On June 10, 2022 CTI BioPharma Corp. (Nasdaq: CTIC) reported two scientific poster presentations from the Company’s pacritinib clinical program at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Congress, being held in Vienna, Austria, June 9-12, 2022 (Press release, CTI BioPharma, JUN 10, 2022, View Source [SID1234615865]).

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"Our presentions today demonstrate that full dose pacritinib achieved higher response rates and a similar, manageable safety profile compared to lower-dose ruxolitinib in patients with myelofibrosis who have moderate or severe thrombocytopenia," said Adam Craig, President and Chief Executive Officer of CTI BioPharma. "As the commercial launch of VONJOTM (pacritinib) in the U.S. continues to exceed our expectations, we are pleased to highlight VONJO’s clinical value as a potential best in class treatment for patients with cytopenic myelofibrosis with platelet counts below 50 × 109/L."

Presentation materials will be available at ctibiopharma.com.

Retrospective Comparison of Patient Outcomes on Pacritinib Versus Ruxolitinib in Patients with Myelofibrosis and Thrombocytopenia (New)

Poster Number: P1069
Session Name: Poster session
Session Date: Friday, June 10, 2022
Presentation Time: 16:30 – 17:45 p.m. CEST (10:30 – 11:45 a.m. ET)
Presenter: Prof. Claire Harrison

Pacritinib is a novel JAK2/IRAK1 inhibitor approved by the U.S. Food and Drug Administration (FDA) for patients with myelofibrosis and thrombocytopenia. Unlike the JAK 1/2 inhibitor ruxolitinib, which must be dose-reduced or held in patients with thrombocytopenia, pacritinib has been studied at full dose regardless of platelet count. In this part of of the Phase 3 PERSIST-2 study, which focuses on retrospectively analyzing outcomes in patients treated with pacritinib versus ruxolitinib, patients were randomized 1:1:1 to pacritinib 200 mg twice daily (BID), pacritinib 400 mg once daily (QD) or best available therapy (BAT), with 45 percent of patients on BAT receiving ruxolitinib.

This analysis demonstrates overall and fatal adverse events occurred at similar rates on pacritinib versus ruxolitinib, as did bleeding events. Cardiac events occurred more commonly on pacritinib, though the difference was largely due to higher rates of grade 1 peripheral edema on pacritinib. There were lower rates of herpes zoster reactivation (n=0 vs. 1), pulmonary aspergilosis (n=1 vs. 0), deep venous thrombosis (n=0 vs. 1) and pulmonary embolism (n=1 vs. 0) on pacritinib and ruxolitinib, respectively. These results show that pacritinib, administered at the full dose of 200 mg BID, yielded higher response rates and a similar safety profile compared to lower-dose ruxolitinib, in patients with myelofibrosis who have moderate or severe thrombocytopenia.

Risk-Adjusted Safety Analysis of Pacritinib in Patients with Myelofibrosis (Encore)

Poster Number: P1068
Session Name: Poster session
Session Date: Friday, June 10, 2022
Presentation Time: 16:30 – 17:45 p.m. CEST (10:30 – 11:45 a.m. ET)
Presenter: Dr. Naveen Pemmaraju

Pacritinib is a novel JAK2/IRAK1 inhibitor that has shown significant activity in patients with myelofibrosis, including those with platelet counts <50 × 109/L. This safety analysis focuses on toxicities of interest for patients treated with pacritinib 200 mg twice daily (BID) and best available therapy (BAT), including ruxolitinib, on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Because the average treatment duration was longer for patients on pacritinib 200 mg BID on PERSIST-2 and PAC203 compared to BAT on PERSIST-2, this analysis presents adverse events rates in these patients corrected for duration of exposure.

This risk-adjusted analysis demonstrates that the safety profile of pacritinib 200 mg BID is comparable to BAT. In particular, rates of bleeding were not elevated on pacritinib 200 mg BID compared to BAT, both overall and in patients with PLT <50 x 109/L. Rates of fatal events, thrombosis, major adverse cardiac events (MACE) and non-melanoma skin cancer were higher on ruxolitinib than pacritinib. These results indicate that pacritinb 200 mg BID may represent a full-dose therapeutic option for patients with myelofibrosis, including those with thrombocytopenia.

About VONJO (pacritinib)
Pacritinib is an oral kinase inhibitor with activity against wild type Janus Associated Kinase 2 (JAK2), mutant JAK2V617F form and FMS-like tyrosine kinase 3 (FLT3), which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Myelofibrosis is often associated with dysregulated JAK2 signaling. Pacritinib has higher inhibitory activity for JAK2 over other family members, JAK3 and TYK2. At clinically relevant concentrations, pacritinib does not inhibit JAK1. Pacritinib exhibits inhibitory activity against additional cellular kinases (such as CSF1R and IRAK1), the clinical relevance of which is unknown.

VONJO is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important VONJO Safety Information
Hemorrhage:
Serious (11%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <100 × 109/L. Serious (13%) and fatal (2%) hemorrhages have occurred in VONJO-treated patients with platelet counts <50 × 109/L. Grade ≥3 bleeding events (defined as requiring transfusion or invasive intervention) occurred in 15% of patients treated with VONJO compared to 7% of patients treated on the control arm. Due to hemorrhage, VONJO dose-reductions, dose interruptions, or permanent discontinuations occurred in 3%, 3%, and 5% of patients, respectively.

Avoid use of VONJO in patients with active bleeding and hold VONJO 7 days prior to any planned surgical or invasive procedures. Assess platelet counts periodically, as clinically indicated. Manage hemorrhage using treatment interruption and medical intervention.

Diarrhea:
VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. The median time to resolution in VONJO-treated patients was 2 weeks. The incidence of reported diarrhea decreased over time with 41% of patients reporting diarrhea in the first 8 weeks of treatment, 15% in Weeks 8 through 16, and 8% in Weeks 16 through 24. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients. None of the VONJO-treated patients reported diarrhea that resulted in treatment discontinuation. Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to no such adverse reactions in patients in the control arm.

Control pre-existing diarrhea before starting VONJO treatment. Manage diarrhea with antidiarrheal medications, fluid replacement, and dose-modification. Treat diarrhea with anti–diarrheal medications promptly at the first onset of symptoms. Interrupt or reduce VONJO dose in patients with significant diarrhea despite optimal supportive care.

Thrombocytopenia:
VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre–existing moderate to severe thrombocytopenia (platelet count <100 × 109/L). VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with pre–existing severe thrombocytopenia (platelet count <50 × 109/L).

Monitor platelet count prior to VONJO treatment and as clinically indicated during treatment. Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than 7 days. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO. Restart VONJO at 50% of the last given dose once the toxicity has resolved.

Prolonged QT interval:
VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 msec was higher in VONJO-treated patients than in patients in the control arm (1.4% vs 1%). QTc increase from baseline by 60 msec or higher was greater in VONJO-treated patients than in control arm patients (1.9% vs 1%). Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients. No cases of torsades de pointes were reported.

Avoid use of VONJO in patients with a baseline QTc of >480 msec. Avoid use of drugs with significant potential for QTc prolongation in combination with VONJO. Correct hypokalemia prior to and during VONJO treatment. Manage QTc prolongation using VONJO interruption and electrolyte management.

Major Adverse Cardiac Events (MACE):
Another Janus associated kinase (JAK)-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

Thrombosis:
Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Secondary Malignancies:
Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which VONJO is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with VONJO, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

Risk of Infection:
Another JAK-inhibitor has increased the risk of serious infections (compared to best available therapy) in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved. Observe patients receiving VONJO for signs and symptoms of infection and manage promptly. Use active surveillance and prophylactic antibiotics according to clinical guidelines.

Interactions with CYP3A4 Inhibitors or Inducers:
Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Avoid concomitant use of VONJO with moderate CYP3A4 inhibitors or inducers.

Drug interruptions due to an adverse reaction occurred in 27% patients who received VONJO 200 mg twice daily compared to 10% of patients treated with BAT. Dosage reductions due to an adverse reaction occurred in 12% of patients who received VONJO 200 mg twice daily compared to 7% of patients treated with BAT. Permanent discontinuation due to an adverse reaction occurred in 15% of patients receiving VONJO 200 mg twice daily compared to 12% of patients treated with BAT.

Please visit View Source for full Prescribing Information and the Medication Guide.

About Myelofibrosis
Myelofibrosis is bone marrow cancer that results in formation of fibrous scar tissue and can lead to thrombocytopenia and anemia, weakness, fatigue and an enlarged spleen and liver. Within the United States, there are approximately 21,000 patients with myelofibrosis, 7,000 of which have severe thrombocytopenia (defined as blood platelet counts of less than 50 x109/L). Severe thrombocytopenia is associated with poor survival and high symptom burden and can occur as a result of disease progression or from drug toxicity with other JAK2 inhibitors, such as JAKAFI and INREBIC.

On June 10, 2022 NuCana plc (NASDAQ: NCNA) reported that data to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress highlighting the activity of NUC-7738, a phosphoramidate transformation of 3’-deoxyadenosine (3’-dA), in a broad range of Acute Myeloid Leukemia (AML) cell lines. NUC-7738 has already shown promise as monotherapy in patients with solid tumors in a Phase 1/2 study (NuTide:701) and will also be combined with a PD-1 checkpoint inhibitor (Press release, Nucana BioPharmaceuticals, JUN 10, 2022, View Source [SID1234615873]).

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The data at EHA (Free EHA Whitepaper) 2022 show that NUC-7738 can suppress the expansion and survival of AML cells by reducing β-catenin signaling, a key pathway in AML. NUC-7738’s effect was observed in multiple different AML cell lines suggesting broad therapeutic potential. Furthermore, it was observed that NUC-7738 resulted in a reduction of the cells that are resistant to standard chemotherapy drugs and thought to be responsible for disease relapse.

These findings, combined with the anti-cancer activity and favorable safety profile of NUC-7738 observed in the NuTide:701 study provide a strong rationale for the evaluation of NUC-7738 in patients with leukemia.

The details of NuCana’s poster presentation at EHA (Free EHA Whitepaper) are as follows:

Title: NUC-7738 regulates β-catenin signaling resulting in reduced proliferation and self-renewal of AML cells
Abstract Number: P459
Presentation Date & Time: Friday June 10, 2022 from 16:30-17:45 CEST (e-poster online at 9:00 CEST)
Presenting Author: Akbar M. Shahid

Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "NUC-7738 has entered Phase 2 development in patients with solid tumors and we have been encouraged by the clinical activity and favorable safety profile we have observed. The data presented at EHA (Free EHA Whitepaper) indicate that NUC-7738 may have applications beyond solid tumors and we are currently evaluating the optimal pathway for NUC-7738’s development for the treatment of hematologic malignancies."

About NUC-7738
NUC-7738 is a ProTide transformation of 3′-deoxyadenosine (3′-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as an anti-cancer agent due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cancer cells, thus overcoming 3’-dA’s key limitations of breakdown, transportation and activation. The cytotoxic effect of NUC-7738 is largely attributed to the generation of the main active anti-cancer metabolite, 3′-dATP. Primarily, 3′-dATP interferes with RNA polyadenylation, causing changes in the expression of genes involved in metabolism, differentiation, and apoptosis, ultimately leading to metabolic stress, cessation of cancer-cell growth and cell death.

On June 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported that updated efficacy and safety results from the teclistamab cohort of the Phase 1b TriMM-2 study (NCT04108195) (Press release, Johnson & Johnson, JUN 10, 2022, View Source [SID1234615890]).1 Teclistamab, an investigational, off-the-shelf, T-cell redirecting bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3 on T-cells, is being studied in combination with the anti-CD38 monoclonal antibody, DARZALEX (daratumumab) subcutaneous (SC) formulation, in patients with relapsed or refractory multiple myeloma (RRMM) who have received three or more prior lines of therapy.1 Patients in the study, including a high proportion with prior anti-CD38 monoclonal antibody exposure, achieved encouraging overall response rates (ORR) with this combination treatment.1 These data will be presented at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress as an oral presentation on Sunday, 12 June (Abstract S188).

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At a median follow-up of 8.6 months (range, 0.3-19.6), 76.5 percent (39/51) of response-evaluable patients enrolled in the study achieved a response, including 36 patients (70.6 percent) who achieved a very good partial response (VGPR) or better.1 In patients with prior anti-CD38 exposure, an ORR of 73.7 percent was achieved.1 The median time to first confirmed response was one month, and responses remained durable and deepened over time.1 At the analysis cut-off, 66.7 percent of patients who achieved a response (26/39) were alive and continuing on therapy.1

"Responders to the combination of teclistamab plus subcutaneous daratumumab included patients with prior exposure to BCMA or anti-CD38 targeted agents, which is encouraging," said Paula Rodríguez-Otero†, M.D., Ph.D., Department of Hematology, Clínica Universidad de Navarra, Pamplona, Spain and principal study investigator. "These data also suggest this steroid-sparing regimen may lead to a clinically efficacious regimen in highly refractory patients."

The open-label, multicentre, multicohort Phase 1b TriMM-2 study is investigating the safety and efficacy of teclistamab in combination with daratumumab SC for patients with RRMM.1 Enrolled patients received a median of five prior lines of therapy, 58.5 percent were triple-class refractory, 30.8 percent were penta-drug refractory, and 63.1 percent were refractory to anti-CD38 treatment.1 Eighty percent of patients were refractory to their last line of therapy.1

As of April 6, 2022, 65 patients received daratumumab SC 1,800mg at the approved schedule plus teclistamab 1.5mg/kg weekly (QW) or 3mg/kg every other week (Q2W) subcutaneously.1 Pre-medications, including steroids, were limited to the two step-up doses and the first full dose of teclistamab.1 Treatment with the combination regimen were tolerable and no unexpected or overlapping toxicities were observed.1 The most common adverse events (AEs) were cytokine release syndrome (CRS) (67.7 percent, all Grade 1 or 2); neutropenia (49.2 percent, 41.5 percent Grade 3 or 4); and anaemia (41.5 percent, 27.7 percent Grade 3 or 4).1 One patient (two percent) had Grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS) which fully resolved.1 Infections were experienced by 67.7 percent of patients (27.7 percent Grade 3 or 4).1 Four patients died from AEs, all unrelated to teclistamab or daratumumab SC treatment.1

"For nearly 20 years, we have been committed to overcoming multiple myeloma and an important part of our strategy is to continue to invest and develop complementary and combinable regimens that improve outcomes for patients and their caregivers," said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "Daratumumab has become a foundational therapy for multiple myeloma, and it is exciting to see how we can continue to grow its potential through combinations with novel treatments."

Pharmacodynamic analyses demonstrate that the combination upregulates CD38+/CD8+ T-cells and proinflammatory cytokines, suggesting the potential for complementary activity.1 Additional studies are needed to fully understand the potential clinical benefit of this biological activity.

The efficacy and pharmacodynamic profile of teclistamab in combination with daratumumab SC in patients refractory to anti-CD38 therapy suggest that higher response rates may be observed in patients with anti-CD38 naïve or sensitive disease who are enrolling in the MajesTEC-3 study (NCT05083169).1,2 The ongoing Phase 3 MajesTEC-3 study compares the efficacy of the teclistamab-daratumumab combination with daratumumab SC in combination with pomalidomide and dexamethasone (DPd) or daratumumab SC in combination with bortezomib and dexamethasone (DVd).2 Patients in the trial must have received one to three prior lines of therapy including a proteasome inhibitor (PI) and lenalidomide; patients who have received only one prior line of therapy must be refractory to lenalidomide.2 Patients who have progressed on or within 60 days of the last dose of lenalidomide given as maintenance therapy are also included.2

"These data suggest the potential of a fully immune-based regimen for patients with heavily pretreated multiple myeloma," said Yusri Elsayed, M.D., M.HSc., Ph.D., Vice President, Disease Area Leader, Hematologic Malignancies, Janssen Research & Development, LLC. "We are committed to the ongoing development of this combination and other treatments for patients who remain in need of new options."

#ENDS#

About Teclistamab
Teclistamab is an investigational, fully humanised, T-cell redirecting, IgG4 bispecific antibody targeting both BCMA (B-cell maturation antigen) and CD3, on T-cells.1 BCMA is expressed at high levels on multiple myeloma cells.3,4,5,6,7 Teclistamab redirects CD3-positive T-cells to BCMA-expressing myeloma cells to induce killing of tumor cells.8

Teclistamab is currently being evaluated in several monotherapy and combination studies.9,10,11,12,13 In 2020, the European Commission (EC) and the United Stated (U.S.) Food and Drug Administration (FDA) both granted teclistamab Orphan Drug Designation for the treatment of multiple myeloma. In January 2021 and June 2021, teclistamab received a PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA) and Breakthrough Therapy Designation (BTD) by the U.S. FDA, respectively. PRIME offers enhanced interaction and early dialogue to optimise drug development plans and speed up evaluation of cutting-edge, scientific advances that target a high unmet medical need.14 The FDA grants BTD to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition based on preliminary clinical evidence that demonstrates the drug may have substantial improvement in at least one clinically significant endpoint over available therapy.15 In December 2021, Janssen submitted a Biologics License Application (BLA) to the FDA seeking approval of teclistamab for the treatment of patients with RRMM; a marketing authorisation application (MAA) was submitted to the EMA for teclistamab approval in January 2022.

About daratumumab and daratumumab SC
Janssen is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. Daratumumab has been approved in eight indications for multiple myeloma, three of which are in the frontline setting, including newly diagnosed patients who are transplant eligible and ineligible.16

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 274,000 patients worldwide.17 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.18

CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.16 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death.16 Daratumumab may also have an effect on normal cells.16 Data across eight Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab based regimens resulted in significant improvement in PFS and/or OS.19,20,21,22,23,24,25,26

For further information on daratumumab, please see the Summary of Product Characteristics at: View Source

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.27 In multiple myeloma, cancerous plasma cells change and grow out of control.27 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.28 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels or kidney failure.29

On June 10, 2022 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported the presentation of novel findings on biomarker development for IRAK4 inhibitor emavusertib, collaborative work from the University of Florida in primary CNS lymphoma (pCNSL), and clinical data from the TakeAim Leukemia and TakeAim Lymphoma studies at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress currently taking place in Vienna, Austria and online until June 12, 2022 (Press release, Curis, JUN 10, 2022, View Source [SID1234615866]).

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"We are delighted to share with our colleagues in Europe our findings regarding IRAK4’s previously undescribed localization in the nucleus of cancer cells. It appears that when IRAK4 is found in the nucleus with active NF-kB proteins p50 and p65, using a technique which we refer to as ‘triple staining,’ this triple nuclear presence is associated with better responses to emavusertib," said James Dentzer, President and Chief Executive Officer of Curis.

"Also at EHA (Free EHA Whitepaper) this year, collaborative work by Dr. Duane Mitchell’s team at the University of Florida is being presented on the potential role of emavusertib in treating pCNSL, including data on one patient who achieved a complete response following previous treatment with ibrutinib," Mr. Dentzer continued. "And finally, in addition to this foundational work on IRAK4 biology, we are presenting data from our TakeAim Lymphoma and TakeAim Leukemia studies as we continue to spread the word on IRAK4 and the utility of inhibiting this important target to our European colleagues."

Curis scientists have discovered previously unknown nuclear accumulation of IRAK4 selectively in acute myeloid leukemia (AML) cells whereas nuclear IRAK4 was not detectable in mature myeloid cells (#2609). IRAK4 nuclear accumulation is significantly correlated with NF-kB activation in bone marrow samples from de novo AML patients and in AML cell lines. The detection of IRAK4 and NF-kB (phospho-p50 and phospho-p65) using nuclear staining of blasts in AML bone marrow samples was defined as ‘triple-positive,’ and patients whose cells did not stain for the nuclear presence of any of the three markers were termed ‘triple-negative.’ Treatment with emavusertib led to a significant decrease in bone marrow blast count in AML patients whose bone marrow sample was triple-positive, whereas no significant decrease in bone marrow blast count was detected in triple-negative cases. The goal of the Company’s biomarker work is to develop a companion diagnostic for emavusertib that is broadly applicable and is intended to identify the patients most likely to benefit from emavusertib treatment.

Research from Curis collaborators at the University of Florida in pCNSL (#2715) show that, in a patient treated on the TakeAim Lymphoma study in the combination arm following a previous ibrutinib containing regimen, the combination of emavusertib and ibrutinib resulted in a complete response. The team also observed that IRAK-4 and NF-kB proteins have elevated expression levels in human pCNSL. Further, in preclinical work, the team showed that emavusertib achieves therapeutically relevant concentrations in brain parenchyma and shows single-agent activity in an aggressive model of pCNSL.

Also presented at the EHA (Free EHA Whitepaper) meeting were previously presented data from the TakeAim Leukemia (#3975) and TakeAim Lymphoma (#3875) studies. TakeAim Leukemia is being orally presented, and TakeAim Lymphoma is the subject of a poster at the meeting. The data from these studies were also presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting last week in Chicago.
About Emavusertib (CA-4948)
Emavusertib is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Additionally, third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutation such as SF3B1 and U2AF1. In addition to inhibiting IRAK4, emavusertib was also designed to inhibit FLT3, a known oncologic driver, which may provide additional benefit in patients with AML and MDS.

About TakeAim Lymphoma
The TakeAim Lymphoma study (NCT03328078) is a Phase 1/2 open-label, dose escalation, dose expansion clinical trial investigating emavusertib as monotherapy and in combination with ibrutinib in patients with R/R hematologic malignancies, such as non-Hodgkins’s lymphoma and other B cell malignancies. After dose escalation in both monotherapy and combination therapy to determine the recommended Phase 2 dose (RP2D), we plan to expand four cohorts for combination treatment: marginal zone lymphoma, activated b-cell diffuse large b-cell lymphoma, primary CNS lymphoma, and patients developing adaptive resistance to ibrutinib monotherapy. The goals of the study are to determine several parameters including safety, maximum tolerated dose (MTD), RP2D and signals of activity.

About TakeAim Leukemia
The TakeAim Leukemia study (NCT04278768) is a Phase 1/2 dose escalation and dose expansion study examining emavusertib use as both monotherapy and in combination with azacitidine or venetoclax in patients with R/R AML or high risk MDS. After dose escalation in both monotherapy and combination therapy to determine the recommended Phase 2 dose, we plan to expand five cohorts: monotherapy in AML patients with spliceosome and FLT3 mutations, monotherapy in patients with MDS and spliceosome mutations and combination therapy with azacitidine or venetoclax in patients without spliceosome or FLT3 mutations. The goals of the study are to determine several parameters including safety, maximum tolerated dose (MTD), RP2D and signals of activity.

On June 10, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that the rationale and plans for its upcoming Phase 3 ZILO-301 (zilovertamab plus ibrutinib targeting ROR1 for patients with Mantle Cell Lymphoma) clinical trial will be highlighted in a poster presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress (Press release, Oncternal Therapeutics, JUN 10, 2022, View Source [SID1234615874]). ZILO-301 is designed to evaluate the efficacy and safety of zilovertamab, an investigational anti-ROR1 monoclonal antibody, plus ibrutinib compared to ibrutinib monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma (R/R MCL).

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Poster Title: Study ZILO-301: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Zilovertamab Plus Ibrutinib vs. Ibrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma
Abstract Number: P1154
Session Title: Indolent and mantle-cell non-Hodgkin lymphoma – Clinical
Session Date and Time: June 10, 2022 at 16:30 CEST
"The recently announced updated interim data from our Phase 1/2 study presented at ASCO (Free ASCO Whitepaper) 2022, provides ample support for the rationale of the design of our global registration Phase 3 study, ZILO-301, evaluating the combination of zilovertamab and ibrutinib in patients with MCL," noted Salim Yazji, M.D., Oncternal’s Chief Medical Officer. "We are excited to pursue a registrational pathway for zilovertamab based on an innovative enrichment study design that we believe can provide both an accelerated approval and regular approval in a single study. We expect to initiate ZILO-301 in the third quarter of 2022."

Zilovertamab is being evaluated in combination with ibrutinib in patients with R/R MCL and chronic lymphocytic leukemia (CLL) in the Phase 1/2 study, CIRM-0001. The most recent interim data update showed an Objective Response Rate (ORR) of 85% and a Complete Response (CR) rate of 41% in 27 evaluable patients with mantle cell lymphoma, both of which compare favorably to the historical ORR of 66% and CR rate of 20% for ibrutinib monotherapy.

The phase 3 study, ZILO-301, will evaluate the potential benefit for patients who achieve either a partial response (PR) or stable disease (SD) during a lead-in with ibrutinib monotherapy. Initially, patients enrolled in ZILO-301 will receive single agent ibrutinib (560 mg daily) for 4 months. Patients with an inadequate response (PR or SD) will be randomized (1:1) to receive zilovertamab or placebo while continuing to receive ibrutinib. The study aims to randomize approximately 250 patients.

Key Inclusion criteria:
Adults with histologically confirmed MCL
Relapsed or refractory with at least 1 prior therapy
Primary Objective
Progression-free survival (PFS) among subjects who had a PR or SD after open-label ibrutinib monotherapy phase and were randomized to receive zilovertamab + ibrutinib or ibrutinib + placebo
Secondary Objectives
Objective Response Rate (ORR) and Duration of Response (DoR)
Complete Response Rate (CR Rate)
Overall Survival (OS)
Proportion of subjects experiencing grade 3 or 4 neutrophil count decrease and overall safety profile
About Zilovertamab

Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL, chronic lymphocytic leukemia (CLL) or MZL, in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.

ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1-expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.