event attendees can access the poster via their SITC (Free SITC Whitepaper) event login. Cygnal’s poster presenters will be available for questions online on Wednesday, November 11 from 5:15 to 5:45 p.m. ET and on Friday, November 13 from 4:40 to 5:10 p.m. ET.

To learn more about Cygnal and exoneural biology, please visit Cygnal’s website.

On November 9, 2020 Alkermes plc (Nasdaq: ALKS) reported the presentation of new data from the ARTISTRY clinical development program for ALKS 4230, Alkermes’ investigational engineered interleukin-2 (IL-2) variant immunotherapy, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 35th Anniversary Annual Meeting, being held virtually Nov. 11-14, 2020 (Press release, Alkermes, NOV 9, 2020, View Source [SID1234570663]). The company will present preliminary safety, tolerability and pharmacokinetic/pharmacodynamic data from the dose-escalation stage of ARTISTRY-2, the ongoing phase 1/2 study evaluating ALKS 4230 administered subcutaneously (SC) either once-weekly or once-every-three-weeks. A detailed analysis of clinical responses observed in ovarian cancer patients and other new updates from ARTISTRY-1, the ongoing phase 1/2 study investigating ALKS 4230 administered intravenously (IV), will also be presented. Both studies are evaluating ALKS 4230 as a monotherapy and in combination with the PD-1 inhibitor pembrolizumab (KEYTRUDA) in patients with heavily pretreated advanced solid tumors.

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"Accumulating evidence across the ARTISTRY clinical program provides insight into ALKS 4230’s potential as a novel treatment option, both as monotherapy in melanoma and in combination with pembrolizumab, for a number of tumor types that do not typically respond to current standards of care. The responses observed with the combination regimen in platinum-resistant ovarian cancer, triple negative breast cancer, and recently in cervical cancer, are encouraging signs of ALKS 4230’s potential utility in these cancers," said Ira Winer, M.D., Ph.D., Associate Professor, Division of Gynecologic Oncology, Wayne State University and Karmanos Cancer Institute. "In addition, the data presented at SITC (Free SITC Whitepaper) from ARTISTRY-2 in patients with advanced solid tumors showed a safety profile and immune response comparable to ALKS 4230 administered intravenously, indicating that ALKS 4230 may offer an alternate subcutaneous dosing option for patients."

"The ALKS 4230 subcutaneous dose-escalation data in heavily pretreated patients with certain solid tumors demonstrated expansion of tumor-killing CD8+ T cells and NK cells consistent with the expansion observed with intravenous dosing of ALKS 4230. These data support the potential for once-weekly or once-every-three-week subcutaneous dosing of ALKS 4230, for which we expect to identify our recommended phase 2 dose by year-end," said Craig Hopkinson, M.D., Chief Medical Officer and Executive Vice President of Research & Development at Alkermes. "Further, based on the durable complete and partial responses observed in the ARTISTRY-1 intravenous dosing study in tumor types with high unmet need and limited treatment options for patients, we are considering potential regulatory strategies that may support expeditious development paths in both monotherapy and combination settings."

The two posters are available on the SITC (Free SITC Whitepaper) website at View Source Highlights from the poster presentations, which reflect data as of Sept. 29, 2020 unless otherwise noted, include:

Poster #671: Phase 1/2 Study of Subcutaneously Administered ALKS 4230, a Novel Engineered Cytokine, as Monotherapy and in Combination With Pembrolizumab, in Patients With Advanced Solid Tumors: ARTISTRY-2
The ongoing dose-escalation stage of ARTISTRY-2 is evaluating the safety and tolerability of ascending doses of SC ALKS 4230 administered either once-weekly (Q7) or once-every-three-weeks (Q21) as lead-in monotherapy for six weeks, followed by combination with pembrolizumab. The pharmacokinetic/pharmacodynamic (PK/PD) data presented include seven dose-escalation cohorts of SC ALKS 4230 (Q7: 0.3, 0.6, 1, 3 mg; Q21: 1, 3, 10 mg):

ALKS 4230 was assessed in 43 heavily pretreated patients with refractory solid tumors. Of these, 30 patients completed the monotherapy lead-in portion of the study and initiated combination treatment with pembrolizumab.
Treatment with SC ALKS 4230 resulted in a dose-dependent increase in circulating natural killer (NK) cells and CD8+ T cells, with an approximately 16-fold and 3-fold expansion, respectively, at the 3 mg Q7 dose. At the 10 mg Q21 dose there was an approximately 6-fold and 3-fold expansion in NK cells and CD8+ T cells, respectively. There was a minimal, non-dose-dependent change in regulatory T (Treg) cells.
The NK and CD8+ T cell expansions observed for the 3 mg Q7 and 10 mg Q21 SC doses were equivalent or greater compared to the expansions observed in ARTISTRY-1 at the 3 µg/kg/day and 6 µg/kg/day IV doses of ALKS 4230, respectively.
Compared to the 6 µg/kg/day IV dose, the recommended phase 2 dose (RP2D) identified for ARTISTRY-1, the 3 mg and 10 mg doses of SC ALKS 4230 induced higher levels of interferon gamma, a cytokine that has been associated with antitumor efficacy in clinical studies.1 Relative to IV ALKS 4230, SC ALKS 4230 induced a lower, transient upregulation of IL-6 concentrations.
ALKS 4230 at the SC doses studied showed a safety and tolerability profile consistent with the anticipated pharmacologic effects and what has been observed with IV ALKS 4230. The most commonly reported adverse events (AEs) across the ARTISTRY-2 study were injection site reactions, fever, chills, fatigue, nausea and lymphopenia. One patient experienced dose-limiting AEs at the 10 mg Q21 dose (grade 3 nausea, vomiting, and fatigue). Following a dose reduction, the patient continued on study.
Preliminary clinical benefit was observed, even in immunotherapy-pretreated patients. As of the data cutoff date, 11 patients had continued on therapy for more than 6 months.
The maximum tolerated dose and the RP2D for SC ALKS 4230 have not yet been determined.
Poster #689: Clinical Outcomes of Ovarian Cancer Patients Treated With ALKS 4230, a Novel Engineered Cytokine, in Combination With Pembrolizumab: ARTISTRY-1 Trial
Data presented from the ongoing ARTISTRY-1 study focused on the subset of PD-1/L1 unapproved patients with progressive, resistant ovarian cancer who received ALKS 4230 administered intravenously in combination with pembrolizumab. These data provide an updated and more in-depth view of responses previously reported at the 2020 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress. In addition, new data on the effects of IV ALKS 4230 monotherapy on the tumor microenvironment (TME) and additional updates from other tumor types were presented.

Of the 13 evaluable ovarian cancer patients in the PD-1/L1 unapproved cohort, five patients with platinum-resistant ovarian cancer experienced clinical benefit, both in terms of durability and deepening of response. As of the data cutoff date, these five patients remained on therapy for a range of approximately 5 to 21 months.
Antitumor activity has also been observed in patients with certain other women’s cancers who received IV ALKS 4230 in combination with pembrolizumab, including a durable immune partial response in triple negative breast cancer and a new partial response in cervical cancer.
An analysis of paired biopsies taken from a melanoma patient who received the 6 µg/kg/day monotherapy dose of IV ALKS 4230 in the dose-escalation phase of ARTISTRY-1 showed an increase in tumor-infiltrating CD8+ T cells and an increase in PD-L1 expression in the TME. In addition, the ratio of CD8+ T cells to Treg cells increased in this patient. High CD8+ T cell/Treg cell ratios, independent of treatment type, have been reported to be associated with better prognosis among multiple tumor types, including ovarian tumors.2 These data provide supporting evidence of ALKS 4230’s immunostimulatory impact on the TME and provide rationale for combining ALKS 4230 with pembrolizumab in ovarian cancer patients.
Among patients in the PD-1/L1 unapproved cohort, treatment-related AEs have been generally transient and manageable, with the majority being grade 1 or 2 in severity. The most commonly reported AEs in this cohort were chills, fever and nausea.
Based on the durable and deepening responses observed with ALKS 4230 in combination with pembrolizumab in ovarian cancer, the company is planning a new prospective study to evaluate this combination regimen in platinum-resistant and bevacizumab-experienced ovarian cancer patients.
About ALKS 4230
ALKS 4230 is an investigational, novel, engineered fusion protein comprised of modified interleukin-2 (IL-2) and the high affinity IL-2 alpha receptor chain, designed to selectively expand tumor-killing immune cells while avoiding the activation of immunosuppressive cells by preferentially binding to the intermediate-affinity IL-2 receptor complex. The selectivity of ALKS 4230 is designed to leverage the proven antitumor effects of existing IL-2 therapy while mitigating certain limitations.

About the ARTISTRY Clinical Development Program
ARTISTRY is an Alkermes-sponsored clinical development program evaluating ALKS 4230 in patients with advanced solid tumors.

ARTISTRY-1 and ARTISTRY-2 are phase 1/2 studies evaluating the safety, tolerability, efficacy and pharmacokinetic and pharmacodynamic effects of ALKS 4230 in patients with refractory advanced solid tumors, in both monotherapy and combination settings with the PD-1 inhibitor pembrolizumab (KEYTRUDA). In ARTISTRY-1, ALKS 4230 is administered as an intravenous infusion daily for five consecutive days. In ARTISTRY-2, ALKS 4230 is administered subcutaneously and is being evaluated with once-weekly and once-every-three-week dosing schedules.

ARTISTRY-3 is a phase 2 study evaluating the clinical and immunologic effects of ALKS 4230 monotherapy administered intravenously on the tumor microenvironment of a variety of advanced, malignant solid tumors.