On December 13, 2022 Cellectis S.A. (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported that it will host a live webcast reviewing updated clinical data on its Phase 1/2a BALLI-01 clinical trial (evaluating UCART22) and on its Phase 1 AMELI-01 clinical trial (evaluating UCART123) that were presented in an oral session on December 12, 2022 at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Cellectis, DEC 13, 2022, View Source [SID1234625188]).

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Preliminary Data from the BALLI-01 Clinical Study

BALLI-01 is a Phase 1/2a open-label dose-escalation trial evaluating the safety and clinical activity of UCART22 given at escalating dose levels after lymphodepletion (LD) with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL). Alemtuzumab was added to the LD regimen to sustain host T-cell and Natural Killer (NK) cell depletion and to promote UCART22 cell expansion and persistence.

Compared to the last clinical update on BALLI-01 at ASH (Free ASH Whitepaper) 2021, the webcast presented data from five additional patients who received UCART22 at dose level 3 (DL3) 5×106 cells/kg after lymphodepletion with FCA. No dose limiting toxicities (DLTs), Grade 2 or higher cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or adverse events of special interest (AESI) were observed.

Evidence of UCART22 anti-tumor activity was observed in 60% (n=3) of the five patients at DL3 after lymphodepletion with FCA:

A patient experienced a durable minimal residual disease (MRD) negative complete response with incomplete count recovery (CRi) that continues beyond 6 months.

A patient experienced an MRD negative complete response (CR) that continues beyond Day 56.

A patient experienced a morphologic leukemia-free state (MLFS) that continues beyond Day 84 (MRD-negative until Day 84; MRD-positive at Day 117).

All three of the responders failed multiple lines of prior therapy including chemotherapy, CD19-directed autologous CAR T cell therapy, and allogeneic stem cell transplant. Additionally, the patient with the MRD negative CR also failed both prior blinatumomab (a CD19-directed bi-specific antibody) and inotuzumab (a CD22-directed antibody-drug conjugate).

"These treatment responses in combination with the safety data are very encouraging for patients with r/r B-cell ALL who have limited, if any, treatment options, especially for those who have failed prior CD19 directed CAR T-cell therapy and allogeneic stem cell transplant’, said Nitin Jain, M.D., The University of Texas MD Anderson Cancer Center, Department of Leukemia, and coordinating investigator for the BALLI-01 study.

Next Steps

Overall, these preliminary data support the continued administration of UCART22 after FCA lymphodepletion in patients with r/r ALL. The Company is now enrolling patients in BALLI-01 with product candidate manufactured fully in-house at DL2 after FCA lymphodepletion. The first patient has been dosed at dose level 2 (DL2) 1×106 cells/kg. The next data set is expected to be released in 2023.

Preliminary Clinical Data from the AMELI-01 Study Presented at ASH (Free ASH Whitepaper) 2022

AMELI-01 is a Phase 1 open-label dose-escalation trial evaluating the safety, tolerability, expansion and preliminary activity of UCART123 given at escalating dose levels after lymphodepletion (LD) with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients with relapsed or refractory acute myeloid leukemia (r/r AML).

The oral presentation reviewed preliminary data from patients who received UCART123 at one of the following dose levels: dose level 1 (DL1) 2.5×105 cells/kg; dose level 2 (DL2) 6.25×105 cells/kg; intermediate dose level 2 (DL2i) 1.5×106 cells/kg; or dose level 3 (DL3) 3.30×106 cells/kg after lymphodepletion with FC ([n=8], DL1 – DL3) or FCA ([n=9], DL2 & DL2i).

Preliminary Safety Data

The FCA LD regimen resulted in robust lymphodepletion for greater than 28 days in all patients. Seven out of nine patients demonstrated UCART123 expansion, with maximum concentration (C max) ranging from 13,177 to 330,530 copies/µg DNA, an almost nine-fold increase compared with FC LD, and a significant increase in area under the curve (AUC)(0-28 days) (p=0.04; FC 10.2±15.7 vs. FCA 34.9±28.4).

Cytokine release syndrome (CRS) occurred in eight patients in the FC arm and nine patients in the FCA arm. In the FC arm, one patient experienced Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and two patients experienced Grade 4 protocol-defined dose limiting toxicities (DLTs) secondary to CRS. In the FCA arm, two patients experienced Grade 5 DLTs secondary to CRS. Grade 4 toxicities are potentially life threatening and Grade 5 toxicities result in death.

Preliminary Efficacy Data

Evidence of UCART123 anti-tumor activity was observed in four patients out of fifteen at DL2 or above with best overall responses in the FCA arm. Two out of eight patients (25%) at DL2 with FCA arm achieved meaningful response:

•
A patient who failed five prior lines of therapy experienced a durable minimal residual disease (MRD) negative complete response (CR) with full count recovery at Day 56 that continues beyond one year.

•
A patient with stable disease achieved greater than 90% bone marrow blast reduction (60% to 5%) at Day 28.

"Exemplary activity was seen in a 64-year-old female with AML who had relapsed after allogeneic stem cell transplantation (allo-SCT) and has maintained a durable MRD-negative complete response for over one year without salvage donor lymphocyte infusion or second allo-SCT," said David A. Sallman, M.D., Moffit Cancer Center, Department of Malignant Hematology, Tampa, FL. "Overall, these encouraging clinical data are a meaningful step forward for patients and support further enrollment into the study. This trial addresses a patient population with severe unmet medical need, where a successful CAR T-cell product candidate could be a major breakthrough."

The preliminary data show that adding alemtuzumab to the FC LD regimen was associated with sustained lymphodepletion and significantly higher UCART123 cell expansion, which correlated with improved anti-tumor activity.

Next Steps: 2-Dose Regimen

Overall, these preliminary data support the continued administration of UCART123 after FCA lymphodepletion in patients with r/r AML. Based on observed UCART123 expansion patterns and cytokine profiles, pursuant to an amended protocol (as described below), a second dose of UCART123 will be given after 10-14 days to allow for additional UCART123 expansion and clinical activity without the use of additional lymphodepletion. The second expansion phase in the setting of reduced disease burden is expected to be safe and allow for clearance of residual disease.

After a protocol-based pause in patient recruitment following a Grade 5 event related to CRS, the protocol treatment strategy has been modified and AMELI-01 has now commenced enrolling patients in the FCA 2-dose regimen arm at DL2, a dose that has already been administered and cleared for safety as a single dose. The arm incorporates the use of prophylactic tocilizumab, which is associated with reduced incidence of CRS.

A copy of the ASH (Free ASH Whitepaper) oral presentation is available on Cellectis’ website.

"These clinically meaningful preliminary data from both the BALLI-01 and AMELI-01 studies are very encouraging for patients and for the future of allogeneic CART-cell therapy. Both ALL and AML are diseases with an urgent need for alternative treatment options for patients, and we are excited to be moving each of these studies forward," said Dr. Mark Frattini, M.D., Ph.D., Chief Medical Officer at Cellectis. "We are now implementing a two-dose regimen arm for our AMELI-01 trial, as well as enrolling patients with in-house manufactured product for our BALLI-01 trial. We look forward to sharing future updates as they become available for both of these clinical studies."

Pipeline Overview

The following chart highlights our and our licensee’s key product candidates:

(1)
ALLO-501 and ALLO-501A are exclusively licensed to Servier and under a joint clinical development program between Servier and Allogene. The ALPHA and ALPHA2 studies targets Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) indications, which are subtypes of NHL.

(2)
Phase 3 may not be required if Phase 2 is registrational.

(3)
ALLO-715 and ALLO-605 target BCMA which is a licensed target from Cellectis. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the BCMA target. Allogene holds global development and commercial rights for this Investigational candidate.

(4)
Allogene is promoting this clinical trial in combination with SpringWorks Therapeutics.

(5)
ALLO-316 targets CD70 which is a licensed target from Cellectis.. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the CD70 target. Allogene holds global development and commercial rights for this investigational candidate.

As of September 21, 2022, Servier has notified Allogene that Servier was discontinuing involvement in the development of CD-19-targeting allogeneic CAR T-cell products.

NATHALI-01 Study (evaluating UCART20x22):

Cellectis is enrolling patients at dose level 1 (50×106 cells) with a fludarabine, cyclophosphamide, and alemtuzumab lymphodepletion regimen in the NATHALI-01 Phase 1 dose-escalation clinical study of UCART20x22. UCART20x22 is Cellectis’ first allogeneic dual CAR T-cell product candidate being developed for patients with relapsed or refractory non-Hodgkin lymphoma and fully designed, developed and manufactured in-house.

MELANI-01 Study (evaluating UCARTCS1):

Cellectis is enrolling patients at dose level 1 (1.0×106 cells/kg) with a fludarabine and cyclophosphamide (FC) lymphodepletion regimen in the MELANI-01 Phase 1 dose-escalation clinical study of UCARTCS1 for patients with relapsed or refractory multiple myeloma (MM).

ASH 2022 Poster Presentation on UCARTCS1, in Collaboration with Amsterdam UMC

On December 10, 2022, the Amsterdam University Medical Center (VUmc location), in collaboration with Cellectis, presented preclinical data in a poster session showcasing Cellectis’ UCARTCS1 product candidate. These initial preclinical data demonstrated anti-tumor activity in vitro and in vivo, supporting the potential benefit of Cellectis’ UCARTCS1 first in-human study MELANI-01.

Collectively, the preclinical data demonstrated that UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in a MM xenograft model. These preclinical data support the ongoing Phase 1 clinical trial with UCARTCS1 in heavily pretreated multiple myeloma patients.

A copy of the poster presentation is available here on Cellectis’ website.

Webcast Information

The event will feature presentations by the management team and will be followed by a live Q&A. A replay of the webcast will be made available under the "Events and Webcasts" section on the Investor page of the Company’s website: View Source

In this context, the listing of the Company’s ordinary shares on Euronext Growth will be suspended on December 13, 2022 until the opening of trading of Cellectis’ ADSs on the Nasdaq Global Market at 3:30 pm (Paris time)/ 9:30 a.m. (New York time).

On December 13, 2022 MAIA Biotechnology, Inc. (NYSE American: MAIA) ("MAIA," "the Company"), reported that regulatory authorities in three European countries, Hungary, Poland, and Bulgaria, have approved the implementation of THIO-101, MAIA’s Phase 2 clinical trial evaluating its lead therapeutic candidate, THIO, in patients with Non-Small Cell Lung Cancer (NSCLC) (Press release, MAIA Biotechnology, DEC 13, 2022, View Source [SID1234625166]). The first patients in THIO-101 were dosed in Australia earlier this year.

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"Adding EU sites to THIO-101 officially makes it a global trial. We believe the data that THIO-101 generates will further validate THIO and be a major step towards bringing effective therapies to lung cancer patients."

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THIO-101 is designed to evaluate THIO’s potential immune system activation effects in NSCLC patients by administering THIO in advance of administration of Regeneron’s anti-PD1 therapy, Libtayo (cemiplimab), allowing for immune system activation and sensitivity to the PD-1 inhibitor to take effect. The primary objectives of the trial are to evaluate the safety and tolerability of THIO administered as a direct anticancer and priming immune system agent prior to cemiplimab administration, as well as to evaluate the clinical efficacy of THIO in patients with advanced NSCLC who either progressed or relapsed through treatment with an immune-check point inhibitor alone or in combination with chemotherapy.

"Adding EU sites to the THIO-101 study increases patient access to THIO on a global scale. Lung cancer is the second most common cancer indication, so addressing it requires worldwide research efforts," said MAIA Chief Medical Officer Mihail Obrocea, M.D. "Adding EU sites to THIO-101 officially makes it a global trial. We believe the data that THIO-101 generates will further validate THIO and be a major step towards bringing effective therapies to lung cancer patients."

"THIO-101 is a critical component of THIO’s clinical development process and it is of the utmost importance that we collaborate with leading cancer institutes in Australia and now in Europe, for a target total of 30 clinical trial sites in six countries," said MAIA Chairman and Chief Executive Officer Vlad Vitoc, M.D. "European sites will be excellent additions to this clinical trial. We look forward to the role they will play in the evolution and expansion of this trial, which will continue validating our telomere-targeting approach."

On December 13, 2022 BeyondSpring Inc. (the "Company" or "BeyondSpring") (Nasdaq: BYSI), a clinical stage global biopharmaceutical company focused on developing innovative cancer therapies, reported data from the ESMO (Free ESMO Whitepaper) Asia Congress 2022 and the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting about the use of lead asset, plinabulin, for the prevention of docetaxel-induced neutropenia (DIN) in non-small cell lung cancer (NSCLC) patients. In addition, data was presented on plinabulin for the prevention of docetaxel-induced neutropenia in breast cancer (BC in the 105 study) at the 2022 San Antonio Breast Cancer Symposium (SABCS). The analyses in the NSCLC studies support the efficacy of plinabulin as a monotherapy in reducing the mean duration of severe neutropenia (DSN) with a >1 day benefit for patients receiving docetaxel and plinabulin (compared to patients not receiving plinabulin) in two independent randomized trials (study 101 and 103).

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"Docetaxel-induced neutropenia can cause life-threatening infections in cancer patients, and the current standard of care, prophylactic treatment with a G-CSF in high-risk patients, has limitations. It has to be administered 24 hours following chemotherapy, and patients can experience post-treatment bone pain, a mild reduction in platelet count and a decline in quality of life," said Dr. Douglas Blayney, professor of medicine (oncology) emeritus at Stanford University Medical School and global principal investigator for the plinabulin neutropenia prevention studies. "The data that we presented at these three conferences demonstrate that plinabulin can provide solutions for some of the challenges seen with G-CSF. Plinabulin is given on the same day as chemotherapy as a short infusion, has minimal associated bone pain, no reduction in platelet count and quality of life is maintained throughout the course of therapy. Importantly, the analyses showed a reduction in mean DSN of one day or more in NSCLC patients receiving plinabulin vs placebo (no G-CSF), which is the gold standard for regulatory review."

Trials Mentioned in the Abstracts

study 101: Phase 2 study of plinabulin and docetaxel (75 mg/m2) docetaxel alone (75 mg/m2) in 2nd/3rd line NSCLC (NCT00630110)
study 103: Phase 3 study of plinabulin and docetaxel (75 mg/m2) docetaxel alone (75 mg/m2) in 2nd/3rd line NSCLC (NCT02504489)
study 105: Phase 2/3 study of plinabulin vs. pegfilgrastim with docetaxel (75 mg/m2) treatment in NSCLC, breast cancer and prostate cancer (NCT03102606)
Poster Presentation at the ASH (Free ASH Whitepaper) Annual Meeting

Title: Prevention of Docetaxel (Doc)-Induced Neutropenia (DIN) with Single Agent Plinabulin (Plin) Versus (vs) Control (No-Treatment or Placebo) in Non-Small Cell Lung Cancer (NSCLC) in Two Randomized Trials

Presentation Number: 1094

Presenter: Dr. Douglas Blayney, professor of medicine (oncology) emeritus at Stanford University Medical School and global principal investigator for the plinabulin neutropenia prevention studies

The presentation summarized data from two randomized NSCLC studies (study 101 and 103), and DIN results were compared between the plinabulin arm and the control arm (placebo or no treatment). The DSN was calculated based on Day 8 absolute neutrophil count (ANC) values in the plinabulin and control arms.

In NSCLC patients, docetaxel 75 mg/m2 is typically used without G-CSF prophylaxis ("no treatment"). This analysis focuses on the effectiveness of plinabulin (20 mg/m2 or its pharmacokinetic equivalent exposure) control for the prevention of DIN in the 101 and 103 studies.
In summary, in these two independent randomized studies, plinabulin demonstrated a superior benefit for Gr4N, Gr3/4N, all GrN and DSN compared to the control. Importantly, in both these randomized studies, there was a reduction in mean DSN of >1 day for plinabulin vs. control.
Oral Presentation at ESMO (Free ESMO Whitepaper) Asia Congress 2022

Title: Superior single agent effectiveness with plinabulin (Plin) versus (vs) placebo (Plac) for docetaxel (Doc)-induced neutropenia (DIN) prevention in non-small cell lung cancer (NSCLC) patients (pts)

Presentation Number: 276MO

Presenter: Dr. Douglas Blayney, professor of medicine (oncology) emeritus at Stanford University Medical School and global principal investigator for the plinabulin neutropenia prevention studies

The presentation summarized DIN data from a non-randomized comparison derived from two different studies: plinabulin data from study 105 and the control (placebo or no treatment) data from study 103.

In the 105 study, NSCLC pts with at least one febrile neutropenia (FN) risk factor received docetaxel 75 mg/m2 with plinabulin (20 mg/m2 or its equivalent of 40 mg fixed dose, n=30).
In the 103 study, patients received docetaxel 75 mg/m2 without plinabulin (placebo; n=224).

In summary, plinabulin was superior for the prevention of DIN and hematologic complications vs control: Grade 4 Neutropenia: 17% with plinabulin vs 40% with placebo (p-value=0.02). In addition, the mean DSN was 0.43 days for plinabulin vs. 1.32 days for placebo (p-value=0.002). There was also a favorable quality of life and safety profile with plinabulin.
Poster Presentation at SABCS

Title: Superior effectiveness of Plinabulin (Plin) versus no-treatment for Docetaxel (Doc)-induced neutropenia (N) and other hematologic complication in breast cancer (BC) patients

Presentation Number: P1-12-10

Presenter: Dr. Douglas Blayney, professor of medicine (oncology) emeritus at Stanford University Medical School and global principal investigator for the plinabulin neutropenia prevention studies

The presentation summarized DIN data for plinabulin from study 105 and the control data (placebo or no treatment) was taken from the literature.

The hematologic complications endpoints from the 27 early breast cancer patients with at least one NCCN high FN risk factor (N=27) from the Phase 3 portion of 105 study were compared with the no-treatment studies from literature where patients were given 75 mg/m2 docetaxel without G-CSF (Harvey et al., JCO, 2006 and Dieras et al., Br J Ca, 1996). Blood sampling in the no-treatment studies (Harvey and Dieras) were infrequent and likely underestimated the true grade 4 neutropenia frequency.
In summary, despite a higher frequency of ANC sampling in cycle 1, plinabulin was superior vs no-treatment for DIN and hematologic complications. Quality of life was maintained, and there were minimal adverse effects including minimal bone pain burden in the plinabulin arm vs. no-treatment.

About Plinabulin

Plinabulin, BeyondSpring’s lead asset, is a selective immunomodulating microtubule-binding agent, which is a potent antigen presenting cell (APC) inducer that is being developed as an anticancer agent. Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anti-cancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells and the second is a CIN prevention benefit. Plinabulin has single agent anti-cancer activity in a number of cancers including small cell lung cancer (SCLC) and multiple myeloma (MM). Plinabulin also exerts early-onset of action in the prevention of chemotherapy-induced neutropenia (CIN) by boosting the number of hematopoietic stem/progenitor cells (HSPCs).

On December 13, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235) a global biotechnology company, reported the final progression-free survival (PFS) analysis of the ALPINE trial demonstrating superior efficacy and a favorable cardiac safety profile for patients receiving BRUKINSA as compared to IMBRUVICA in a global phase 3 trial in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) (Press release, BeiGene, DEC 13, 2022, View Source [SID1234625178]). These data will be presented (Abstract #LBA-6) during the late-breaking session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans and simultaneously published in The New England Journal of Medicine. The paper’s lead author Jennifer Brown, M.D., Ph.D., Director, CLL Center at Dana-Farber Cancer Institute will present these data.

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Dr. Brown noted that "PFS is the gold standard for measuring efficacy in CLL clinical trials. The ALPINE data showing superior efficacy and consistent benefit across patient subgroups including patients with high-risk del(17p)/TP53, along with a favorable cardiovascular safety profile, provide compelling evidence for BRUKINSA as a practice-changing Bruton’s tyrosine kinase (BTK) inhibitor for patients with CLL."

"BRUKINSA was specifically designed to maximize BTK occupancy and minimize off-target effects. Our clinical development programs were intended to test for a differentiated efficacy and safety profile," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "We believe the ALPINE PFS data and cardiac safety results for BRUKINSA, including an absence of cardiac death, demonstrate a meaningful advance in outcomes for patients with CLL."

In this final analysis, BRUKINSA achieved superior PFS over ibrutinib (HR: 0.65 [95% CI, 0.49-0.86] p=0.0024, for both Independent Review Committee [IRC] and investigator). At 24 months, the investigator-assessed PFS rates were 78.4% for BRUKINSA compared to 65.9% with ibrutinib. The PFS benefit was observed across all major subgroups, including high-risk del(17p)/TP53 (HR: 0.52; [95% CI, 0.30-0.88]), as assessed by IRC. BRUKINSA also demonstrated higher overall response rate (ORR), with a response rate of 80.4% versus 72.9% (two-sided p=0.0264), as assessed by IRC.

BRUKINSA was generally well-tolerated with fewer adverse events leading to treatment discontinuation compared with ibrutinib (15.4% vs. 22.2%). There was a lower rate of cardiac disorders for BRUKINSA compared with ibrutinib (21.3% vs 29.6%), and cardiac disorders leading to treatment discontinuation occurred in one BRUKINSA patient versus 14 ibrutinib patients (0.3% vs. 4.3%). No patient receiving BRUKINSA died due to a cardiac adverse event; six patients receiving ibrutinib experienced a fatal cardiac adverse event (0% vs. 1.9%). The most commonly reported treatment emergent adverse events (≥20%) with BRUKINSA and ibrutinib were diarrhea (16.0% vs. 24.1%), hypertension (14.8% vs. 11.1%), neutropenia (22.8% vs. 18.2%), COVID-19 (23.1% vs. 17.9%), and upper respiratory tract infection (21.0% vs. 14.2%).

CLL is the most common type of leukemia in adults, accounting for about one-quarter of new cases of leukemia in the United States.1 The condition is characterized by consecutive relapses, with response to therapy ultimately determining clinical benefit, including survival.

BeiGene’s sNDA for BRUKINSA in CLL is currently under review with the FDA and has a target action date of January 20, 2023.

Investor Events

Tuesday, December 13, 2022 – BeiGene will host a webcast and conference call following the ALPINE late-breaker presentation at 2:00 p.m. CST. BeiGene senior management along with invited medical experts will review the presented data and join for a Q&A panel.
Dial in: 855-303-0072; Passcode: 306575
Tuesday, December 13, 2022 – BeiGene will host a webcast in Chinese at 6:00 p.m. CST/December 14, 2022 8:00 a.m. China time to capture company presentations at ASH (Free ASH Whitepaper). BeiGene senior management will review highlights of the presented data.
Dial in: +86 10 8783 3177 or +86 10 5387 6330; Passcode: 03233799
These events can be accessed live from the Investors section of BeiGene’s website at View Source, View Source or View Source Archived replays will be posted for 90 days following both events.

About ALPINE

ALPINE is a randomized, global Phase 3 trial (NCT03734016) comparing BRUKINSA against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia CLL or SLL. In the trial, a total of 652 patients across Europe (60%), the United States (17%), China (14%), New Zealand and Australia (9%) were randomized into two arms, with the first receiving BRUKINSA (160 mg orally twice daily) and the second receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity.

The primary endpoint of overall response rate (ORR), defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and IRC using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. There was pre-specified hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include PFS and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events.

Interim study results from ALPINE were published online in Journal of Clinical Oncology in November 2022 (DOI: 10.1200/JCO.22.00510).

About BRUKINSA

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 was specifically designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

BRUKINSA is supported by a broad clinical program which includes more than 4,700 subjects in 35 trials in more than 30 geographies. To date, BRUKINSA is approved in more than 60 markets, including the United States, China, the European Union, Great Britain, Canada, Australia, South Korea, Switzerland, and additional international markets.

On December 13, 2022 Amgen (NASDAQ: AMGN) reported the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) reported that it will present results from the E1910 randomized Phase 3 trial (Press release, Amgen, DEC 13, 2022, View Source [SID1234625175]). This is the first study to demonstrate superior overall survival (OS) with BLINCYTO added to consolidation chemotherapy over current standard of care (multiagent consolidation chemotherapy) in newly diagnosed adult patients with Philadelphia chromosome-negative B-ALL who were measurable residual disease (MRD)-negative following induction and intensification chemotherapy. These results were featured in a press briefing on Monday, Dec. 12 at 8:30 a.m. CT and presented on Tuesday, Dec. 13 at 9 a.m. CT as a late breaking oral presentation (LBA1) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in New Orleans.

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Experience the full interactive Multichannel News Release here: View Source

"Treatment with BLINCYTO in addition to consolidation chemotherapy reduced the risk of death by 58% compared to chemotherapy alone. We are pleased by this remarkable improvement in overall survival, and we look forward to sharing these data with regulatory authorities as soon as possible," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "Amgen continues to advance a robust development program for BLINCYTO, with a focus on minimizing chemotherapy and a subcutaneous formulation to help address remaining unmet needs for patients with B-ALL."

The Phase 3 randomized trial (E1910), activated in December 2013, evaluated the safety and efficacy of BLINCYTO added to standard of care consolidation chemotherapy compared to chemotherapy alone in patients with newly diagnosed B-ALL with no MRD after induction and intensification chemotherapy. The primary endpoint was OS and key secondary endpoints included relapse-free survival, MRD status, and incidence of adverse events. Based on a recommendation by the ECOG-ACRIN Data Safety Monitoring Committee and consistent with the pre-defined efficacy threshold, results from the planned interim analysis are now reported due to overwhelming efficacy reported in the BLINCYTO arm.

With a median follow up of 43 months, the study met its primary endpoint with a significant improvement in overall survival favoring the BLINCYTO arm; median OS was not reached vs. 71.4 months in the control arm (hazard ratio [HR] = 0.42, 95% CI: 0.24 – 0.75; two-sided p=0.003). After about 3.5 years of follow-up, 83% of the patients who went on to receive additional standard consolidation chemotherapy plus experimental BLINCYTO were alive versus 65% of those who received chemotherapy only. No new safety signals were reported for the combination.

"Adults with newly diagnosed ALL can achieve a high rate of complete remission with chemotherapy, but frequently relapse and have disappointing survival rates.1,2 Historically, outcomes for newly diagnosed adults with ALL have been significantly worse than for children, where up to 90% of patients are cured with frontline therapy.3,4 In this study, survival rates for adults when blinatumomab was added to chemotherapy are significantly improved in patients with MRD-negative remission, approaching those we have seen in children," said Selina M. Luger, M.D., professor of hematology-oncology at the University of Pennsylvania’s Abramson Cancer Center and Perelman School of Medicine, chair of the ECOG-ACRIN Leukemia Committee and an investigator on the study. "Moreover, the data provide additional clinical evidence supporting the recent guideline updates for adult ALL recommending blinatumomab as consolidation in both MRD-positive and MRD-negative patients."

Data from the trial will be submitted to global regulatory authorities, including where BLINCYTO has been previously approved.

Study E1910 was designed and conducted independently from industry with public funding. The ECOG-ACRIN Cancer Research Group sponsored the trial with funding from the National Cancer Institute (NCI), part of the National Institutes of Health. Other NCI-funded network groups took part in the study. In addition, Amgen provided BLINCYTO and support through an NCI Cooperative Research and Development Agreement (CRADA).

E1910 Study Design
In the E1910 Phase 3 randomized trial, 488 patients aged 30-70 with newly diagnosed B-ALL were enrolled. All participants initially received 2.5 months of combination induction chemotherapy (step 1). After remission induction (step 1), if patients were in complete remission, they continued on-study and received an intensification course of high dose chemotherapy (step 2). Subsequently, their remission and MRD status were determined. All patients were then randomized/assigned to receive four cycles of consolidation chemotherapy with or without four 28-day cycles of BLINCYTO (step 3). Following FDA approval of blinatumomab for MRD-positive patients in March 2018, MRD-positive participants were assigned to the blinatumomab arm. MRD-negative patients continued to be randomized. After completion of consolidation chemo +/- BLINCYTO, patients were given 2.5 years of chemotherapy maintenance therapy timed from the start of the intensification cycle (step 4).

For more information, please visit ClinicalTrials.gov.

About BLINCYTO (blinatumomab)
BLINCYTO is a BiTE (bispecific T-cell engager) immuno-oncology therapy that targets CD19 surface antigens on B cells. BiTE molecules fight cancer by helping the body’s immune system detect and target malignant cells by engaging T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. By bringing T cells near cancer cells, the T cells can inject toxins and trigger cancer cell death (apoptosis). BiTE immuno-oncology therapies are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration and is approved in the U.S. for the treatment of:

relapsed or refractory CD-19 positive B-cell precursor ALL in adults and children.
CD-19 positive B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and children. This indication is approved under accelerated approval based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In the European Union (EU), BLINCYTO is indicated as monotherapy for the treatment of:

adults with Philadelphia chromosome negative CD19 positive relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
adults with Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.
pediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation
IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications

BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions

Cytokine Release Syndrome (CRS): CRS, which may be life-threatening or fatal, occurred in 15% of patients with R/R ALL and in 7% of patients with MRD-positive ALL. The median time to onset of CRS is 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Closely monitor and advise patients to contact their healthcare professional for signs and symptoms of serious adverse events such as fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome, and hemophagocytic histiocytosis/macrophage activation syndrome. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS.
Neurological Toxicities: Approximately 65% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. The median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache and tremor. Severe, life–threatening, or fatal neurological toxicities occurred in approximately 13% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.
Infections: Approximately 25% of patients receiving BLINCYTO in clinical trials experienced serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.
Tumor Lysis Syndrome (TLS), which may be life-threatening or fatal, has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.
Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.
Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.
Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment with a median time to onset of 3 days. In patients receiving BLINCYTO, although the majority of these events were observed in the setting of CRS, some cases of elevated liver enzymes were observed outside the setting of CRS, with a median time to onset of 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase, and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.
Pancreatitis: Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical trials and the post-marketing setting. Evaluate patients who develop signs and symptoms of pancreatitis and interrupt or discontinue BLINCYTO and dexamethasone as needed.
Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and antileukemic chemotherapy.
Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).
Immunization: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions including "gasping syndrome," which is characterized by central nervous system depression, metabolic acidosis, and gasping respirations, can occur in neonates and infants treated with benzyl alcohol-preserved drugs including BLINCYTO (with preservative). When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing < 22 kg.
Adverse Reactions

The most common adverse reactions (≥ 20%) in clinical trial experience of patients with MRD-positive B-cell precursor ALL (BLAST Study) treated with BLINCYTO were pyrexia (91%), infusion-related reactions (77%), headache (39%), infections (pathogen unspecified 39%), tremor (31%), and chills (28%). Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection.
The most common adverse reactions (≥ 20%) in clinical trial experience of patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (TOWER Study) treated with BLINCYTO were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia.
Adverse reactions that were observed more frequently (≥ 10%) in the pediatric population compared to the adults with relapsed or refractory B-cell precursor ALL were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).
In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).
Dosage and Administration Guidelines

BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm.
It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose).