Monthly Archives: August 2021

Lomecel-B, Longeverons proprietary off-the-shelf cell therapy for aging frailty, failed the six-minute walk test (6MWT) endpoint of a Phase IIb study, according to a statement published by the Miami-based biotech on Friday. Despite the apparent flop, the company noted Lomecel-B led to a significant dose-response curve in the 6MWT compared with placebo at 180 days.

Investors have responded positively to the results of the Phase IIb trial, with shares in the company increasing by over 10% premarket Friday morning.

Longeverons Lomecel-B cell therapy is an allogeneic product consisting of medicinal signaling cells (MSCs) derived from adult bone marrow that has been culture-expanded in the companys cell-processing facility.

In the Phase IIb trial of the drug, researchers assessed the efficacy and safety of a peripheral intravenous infusion of four doses of the therapy: 25 million cells (n=37), 50 million cells (n=31), 100 million cells (n=34), and 200 million cells (n=16). Another 30 patients were randomized to receive placebo. The active therapy was compared with placebo in terms of signs and symptoms of aging frailty, such as exercise tolerance and mobility.

Patients in the study were between 70 and 85 years of age and were required to have a 6MWT of 200 to 400 meters at screening. Additionally, patients were required to have a Canadian Health and Safety Assessment (CHSA) Clinical Frailty Scale score of 5 (mildly frail) or 6 (moderately frail) to be considered for entry.

The primary analysis compared the baseline change in 6MWT distance for each of the four dose cohorts with placebo at day 180. According to the company, researchers observed statistically significant increases in the 6MWT distance among patients randomly assigned to 50 million, 100 million and 200 million cells. In contrast, there was no significant change for the placebo group or the lowest Lomecel-B dose group.

In an adjusted analysis corrected for comparisons using the Hochberg method, however, the four different doses of Lomecel-B did not demonstrate a significant placebo-adjusted difference (25 million =-0.2, p=0.9902; 50 million =27.7, p=0.1279; 100 million =16.8, p=0.3472; 200 million =41.3, p=0.0635).

In the secondary analysis, which was used to assess a dose-response relationship for the 6MWT, researchers found a statistically significant dose-response curve at the 180-day follow-up period. Significant differences were also observed from placebo at day 270, a pre-specified exploratory endpoint.

Improving physical function in older adults with frailty is one of the primary goals in geriatric medicine, according to a statement made by Dr. Jorge G. Ruiz, M.D, geriatrician at the Miami Veterans Affairs Healthcare System, Geriatric Research, Education and Clinical Center (GRECC), a site involved in the study. I would consider these results clinically significant and relevant for the older veteran population since one third of American Veterans older than 65 years have frailty.

Longeverons chief executive officer, Geoff Green, emphasized the positive findings that showed a significant dose-response curve with the therapy. Furthermore, the safety profile of Lomecel-B continues to look very good, he added, with no Lomecel-B related serious adverse events reported in this study, which is consistent with previous clinical trial data.

The company says a team of independent frailty experts will soon review the study data during an upcoming steering committee. Findings from the meeting will be used to plan next steps for the program. Longeveron also plans to present the trial data on September 29 at the 2021 International Conference on Frailty and Sarcopenia Research (ICFSR).

We look forward to engaging with our experts and potentially regulatory authorities to review the data and to advance into the next trial, said Green. He noted that the company expects to begin a Phase I/II HERA trial sometime this quarter. This study will assess the effect of Lomecel-B on immune response to the influenza vaccination in patients with aging frailty. Another Phase II Japanese Aging Frailty trial is also expected to launch this year.

See the original post:
Longeveron's Cell Therapy Shows Mixed Results in Aging Frailty - BioSpace

SAN DIEGO--(BUSINESS WIRE)--Artiva Biotherapeutics, Inc. (Artiva), an oncology company focused on developing and commercializing primary allogeneic natural killer (NK) cell therapies to treat cancer, today announced the expansion of the Companys U.S. facilities in San Diego. The new 52,000-square-foot facility will include research and process development laboratories and a multi-suite custom-built Good Manufacturing Practices (GMP) manufacturing center to support NK and CAR-NK cell production for Artivas pipeline development and clinical trial supply. The new facility and capabilities will be in addition to Artivas continued research and GMP manufacturing at its partner GC LabCells state-of-the-art 300,000-square-foot Cell Center, which comprises research labs, process development labs, and a 50,000-square-foot GMP cell therapy manufacturing facility in the Republic of Korea.

Artivas new San Diego R&D and manufacturing facility is an important element of the Companys expansion and will support research and development for our evolving pipeline of optimized NK and CAR-NK cell therapies for the treatment of cancer, said Peter Flynn, PhD, COO of Artiva. The custom-built manufacturing center will produce clinical product and position Artiva for pivotal studies and potential commercial supply.

Artivas manufacturing-first approach, leveraging more than 10 years of pioneering NK cell therapy R&D by GC LabCell, has enabled us to successfully initiate clinical trials of our first allogeneic, cryopreserved, off-the-shelf NK cell therapy and positions us to file INDs on two novel and distinct CAR-NK cell therapy programs in 2022, added Fred Aslan, M.D., CEO of Artiva. Now with our new facility, we continue to expand and build on our leadership position in the evolving field of allogeneic cell therapies.

Artivas San Diego NK cell therapy research and GMP manufacturing facility will be located at 5505 Morehouse Drive, a building being newly redeveloped by Alexandria Real Estate Equities, Inc. The facility build-out is already underway and is anticipated to be completed in 2022.

We are honored that Artiva approached us to partner on the build-out of this critical new research and manufacturing center that will support the company in its mission to develop and deliver safe, effective and versatile cancer therapies, said Daniel Ryan, Co-Chief Investment Officer and San Diego Regional Market Director of Alexandria Real Estate Equities, Inc.

Artivas cell therapies are designed to leverage the innate anti-tumor biology and safety features of NK cells. The therapies are further optimized using Artivas AlloNK platform for targeted anti-cancer activity by either genetically expressing chimeric antigen receptors (CARs) to drive tumor cell engagement or combining with therapeutic antibodies or innate-cell engagers for antibody-dependent cellular cytotoxicity (ADCC) enhancement. Artivas manufacturing platform supports large-scale production and cryopreservation of off-the-shelf allogeneic NK cell therapies and proprietary CAR-NK and NK-specific gene-editing technologies to augment therapeutic activity.

Artivas Pipeline of NK Cell Therapies for Cancer

Artivas pipeline includes AB-101, an ADCC enhancer NK-cell therapy for use in combination with monoclonal antibodies or innate-cell engagers. The company is currently advancing a Phase 1/2 clinical trial of AB-101 in combination with rituximab for the treatment of relapsed or refractory B-cell lymphomas. The companys CAR-NK programs include AB-201, a novel HER2-specific CAR-NK cell therapy for the treatment of HER2+ solid tumors, and AB-202, a CD19-specific CAR-NK cell therapy for the treatment of B-cell malignancies, both with plans to file INDs in 2022.

About Artiva Biotherapeutics

Artivas mission is to deliver highly effective, off-the-shelf, allogeneic natural killer (NK) cell-based therapies that are safe and accessible to cancer patients. The company has entered into therapeutic NK cell collaborations and/or license agreements with Merck and with Affimed N.V. Artivas AlloNK platform incorporates cell expansion, activation and engineering technology developed by the Companys corporate partner, GC LabCell, a member of the GC family of companies, one of the Republic of Koreas leading biopharmaceutical groups. Artiva is headquartered in San Diego. For more information, visit http://www.artivabio.com.

View original post here:
Artiva Biotherapeutics Establishes U.S. Research and Manufacturing Facility for NK Cell Therapy Pipeline Development and Clinical Supply - Business...

Julie M. Vose, MD, MBA, discusses future research efforts with CAR T-cell therapy in lymphoma.

Julie M. Vose, MD, MBA, Neumann M. and Mildred E. Harris Professor, chief, Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, discusses future research efforts with CAR T-cell therapy in lymphoma.

Ongoing clinical trials are evaluating CAR T-cell therapies, as well as other types of treatment, for patients with lymphoma, Vose says. Moreover, some studies are investigating different designs of CAR T-cell therapies, utilizing CAR T-cell therapy in various subtypes of lymphoma, and potentially incorporating the cellular therapy into earlier lines of treatment, Vose says.These efforts may yield opportunities to decrease CAR T-cell therapyrelated toxicities for patients, Vose explains.

Additionally, research efforts are evaluating whether combination regimens with CAR T-cell therapies and other agents, such as BTK inhibitors, are feasible for patients with lymphoma, Vose says. It may also be possible to utilize pre- and post-CAR T-cell therapy radiation to try to enhance efficacy, Vose continues. Additionally, evaluating different types of monoclonalantibodies, bispecific antibodies, or other new agents alone or in combination with CAR T-cell therapy could lend future treatment options for patients, Vose concludes.

Here is the original post:
Dr. Vose on Future Research Efforts With CAR T-Cell Therapy in Lymphoma - OncLive

Keith Stewart, MD, ChB, MBA: Nina, lets move on to the granddaddy of BCMA-targeted agents, which is CAR T therapy, with chimeric antigen receptor T cells. Lets set the stage. Tell the audience where were at with CAR T therapy, particularly with respect to FDA approvals.

Nina Shah, MD: With BCMA and CAR T-cell therapy, theres 1 product approved, which is IDE-CEL [idecabtagene vicleucel]. Thats approved for patients with at least 4 prior lines of therapy. The data that led to approval was the PRIMA study, which showed a progression-free survival [PFS] of 8.3 months, and 8.7 months, but in the 450-mg dosewhich is going forward, the FDA-approved dosethe PFS was 12 months and 20 months if youve gotten a CR [complete response]. Thats the first approved product. There are other products coming down the line. Were hoping to see how we might be able to transition from a research thing to a standard-of-care thing, much as our lymphoma colleagues did.

Keith Stewart, MD, ChB, MBA: If I understand it correctly, its approved only for people whove had at least 4 lines of prior therapy?

Nina Shah, MD: Correct.

Keith Stewart, MD, ChB, MBA: Do you think thats fair, or do you think the FDA was harsh on that company with that?

Nina Shah, MD: They were a little harsh considering that the clinical trial enrollment criteria were at least 3 prior lines, but what ended up happening is that the patients were so sick, they went on the trial, did so well, and that made the FDA say, If youre going to have any risks for a therapy, it has to match the benefit, and it looks like your fourth-line people are doing as well as the third lines. In fact, there was an analysis this year to look at that. It showed that. So they figured it was OK to use IDE-CEL [idecabtagene vicleucel] in the later lines because the patients would still benefit from it. Its going to be hard for us to get there. Youre going to be using daratumumabRVd [lenalidomide, bortezomib, dexamethasone] up front, and then youre going to use carfilzomib second, selinexor, melphalanI dont know whats going to happen. But theres going to be a single-agent dexamethasone going onto the fourth line.

Keith Stewart, MD, ChB, MBA: Youre going to end up using 4 drugs, plus data, and rather than maintenance when we fail, youre going to go to the CME [continuing medical education]. Thats my guess.

Nina Shah, MD: Yeah. If the insurance company loves it. Correct.

Keith Stewart, MD, ChB, MBA: If the insurance company eventually loves it, and if its up to date. Youre right. Christina, what about adverse effects? Weve heard that these can be quite toxic therapies. Whats your experience with toxicity?

Cristina Gasparetto, MD: Yeah. Fortunately, the majority of patients will adapt, but to develop CRS, cytokine release syndrome, also with cortisol, we learned how to manage this type of toxicity over the last few years. If you look at the toxicity profile, we dont see a lot of the grade 3 and 4. Its more manageable with the tocilizumab [Actemra] intervention. In neurotoxicity as well, to learn to mitigate, theres an association between higher neurotoxicity with a high tumor burden. The study tried to bridge patients, to decrease the tumor burden, to minimize. Thats very important as well. In early intervention, it looks like theres also a link between prior CRS and neurotoxicity. So early intervention with tocilizumab or steroids, and were learning how to use the CAR T-cell as well.

Keith Stewart, MD, ChB, MBA: Joe, todays theme, as were learning, is how to manage this. Do you have any sense of CAR T in the same theme emerging?

Joseph Mikhael, MD: Yeah, I absolutely do. Were not discussing the detail, but lets unfortunately remember that some of the earliest CAR T trials in myeloma left a significant fraction of patients with real, very significant toxicity and even death. So I agree. You know, we have groups around the world that are convening to enhance our management of CRS, of the neurological toxicities that can emerge, and even cytopenia. Theres a deliberate learning curve. Even within the KarMMa trial that Nina described, there was a learning curve. Were becoming more aggressive in using, as Cristina said, the tocilizumab early up front, so it will become significantly safer. Theres always going to be a boutique component to it, Keith. Right? At least until we can start doing AlloCAR T [allogeneic CAR T-cell therapy] or over-the-counter AlloCAR T. Its still going to involve someone having their T cells collected, weeks to do manufacturing, etc, but its going to become considerably safer. It will be safer earlier in the disease course when people arent as beaten down by their myeloma therapy.

Keith Stewart, MD, ChB, MBA: Joe, who would be there? If I work in a community, I want to know who to send to you for CAR T therapy. Whom should I be sending?

Joseph Mikhael, MD: Aligned to the criteria, its interesting. This triple-class refractory space is becoming quite congested. We have selinexor [Xpovio], we have belantamab mafodotin, we have melphalan flufenamidethe artist formerly known as Melflufenand now we have CAR T. Any of those are legitimate medications in that space. We tend to move toward CAR T as quickly as we can because the response rates are double the response rates of any of the other drugs, to be respectful but true. Were seeing response rates over 60%, 70%, and evenas were going to discuss in a moment90%. When you have a patient that you feel can go through the process, which is a little less onerous compared with transplant, with the exception of renal function. Right now, if someone has compromised renal function, were still working through how to do that. But if theyre going to have access to a transplant-like centertheyre the ones that are basically doing CAR TId be favor looking into CAR T-cell therapy after those 4 lines of prior therapy. We hope, with time, that well have indications for CAR T that can allow us to do the therapy earlier.

Keith Stewart, MD, ChB, MBA: Sagar, what about the health of the patient? Is this for everybody? Is it only for the young? Where do you draw the line for this?

Sagar Lonial, MD, FACP: If you draw the line at, Could I take them through the transplant or not? then youre probably missing a lot of people whom you could give CAR T cells to because, in general, its better tolerated than that. Its the frail patient who cant get through it, but dont let age or anything else make that determination. Its harder to make this determination than it is for transplant eligibility.

Keith Stewart, MD, ChB, MBA: We talked about belantamab mafodotin a moment ago. If you saw a patient referred who failed everything in the community, would you use belantamab mafodotin or CAR T?

Sagar Lonial, MD, FACP: Are you asking me?

Keith Stewart, MD, ChB, MBA: Yeah.

Sagar Lonial, MD, FACP: To me, you go through the potential risks and benefits of each of the 2 treatments and lay it out for the patient. There are patients who say, I dont want to go into the hospital for whatever youre going to do to me. That takes CAR T cells away. You describe CRS to them, even though its mild in most patients, but they dont want to be put through that risk. There are other patients to whom any concern about loss of the ability to read or to drive is a deal breaker. For those folks, you know the BLMF is not necessarily going to be the right answer either. Theres a little more to this.

Keith Stewart, MD, ChB, MBA: Let me ask you the same exact question. A patient comes in who was referredand they want some kind of BCMA-targeted therapy. Which of the 2 would you steer the patient toward, or is it individualized? Does cost factor in?

Nina Shah, MD: Yeah. All things are equal. For example, if the patient has support and desire to come to the center, I would pick CAR T-cell therapy because its 1 and done, and has a higher overall response rate and, at this time, a higher PFS. But thats not always the case or isnt always possible because there may be different factors that go into this. But if theyre coming to me, Id like to be able to offer it. The next question is: Can we offer it? Will the commercial scale up be enough to do that? That will be another question for the patients.

Keith Stewart, MD, ChB, MBA: Very good.

Transcript Edited for Clarity

Go here to read the rest:
Using CAR T Therapy for Relapsed/Refractory Myeloma - OncLive

Anita Kumar, MD, discusses navigating CAR T-cell therapyrelated toxicities in mantle cell lymphoma.

Anita Kumar, MD, medical oncologist, Regional Care Network Medical Site Director, MSK Basking Ridge, Memorial Sloan Kettering Cancer Center, discusses navigating CAR T-cell therapyrelated toxicities in mantle cell lymphoma (MCL).

In MCL, treatment with the CAR T-cell therapy brexucabtagene autoleucel (brexu-cel; Tecartus) is associated with a risk of adverse effects, including cytokine release syndrome (CRS) and neurotoxicity, Kumar says. Findings from the phase 2 ZUMA-2 trial (NCT02601313), which data led to the July 2020 FDA approval of brexu-cel, revealed that 15% and 31% of patients developed grade 3 or higher CRS and neurotoxicity, respectively.

To mitigate the toxicity risk with brexu-cel, patients should be well selected, Kumar explains. Factors such as age, comorbidities, and disease status, including tumor burden and time of initial treatment, could be potential predictors for toxicity, Kumar says. As such, the field should work toward developing a greater understanding of how to select patients to optimize efficacy and quality of life, Kumar concludes.

Continued here:
Dr. Kumar on Navigating CAR T-Cell TherapyRelated Toxicities in MCL - OncLive

SUZHOU and SHANGHAI, China, and PALO ALTO, Calif., Aug. 16, 2021 /PRNewswire/ -- Gracell Biotechnologies Inc. (NASDAQ: GRCL) ("Gracell"), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, today announced an exclusive license agreement with FutureGen Biopharm ("FutureGen"), an innovative biopharmaceutical company, to develop engineered immune cell therapies targeting Claudin 18.2 ("CLDN18.2") in solid tumors.

The collaboration aims to leverage Gracell's extensive experience in immune cell therapy in synergy with FutureGen's fully human CLDN18.2 antibodies to develop, manufacture and commercialize novel immune cell therapies for the treatment of patients with CLDN18.2 positive cancers.

CLDN18.2 is a tumor-specific marker that is overexpressed in a variety of tumor tissues, including in gastric or gastroesophageal junction cancers, pancreatic cancers and esophageal cancers, but rarely expressed in normal human tissues. This feature supports the therapeutic potential of CLDN18.2 as a key target for immune cell therapies.In particular, gastric cancer (around 70%[1] CLDN18.2 expression) is among the most frequently diagnosed malignancies worldwide and the second leading cause of cancer-related death. An estimated 1,033,701 new cases and 782,685 deaths occurred in 2018[2], representing a highly unmet medical need in treating gastric cancer.

"Gracell has been making significant progress in developing innovative CAR-T therapies for solid tumors as well as hematological malignancies," Dr. William (Wei) Cao, Founder, Chairman and Chief Executive Officer of Gracell said. "This partnership with FutureGen marks another key milestone in our persistent efforts for treating solid tumors. Moving forward, we expect to explore more strategic alliances to identify additional targets that maximize the value of our highly differentiated technology platforms and eventually benefit cancer patients worldwide."

"Gracell has been optimizing its proprietary Enhanced CAR technology to improve CAR-T cell persistence and efficacy in solid tumors. The preliminary clinical investigator-initiated trial data of our first generation Enhanced CAR-T for solid tumors has shown tolerability and preliminary efficacy. These initial results have been accepted to be published soon in Cellular & Molecular Immunology," said Dr. Lianjun Shen, Senior Vice President, Head of Research and Development at Gracell. "We are very excited to partner with FutureGen to develop next generation immune cell therapies against CLDN18.2-expressing malignancies, and hope to unlock significant potential of our next generation Enhanced CAR-T therapies for solid tumors, one of our founding missions."

Dr. Zhaoyu Jin, the Founder and Chief Executive Officer of FutureGen said, "The specific CLDN18.2 antibody has been developed through our innovative STEP and CAP technology platforms. The fine-tuned affinity of antibody for CAR-T application may eliminate CLDN18.2 positive tumor cells more specifically with better safety profile. We are very excited to collaborate with Gracell, a lead company in the cell and gene therapy industry, to leverage their innovative Enhanced CAR-T technology platform and experience in the field and our proprietary cutting-edge technologies to develop advanced treatments across solid tumors."

Under the terms of the agreement, FutureGen will receive an upfront payment and will be eligible to receive additional payments based on the achievement of non-clinical validation, clinical development and commercialization milestones, as well as low single-digit royalties.

About CLDN18.2

CLDN18.2, a small transmembrane protein with four transmembrane domains and two extracellular loops, is overexpressed in a significant proportion of gastric cancers and esophageal adenocarcinomas. The restricted expression makes it a promising target for the treatment of gastric or gastroesophageal junction cancers, pancreatic cancers, etc.Overall, CLDN18.2 is prevalently expressed in the cancer tissues of approximately 70% of gastric cancer patients and approximately 60% of pancreatic cancer patients. CLDN18.2-specific antibodies developed to target CLDN18.2 have exhibited anti-tumor activity in preclinical studies.[3]

About Enhanced CAR

Enhanced CAR is Gracell's proprietary technology that further strengthens the functionality of CAR-T cells, for example by overcoming the immunosuppressive tumor micro-environment (TME) and/or increasing cytokine signaling. Gracell utilizes gene editing technologies to edit some check point inhibitor(s) or/and cytokine(s) or cytokine receptor(s) on CAR-T cells to release potential suppression from tumor cells and other suppressive immune cells in tumor tissue to enhance CAR-T cells' functionality. Our second generation Enhanced CAR technology can be implemented to many other targets in several types of solid tumors.

About Gracell

Gracell Biotechnologies Inc.("Gracell") is a global clinical-stage biopharmaceutical company dedicated to discovering and developing breakthrough cell therapies. Leveraging its pioneering FasTCAR and TruUCAR technology platforms, Gracell is developing a rich clinical-stage pipeline of multiple autologous and allogeneic product candidates with the potential to overcome major industry challenges that persist with conventional CAR-T therapies, including lengthy manufacturing time, suboptimal production quality, high therapy cost and lack of effective CAR-T therapies for solid tumors. For more information on Gracell, please visit http://www.gracellbio.com.Follow @GracellBio on LinkedIn.

About FutureGen

FutureGen Biopharm ("FutureGen") focuses on precise cancer immunotherapy and drives the development of novel therapeutics through the world's leading antibody engineering technology. The company has developed a Structure-based Targeted Evolution Platform ("STEP") and Cell-based Antibody Panning ("CAP") for antibody discovery and engineering with proprietary intellectual property rights, which can quickly and efficiently screen and optimize a series of candidate drugs that have the potential to be best-in-class antibodies with specific epitopes, ideal affinity and activity, and finest developability. Currently, the ADCC enhanced CLDN18.2 antibody for gastric cancer and pancreatic cancer is at the clinical trial stage, and multiple bispecific therapeutic antibodies are at pre-clinical stage. For more information on FutureGen Biopharm, please visit http://www.futuregen.com.cn/.

Cautionary Noted Regarding Forward-Looking Statements

Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to the expected trading commencement and closing date of the offering. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including factors discussed in the section entitled "Risk Factors" in Gracell's most recent annual report on Form 20-F as well as discussions of potential risks, uncertainties, and other important factors in Gracell's subsequent filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Gracell specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Readers should not rely upon the information on this page as current or accurate after its publication date.

[1] Clinical Implications of Claudin18.2 Expression in Patients With Gastric Cancer[2]Hsu A, Chudasama R, Almhanna K, Raufi A. Targeted therapies for gastroesophageal cancers.Ann. Transl. Med. (2020) 8:1104. doi: 10.21037/atm-20-3265[3]The full-length Claudin 18.2 to accelerate antibody drug development

Media contact

Marvin Tang[emailprotected]

Investor contactGracie Tong[emailprotected]

SOURCE Gracell Biotechnologies Inc.

Read more:
Gracell Biotechnologies Signs Exclusive License Agreement with FutureGen Biopharm to Develop Engineered Immune Cell Therapies Targeting Claudin 18.2...

The open-label, randomized BRUIN trial will compare LOXO-305 to investigators choice of either ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Approximately 500 patients will be enrolled in the study.

"MCL patients who have been treated with a covalent BTK inhibitor have very few therapeutic options, and outcomes are extremely poor. LOXO-305 has demonstrated a promising efficacy profile in these patients, a setting where we urgently need new therapies," said Michael Wang, MD, Puddin Clarke Endowed professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, in a press release.

The primary end point of BRUIN is progression-free survival (PFS), and the secondary end points include event-free survival, time to treatment failure, time to worsening of MCL-related symptoms, comparative tolerability, overall response rate (ORR), duration of response, and overall survival.

A confirmed diagnosis of MCL is required for inclusion in the study as well as being previously treated with at least 1 prior line of systemic therapy for MCL, having measurable disease per Lugano criteria, having an ECOG performance status of 0 to 2, and having adequate laboratory values at baseline.

In the case of prior treatment with an FDA-approved or investigational BTK inhibitor, patients are ineligible to enroll in the study. According to the criteria, patients are also excluded if they have a history of bleeding diathesis, stroke, or intracranial hemorrhage within 6 months of randomization, and prior allogeneic stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. In addition, patients with significant cardiovascular disease, and other comorbidities that may interfere with study treatment are not eligible to enroll.

Treatment with LOXO-305 has already shown promise for the treatment of 323 patients with previously treated B-cell malignancies. In the phase 1/2 BRUIN study, the use of the agent was investigated in patients with MCL, chronic lymphocytic leukemia/small lymphocytic leukemia, Waldenstroms macroglobulinemia (WM), and other B-cell malignancies. The patients were pretreated with a BTK inhibitor (95%), anti-CD20 antibody (98%), chemotherapy (92%), lenalidomide (Revlimid; 20%), autologous transplant (25%), CAR T-cell therapy (5%), and ASCT.3

According to data presented during the 2020 American Society of Hematology Annual Meeting, the ORR observed with LOXO-305 in 59 efficacy-evaluable patients from the MCL cohort was 52% (95% CI, 38%-65%), which included 14 complete and 15 partial responses. The median time to the first response in these patients was 1.8 months.

In the WM cohort of 19 efficacy-evaluable patients, the ORR observed was 68% (95% CI, 44%-87)%, which notably was similar in patients who were previously treated with a BTK inhibitor (69%; 95% CI, 39%-91%). Further, 4 out of 8 patients with follicular lymphoma had a response to LOXO-305, in addition to 75% of the evaluable Richter's transformation cohort, and 8 out of 35 patients with other B-cell malignancies, including diffuse large B-cell lymphoma and marginal zone lymphoma.

The most commonly reported adverse events (AEs) with LOXO-305 in the phase 1/2 BRUIN study were fatigue (20%), diarrhea (17%), and contusion (13%). Eight percent of patients had dose interruptions due to AEs, while 2.2% had dose reduction, and 1.5% permanently discontinued treatment with LOXO-305.

LOXO-305 was designed to overcome some of the limitations seen with current BTK therapies and we believe the promising efficacy and tolerability data demonstrate its potential to be an important new treatment option for MCL patients, said David Hyman, MD, chief medical officer of Loxo Oncology at Lilly, in a press release.

References:

1. Mato AR, Pagel JM, Coombs CC, et al. 542LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 bruin study. . Presented at: 2020 ASH Annual Meeting and Exposition. December 4-8, 2020; Virtual. Abstract 542.

2. Study of BTK inhibitor LOXO-305 versus approved BTK inhibitor drugs in patients withmantle cell lymphoma(MCL) (BRUIN-MCL-321). Clnicaltrials.gov. Accessed August 17, 2021. https://bit.ly/3CXTgu4

3. Loxo Oncology at Lilly announces updated data from the phase 1/2 BRUIN Clinical Trial for LOXO-305 in mantle cell lymphoma and non-Hodgkin lymphomas at the American Society of Hematology (ASH) Annual Meeting. News release. Loxo Oncology at Lilly. December 5, 2020. accessed August 17, 2021. https://prn.to/37QNw7a

Continued here:
Head-To-Head Phase 3 Trial To Evaluate BTK Inhibitors in MCL - Targeted Oncology