On June 4, 2021 Shanghai Yingli Pharmaceuticals Ltd (Yingli Pharma), a clinical stage pharmaceutical company providing new therapies for cancer and metabolic diseases, reported that there will be three presentations on clinical trials sponsored by the company at the annual meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) June 4-7, 2021 (Press release, Yingli Pharmaceutical, JUN 4, 2021, View Source [SID1234583604]).

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Linperlisib in Peripheral T cell lymphoma

The clinical trial report entitled "A phase Ib study of a PI3Kδ inhibitor Linperlisib in patients with relapsed or refractory peripheral T-cell lymphoma" was presented at the June 4, 2021 proceedings of the conference.

In this phase Ib study that enrolled 38 relapsed and refractory Peripheral T cell lymphoma patients, linperlisib, a novel oral PI3Kδ inhibitor, was evaluated as monotherapy for safety, tolerability and efficacy at recommended phase 2 dose of 80mg once daily. The clinical data from an interim data cutoff was presented at ASCO (Free ASCO Whitepaper) by Dr. Jie Jin, professor of First Hospital Affiliated with Zhe Jiang Medical University. Top line data from this study indicated that for the 38 r/r PTCL patients enrolled, 30 were evaluable. As of the data cutoff, an Overall Response Rate (ORR) of 70% was reported of which 33% were complete responses. A 100% disease control rate was also observed. Linperlisib was well-tolerated with Grade 1 and Grade 2 adverse events most frequently observed, and with limited Grade 3 adverse events of neutrophil decrease in 4 pts, (10.5%), and 1 (2.6%) case each of leukopenia, thrombocytopenia, blood lipase increase, pneumonia and stomatitis.

"Peripheral T cell lymphoma is a devastating and aggressive lymphoma where patients have very few treatment options in the relapsed and refractory setting," said Dr. Jie Jin. "The results of this Phase1b clinical trial suggest that linperlisib is a promising PI3Kδ selective inhibitor with important anti-tumor properties in this indication, and we hope it will be able to bring clinical benefits of linerlisib to patients suffering from this serious disease. Globally, there are no PI3K inhibitors that have been approved for the treatment of T cell lymphomas. In China, no PI3K inhibitors have been approved for any indications. By evaluating linperlisib for its safety, tolerability and efficacy, we are optimistic that this novel oral therapy will advance into registration clinical trials in PTCL for regulatory approval."

Linperlisib evaluated in advanced solid tumors

Another clinical study of linperlisib was also presented at ASCO (Free ASCO Whitepaper) entitled "A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors". In this study that enrolled 78 advanced solid tumor patients, linperlisib monotherapy was evaluated for safety, tolerability, and durability at the recommended phase2 dose of 80 mg once daily, the dose previously established for the treatment of lymphomas. The clinical data from an interim analysis of this study was presented by Dr. Jin Li, Professor and Oncologist at Shanghai East Hospital.

Linperlisib is an immunomodulatory PI3Kδ inhibitor in solid tumors that has been demonstrated to alter the tumor immune microenvironment in preclinical research. "These properties of solid tumors are a challenge for therapeutic intervention because the regulatory immune cells will frequently repress an anti-tumor immune response. Our hypothesis is that linperlisib will unleash the anti-tumor suppression in a beneficial manner for patient treatments", said Zusheng Xu, General Manager of Yingli Pharma.

In the open-label Phase 1b study including 15 advanced solid tumor types, linperlisib was demonstrated to be safe and well-tolerated. The most common treatment related adverse events were Grade 1 and Grade 2, with the Grade 3 TRAE of neutropenia (3.8%), diarrhea (2.6%), elevated γ-glutaminase (1.3%) and leukopenia (1.3%) observed. The disease control rate with linperlisib monotherapy was reported to be 41.4%, with one complete response observed in a patient with thymic carcinoma.

Dr. Jin Li stated "Linperlisib is a PI3K inhibitor with a distinct chemical structure highly selective to the δ isoform, compared to other PI3K inhibitors. The preliminary clinical findings are supportive of Linperlisib demonstrating a favorable safety profile with very limited off-target effects that have been associated with other PI3K inhibitors in the clinic. We were pleased to see that Linperlisib can be administered to patients with advanced solid tumors in a manner that is safe and well-tolerated. Linperlisib has great potential for combination therapies and additional indications in the future. We committed to investigating how this new PI3K inhibitor can improve the health condition of patients suffering from advanced solid tumors."

YL-13027, a novel and selective TGFβR1 inhibitor in a Phase 1 dose escalation study

A first-in-human clinical trial of YL-13027, an oral, potent, and selective TGFβR1 inhibitor, is being presented at the ASCO (Free ASCO Whitepaper) meeting, entitled "A phase I study of a TGF-β receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors".

TGFβ signaling is known to be a driver contributing to the immunosuppressive properties of many solid tumors. In principle, agents that interfere with TGFβ signaling may be beneficial towards interrupting tumor progression and supplying additional targets for anti-cancer therapies. YL-13027 was developed as a potent small molecule inhibitor of TGFβR1, a tyrosine kinase, and has demonstrated anti-tumor efficacy in preclinical models. In this open-label phase1 dose escalation study, the initial safety evaluation of YL-13027 was presented. The most frequent treatment related adverse events in twelve patients who had completed Cycle 1 safety evaluation period as of the data cut, were the following (all Grades/≥Grade 3): γ-glutamyl transferase elevation (38.5%/7.7%), hemoglobin decrease (38.5%/0%), blood alkaline phosphatase elevation (23.1%/7.7%), AST (23.1%/0%), and blood phosphorus decrease (23.1%/0%). Of the 6 evaluable patients with advanced solid tumors treated as of the data cutoff date, 1 triple negative breast cancer patient had a confirmed Partial Response.

"In recent years, immunotherapy has gradually replaced chemotherapy and radiotherapy, and has shown good clinical results for different types of advanced solid tumors, but we still encounter bottlenecks in terms of safety, tolerability and tumor indication selection” said Dr. Jin Li, professor of Shanghai East Hospital, and a lead investigator on the study. "YL-13027 has demonstrated to be a safe and tolerable oral agent that is highly selective for TGFβR1 over TGFβR2. These results are giving us confidence for the dose escalation of YL-13027, and its performance on other tumor types and combination therapies. We are very optimistic about the further development of YL-13027 as an anti-cancer agent."

Schedule for Linperlisib and YL-13027 presentations at ASCO (Free ASCO Whitepaper)

Abstract # 7531; ‘A phase Ib study of a PI3Kδ inhibitor Linperlisib in patients with relapsed or refractory peripheral T-cell lymphoma’ is being presented in the Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia Session. Citation: J Clin Oncol 39, 2021 (suppl 15; abstr 7531)

Abstract # 3099; ‘A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors’ is being presented in the Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology Session. Citation: J Clin Oncol 39, 2021 (suppl 15; abstr 3099)

Abstract # 3098; ‘A phase I study of a TGF-β receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors’ is being presented in the Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology Session. Citation: J Clin Oncol 39, 2021 (suppl 15; abstr 3098)

About Linperlisib

Linperlisib (YY-20394) is a highly selective and potent PI3Kδ inhibitor that has shown favorable safety profile, exciting anti-tumor activities, and good PK and pharmaceutical properties as an oral once-a-day agent in late-stage clinical development. A phase 1 clinical trial was completed in 2020 demonstrating linperlisib to be a safe and tolerable agent, and a recommended phase 2 dose of 80 mg QD was established. Linperlisib received FDA Orphan Drug Designations for FL, CLL/SLL, and T cell lymphoma. Linperlisib was awarded NMPA Breakthrough Therapy status in China. A clinical trial in r/r FL for 93 patients having 2 or more prior systemic therapies has been completed and submitted for marketing approval in China. Additional linperlisib clinical trials are ongoing in other lymphomas, solid tumors, and in combination with gemcitabine/oxaliplatin in r/r DLBCL.

About YL-13027

YL-13027 is a potent small molecule antagonist of TGFβR1 kinase activity in early-stage clinical development. The compound was optimized with selectivity against TGFβR2 and other tyrosine kinases, differentiating YL-13027 from other inhibitors blocking TGFβ signaling. In preclinical studies, YL-13027 demonstrated anti-tumor efficacy and combination benefit with immunotherapy. In IND-enabling studies, YL-13027 showed reliable dose-proportionality and pharmacokinetic properties, and the agent proved to be safe and tolerable in toxicity studies. A phase 1 dose escalation of YL-13027 is continuing to establish a recommended phase2 dose of YL-13027.

On June 4, 2021 Amphivena Therapeutics, a clinical-stage oncology company focused on developing immune-therapeutics that restore anti-cancer immunity to patients, reported a favorable safety profile for AMV564 and clinical responses including a CR in patients with advanced relapsed or refractory solid tumors (Press release, Amphivena Therapeutics, JUN 4, 2021, View Source [SID1234583602]). The poster presentation at the 2021 virtual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting disclosed the first comprehensive set of clinical results from Amphivena’s Phase 1 dose escalation study of AMV564 dosed subcutaneously (sc) as monotherapy or in combination with pembrolizumab, including in post checkpoint treatment failures.

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Poster authors representing Duke University, The Christ Hospital of Cincinnati, OH, MD Anderson Cancer Center, NEXT Oncology, and Moffitt Cancer Center concluded that AMV564 delivered subcutaneously was well tolerated with no dose-limiting toxicities and no maximum tolerated dose reported. Additionally, clinical responses were observed in both monotherapy and combination therapy patients, including durable stable disease, mixed responses, and a RECIST v1.1 complete response (ovarian cancer patient treated with AMV564 monotherapy). Importantly, no cases of CRS were observed at the planned dose expansion doses.

According to Patrick Chun, M.D., Amphivena vice president of clinical development, "T cell engagement has proven to be a viable immunotherapeutic strategy in cancer. However, previous technologies have been limited by toxicity (CRS), exposure, and attenuated efficacy. With this data, we are clearly differentiating Amphivena from other companies in the space. Our unique approach uses T cell engagers that target MDSCs, thus attenuating the immunosuppressive milieu in cancer patients, while simultaneously limiting CRS, which has been the primary adverse event of concern with this class of molecules. Based on the clinical safety and pharmacokinetic profiles, along with clinical activity, we believe it is imperative to further explore AMV564 in selected solid tumor indications and alternative dosing regimens, including once weekly dosing."

The poster presents data that AMV564 induced expansion of tumor-specific T-cell clones and clinical responses when administered as a monotherapy and in combination with a checkpoint inhibitor, including in patients who have previously progressed with checkpoint inhibitor treatment. Strong induction of IFNγ was observed with monotherapy and especially in combination, with comparatively low IL6, favorable with respect to both safety and induction of anti-tumor response pathways.

The Phase 1 dose escalation study (NCT04128423) enrolled 30 patients (20 monotherapy, 10 combination therapy). The majority of patients received three or more lines of prior therapy (70% of monotherapy patients, 50% of combination therapy patients) including 35% of monotherapy patients and 10% of combination therapy patients who received prior checkpoint-inhibitor therapy.

Details of the Presentations:

Title: Results of a phase 1 dose-escalation study of AMV564, a novel T-cell engager, alone and in combination with pembrolizumab in patients with relapsed/refractory solid tumors
Authors: Niharika B. Mettu, et al.
Abstract Number: 2555

The full abstract and poster will be available on the ASCO (Free ASCO Whitepaper) Annual Meeting 2021 and Amphivena website (View Source) as of 9:00AM EDT on Friday, June 4th.

About AMV564

AMV564 is a product of Amphivena’s proprietary ReSTORETM (Relieve Suppression of T cells in Oncology and Reinvigorate Effectors) platform of bivalent T-cell engagers. The investigational drug candidate has been shown to relieve immune suppression via targeted depletion of immunosuppressive MDSC and drive T cell activation and polarization to restore anti-cancer immunity. To date, over 80 patients have received AMV564 across three Phase 1 clinical trials for patients with solid tumors, acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS).

On June 4, 2021 Seres Therapeutics, Inc. (Nasdaq: MCRB), a leading microbiome therapeutics company, reported data from their collaboration with the University of Cologne (Köln, Germany) demonstrating that decreased microbiome diversity in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is associated with poor clinical outcomes including mortality and increased incidence of intestinal graft-versus-host disease (GvHD) (Press release, Seres Therapeutics, JUN 4, 2021, View Source [SID1234583601]). The data are being presented in an oral presentation at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place virtually. A separate poster presentation, including data from a collaboration with Memorial Sloan Kettering Cancer Center (New York, NY), established a significant association between microbiome composition and response to immune checkpoint inhibitor (ICI) treatment in patients who have metastatic melanoma, metastatic lung (NSCLC), urothelial, or renal cancer.

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Seres is advancing development programs in oncology to evaluate the potential of microbiome therapeutics to modulate host immunity or inflammation to improve response and tolerability of cancer treatments. This includes SER-155, an investigational, oral, rationally-designed, cultivated microbiome therapeutic, which is advancing into a Phase 1b clinical trial to reduce the incidence of antibiotic-resistant bacterial infections and GvHD in patients following transplant procedures.

"Disruption of microbiome-modulated functions can impact clinical outcomes for patients being treated for cancer, including those who are undergoing allogeneic hematopoietic stem cell transplantation and those treated with cancer immunotherapy," said Lisa von Moltke, M.D., Chief Medical Officer at Seres. "The findings we are presenting at ASCO (Free ASCO Whitepaper) provide further evidence that our SER-155 program, as well as our earlier stage oncology programs, will help to advance our understanding of the potential of microbiome therapeutics to work with the body’s immune system to improve cancer treatment outcomes."

Clinical Evidence of Impact of Microbial Diversity on Mortality and GvHD in HSCT Patients

In collaboration with the University of Cologne, a prospective observational study was conducted to evaluate changes in microbial diversity over time in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients undergoing allogeneic HSCT and the impact on clinical outcomes. Patients were administered antibiotics as empiric treatment for febrile neutropenia or as targeted treatment and were monitored for incidence of GvHD. Stool was collected on a weekly basis prior to an HSCT procedure and up to 28 days post HSCT, with additional samples collected at days 56, 90, and 365, as well as upon diagnosis of intestinal GvHD. Gut microbiome profiles were generated from 381 stool samples (representing 65 subjects) to evaluate the relationship between gastrointestinal microbial diversity over time and clinical outcome.

"Frequent complications associated with stem cell transplantation include antibiotic-resistant infection and GvHD. Current treatments for the prevention of GvHD rely on increased immunosuppression, leaving the patient susceptible to a host of bacterial infections – and offer limited efficacy. The findings from this prospective study demonstrate a need for continued investigation into the use of microbiome therapeutics to reduce morbidity and mortality among transplant recipients," said Christopher Ford, Ph.D., Senior Director, Computational Microbiome Sciences at Seres Therapeutics and co-author of the presentation.

Twenty-eight patients (42%) developed intestinal GvHD and 16 (25%) died prior to study completion. Across all subjects, a decline in microbiome diversity was observed immediately following HSCT. Decreased diversity and intestinal domination by two bacterial groups – Enterococcus and Enterobacteriaceae – was significantly associated with mortality across the study time course (p<0.001). Further, patients who ultimately developed intestinal GvHD had a significantly lower diversity at the time of stem cell engraftment (p<0.05) and that lower diversity was maintained throughout the study period.

Evaluation of Microbiome Composition in Correlation to Cancer-Specific Immune Checkpoint Inhibitor (ICI) Response

A study conducted with Memorial Sloan Kettering explored the relationship between microbiome composition and ICI response in patients with metastatic melanoma, metastatic lung (NSCLC), urothelial, or renal cancer. Fecal microbiome samples were collected from 94 patients (metastatic melanoma, n=17, NSCLC, n=44, urothelial, n=23, renal cancer, n=10) immediately before ICI therapy. Bacterial genomic DNA was isolated and profiled by whole metagenomic sequencing to evaluate bacterial signatures associated with response (R) and nonresponse (NR).

Treatment included anti-PD(L)1 monotherapy (n=51), anti-PD1 + anti-CTLA4 combination therapy (n=17), or a combination of anti-PD1 and chemotherapy (n=26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Ordination of microbiome data from all four cancers reveals a small cluster of patients that were NR regardless of cancer type. Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs. NR, PERMANOVA, p=0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p=0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three of the four cancer types. The relationship observed in this study was also identified and corroborated in pre-clinical models of ICI response. In these models, NR was characterized by active tumor growth in mice and a lack of induction of cytotoxic CD8+ T cells after ICI treatment.

About SER-155

SER-155, an investigational oral consortium of cultivated bacteria, is a microbiome therapeutic candidate intended to advance into clinical development. SER-155 is designed using microbiome biomarker data from human clinical data, human cell-based assays, and in vivo disease models, with the aim to decrease infection and translocation of antibiotic-resistant bacteria in the gastrointestinal tract and modulate host immune responses to decrease GvHD. The rationale for this program is based in part on published clinical evidence from Seres’ collaborators at Memorial Sloan Kettering Cancer Center showing that allogeneic HSCT patients with decreased diversity of commensal microbes are significantly more likely to die due to infection and/or lethal GvHD. SER-155 was developed using Seres’ reverse translational discovery platform to reduce morbidity and mortality due to gastrointestinal infections, bacteremia and GvHD in immunocompromised patients, including in patients receiving allogeneic HSCT or solid organ transplants.

On June 4, 2021 Kite, a Gilead Company (Nasdaq: GILD), reported that results from the primary analysis of ZUMA-3, a global, multicenter, single-arm, open-label Phase 1/2 study evaluating its chimeric antigen receptor (CAR) T-cell therapy Tecartus (brexucabtagene autoleucel) in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) (Press release, Kite Pharma, JUN 4, 2021, View Source [SID1234583600]). The data were simultaneously published in The Lancet and presented during an oral session at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting from June 4 – 8 (Abstract #7002).

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"Outcomes in adults with acute lymphoblastic leukemia are poor relative to what is observed in children, with less than half of people over 20 years of age expected to survive the illness. It is on this background that CAR T-cell therapy with brexucabtagene autoleucel was tested in adults with relapsed B-ALL in ZUMA-3," said Bijal Shah, MD, ZUMA-3 investigator and medical oncologist, Moffitt Cancer Center, Tampa, Florida. "In this international, multicenter study, we observed a response rate of 71%. Importantly, the majority of these responses were associated with undetectable minimal residual disease."

In the pivotal Phase 2 portion of the trial, 71 patients with relapsed or refractory disease were enrolled. Among treated patients (n=55), 47% had received three or more prior therapies. At a median follow-up of 16.4 months, 71% of treated patients achieved a complete response (CR) or CR with incomplete hematological recovery (CRi), with 31% in ongoing response at data cut-off. 97% of those responders had deep molecular remission, with undetectable minimal residual disease (MRD), and median overall survival (OS) among all responders was not reached. Among 25 patients with prior blinatumomab treatment, the CR/CRi rate was 60%. Among all treated patients, median duration of response (DOR), relapse-free survival (RFS), and OS were 12.8 months, 11.6 months and 18.2 months, respectively.

Grade ≥3 adverse events occurred in 95% of patients, with anemia (49%) and pyrexia (36%) most frequently reported. Grade ≥3 cytokine release syndrome (CRS) and neurologic events occurred in 24% and 25% of patients, respectively, and were generally reversed with treatment. Two Grade 5 treatment-related events occurred (one brain herniation and one case of septic shock).

Based on these data, the U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) and granted Priority Review designation for Tecartus for the treatment of adult patients with relapsed or refractory B-cell precursor ALL, with a target action date under the Prescription Drug User Fee Act (PDUFA) of October 1, 2021. If approved, Tecartus would become the first and only CAR T-cell therapy approved for adults (≥18 years old) with relapsed or refractory ALL.

"The data presented at ASCO (Free ASCO Whitepaper) today validate the response rates seen in the Phase 1 portion of the ZUMA-3 study and the transformative potential of Tecartus in adult patients with ALL," said Frank Neumann, MD, PhD, Kite’s Global Head of Clinical Development. "We have already seen the impact of Tecartus for patients with relapsed or refractory mantle cell lymphoma, and these new data are a significant next step in our continued commitment in developing our therapies for patients with leukemias and lymphomas."

In 2016, Tecartus received Breakthrough Therapy Designation in recognition of the unmet medical need in adult patients with relapsed or refractory B-cell precursor ALL. Tecartus is currently approved for the treatment of relapsed or refractory mantle cell lymphoma, as the first and only CAR T-cell therapy to receive accelerated approval from the FDA in this indication. The Tecartus U.S. Prescribing Information has a Boxed Warning in its product label regarding the risks of cytokine release syndrome (CRS) and neurologic toxicities, and Tecartus is approved with a risk evaluation and mitigation strategy (REMS) due to these risks; see below for Indication and Important Safety Information.

Tecartus has not been approved by any regulatory agency for the treatment of adult patients with relapsed or refractory ALL. Its safety and efficacy are currently under review by the FDA for this indication.

About ALL
ALL is an aggressive type of blood cancer that can also involve the lymph nodes, spleen, liver, central nervous system and other organs. Approximately 1,030 adults are treated annually for relapsed or refractory ALL. Survival rates remain very poor in adult patients with relapsed or refractory ALL, with a median overall survival of approximately eight months with the most commonly used therapeutic agents.

B-cell precursor ALL is the most common form of the disease, accounting for approximately 75 percent of cases. Treatment for this form is typically associated with inferior outcomes compared with other types of ALL.

About ZUMA-3
ZUMA-3 is an ongoing international multicenter, registrational Phase 1/2 study in adult patients (≥18 years old) with ALL whose disease is refractory to or has relapsed following first standard systemic therapy with remission of 12 months or less, after two or more lines of systemic therapy or after allogeneic stem cell transplantation. The objectives of the study are to evaluate the safety and efficacy of Tecartus in this patient population.

About Tecartus
Tecartus is an autologous, anti-CD19 CAR T-cell therapy. Tecartus uses the XLP manufacturing process that includes T cell enrichment, a necessary step in certain B-cell malignancies in which circulating lymphoblasts are a common feature. In addition to adult ALL, Tecartus is also currently being evaluated in pediatric ALL. The use of Tecartus in both cancer types is investigational, and its safety and efficacy have not been established in these cancer types.

Tecartus Indication
Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

This indication is approved under accelerated approval based on overall response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

U.S. IMPORTANT SAFETY INFORMATION
BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred in patients receiving Tecartus. Do not administer Tecartus to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic toxicities, including life-threatening reactions, occurred in patients receiving Tecartus, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Tecartus. Provide supportive care and/or corticosteroids as needed.
Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program.
Cytokine Release Syndrome (CRS), including life-threatening reactions, occurred following treatment with Tecartus. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving Tecartus, including ≥ Grade 3 CRS in 18% of patients. Among the patients who died after receiving Tecartus, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, key manifestations (>10%) included fever (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (37%), headache (24%), fatigue (19%), nausea (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (12%), and diarrhea (11%). Serious events associated with CRS included hypotension, fever, hypoxia, acute kidney injury, and tachycardia.

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of Tecartus. Following infusion, monitor patients for signs and symptoms of CRS daily for at least seven days at the certified healthcare facility, and for four weeks thereafter. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated.

Neurologic Toxicities, including those that were life-threatening, occurred following treatment with Tecartus. In ZUMA-2, neurologic events occurred in 81% of patients, 37% of whom experienced Grade ≥3 adverse reactions. The median time to onset for neurologic events was six days (range: 1 to 32 days). Neurologic events resolved for 52 out of 66 (79%) patients with a median duration of 21 days (range: 2 to 454 days). Three patients had ongoing neurologic events at the time of death, including one patient with serious encephalopathy. The remaining unresolved neurologic events were either Grade 1 or Grade 2. Fifty-four (66%) patients experienced CRS by the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. 85% of all treated patients experienced the first CRS or neurological event within the first seven days after Tecartus infusion.

The most common neurologic events (>10%) included encephalopathy (51%), headache (35%), tremor (38%), aphasia (23%), and delirium (16%). Serious events including encephalopathy, aphasia, and seizures occurred.

Monitor patients daily for at least seven days at the certified healthcare facility and for four weeks following infusion for signs and symptoms of neurologic toxicities and treat promptly.

REMS Program: Because of the risk of CRS and neurologic toxicities, Tecartus is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program which requires that:

Healthcare facilities that dispense and administer Tecartus must be enrolled and comply with the REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after Tecartus infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer Tecartus are trained in the management of CRS and neurologic toxicities. Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Severe Infections: Severe or life-threatening infections occurred in patients after Tecartus infusion. In ZUMA-2, infections (all grades) occurred in 56% of patients. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients after Tecartus infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

In immunosuppressed patients, including those who have received Tecartus, life-threatening and fatal opportunistic infections, including disseminated fungal infections (eg, candida sepsis and aspergillus infections) and viral reactivation (eg, human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. In ZUMA-2, Grade ≥3 cytopenias not resolved by Day 30 following Tecartus infusion occurred in 55% of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). Monitor blood counts after infusion.

Hypogammaglobulinemia and B-cell aplasia can occur in patients receiving treatment with Tecartus. In ZUMA-2, hypogammaglobulinemia occurred in 16% of patients. Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement. The safety of immunization with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during treatment, and until immune recovery following treatment with Tecartus.

Secondary Malignancies may develop. Monitor life-long for secondary malignancies. In the event that one occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status or seizures, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous activities, such as operating heavy or potentially dangerous machinery, during this period.

Adverse Reactions: The most common adverse reactions (incidence ≥ 20%) were pyrexia, CRS, hypotension, encephalopathy, fatigue, tachycardia, arrhythmia, infection – pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, edema, motor dysfunction, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, and aphasia. Serious adverse reactions occurred in 66% of patients. The most common serious adverse reactions (> 2%) were encephalopathy, pyrexia, infection – pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections.

On June 4, 2021 The US Oncology Network (The Network), US Oncology Research and Ontada reported that Results from the first phase of the broad, collaborative MYLUNG Consortium research study in metastatic non-small cell lung cancer (mNSCLC) were released at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, US Oncology, JUN 4, 2021, View Source [SID1234583599]). The findings provide a close-up look at current biomarker testing rates and turnaround times for patients with mNSCLC treated in community practices within The Network. Most notably, Protocol 1 findings show that there are barriers that must be addressed as more than 80 percent of NSCLC is detected at Stage 4 and median time from diagnosis to first-line therapy is about five weeks.

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"The pace and development of treatments in non-small cell lung cancer is dramatic," said Makenzi Evangelist, MD, principal investigator for the MYLUNG Consortium’s Protocol 2 and oncologist with New York Oncology Hematology (NYOH), a practice in The Network. "There are already several targeted therapies to treat subsets of populations, and many more are in the pipeline that hold incredible potential. Unfortunately, barriers exist that prevent the necessary comprehensive biomarker testing that enables the use of these treatments. The MYLUNG Consortium study will be invaluable in identifying these obstacles and developing practical interventions that will allow us to fulfill the promise of precision medicine for patients with this difficult cancer."

Dr. Evangelist presented the findings during an oral presentation at ASCO (Free ASCO Whitepaper) titled, "Biomarker tissue journey among patients with untreated metastatic non-small cell lung cancer (mNSCLC) in The US Oncology Network community practices." (ASCO Abstract 9004).

The MYLUNG Consortium is a collaborative and innovative research study comprised of three protocols over a five-year period. Protocol 1, which was just completed, is a retrospective study of more than 3,500 patients with mNSCLC that investigated the following areas: testing rates for ALK, BRAF, EGFR, ROS1, and PD-L1 mutations; use of the full next-generation sequencing panel (NGS); time from NSCLC diagnosis to first-line therapy; turnaround times from biomarker orders to results; and time from NSCLC diagnosis to test results.

"We have derived significant insights from the study data so far," noted Sarah Alwardt, PhD, vice president of Operations for Ontada. "We are now able to see where there are gaps regarding targeted therapy. This real-world study showed that while most patients had at least one biomarker test result available prior to first-line therapy, less than 50 percent had five or more biomarkers tested. Consequently, a large percentage of patients were not given the opportunity for a targeted therapy."

Additionally, the median time from diagnosis to first-line therapy was about five weeks, a concern for patients anxiously waiting for treatment. Turnaround time from testing orders to results was about two weeks, indicating the need to get test results to physicians sooner so they have all critical information in front of them during development of the treatment plan. Next Generation Sequencing testing improved over time, suggesting comprehensive testing is increasing. Most of the population was diagnosed at advanced disease, with roughly over 80 percent detected at stage 4.

"Protocol 1 provides a look at what was happening retrospectively based on clinical data abstraction, allowing us to draw some early conclusions about historical baseline trends for testing patterns," noted Robert L. Coleman, MD, FACOG, FACS, chief scientific officer of US Oncology Research and the MYLUNG Consortium program principal investigator. "Retrospective studies like this help us understand where we are as far as testing behaviors, while also identifying gaps in the data that need to be filled with the prospective research the MYLUNG Consortium will address in the next protocols."

Data from Protocol 1 will be compared to the next phase of the MYLUNG Consortium study, Protocol 2, which will evaluate contemporary ordering practices and turnaround times prospectively. It will enroll about 1,000 patients from approximately 11 sites and will monitor the real-world patient journey from presentation through their first line of cancer therapy, focusing on how diagnostic biomarker information is obtained, utilized and operationalized in decision-making. Patients are currently being enrolled in this stage of the study.

The final phase of the study, Protocol 3, will serve as a platform upon which prospectively assessed interventional strategies in patient-engagement algorithms will be conducted. Up to 7,500 patients from approximately 20 participating sites will be recruited over a five-year period. Individual clinical trials will integrate findings from the previous protocols and explore new processes and associated outcomes. The goal is to help providers make the best treatment recommendations based on the data available while improving access to testing and appropriate therapies for patients with mNSCLC.

The MYLUNG Consortium study is enabled through a unique collaboration of various organizations and stakeholders working together across the spectrum of NSCLC drug development, therapy and care. The number of consortium participants continues to grow, all bringing unique perspectives to this innovative study. It brings together providers and researchers in The Network, US Oncology Research and Ontada with life sciences companies Amgen, AstraZeneca, Eli Lilly and Company, Genentech (a member of the Roche Group), and Mirati Therapeutics, Inc. Patient advocacy groups LUNGevity and GO2 Foundation for Lung Cancer are also participating, playing a key role in the study by keeping the focus on patients. Healthcare provider members include Illinois Cancer Specialists, Maryland Oncology Hematology, Minnesota Oncology, New York Oncology Hematology, Oncology Hematology Care, Rocky Mountain Cancer Centers, Southern Cancer Center, Virginia Cancer Specialists, Virginia Oncology Associates, Willamette Valley Cancer Institute and Research Center and Woodlands Medical Specialists.

Read more about the MYLUNG Consortium here. To schedule a media interview with one of the study investigators, contact Claire Crye at [email protected].