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 EMD Serono, the Healthcare business sector of Merck KGaA, Darmstadt, Germany in the US and Canada, reported key clinical advancements for berzosertib (M6620), an investigational, potent and selective ataxia telangiectasia and Rad3-related (ATR) inhibitor (Press release, EMD Serono, APR 12, 2021, View Source [SID1234577932]). Berzosertib is the leading asset in the company’s DNA damage response (DDR) inhibitor program and one of the most advanced ATR inhibitors in oncology clinical development industry-wide.

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Results from a Phase II proof-of-concept study conducted by the US National Cancer Institute (NCI) (NCT02487095)* and published in Cancer Cell showed that berzosertib in combination with the chemotherapy topotecan resulted in an objective response rate (ORR) of 36% among patients with relapsed small cell lung cancer (SCLC), including durable responses among a majority of responding patients with platinum-resistant disease.1 The NCI is also conducting a separate Phase II trial of berzosertib in combination with topotecan versus topotecan monotherapy in SCLC that has relapsed (NCT03896503)* which is currently the only randomized controlled trial of the combination in this population.

EMD Serono also initiated a global Phase II study to further assess berzosertib in combination with topotecan for the treatment of relapsed, platinum-resistant SCLC (DDRiver SCLC 250). The first patient has been enrolled in the open-label, single-arm trial, which plans to include approximately 80 participants at about 41 study sites across Asia, Europe, and North America.

"Small-cell neuroendocrine cancers, including small cell lung cancer, are associated with very poor prognoses, and are a major clinical challenge with no effective therapeutic options. In this study, the combination of berzosertib and topotecan showed higher than expected response rates and durable responses in patients with platinum-resistant SCLC, highlighting the therapeutic potential of this combination for patients with this recalcitrant cancer type," said Anish Thomas, MBBS, M.D., investigator and NIH Lasker Clinical Research Scholar at the Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, and lead investigator of the study. Dr. Thomas is collaborating with Merck KGaA, Darmstadt, Germany through a Cooperative Research and Development Agreement (CRADA).

Topotecan is the chemotherapeutic standard-of-care for second-line treatment of SCLC and is associated with low response rates, particularly in platinum-resistant disease.1 Findings from the NCI study highlight the vulnerability of SCLC tumors to ATR inhibition as a result of high levels of replication stress and the potential for the combination of berzosertib and topotecan to enhance the efficacy of topotecan among chemotherapy-resistant patients.1 These data build on earlier published results from Phase I of this study which also suggested a potential benefit of this combination in participants with platinum-resistant SCLC.2

"We are encouraged by these promising results, and are eager to further investigate berzosertib in a potentially registrational trial in SCLC as part of our front-running leadership in the research of DNA damage response," said Danny Bar-Zohar, M.D., Global Head of Development for the Healthcare business sector of Merck KGaA, Darmstadt, Germany.

These results are in addition to results from an NCI-sponsored open-label, randomized, Phase II study (NCI protocol 9944) evaluating berzosertib in combination with gemcitabine versus gemcitabine alone for the treatment of recurrent, platinum-resistant high-grade serous ovarian cancer, which were published in The Lancet Oncology in 2020. The study, conducted through a separate CRADA between NCI and Merck KGaA, Darmstadt, Germany, showed a benefit of adding berzosertib to gemcitabine in this treatment setting including improvement in progression-free survival, and is the first randomized study of an ATR inhibitor in any tumor type.3

As part of its new DDRiver Clinical Trials program, the company is investigating DDR inhibitor targeting pathways across more than ten trials in various tumor types.

NCI Study Results
In the Phase II single-arm study of berzosertib plus topotecan in patients with SCLC whose disease had progressed on prior therapy, 25 patients were evaluable for the primary endpoint of ORR as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and the secondary endpoints of progression-free survival (PFS) and overall survival (OS) and duration of response (DOR). Berzosertib 210 mg/m2 was administered intravenously on days 2 and 5, and topotecan 1.25 mg/m2 was given intravenously on days 1 through 5 in 21-day cycles; treatment continued until disease progression.1

The confirmed ORR was 36% (95% CI, 18.0–57.5; all partial response).1 Most patients (68.0%) experienced tumor regressions.1 Responses were observed in patients with both platinum-sensitive (60.0% [95% CI, 14.7–94.7]) and platinum-resistant (30.0% [95% CI, 11.9–54.3]) disease.1 Median DOR was 6.4 months (95% CI, 1.1–14.3), and four of the six (66.7%) responders with platinum-resistant SCLC had DOR of more than 6 months.1 Median PFS was 4.8 months (95% CI, 2.8–7.4), with PFS rates at 4 months and 6 months of 60.0% (95% CI, 38.4-76.1) and 36.0% (95% CI, 18.2–54.2).1 Median OS was 8.5 months (95% CI, 5.6-13.6);1 OS rates at 6 months and 12 months were 68.0% (95% CI, 46.1–82.5) and 32.0% (95% CI, 15.2–50.2).1

Among 26 patients evaluable for safety, the most common treatment-related adverse events (AE) were anemia (96.2%), lymphopenia (96.2%), thrombocytopenia (92.3%), and neutropenia (50.0%), nausea (50.0%) and vomiting (42.3%).1 The most common grade 3 or 4 AEs were lymphopenia (69.2%), thrombocytopenia (57.7%), anemia (53.8%), and neutropenia (15.4%).1 No treatment-related deaths occurred.1 Most AEs were attributable to topotecan, which as monotherapy is associated with a high frequency of myelosuppression.1,4

*Additional information on these clinical trials are available at clinicaltrials.gov, through identifier numbers NCT02487095 and NCT03896503. Patients interested in enrolling in these berzosertib and topotecan combination clinical trials can call the National Cancer Institute’s toll-free number 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615).

About Small Cell Lung Cancer
Of the estimated 1.6 million new lung cancer cases diagnosed worldwide each year, approximately 15% are SCLC.5 SCLC is the most aggressive form of lung cancer, characterized by a rapid doubling time and widespread metastases,6 and approximately two-thirds of patients present with extensive disease that has metastasized, when first found.7 The median survival time for patients with SCLC is 7 months,5 and the relative five-year survival rate is just 7%.8

About Berzosertib
Berzosertib is an investigational, potent and selective inhibitor of the ataxia telangiectasia and Rad3-related (ATR) protein that blocks ATR activity in cells. Berzosertib is the first ATR inhibitor evaluated in a randomized clinical trial in any tumor type,3 and it is the lead candidate in EMD Serono’s DNA Damage Response (DDR) inhibitor portfolio. It is currently being investigated in a number of internal and external studies with early phase I/II data in small cell lung cancer, ovarian cancer, and various solid tumors.3,9 Berzosertib, formerly known as VX-970, was licensed from Vertex Pharmaceuticals in 2017. Berzosertib is not approved for any use anywhere in the world.

References

Thomas A, Takahashi N, Rajapakse V, et al. Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell 39 (4), 2021, pp.566-579.
Thomas, A., Redon, C. E., Sciuto, L., Padiernos, E., Ji, J., Lee, M. J., Yuno, A., Lee, S., Zhang, Y., Tran, L., et al. (2018). Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. J Clin Oncol36, 1594-1602.
Konstantinopoulos PA, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020 Jul;21(7):957-968. doi: 10.1016/S1470-2045(20)30180-7. Epub 2020 Jun 15. PMID: 32553118.
von Pawel, J., Schiller, J. H., Shepherd, F. A., Fields, S. Z., Kleisbauer, J. P., Chrysson, N. G., Stewart, D. J., Clark, P. I., Palmer, M. C., Depierre, A., et al. (1999). Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17, 658-667.
Wang S, et al. Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages. Sci Rep. 2017;(1):1339.
Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-72.
American Cancer Society.Small Cell Lung Cancer Stages. View Source (Accessed April 8, 2021).
American Cancer Society. Lung Cancer Survival Rates. View Source (Accessed April 8, 2021).
Yap TA, et al. Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors. J Clin Oncol. 2020 Sep 20;38(27):3195-3204. doi: 10.1200/JCO.19.02404. Epub 2020 Jun 22. PMID: 32568634; PMCID: PMC7499606.
All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group Website. In case you are a resident of the USA or Canada please go to www.emdgroup.com/subscribe to register again for your online subscription of this service as our newly introduced geo-targeting requires new links in the email. You may later change your selection or discontinue this service.

On April 12, 2021 Y-mAbs Therapeutics, Inc. (the "Company" or "Y-mAbs") (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 Dr. Sebastian Chung from Memorial Sloan Kettering Cancer Center ("MSK") presented a virtual poster discussing the SADA technology platform for pre-targeted radioimmunotherapy against GPA33 in a xenograft model of colorectal peritoneal carcinomatosis at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting on April 10, 2021 (Press release, Y-mAbs Therapeutics, APR 12, 2021, View Source [SID1234577900]).

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The SADA technology utilizes a pre-targeted payload delivery method where antibody constructs assemble in tetramers and bind to the tumor target. Unbound constructs predictably disassemble into smaller antibody fragments and are excreted through the kidneys within hours after administration. In a second infusion, a radioactive payload binds to the antibody constructs to radiate the tumor. Y-mAbs expects to submit its first IND for a SADA construct targeting GD2 in the fourth quarter of 2021.

The GPA33-SADA construct was created using the SADA technology, which was licensed by the Company from MSK and Massachusetts Institute of Technology ("MIT") in April 2020. In a xenograft model of colorectal peritoneal carcinomatosis, GPA33-SADA showed a favorable tumor to blood ratio radioactivity uptake of 122 measured 24 hours after injection. GPA33 is expressed on 95% of all colorectal cancers. An IND for the GPA33-SADA is targeted for next year.

Researchers at MSK developed GPA33-SADA, which is exclusively licensed by MSK and MIT to Y-mAbs. As a result of this licensing arrangement, both MSK and MIT have institutional financial interests related to the compound and Y-mAbs.

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 Transgene (Paris:TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported that Management will participate in the upcoming investor events set out below (Press release, Transgene, APR 12, 2021, View Source [SID1234577933]):

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– SmallCap Event – Digital event
14 & 15 April 2021

– KEMPEN LIFE SCIENCES CONFERENCE – 2021 Thematic Virtual Series
21 April 2021 – Immuno and Targeted Oncology

– Spring European Midcap Event – Digital event
22 & 23 June 2021