On June 12, 2022 Day One Biopharmaceuticals (Nasdaq: DAWN), a clinical-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, reported positive initial data from the first 22 Response Assessment for Neuro-Oncology ("RANO")-evaluable patients enrolled in the ongoing, open-label, single-arm, pivotal Phase 2 FIREFLY-1 clinical trial (Press release, Day One, JUN 12, 2022, View Source [SID1234615929]). FIREFLY-1 is evaluating tovorafenib (DAY101) as once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG, which is the most common brain tumor diagnosed in children and for which there are no approved therapies and there is no standard of care. The primary endpoint of the FIREFLY-1 trial is ORR by RANO criteria as assessed by blinded independent central review. Tovorafenib is an investigational, oral, brain-penetrant, highly-selective type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway. FIREFLY-1 is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and is designed to support the potential regulatory approval of tovorafenib.

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Initial data from the first 25 patients enrolled in the trial demonstrate:

64% ORR and 91% CBR (partial response/unconfirmed partial response + stable disease) in the 22 RANO-evaluable patients:

14 partial responses (13 confirmed responses and 1 unconfirmed response)

6 patients with stable disease

All patients with stable disease (n=6) were noted to have tumor shrinkage, ranging between 19% and 43%

Responses were observed in patients with both BRAF fusions and BRAF V600E mutations who received prior MAPK-targeted therapy

The median-time-to-response was 2.8 months

A heavily-pretreated population, with a median of 3 prior lines of therapy (range: 1-9)

All patients who responded remain on therapy (n=14) and no patients have discontinued treatment due to treatment-related adverse events.

Initial safety data, based on the first 25 patients, indicated monotherapy tovorafenib to be generally well-tolerated. The majority of adverse events (AEs) were grade 1 or 2 in nature; the most common ( ≥25% any grade) treatment related AEs were increase in blood creatine phosphokinase, rash, and hair color changes. Treatment-related AEs of grade 3 or greater occurred in nine patients (36%).

"These initial findings underscore the potential of tovorafenib monotherapy to become a significant and transformative new option for relapsed/progressive pLGG, a pediatric brain tumor with no approved treatments today," said Samuel Blackman, M.D., Ph.D., co-founder and chief medical officer of Day One. "With the registrational cohort fully enrolled, patient follow-up is ongoing, and we look forward to the topline data from the complete study population in the first quarter of 2023. Based on these positive initial data, we plan to begin the pivotal Phase 3 FIREFLY-2 clinical trial evaluating tovorafenib as a front-line therapy in pLGG to evaluate whether tovorafenib can provide benefit early in the disease development."

"These initial data demonstrate significant anti-tumor activity in children with relapsed/progressive pLGG, including children who are refractory to available therapies. Pediatric low-grade glioma is a truly challenging disease in which children face years of aggressive regimens that can carry a long-term impact on learning, cognition, and quality of life," said Roger Packer, M.D., senior vice president, Center for Neuroscience and Behavioral Medicine, and director, Brain Tumor Institute, Children’s National Hospital.

Day One plans to present additional interim trial results from FIREFLY-1 at an upcoming medical conference in the second half of 2022. Day One anticipates releasing topline results for the full FIREFLY-1 pivotal study population in the first quarter of 2023. If the data are supportive, Day One expects to submit a new drug application (NDA) to the United States Food and Drug Administration (FDA) in the first half of 2023.

Expanding Development of Tovorafenib in Front-Line pLGG

Based on these initial FIREFLY-1 data, Day One plans to expand the development of tovorafenib as a front-line therapy for patients newly diagnosed with pLGG. The global, pivotal Phase 3, registrational clinical trial ("FIREFLY-2/LOGGIC") will evaluate once-weekly monotherapy tovorafenib in newly-diagnosed patients with pLGG. The FIREFLY-2/LOGGIC study is designed to evaluate the efficacy and safety of tovorafenib in patients with newly-diagnosed pLGG harboring a known activating BRAF alteration. The study is a randomized, monotherapy, open-label trial aiming to enroll approximately 400 patients aged 6 months to 25 years across approximately 100 sites globally, including in the U.S., Europe and Asia. Participants will be randomized to either tovorafenib (Arm 1) or an investigator’s choice of one of three standard of care chemotherapy options (Arm 2). The primary endpoint will be the ORR based upon RANO criteria as reported by Blinded Independent Central Review. Secondary endpoints will include safety, progression-free survival, duration of response, functional outcomes, and quality of life measures.

Day One will conduct the FIREFLY-2/LOGGIC trial in collaboration with the Low-Grade Glioma in Children (LOGGIC) consortium, a group of internationally recognized experts in pLGG research, and an extensive network of pediatric oncology centers, including Hopp Children’s Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ) and the Brain Tumor Group of the European Society for Paediatric Oncology (SIOPE BTG). Day One expects to dose the first patient in FIREFLY-2/LOGGIC trial in the third quarter of 2022.

Conference Call and Webcast Information

Day One will host a conference call and webcast tomorrow, June 13, 2022, at 8:00 a.m. Eastern Time. To participate by telephone, please dial 844-713-6132 (Domestic) or 1-213-320-2543 (International). The conference ID number is 3568447. The webcast will be made available for replay on the Company’s website beginning approximately two hours after the event and will be available for 30 days following the live presentation.

About Pediatric Low-Grade Glioma

Pediatric low-grade glioma (pLGG) is the most common brain tumor diagnosed in children, accounting for 30% – 50% of all central nervous system tumors. BRAF wild-type fusions are the most common cancer-causing genomic alterations in pediatric low-grade gliomas. These genomic alterations are also found in several adult and pediatric solid tumors. Currently approved BRAF inhibitors are only active in tumors harboring BRAF V600 mutations, exhibit limited activity in brain tumors, and cannot be used in patients harboring BRAF fusions.

Pediatric low-grade glioma can impact a child’s health in many ways depending on tumor size and location, including vision loss and motor dysfunction. There are no approved therapies for pLGG, and current treatment approaches are associated with significant acute and life-long adverse effects. While most children with pLGG survive their cancer, children who do not achieve remission following surgery may face years of increasingly aggressive therapies that can have lasting effects on learning, cognition, and quality of life. Due to the indolent nature of pLGG, patients receive multiple years of systemic therapy.

About Tovorafenib

Tovorafenib is an investigational, oral, brain-penetrant, highly-selective type II pan-RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway, which is being investigated in primary brain tumors or brain metastases of solid tumors. Tovorafenib has been studied in over 250 patients to date. Currently tovorafenib is under evaluation in a pivotal Phase 2 clinical trial (FIREFLY-1) among pediatric, adolescent and young adult patients with pediatric low-grade glioma (pLGG), which is an area of considerable unmet need with no approved therapies. Tovorafenib is also being evaluated alone or as a combination therapy for adolescent and adult patient populations with recurrent or progressive solid tumors with MAPK pathway aberrations (FIRELIGHT-1). Tovorafenib has been granted Breakthrough Therapy and Rare Pediatric Disease designations by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pLGG harboring an activating RAF alteration. Tovorafenib has also received Orphan Drug designation from the FDA for the treatment of malignant glioma, and from the European Commission (EC) for the treatment of glioma.

About the Pacific Pediatric Neuro-Oncology Consortium

The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium with study sites within the United States, Canada, Europe and Australia dedicated to bringing new therapies to children and young adults with brain tumors.

On June 12, 2022 Novartis reported long-term results from the ELIANA pivotal clinical trial of Kymriah (tisagenlecleucel), the first-ever approved CAR-T cell therapy, in children and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), with a maximum survival follow-up of 5.9 years (Press release, Novartis, JUN 12, 2022, View Source [SID1234615909]). For the 79 patients treated with Kymriah in this study, the five-year overall survival (OS) rate was 55% (95% CI, 43-66), while the median event-free survival (EFS) for patients in remission within three months of infusion (n=65) was 43.8 months. These findings demonstrate the curative potential of Kymriah, the only CAR-T cell therapy available for these patients who previously had limited treatment options. These data were presented as an oral presentation during the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (Abstract #S112)1.

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"These data mark a moment of profound hope for children, young adults and their families with relapsed or refractory B-cell ALL, as relapse after five years is rare," said Stephan Grupp, MD, PhD, Section Chief of the Cellular Therapy and Transplant Section, and Inaugural Director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy at Children’s Hospital of Philadelphia (CHOP). "Since the approval of Kymriah nearly five years ago, we have been able to offer a truly game-changing option to patients who previously faced a five-year survival rate of less than 10 percent."

This long-term follow up of ELIANA demonstrated the potential for Kymriah to transform cancer treatment in pediatric and young adult patients with r/r B-cell ALL, significantly improving outcomes with durable responses and a consistent safety profile in this patient population1:

Eighty-two percent of patients experienced remission (either complete remission [CR] or CR with incomplete hematologic recovery within three months after infusion) (95% CI, 72-90)
For patients in remission, the five-year relapse-free survival (RFS) rate was 44% (95% CI, 31-56) and the median RFS was 43 months
No new or unexpected adverse events were reported during long-term follow-up
"At Novartis, we strive for cures. With nearly six-year follow-up data in these pediatric and young adults treated for B-cell ALL, we have our strongest evidence yet that one-time treatment with Kymriah has curative potential," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development. "These results strengthen our confidence in CAR-T cell therapies as a truly transformative and paradigm-shifting advance in cancer care, as well as our commitment to continue developing this technology with next-generation platforms."

Additional updates on the Novartis CAR-T program presented at the 2022 EHA (Free EHA Whitepaper) Congress include new data from more patients and longer follow-up from the first-in-human dose-escalation trials with YTB323 in adults with r/r diffuse large B-cell lymphoma and PHE885 in adults with r/r multiple myeloma, the first Novartis CAR-T cell therapies developed using the Novartis T-Charge platform2,3,4. Visit View Source to learn more about these data and our ongoing commitment to reimagining cancer care with CAR-T cell therapies.

About Kymriah
Kymriah is the first-ever FDA-approved CAR-T cell therapy. It is a one-time treatment designed to empower patients’ immune systems to fight their cancer. Kymriah is currently approved for the treatment of r/r pediatric and young adult (up to and including 25 years of age) acute lymphoblastic leukemia (ALL), r/r adult diffuse large B-cell lymphoma (DLBCL) and r/r adult follicular lymphoma1.

About the ELIANA Trial
ELIANA was the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain. The trial was an open-label, multicenter, single-arm, global Phase II trial investigating the efficacy and safety of Kymriah in pediatric and young adult patients in r/r B-cell ALL who were primary refractory, chemorefractory, relapsed after, or were not eligible for allogeneic stem cell transplantation (SCT). The primary endpoint was overall remission rate (ORR), defined as best overall response of CR or CR with incomplete blood count recovery (CRi) within 3 months and maintained for ≥28 day. The secondary endpoints include CR/CRi with undetectable minimal residual disease (MRD), duration of remission, event-free survival, overall survival, cellular kinetics and safety5.

About T-Charge
T-Charge is a next-generation CAR-T platform, innovated at the Novartis Institutes for BioMedical Research (NIBR), that will serve as the foundation for various new investigational CAR-T cell therapies in the Novartis pipeline. By implementing the T-Charge platform, we aim to revolutionize CAR-T cell therapy with new products that have the potential to offer patients a higher likelihood of better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events. The T-Charge platform preserves T cell stemness (T cell ability to self-renew and mature), an important T cell characteristic closely tied to its therapeutic potential, which results in a product containing greater proliferative potential and fewer exhausted T cells. With T-Charge, CAR-T cell expansion occurs primarily within the patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo). The T-Charge platform, which implements important process efficiencies, will be rapid, compared with traditional CAR-T, and reliable, through simplified processes and streamlined quality control. Multiple CAR-T therapies, including YTB323 and PHE885, are being developed using the Novartis T-Charge platform.

About Novartis commitment to Oncology Cell Therapy
As part of the unique Novartis strategy to pursue four cancer treatment platforms – radioligand therapy, targeted therapy, immunotherapy and cell and gene therapy – we strive for cures through cell therapies in order to enable more patients to live cancer-free. We will continue to pioneer the science and invest in our manufacturing and supply chain process to further advance transformative innovation.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of the Novartis commitment to CAR-T cell therapy.

We have made strong progress in broadening our delivery of Kymriah, which is currently available for use in at least one indication in 30 countries and at more than 370 certified treatment centers, with clinical and real-world experience from administration to more than 6,900 patients. We continue to pioneer in cell therapy, leveraging our vast experience to develop next-generation CAR-T cell therapies. These therapies will utilize our new T-Charge platform being evaluated to expand across hematological malignancies and bring hope for a cure to patients with other cancer types.

On June 11, 2022 AbbVie (NYSE: ABBV) reported primary results from the large B-cell lymphoma (LBCL) expansion cohort in the EPCORE NHL-1 phase 2 clinical trial evaluating epcoritamab (DuoBody-CD3xCD20), an investigational subcutaneous bispecific antibody (Press release, AbbVie, JUN 11, 2022, View Source [SID1234615901]). In this study, epcoritamab demonstrated efficacy with durable responses in patients who had previously received at least two prior lines of anti-lymphoma therapy including chimeric antigen receptor (CAR) T-cell therapy. These data were presented today in a late-breaking oral presentation as a part of the Presidential Symposium at the 27th Annual Meeting of the European Hematology Association (EHA) (Free EHA Whitepaper) (EHA2022) in Vienna, Austria (Abstract #LB2364).

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"Large B-cell lymphoma is a fast-growing, difficult to treat type of aggressive non-Hodgkin’s lymphoma. Some treatment approaches like chemotherapy and immunotherapy have been in place for decades and newer treatments like CAR T-cell therapies involve multiple steps before a patient can begin treatment so there is still a need for additional treatment options," said Professor Catherine Thieblemont, head of the Hemato-Oncology Department at Hôpital Saint-Louis, Paris, France. "The data presented today suggest that epcoritamab has the potential to provide patients living with LBCL an accessible, effective treatment with a safety profile that may fulfill an unmet need."

The study cohort, which included 157 relapsed/refractory LBCL patients, previously treated with a median of three lines of prior therapy, demonstrated an overall response rate (ORR) of 63 percent and a complete response (CR) rate of 39 percent. Baseline characteristics included 61 percent of patients who were refractory to primary treatment, 20 percent who had prior autologous stem cell transplantation (ASCT), and 39 percent who were treated with CAR T-cell therapy (75 percent of those refractory to CAR T). Patients enrolled in the study who were naïve to CAR T-cell therapy achieved a 69 percent ORR and a 42 percent CR and patients who received prior CAR T-cell therapy achieved a 54 percent ORR and a 34 percent CR. After a median follow up of 10.7 months, the median duration of response (mDOR) was estimated to be 12 months, while the mDOR among patients achieving a CR was not reached, with 89 percent still in CR at nine months. Topline results from this study were previously announced in April 2022.

The safety profile of epcoritamab was consistent with previous findings. The majority of treatment-emergent AEs (TEAEs) occurred during the first 12 weeks of treatment and resolved. The most common TEAEs of any grade (greater than or equal to 15 percent) included cytokine release syndrome (CRS) (49.7 percent), pyrexia (23.6 percent), fatigue (22.9 percent), neutropenia (21.7 percent), diarrhea (20.4 percent), injection site reaction (19.7 percent), nausea (19.7 percent) and anemia (17.8 percent). The most common Grade 3 or 4 TEAEs (greater than or equal to 5 percent) included neutropenia (14.6 percent), anemia (10.2 percent), neutrophil count decrease (6.4 percent), and thrombocytopenia (5.7 percent). The observed Grade 3 CRS was 2.5 percent. No Grade 4/5 CRS was observed.

"The epcoritamab data suggests a potentially compelling clinical profile for patients with relapsed/refractory LBCL, which currently have limited treatment options," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie. "Our partnership with Genmab allows us to continue exploring new standards of care for patients with blood cancer."

Epcoritamab is being co-developed by AbbVie and Genmab as part of the companies’ broad oncology collaboration. The companies remain committed to evaluating epcoritamab as a monotherapy, and in combination, across lines of therapy for a variety of hematologic malignancies, including an ongoing phase 3, open-label, randomized trial evaluating epcoritamab as a monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) (NCT: 04628494).

About Large B-cell Lymphoma (LBCL)
LBCL is a fast-growing type of non-Hodgkin’s lymphoma (NHL) – a cancer that develops in the lymphatic system – that affects B-cell lymphocytes, a type of white blood cell. There are an estimated 150,000 new LBCL cases each year globally. LBCL includes DLBCL, which is the most common type of NHL worldwide and accounts for approximately 31 percent of all NHL cases.1,2,3,4

About the EPCORE NHL-1 Trial
EPCORE NHL-1 an open-label, multi-center safety and preliminary efficacy trial of epcoritamab including a phase 1 first-in-human, dose escalation part; a phase 2 expansion part; and an optimization part. The trial was designed to evaluate subcutaneous epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-NHL, including LBCL and DLBCL, the most common subtype of LBCL. The dose escalation findings, which determined the recommended phase 2 dose, were published in The Lancet in 2021. In the phase 2 expansion part, additional patients are treated with epcoritamab to further explore the safety and efficacy of epcoritamab in three cohorts of patients with different types of relapsed/refractory B-NHLs who had limited therapeutic options.

The primary endpoint of the phase 2 expansion part was ORR as assessed by an IRC. Secondary efficacy endpoints included duration of response, complete response rate, progression-free survival, and time to response as determined by the Lugano criteria. Overall survival, time to next therapy, and rate of minimal residual disease negativity were evaluated as secondary efficacy endpoints.

About Epcoritamab
Epcoritamab is an investigational IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response towards target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B-cells and induces T cell mediated killing of CD20+ cells.5 CD20 is expressed on B-cells and a clinically validated therapeutic target in many B-cell malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.6,7 Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ broad oncology collaboration.

About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world’s most widespread and debilitating cancers. As we work to have a remarkable impact on people’s lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit View Source

On June 11, 2022 EORTC reported that Acute myeloid leukemia (AML) predominantly occurs in older adults over 65 years, who exhibit a lower tolerance to conventional induction chemotherapy (IC) compared with younger patients (Press release, EORTC, JUN 11, 2022, View Source [SID1234615902]). Despite treatment with IC, older patients with AML have poor long-term survival without hematopoietic stem cell transplantation (HSCT). For the past decade, DNA-hypomethylating agents such as decitabine have been considered a safer alternative for patients who are unfit for IC. Prolonged (10-day) decitabine treatment has shown promising efficacy in previous studies with older patients with AML, and may be a more suitable treatment before HSCT than IC in fit patients.

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The open-label randomized phase III study of the EORTC Leukemia group, GIMEMA, CELG, and GMDSSG (NCT02172872) compared the efficacy and safety of 10-day decitabine with conventional 3+7 IC as a treatment before HSCT in older (≥60 years) patients with newly diagnosed AML. Patients with at least stable disease and an HLA-matched donor were encouraged to undergo HSCT after ≥1 treatment cycle.

The rate of HSCT in decitabine-treated patients was similar to IC-treated patients (40% vs 39%). Although IC achieved higher complete remission rates compared with decitabine (61% vs 48%), the overall survival was comparable, with a median overall survival of 15 months in the decitabine group and 18 months in the IC group. At 4 years, 26% of patients from the decitabine arm and 30% of patients
from the IC arm were alive. A notable difference between the treatment arms was the incidence of grade 3–5 adverse events before HSCT. Decitabine treatment showed lower incidences of febrile neutropenia, platelet reduction, oral mucositis, and diarrhea. In addition, the 30-day mortality rate was 3.6% for decitabine compared with 6.4% for IC.

In conclusion, decitabine treatment for older patients with AML exhibited a superior safety profile compared with IC while maintaining similar overall survival and rates of HSCT. The results of this study will be presented by Prof. Michael Lübbert on Saturday, June 11.

Presenter: Prof Dr med Michael Lübbert
Affiliation: Universitätsklinikum Freiburg, Freiburg, Germany
Presentation: S125 will be presented by Prof Michael Lübbert | Saturday, June 11, 2022 | 16:30 –17:45 CEST | Hall A7, Messe Wien Exhibition & Congress Center, Vienna, Austria.

About the EHA (Free EHA Whitepaper) Annual Congress

Every June, EHA (Free EHA Whitepaper) organizes its Annual Congress in a major European city. In 2020 and 2021, the format was virtual due to COVID-19. However, this year, EHA (Free EHA Whitepaper) has organized a Hybrid congress for the first time. The Congress is aimed at health professionals working in or interested in the field of hematology. The scientific program topics range from stem cell physiology and development to leukemia, lymphoma, diagnosis and treatment, red blood cells, white blood cells and platelet disorders, hemophilia and myeloma, thrombosis and bleeding disorders, as well as transfusion and stem cell transplantation.

On June 11, 2022 CRISPR Therapeutics (Nasdaq: CRSP), a biopharmaceutical company focused on creating transformative gene-based medicines for serious diseases, reported that positive results from the Company’s ongoing Phase 1 COBALT-LYM trial evaluating the safety and efficacy of CTX130, its wholly-owned allogeneic CAR-T cell therapy targeting CD70 for the treatment of both solid tumors and certain hematologic malignancies (Press release, CRISPR Therapeutics, JUN 11, 2022, View Source [SID1234615903]).

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"We are very pleased with the preliminary results from our COBALT-LYM trial, which showed efficacy and safety that suggest that CTX130, the first allogeneic CAR-T directed against the novel target CD70, can produce deep responses in patients with relapsed or refractory T cell lymphomas," said Samarth Kulkarni, Ph.D., Chief Executive Officer of CRISPR Therapeutics. "Additionally, we may be able to further optimize the profile by continuing our consolidation dosing strategy. These data reinforce our belief that engineered cell therapies are the future in our fight against cancer and we are well-positioned to be leaders in this field."

"While overall survival in a subset of patients with T cell lymphoma has improved with front-line combination chemotherapy, relapsed or refractory patients continue to have very limited treatment options," said Swaminathan P. Iyer, M.D., Professor, Lead of the T Cell Lymphoma Program, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The data from the CTX130 trial demonstrate the potential of cell therapies as a new treatment modality for these patients. I am particularly encouraged by the response rates and safety data, which suggest that treatment with CTX130 could elicit clinically meaningful responses, including complete responses, in patients with difficult-to-treat T cell lymphomas."

COBALT-LYM Trial Overview
The Phase 1 COBALT-LYM trial is an open-label, multicenter clinical trial evaluating the safety and efficacy of CTX130 in adult patients with relapsed or refractory T or B cell malignancies. Dose escalation of CTX130 was performed in adult patients with relapsed or refractory T cell lymphoma, with at least 10% expression of CD70. Patients who received prior treatment with any CD70 targeting agents were not eligible.

Patients received three days of lymphodepleting chemotherapy, consisting of fludarabine at 30 mg/m2/day and cyclophosphamide at 500 mg/m2/day, followed by a single CTX130 infusion. Patients completed screening in as few as five days, and the median time from enrollment to the start of lymphodepleting chemotherapy was only three days. This timeline was possible because there is no need for leukapheresis or bridging chemotherapy, and CTX130 is available at the site before a patient is enrolled. Additionally, patients who showed clinical benefit from the first CTX130 infusion could be re-dosed following disease progression.

As of the April 26, 2022, data cutoff, 19 patients with T cell malignancies had been enrolled, of which 18 patients had received CTX130 with at least 28 days of follow-up and are included in the analysis. Prior to enrollment, all patients were heavily pre-treated, with a median of four systemic therapies. Additionally, all patients were refractory to their last line of therapy. Eight patients had peripheral T-cell lymphoma (PTCL) and 10 patients had cutaneous T-cell lymphoma (CTCL).

The primary endpoints include safety as measured by the incidence of dose limiting toxicities (DLTs) and overall response rate (ORR). Key secondary endpoints include progression free survival (PFS) and overall survival (OS).

Safety
CTX130 was well tolerated across all dose levels. The adverse events of interest for all evaluable patients are shown in the table below.

There were no cases of Graft versus Host Disease (GvHD); no dose limiting toxicities (DLTs); and no instances of tumor lysis syndrome (TLS).

All cases of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were Grade 1 or 2 per the American Society for Transplantation and Cellular Therapy (ASTCT) criteria and either required no specific intervention or resolved following standard CRS management. Neither the frequency nor severity of CRS has increased in patients who were re-dosed with CTX130.

There was a sudden death in one patient with William’s syndrome in the context of a lung infection, deemed unrelated to CTX130. There were no treatment related deaths in the trial. Overall, CTX130 has an emerging safety profile that is well tolerated.

Clinical Activity
Deep responses were seen with CTX130 in a significant fraction of patients at DL3 and above. Data are shown below for the 18 patients who received CTX130 and had at least 28 days of follow-up. Disease assessment was performed by investigator review according to the 2014 Lugano Response Criteria for PTCL or the International Society for Cutaneous Lymphoma Response Criteria (Olsen criteria) for CTCL, as appropriate.

Patients were heavily pre-treated with a median of four systemic therapies prior to enrollment in the study. None of the 18 patients had achieved a complete response (CR) in their previous line of therapy.

Median CD70 expression among the patients was 90%. Responses were observed across all levels of CD70 expression.

Clinically meaningful responses were observed with CTX130 with a higher percentage of patients responding at higher dose levels. At DL3 and above, ORR was 70% with 30% of patients achieving a CR. In addition, 90% of patients at DL3+ had clinical benefit defined as a stable disease or better response. These responses were largely consistent in both PTCL and CTCL with ORRs of 80% and 60%, respectively, at DL3+.

Broad activity and deep responses were seen in all disease compartments including lymph nodes, skin and blood in patients with CTCL following treatment with CTX130.
These preliminary data demonstrate that CTX130 has the potential to provide meaningful clinical benefit with a well-tolerated safety profile. Given the inherent difficulties and potential risks of manufacturing a CAR-T therapy from a patient’s own diseased T cells, allogeneic cellular therapy approaches for T cell lymphoma have greater potential to address the unmet need in this patient population.

CTX130 is currently being investigated in two ongoing Phase 1 clinical trials for the treatment of various subtypes of lymphoma (COBALT-LYM) or relapsed or refractory renal cell carcinoma (COBALT-RCC), respectively. Additional details on COBALT-LYM may be found at clinicaltrials.gov, using identifier: NCT04502446. In parallel, the Company continues to advance the rest of its immuno-oncology portfolio.

The Company plans to recap this data during the CRISPR Therapeutics Innovation Day, an event focused on early research and development, on June 21, 2022, at 2:00 pm ET.

Innovation Day Webcast
A live webcast of the event will be available on the "Events & Presentations" page in the Investors section of the Company’s website at View Source A replay of the webcast will be archived on the Company’s website for 30 days following the presentation. Please contact [email protected] for any questions regarding the event.

About CTX130
CTX130, a wholly-owned program of CRISPR Therapeutics, is a healthy donor-derived gene-edited allogeneic CAR-T investigational therapy targeting cluster of differentiation 70, or CD70, an antigen expressed on various solid tumors and hematologic malignancies. CTX130 is being developed for the treatment of both solid tumors, such as renal cell carcinoma, and T-cell and B-cell hematologic malignancies. CTX130 is being investigated in two ongoing independent Phase 1, single-arm, multi-center, open-label clinical trials that are designed to assess the safety and efficacy of several dose levels of CTX130 for the treatment of relapsed or refractory renal cell carcinoma and various subtypes of lymphoma, respectively. CTX130 for the treatment of T-cell lymphoma has received Orphan Drug Designation from the FDA.

About COBALT-LYM
The ongoing Phase 1 single-arm, multi-center, open label clinical trial, COBALT-LYM, is designed to assess the safety and efficacy of several dose levels of CTX130 for the treatment of relapsed or refractory T- or B-cell malignancies.

About COBALT-RCC
The ongoing Phase 1 single-arm, multi-center, open label clinical trial, COBALT-RCC, is designed to assess the safety and efficacy of several dose levels of CTX130 for the treatment of relapsed or refractory Renal Cell Carcinoma.