On June 15, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported at the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland and presented updated data from the Phase 1 ALPHA/ALPHA2 trials of ALLO-501/501A in 33 CAR T naïve patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) treated with the Alloy manufacturing process material across different CAR T dosing and lymphodepletion regimens (Press release, Allogene, JUN 15, 2023, View Source [SID1234632717]). Earlier in June, data from the 12 patients, a subset of these 33 CAR T naïve patients, who received regimen being utilized in ongoing Phase 2 trials was presented at American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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"We believe these data provide strong support for the ability of our product candidates to induce durable complete remissions at a rate similar to approved autologous CD19 CAR T therapies," said Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer. "The design and execution of our Phase 1 ALPHA/ALPHA 2 trials enabled a systematic evaluation of potential Phase 2 treatment regimens. Based on these data, we were able to select an optimal dosing regimen that we believe will be capable of delivering the benefit of CAR T treatment to patients without the lengthy wait time and risk of manufacturing failure associated with autologous CAR T. We have now turned our attention to enrolling our potentially pivotal Phase 2 trials as quickly as possible."

The updated analysis (data cutoff April 20, 2023) of ALPHA/ALPHA2 examined data from all 33 CAR T-naïve patients with r/r LBCL who were treated with a single infusion or consolidation therapy (two planned infusions) of ALLO-501/501A manufactured using the Alloy manufacturing process. Patients received lymphodepletion with fludarabine (30 mg/m2/day x 3 days) and cyclophosphamide (300 mg/m2/day x 3 days) and varying doses of ALLO-647 (from 13 mg/day to 30 mg/day x 3 days).

The median time from enrollment to the start of therapy was three days and 100% of patients received product per specifications. No patients received bridging therapy. The dosing breakdown for the 33 patients included in this data set is as follows:

12 patients treated with a single dose of ALLO-501/501A and FCA90 lymphodepletion (Phase 2 regimen; recap of the ASCO (Free ASCO Whitepaper) 2023 data presentation)
6 patients treated with a single dose of ALLO-501/501A and FCA<90 lymphodepletion
15 patients treated with consolidation dosing of ALLO-501/501A and split lymphodepletion
CAR T- Naïve Patients with r/r LBCL
Alloy Manufacturing Process
All
(N=33) Phase 2
Regimen (N=12) FCA<90
(N=6) Consolidation
Dosing (N=15)
Overall Response Rate (ORR), n (%) 19 (58) 8 (67) 3 (50) 8 (53)
Complete Response Rate (CR), n (%) 14 (42) 7 (58) 1 (17) 6 (40)
6 Month Complete Response, n (%) 10 (30) 5 (42) 0 5 (33)

Seven of 12 (58%) patients receiving the Phase 2 regimen achieved a CR and five (42%) maintained a CR through Month 6. Of the five patients who were in CR at 6 months, four (80%) remained in CR. The fifth patient had disease progression at 24 months. The median duration of response was 23.1 months with three patients remaining in remission for over 24 months and the longest remaining in remission for over 31 months. Across all 33 patients the CR rate was 42% with 30% maintaining a CR at Month 6. These results indicate complete responses are more common with lymphodepletion regimens containing 90 mg of ALLO-647 (FCA90). Median duration of response for both the overall population (n=33) and the patients treated with the Phase 2 regimen (n=12) was 23.1 months.

CAR T- Naïve Patients with r/r LBCL
All
(N=33) Phase 2
Regimen (N=12) FCA<90
(N=6) Consolidation
(N=15)
All Gr
N (%) Gr 3+
N (%) All Gr
N (%) Gr 3+
N (%) All Gr
N (%) Gr 3+
N (%) All Gr
N (%) Gr 3+
N (%)
CRS 8 (24) 0 4 (33) 0 1 (17) 0 3 (20) 0
Neurotoxicity 13 (39) 2 (6) 4 (33) 0 2 (33) 0 7 (47) 2 (13)
ICANS 0 0 0 0 0 0 0 0
GvHD 0 0 0 0 0 0 0 0
IRR 16 (49) 3 (9) 8 (67) 0 3 (50) 1 (17) 5 (33) 2 (13)
Infection 19 (58) 5 (15) 8 (67) 1 (8) 3 (50) 1 (17) 8 (53) 3 (20)
Prolonged Gr3+ Cytopenia - 4 (12) - 2 (17) - 0 - 2 (13)

Across the 33 patients, treatment was generally well tolerated with no incidences of Grade 3 or greater cytokine release syndrome, and no cases of immune effector cell-associated neurotoxicity syndrome or graft versus host disease. Cytopenia and infections were manageable and comparable to the experience with autologous CAR T cell therapies in patients with r/r LBCL.

The ALPHA/ALPHA2 Phase 1 trials were designed to assess the safety, tolerability, and preliminary efficacy at increasing dose levels of ALLO-501 and ALLO-501A, allogeneic CAR T cell product candidates that target CD19. In addition to exploring multiple cell doses, these studies evaluated various doses of ALLO-647, Allogene’s proprietary lymphodepleting antibody designed to prevent premature rejection of AlloCAR T cells. Allogene is currently enrolling the potentially pivotal Phase 2 ALPHA2 trial of ALLO-501A in LBCL and expects to complete enrollment in 1H2024. The Company expects to open trial sites in Europe, Canada and Australia during 2023.

About ALLO-501 and ALLO-501A
ALLO-501 and ALLO-501A are anti-CD19 AlloCAR T investigational products for the treatment of large B cell lymphoma. ALLO-501A, a next-generation anti-CD19 AlloCAR T, eliminates the rituximab recognition domains in ALLO-501, which could allow for use in a broader patient population, including NHL patients with recent rituximab exposure. This product candidate is currently being studied in an ongoing potentially pivotal Phase 2 trial. In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to ALLO-501A in r/r LBCL.

On June 15, 2023 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global biotechnology company, reported that it will present data on its Bruton’s tyrosine kinase inhibitor (BTKi) BRUKINSA (zanubrutinib) at the 17th International Conference on Malignant Lymphoma (ICML), which is taking place from June 13-17 in Lugano, Switzerland (Press release, BeiGene, JUN 15, 2023, View Source [SID1234632709]).

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"The data presented at ICML provide further evidence supporting our confidence in BRUKINSA. Notably, an updated analysis with a median follow-up of 20.2 months, reinforced previous results from the Phase 2 ROSEWOOD trial of BRUKINSA in combination with obinutuzumab," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology. "We recently announced EMA acceptance of our filing for BRUKINSA in combination with obinutuzumab as a treatment for patients with relapsed or refractory follicular lymphoma who received at least two prior lines of therapy; and additional worldwide regulatory submissions are ongoing."

In an updated analysis from the Phase 2 ROSEWOOD trial shared as an oral presentation at ICML, BRUKINSA in combination with obinutuzumab demonstrated clinically meaningful activity and was generally well-tolerated in patients with heavily pretreated relapsed or refractory (R/R) follicular lymphoma (FL).

BRUKINSA in combination with obinutuzumab showed an overall response rate of 69.0% versus 45.8% in the obinutuzumab arm (p = 0.0012) and median follow-up of 20.2 months. The complete response rate for BRUKINSA in combination with obinutuzumab was 39.3% compared to 19.4% for obinutuzumab alone. Non-hematologic treatment-emergent adverse events of any grade that occurred more frequently (>5% difference) in the combination group were petechiae (6.3% vs. 0%) and herpes zoster infection (6.3% vs. 0%); in contrast, pyrexia (13.3% vs. 19.7%) and infusion-related reaction (2.8% vs. 9.9%) occurred more frequently in patients receiving obinutuzumab alone.

These results will be presented on June 16, 2023, 3:30 – 5:00 pm CEST. (Abstract #81)

Demonstrating a commitment to developing rigorous evidence for potential new treatments for rare hematologic malignancies, BeiGene will detail the trial design of its Phase 3 MAHOGANY study (NCT05100862) of BRUKINSA plus obinutuzumab versus lenalidomide plus rituximab in R/R FL or marginal zone lymphoma in an oral presentation during the Ongoing Trials Session. (Abstract #994)

Additional Data Further Demonstrate Safety and Efficacy Profile for BRUKINSA

At a median follow-up of 43.7 months, extended follow-up data from the pivotal Phase 3 SEQUOIA study (NCT03336333) showed BRUKINSA efficacy was maintained in patients with treatment-naïve CLL/SLL without del(17p) and patients with del(17p) receiving BRUKINSA continued to show progression-free survival (PFS) benefit consistent with the randomized cohort. Rates of atrial fibrillation remained low, and no new safety signals were identified. BRUKINSA continues to be well tolerated over time, with low rates of treatment discontinuation. (Abstract #154)

In a subgroup analysis of the Phase 3 ALPINE trial (NCT03734016), BRUKINSA showed improved PFS over ibrutinib in patients in China with R/R chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), consistent with the global study population. A favorable safety profile was also observed with BRUKINSA compared with ibrutinib, with lower rates of treatment discontinuations and serious adverse events. (Abstract #592)

Preliminary results for the CLL/SLL subgroup of an ongoing Phase 2 trial (NCT04116437) evaluating BRUKINSA in patients with various previously treated with B-cell malignancies who are intolerant to ibrutinib and/or acalabrutinib, demonstrated that treatment with BRUKINSA was well-tolerated and unlikely to lead to recurrence of intolerant adverse events experienced with prior BTK-inhibitor therapy, suggesting BRUKINSA may be a treatment option for these patients. (Abstract #345)

Initial findings from a Phase 2 trial (NCT03824483) of long-term follow-up of BRUKINSA, obinutuzumab and venetoclax (BOVen) demonstrated high rates of durable undetectable minimal residual disease (MRD) in CLL/SLL patients administered BOVen. Of the 46 patients meeting MRD criteria to cease treatment, median time from end of treatment to MRD conversion was 29.8 months. The most common grade ≥3 adverse events were neutropenia (23.1%), thrombocytopenia (7.7%), lung infection (5.8%) (Abstract #153)

More details on BeiGene’s abstracts are available in the ICML online program.

About BRUKINSA (zanubrutinib)

BRUKINSA is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

BRUKINSA is supported by a broad clinical program which includes more than 4,900 patients in 35 trials across 29 markets. To date, BRUKINSA is approved in more than 65 markets around the world, including the United States, China, the European Union, Great Britain, Canada, Australia, South Korea, and Switzerland. The product information may differ from country to country. Prescribers should consult the product information approved in their respective country.

IMPORTANT U.S. SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher hemorrhage, including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 3.6% of patients treated with BRUKINSA monotherapy in clinical trials, with fatalities occurring in 0.3% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 30% of patients.

Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 24% of patients, most commonly pneumonia (11%), with fatal infections occurring in 2.9% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred. Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (22%), thrombocytopenia (8%) and anemia (7%) based on laboratory measurements, developed in patients treated with BRUKINSA monotherapy. Grade 4 neutropenia occurred in 11% of patients, and Grade 4 thrombocytopenia occurred in 2.8% of patients.

Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 13% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was non-melanoma skin cancer reported in 7% of patients. Other second primary malignancies included malignant solid tumors (5%), melanoma (1.2%), and hematologic malignancies (0.5%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

Cardiac Arrhythmias

Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 3.7% of 1550 patients treated with BRUKINSA monotherapy, including Grade 3 or higher cases in 1.7% of patients. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.2% of patients.

Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment.

Embryo-Fetal Toxicity

Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Adverse Reactions

In this pooled safety population, the most common adverse reactions, including laboratory abnormalities, in ≥30% of patients who received BRUKINSA (N=1550) included decreased neutrophil count (42%), upper respiratory tract infection (39%), decreased platelet count (34%), hemorrhage (30%), and musculoskeletal pain (30%).

Drug Interactions

CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily. For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.

CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.

Specific Populations

Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily.

U.S. INDICATIONS

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with:

Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen
The MCL and MZL indications are approved under accelerated approval based on overall response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Please see full U.S. Prescribing Information at www.beigene.com/PDF/BRUKINSAUSPI.pdf and Patient Information at www.beigene.com/PDF/BRUKINSAUSPPI.pdf

On June 14, 2023 Maru Therapeutics reported the company signed a business agreement with TS Bio on May 8 for joint research and development of CAR-NK cell therapy (Press release, Maru Therapeutics, JUN 14, 2023, View Source [SID1234643988]). Accordingly, the two companies plan to establish a strategy for the development of blood-based CAR-NK cell therapy and begin full-scale cooperation for (non-)clinical research.

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Cell manufacturing (CMO) during the joint research and development process between the two companies is planned to be carried out at TS Bio’s central research center at the GMP level.

Maru Therapeutics CEO Sangman Ahn said, "Maru’s innovative platform technology has the scalability to be applied to various immune cells and carcinomas," and added, "Through this collaboration, we will not only expand our R&D area with TS Bio, but also accelerate development." "We will accelerate it," he said.

On June 14, 2023 T-Cure Bioscience, Inc., a privately held company focused on developing T cell receptor (TCR) therapy products for the treatment of solid tumors, reported that the management will present virtually at the following upcoming healthcare conferences (Press release, T-Cure Bioscience, JUN 14, 2023, View Source;utm_medium=rss&utm_campaign=june-14-2023-t-cure-bioscience-announces-dr-gang-zeng-guest-speaker-at-two-upcoming-immunotherapy-summits-2 [SID1234632775]):

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11th Annual Immuno-oncology Summit, August 7-9th in Boston

"Emerging Cell-based Immunotherapies" venue on Aug 8. Brochure PDF – https://immuno-oncologysummit.com/docs/librariesprovider48/brochures/23/Immuno-Oncology-Summit-Final-Brochure-2023.pdf

8th CAR-TCR Summit, Aug 29th-Sept 1st in Boston

"De-risking TCRs to Ensure Safety". Find out more here: View Source #CARTCR #immunotherapy #celltherapy #celltherapies #cellandgene #immunology

On June 14, 2023 LAVA Therapeutics N.V. (Nasdaq: LVTX), a clinical-stage immuno-oncology company focused on developing its proprietary Gammabody platform of bispecific gamma-delta T cell engagers, reported its decision to rationalize its pipeline and prioritize its lead solid tumor program (Press release, Lava Therapeutics, JUN 14, 2023, View Source [SID1234632728]). The Company will continue to advance LAVA-1207, its Gammabody program designed to target the prostate-specific membrane antigen (PSMA) as well as earlier stage programs. The ongoing clinical trial of LAVA-051 targeting CD1d expressing hematological tumors, including multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) will be discontinued (NCT04887259).

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LAVA-051 was being evaluated in an open-label, muti-center Phase 1/2a clinical trial in patients with relapsed or refractory CLL and MM to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary anti-tumor activity of LAVA-051. The decision to discontinue LAVA-051’s clinical trial follows a recent review of the competitive landscape that has continued to evolve. The decision is not due to safety concerns.

"We started this trial to investigate the potential for a bispecific gamma-delta T cell engager to help patients with hematological malignancies. We are pleased the trial data to date showed a favorable safety profile, gamma delta T cell activation, and early signals of potential anti-tumor activity in CLL and MM," said Steve Hurly, chief executive officer at LAVA. "However, there have been significant advancements in the treatment of multiple myeloma and chronic lymphocytic leukemia. As a result, we have decided to discontinue this trial and focus our resources on LAVA-1207, partnered programs, and our pipeline. This is a decision to prioritize our programs with the greatest potential to benefit patients. We are grateful to the patients, their families, and the investigators who participated in the trial and contributed to this research on the Gammabody platform. We garnered a lot of knowledge from this trial and are resolute in our commitment to apply these learnings to the Gammabody platform, to contribute to the development of immuno-oncology products to treat patients with cancer in areas of unmet need."

LAVA-1207 is a Gammabody designed to target the prostate-specific membrane antigen (PSMA) to trigger the potent and preferential killing of PSMA-positive tumor cells in patients with metastatic castration-resistant prostate cancer (mCRPC). The ongoing Phase 1/2a study of LAVA-1207 in patients with therapy refractory mCRPC has thus far demonstrated a favorable safety profile as well as preliminary signs of anti-tumor activity with disease stabilization and PSA reduction during dose escalation in this heavily pretreated patient population.

Dr. Charles Morris, LAVA’s Chief Medical Officer, added, "We are excited about the potential for LAVA-1207 in patients with mCRPC. Immunotherapies have yet to firmly establish a role in the treatment of mCRPC and there is a clear unmet need for new therapies in patients who have progressed on currently approved treatments. Enrollment in our Phase 1/2a study of LAVA-1207 has been encouraging and we remain optimistic about the potential for the Gammabody platform."

The Company expects that the discontinuation of this LAVA-051 trial and its focus on the LAVA-1207 program will result in cost savings that will extend its cash runway further into 2026.