On December 9, 2019 STORM Therapeutics, the biotechnology company focused on the discovery of small molecule therapies modulating RNA epigenetics reported, that its collaborator Dr. Konstantinos Tzelepis, Sir Henry Wellcome Fellow and visiting scientist at the Wellcome Sanger Institute, received the ASH (Free ASH Whitepaper)-BSH Abstract Achievement Award for his work on STORM Therapeutics’ lead programme, METTL3, at the 61st Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) held on 7th-10th December 2019 in Orlando, Florida (Press release, STORM Therapeutics, DEC 9, 2019, View Source;exposition-300971436.html [SID1234552158]).

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Dr. Tzelepis received the meritorious award for his abstract entitled ‘Pharmacological Inhibition of the RNA m6a Writer METTL3 As a Novel Therapeutics Strategy for Acute Myeloid Leukemia’ at the Abstract Achievement Award Ceremony which was held on Saturday, 7th December 2019 at 3:30pm (EST) at the Orange County Convention Center in Exhibit Hall B2-B4.

Dr. Tzelepis’s work, which was carried out in collaboration with the Wellcome Sanger Institute and the University of Cambridge, was presented in an oral presentation during the "802. Chemical Biology and Experimental Therapeutics: Novel Compounds and Mechanisms of Action" session on Sunday, 8th December 2019 at 9:30am-11:30am (EST) at the Orange County Convention Centre. The abstract and talk encapsulated the ground-breaking work made on targeting RNA modifying enzymes for cancer treatment and described the recent progress made with the METTL3 inhibitor.

STORM has identified small molecule inhibitors of METTL3 that are orally bioavailable and show pronounced anti-tumour efficacy in physiologically relevant, proof of concept animal models of Acute Myeloid Leukaemia (AML). The talk demonstrated that small molecule inhibition of METTL3 produces the same phenotype and effects previously described in one of STORM’s founder scientists’ publications using genetic models and validates METTL3 as a druggable target for cancer.

Keith Blundy, CEO of STORM Therapeutics, said: "STORM is progressing fast in its preclinical work with our multiple programmes to showcase the capabilities of our novel platform. STORM is a pioneer in RNA epigenetics and we are very pleased to hear that our collaborator is being recognized for the partnership research of METTL3. As the first company in the world to demonstrate in vivo activity of an RNA methyltransferase inhibitor, we are excited to be leading the field as we look to develop these highly innovative new treatment options for cancer patients."

On December 8, 2019 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported clinical data from three trials of its BTK inhibitor BRUKINSA (zanubrutinib) were presented at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL (Press release, BeiGene, DEC 8, 2019, View Source [SID1234552052]). In two oral presentations of BRUKINSA in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), the drug candidate demonstrated consistent safety and a high overall response rate (ORR); in the poster presentation of BRUKINSA combined with BeiGene’s investigational anti-PD-1 antibody tislelizumab in patients with previously treated B-cell malignancies, the combination treatment showed preliminary efficacy and was generally well tolerated.

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"The data presented today showing clinical activity and tolerability of BRUKINSA in patients with CLL or SLL are promising for its potential use in patients living with these cancers," said Constantine S. Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at the Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia. "BTK inhibitors have become an important standard of care for B-cell malignancies, offering the potential for durable responses with manageable safety profiles. It’s encouraging to have more evidence that zanubrutinib can be effective in treating CLL or SLL, including in patients with del(17p) who typically have a worse prognosis and few treatment options."

"The results presented today on BRUKINSA, a BTK inhibitor designed to maximize target occupancy and minimize off-target binding, demonstrated robust clinical activity and a safety profile consistent with what we’ve observed to date in our clinical trials, including safety data that supported the recent U.S. FDA accelerated approval in patients with previously treated mantle cell lymphoma," said Jane Huang, M.D., Chief Medical Officer, hematology at BeiGene. "CLL or SLL is the most common type of leukemia in adults, and despite the advancements of BTK inhibitor therapy for these cancers, there remains a need for highly selective BTK inhibitors capable of promoting long-term responses, and with a safety profile that is tolerable over time. The results presented here today further demonstrate the potential for BRUKINSA to help people living with these persistent, life-threatening cancers."

Initial Results from SEQUOIA Trial Arm C in Treatment-Naïve (TN) CLL or SLL Patients with Del(17p)

Presentation 499

Initial results from Arm C in the open-label, Phase 3 SEQUOIA trial (NCT03336333) of BRUKINSA as a monotherapy demonstrated a high ORR in patients with TN CLL or SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)]. The safety profile was consistent with that observed in previous clinical trials of BRUKINSA in B-cell malignancies. At the data cutoff of August 7, 2019, with a median follow-up of 10 months, initial results included:

The ORR was 92.7% (101/109); the partial response (PR) rate was 78.9% (86/109); the PR rate with lymphocytosis was 11.9% (13/109); and the complete response (CR) rate was 1.9% (2/109); only four cases of disease progression occurred;

36.7% of patients (40/109) experienced at least one grade ≥3 adverse event (AE) and only one patient discontinued treatment due to AEs;

The most common grade ≥3 AEs, occurring in more than two patients, were neutropenia (10.1%), pneumonia (3.7%) and hypertension (2.8%);

23.9% of patients (26/109) experienced at least one serious AE; and

One patient experienced a fatal AE, pneumonia leading to sepsis and death, which was considered related to treatment drug by the study investigator.
Updated Results from a Phase 1/2 Trial in Patients with CLL or SLL

Presentation 500

Updated results from the open-label, dose-escalation, single-arm, global Phase 1/2 trial (NCT02343120) showed that BRUKINSA was generally well-tolerated and active in patients with relapsed/refractory (R/R) or TN CLL/SLL, irrespective of del(17p) status (n=123; 101 R/R, 22 TN). At the data cutoff of May 8, 2019, with a median follow-up of 29.5 months, results included:

The ORR was 95.9% (118/123); the PR rate was 73.2% (90/123); the PR rate with lymphocytosis was 6.5% (8/123); the CR rate was 16.3% (20/123), including one patient who achieved a CR with incomplete bone marrow recovery;

The median duration of treatment was 25.8 months and 80% of patients (98/123) remained on study treatment; two-year progression-free survival (PFS) was 91% in R/R patients and 95% in TN patients;

61.8% of patients (76/123) experienced at least one grade ≥3 AE and only five patients discontinued treatment due to AEs;

The most common AEs (≥ 20%) were contusion (47.2%), upper respiratory tract infection (42.3%), diarrhea (31.7%), cough (29.3%), headache (23.6%), and fatigue (20.3%);

47.2% of patients (58/123) experienced at least one serious AE; and

One patient experienced a fatal AE, neoplasm-malignant recurrent squamous cell carcinoma, considered unrelated to treatment drug by the study investigator.
BRUKINSA in Combination with PD-1 Inhibitor Tislelizumab in Patients with Previously Treated B-Cell Lymphoid Malignancies

Presentation 1594

Preliminary findings from the open-label, multicenter, Phase 1b trial (NCT02795182) showed that BRUKINSA in combination with the investigational anti-PD-1 antibody tislelizumab demonstrated a generally manageable toxicity profile in patients with R/R B-cell malignancies. A total of 70 patients enrolled in the trial, including 54 patients with aggressive non-Hodgkin’s lymphomas (NHLs) which consist of diffuse large B-cell lymphoma, transformed follicular lymphoma, Richter’s transformation, and central nervous system (CNS) lymphoma. At the data cutoff of August 31, 2019, with a median follow-up of 8.1 months, preliminary findings included:

Of the 54 patients with aggressive NHLs, the ORR was 37.0% (20/54); the PR rate was 20.4% (11/54); the CR rate was 16.7% (9/54); stable disease (SD) rate was 9.3% (5/54);

71.4% of patients (50/70) experienced at least one grade ≥3 AE and 14.3% of patients (10/70) discontinued BRUKINSA and/or tislelizumab treatment due to AEs;

The most common grade ≥3 AEs were neutropenia (12.9%), anemia (10.0%), thrombocytopenia (7.1%), pneumonia (5.7%), neutrophil count decreased (5.7%), tumor lysis syndrome (4.3%), sepsis (4.3%), immune-mediated enterocolitis (4.3%), hypertension (4.3%), lymphocyte count decreased (2.9%), hemolytic transfusion reaction (2.9%), febrile neutropenia (2.9%), back pain (2.9%), acute kidney injury (2.9%), abscess limb (2.9%), and abdominal pain (2.9%);

Grade ≥3 immune-related AEs (irAEs) were reported in 15.7% of patients (11/70) with immune-mediated enterocolitis (4.3%), and pneumonitis (2.9%) occurring in more than one patient; and

Five patients experienced fatal AEs, four of which in the setting of progressive disease were considered unrelated to treatment including multi-organ dysfunction, septic shock and pneumonia, respiratory failure, and aspiration pneumonia, and one of toxic epidermal necrolysis which was considered related to treatment by the study investigator.
About BRUKINSA (zanubrutinib)

BRUKINSA (zanubrutinib) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad pivotal clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. BRUKINSA was granted accelerated approval by the U.S. FDA to treat adult patients with MCL who have received at least one prior therapy in November 2019. This accelerated approval is based on overall response rate (ORR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

New Drug Applications (NDAs) in China for relapsed refractory (R/R) MCL and R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have been accepted by the China National Medical Products Administration (NMPA) and granted priority review and are pending approval.

BRUKINSA is not approved for use outside the United States. BRUKINSA is not approved for the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma.

IMPORTANT SAFETY INFORMATION FOR BRUKINSA (ZANUBRUTINIB)

Warnings and Precautions

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher bleeding events including intracranial and gastrointestinal hemorrhage, hematuria and hemothorax have been reported in 2% of patients treated with BRUKINSA monotherapy. Bleeding events of any grade, including purpura and petechiae, occurred in 50% of patients treated with BRUKINSA monotherapy.

Bleeding events have occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Co-administration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.

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

Infections

Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA monotherapy. Grade 3 or higher infections occurred in 23% of patients treated with BRUKINSA monotherapy. The most common Grade 3 or higher infection was pneumonia. Infections due to hepatitis B virus (HBV) reactivation have occurred.

Consider prophylaxis for herpes simplex virus, pneumocystis jiroveci pneumonia and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (27%), thrombocytopenia (10%) and anemia (8%) based on laboratory measurements, were reported in patients treated with BRUKINSA monotherapy.

Monitor complete blood counts during treatment and treat using growth factor or transfusions, as needed.

Second Primary Malignancies

Second primary malignancies, including non-skin carcinoma, have occurred in 9% of patients treated with BRUKINSA monotherapy. The most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin), reported in 6% of patients. Advise patients to use sun protection.

Cardiac Arrhythmias

Atrial fibrillation and atrial flutter have occurred in 2% of patients treated with BRUKINSA monotherapy. Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher events were reported in 0.6% of patients treated with BRUKINSA monotherapy. Monitor signs and symptoms for atrial fibrillation and atrial flutter and manage as appropriate.

Embryo-Fetal Toxicity

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

Adverse Reactions

The most common adverse reactions in > 10% of patients who received BRUKINSA were neutrophil count decreased (53%), platelet count decreased (39%), upper respiratory tract infection (38%), white blood cell count decreased (30%), hemoglobin decreased (29%), rash (25%), bruising (23%), diarrhea (20%), cough (20%), musculoskeletal pain (19%), pneumonia (18%), urinary tract infection (13%), hematuria (12%), fatigue (11%), constipation (11%), and hemorrhage (10%). The most frequent serious adverse reactions were pneumonia (11%) and hemorrhage (5%).

Drug Interactions

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

CYP3A Inducers: Avoid coadministration with moderate or strong CYP3A inducers.

Specific Populations

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

INDICATION

BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

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

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

About the Zanubrutinib Clinical Trial Program

Clinical trials of zanubrutinib include:

Fully-enrolled Phase 3 ASPEN clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib (NCT03053440), currently the only approved BTK inhibitor for WM;

Phase 3 SEQUOIA trial comparing zanubrutinib with bendamustine plus rituximab in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (NCT03336333);

Phase 3 ALPINE trial comparing zanubrutinib to ibrutinib in patients with relapsed/refractory (R/R) CLL/SLL (NCT03734016);

Phase 2 trial in combination with GAZYVA (obinutuzumab) in patients with R/R follicular lymphoma (FL) (NCT03332017);

Phase 3 trial comparing zanubrutinib and rituximab to bendamustine and rituximab in patients with untreated MCL (NCT04002297);

Phase 2 MAGNOLIA trial in patients with R/R marginal zone lymphoma (MZL) (NCT03846427);

Phase 2 ROSEWOOD trial (NCT03332017) in China comparing obinutuzumab and zanubrutinib vs obinutuzumab alone in treating patients with R/R FL;

Completed Phase 2 trials in patients with R/R MCL (NCT03206970) and R/R CLL/SLL (NCT03206918); and

Completed enrollment in Phase 2 clinical trial in patients with WM (NCT03332173).
About Tislelizumab

Tislelizumab (BGB-A317) is an investigational humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug candidate produced from BeiGene’s immuno-oncology biologics program and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

Select ongoing clinical trials of tislelizumab include a Phase 3 clinical trial in patients with second-line or third-line non-small cell lung cancer (NSCLC); a Phase 3 clinical trial in first-line patients with hepatocellular carcinoma (HCC); a Phase 3 clinical trial in second-line patients with esophageal squamous carcinoma (ESCC); a Phase 3 clinical trial in first-line patients with gastric cancer (GC); a Phase 3 clinical trial in first-line patients with ESCC; and a Phase 2 clinical trial in second- or third-line patients with HCC. The aforementioned trials are enrolling patients in multiple countries, including the United States, Europe, and China.

In addition to a pivotal Phase 2 clinical trial in patients with relapsed or refractory (R/R) classical Hodgkin’s lymphoma (cHL) and a pivotal Phase 2 clinical trial in patients with locally advanced or metastatic urothelial cancer, BeiGene is conducting a Phase 3 clinical trial in first-line patients with non-squamous NSCLC; a Phase 3 clinical trial in first-line patients with squamous NSCLC; a Phase 3 clinical trial in patients with first-line nasopharyngeal cancer (NPC); a Phase 3 clinical trial in first-line patients with urothelial carcinoma (UC); a Phase 3 clinical trial in patients with localized ESCC; and a Phase 2 trial in patients with MSI-H or dMMR solid tumors. These studies have been enrolling patients primarily in China.

New drug applications (NDA) for tislelizumab in patients with R/R cHL and in patients with previously treated locally advanced or metastatic UC have been accepted and granted priority review by the China National Medical Products Administration (NMPA, formerly known as CFDA). BeiGene has full development and commercial rights to tislelizumab worldwide.

On December 8, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported that four posters relating to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, and eltanexor, its next generation SINE compound, will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019 in Orlando (Press release, Karyopharm, DEC 8, 2019, View Source [SID1234552038]). The four posters include: updated data from the Kyprolis (carfilzomib) arm of the Phase 1b/2 STOMP study evaluating selinexor in combination with backbone therapies in patients with relapsed or refractory multiple myeloma; new data from the Revlimid (lenalidomide) plus selinexor arm of the STOMP study evaluating this combination in patients with newly diagnosed multiple myeloma; encore data highlighting the previously disclosed comparison of patients in the STORM study, Karyopharm’s Phase 2b study evaluating XPOVIO in patients with heavily pretreated, triple class refractory multiple myeloma, to matched patients from the MAMMOTH study; and new Phase 1/2 data evaluating eltanexor in patients with higher-risk myelodysplastic syndrome (MDS).

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"Efficacy data from our ongoing STOMP study investigating selinexor in combination with standard of care anti-myeloma agents continue to demonstrate a strong rationale for selinexor’s potential expanded role in the future multiple myeloma treatment paradigm," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "The Kyprolis arm of the STOMP study continues to show clear signs of clinical activity, including a complete response rate of 21%, in patients with heavily pretreated Kyprolis-naïve multiple myeloma. Additionally, preliminary data from the Revlimid arm of the Phase 1b/2 STOMP study show early but encouraging clinical activity, including in one patient who achieved a complete response, in patients with multiple myeloma in the front-line setting. And finally, we are pleased to be presenting new data from the eltanexor program showing impressive early activity, including a high rate of complete responses in elderly patients with higher-risk MDS."

Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Kyprolis and Low-dose Dexamethasone (SKd) in Patient with Relapsed or Refractory Multiple Myeloma

In this arm of the Phase 1b/2 STOMP study, oral selinexor (dosed once-weekly) is being evaluated in combination with Kyprolis (56mg/m2 or 70mg/m2 once weekly) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed refractory multiple myeloma who have received at least two prior therapies, which can include previous treatment with a proteasome inhibitor, one or more immunomodulatory drugs (e.g., Revlimid or Pomalyst) or Darzalex. The median number of prior treatments was four (range: 2-8). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SKd Patients as of 1-Oct-20192
Category N ORR CR VGPR PR
All (Kyprolis-naïve) 14 10 (71%) 3 (21%) 7 (50%) -
Key: ORR=Overall Response Rate (CR+VGPR+PR); CR=Complete Response; VGPR=Very Good Partial Response; PR=Partial Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data

All patients had reductions in M-protein from baseline, with 71% of patients experiencing a reduction of ≥90%. Median progression-free survival (PFS) has not yet been reached.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (71%), fatigue (43%), anorexia (36%), vomiting (36%) and weight loss (36%), and were mostly Grade 1 and 2 events. As expected, the most common treatment-related Grade ≥3 AEs were hematologic AEs and included thrombocytopenia (64%), anemia (14%) and leukopenia (14%). The recommended Phase 2 dose (RP2D) was identified as selinexor 80mg and Kyprolis 56mg/m2 and enrollment continues using this regimen.

New Data from Phase 1b/2 STOMP Study Evaluating the All Oral Combination of Selinexor with Revlimid and Low-dose Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

In this all oral arm of the Phase 1b/2 STOMP study in patients with newly diagnosed multiple myeloma, selinexor (60mg once-weekly) is being combined with Revlimid (25mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SRd Patients as of 1-Oct-20192
Category N3 ORR CR VGPR4 PR
All 7 6 (86%) 1 (14%) 4 (57%) 1 (14%)
Key: ORR=Overall Response Rate (CR+VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 One patient was not evaluable for response due to withdrawn consent prior to disease follow-up
4 One VGPR was confirmed on Oct 10, 2019 (after data cut); two VGPR are unconfirmed

The data are early and the median PFS was not reached. Among the patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were diarrhea (63%), weight loss (63%), nausea (50%), constipation (38%), fatigue (38%), hypokalemia (38%) and insomnia (38%) and were mostly Grade 1/2. The most common Grade ≥3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (25%). Amongst the five patients evaluable for dose limiting toxicities (DLTs), there were no DLTs observed.

Comparison of Overall Survival Rates Between the Phase 2b STORM Study and the MAMMOTH Study

Another key presentation at ASH (Free ASH Whitepaper) 2019 highlights encore data comparing the overall survival (OS) rate from the retrospective MAMMOTH study (Leukemia, 2019). The MAMMOTH study evaluated outcomes of patients with relapsed or refractory multiple myeloma (RRMM) treated at major academic medical centers. This ASH (Free ASH Whitepaper) presentation highlighted results from a comparison of outcomes from patients with RRMM after their disease became refractory to CD38 monoclonal antibodies with a matched cohort of patients from Karyopharm’s Phase 2b STORM study, which served as the basis for the XPOVIO accelerated approval. Thus, patients in STORM who received selinexor and dexamethasone as first line of therapy after their disease became triple class refractory (n=64) were compared with matched patients receiving currently available therapies from the MAMMOTH cohort (n=128), showed an unadjusted hazard ratio (HR) for death of 0.64 (p=0.043), while an adjusted analysis, which takes into consideration differences in baseline characteristics between the two groups, showed a HR of 0.55 (p=0.009). The median OS of patients in STORM was 10.4 months and in MAMMOTH was 6.9 months. These results are consistent with previous presented results of STORM patients versus those from the Flatiron Health Analytics Database (FHAD) from patients with RRMM treated primarily in the community setting (Richardson, et al. ASCO (Free ASCO Whitepaper) 2019). In that analysis, the median OS of patients in STORM was 10.4 months and in FHAD was 5.8 months (p=0.036).

Updated Phase 1/2 Clinical Data for Oral Eltanexor in Elderly Patients with Higher-Risk MDS

This Phase 1/2 study is evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10mg or 20mg once-daily for 5 days per week) in elderly patients with higher-risk MDS. All patients were refractory to hypomethylating agents. The following table is a summary of the efficacy results:

Best Responses1 in Eltanexor Patients2
Category N ORR mCR SD
All patients 20 7 (35%) 7 (35%) 5 (25%)
Key: ORR=Overall Response Rate (mCR+HI [not observed]); mCR=Complete Response without marrow recovery; HI=Hematologic Improvement; SD=Stable Disease
1 Responses assessments were made by the treating physician according to the 2006 International Working Group (IWG) Response Criteria for MDS
2 Based on interim unaudited data

Median overall survival was 10.6 months. The most common treatment-related AEs were hematologic, gastrointestinal and constitutional. The most common non-hematologic treatment-related AEs were nausea (45%), decreased appetite (40%), fatigue (35%), diarrhea (35%) and dysgeusia (25%); the vast majority were Grade 1 or 2. The most common Grade ≥3 AEs were anemia (30%), neutropenia (25%), thrombocytopenia (20%) and leukopenia (15%). AEs were dose-dependent and managed with supportive care and dose modification. This Phase 1/2 study remains ongoing.

Other Key Selinexor Presentations

An additional investigator-sponsored study, which will be presented on Monday, December 9, 2019, highlights data from a Phase 1 trial investigating the combination of selinexor and ibrutinib in 33 heavily pretreated, high-risk patients with chronic lymphocytic leukemia or non-Hodgkin lymphoma. This combination was tolerable and demonstrated encouraging efficacy in this high-unmet need patient population warranting additional future clinical investigation.

Details for these ASH (Free ASH Whitepaper) 2019 presentations are as follows:

Poster Presentations – Company-Sponsored Studies

Title: Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma
Presenter: Darrell White, Dalhousie University
Abstract #: 3165
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)
Presenter: Cristina Gasparetto, Duke University Medical Center
Abstract #: 3157
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies
Presenter: Luciano Costa, University of Alabama at Birmingham
Abstract #: 3125
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Date and Time: Date: Sunday, December 8, 2019; 6:00 PM – 8:00 PM ET
Location: Orange County Convention Center, Hall B

Title: Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome
Presenter: Sangmin Lee, Weill Cornell School of Medicine
Abstract #: 2997
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Poster II
Date and Time: Sunday, December 8, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

Poster Presentations – Investigator-Sponsored Studies

Title: Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study
Presenter: Deborah Stephens, Huntsman Cancer Institute, University of Utah
Abstract #: 4310
Session: 642. CLL: Therapy, excluding Transplantation: Poster III
Date and Time: Monday, December 9, 2019; 6:00-8:00 PM ET
Location: Orange County Convention Center, Hall B

PDF copies of these presentations will be available here following conclusion of the presentations at the meeting.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), in recurrent gliomas (KING) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.

On December 8, 2019 TG Therapeutics, Inc. (NASDAQ: TGTX), reported triple therapy data from the Phase I/II study of ublituximab (TG-1101), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, in combination with umbralisib (TGR-1202), the Company’s oral, dual inhibitor of PI3K delta and CK1 epsilon, and venetoclax, in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) (Press release, TG Therapeutics, DEC 8, 2019, View Source [SID1234552039]). Data from this trial were presented this morning during an oral session at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

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Michael S. Weiss, Executive Chairman and Chief Executive Officer, stated, "We are extremely pleased to share the first data from the triple combination of U2 (umbralisib and ublituximab) and venetoclax, which we believe has the potential to offer patients with CLL a highly active, time-limited, and generally well tolerated treatment option. It was exciting to see that for those patients followed for at least 12 months at the time of the presentation, there was a 100% ORR, and all of those patients achieved MRD negativity in the peripheral blood, with 7 of those 9 patients also achieving MRD negativity in the bone marrow. We look forward to updating these data at future conferences as more patients are followed for 12 months and longer." Mr. Weiss continued, "We were also excited to see that 87% of patients responded to the U2 combination after just three months of treatment prior to the introduction of venetoclax. We believe this further demonstrates the activity of the U2 combination that is being studied in our UNITY-CLL Phase 3 trial, which we expect data from in the coming weeks or months."

Below are highlights from the oral presentation.

Title: A Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

This oral presentation includes data from patients with relapsed or refractory CLL treated with the triple combination of ublituximab, umbralisib, and venetoclax. Twenty-seven patients were evaluable for safety and 23 were evaluable for efficacy. Data highlights include:

Regimen was administered with 3 cycles of U2 induction/debulking to reduce the risk of tumor lysis syndrome (TLS), followed by the combination of umbralisib and venetoclax starting in cycle 4. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy.
Overall response rate (ORR) of 87% (20/23) after U2 induction period at cycle 3, prior to introduction of venetoclax, in relapsed/refractory CLL patients, including patients refractory to ibrutinib
U2 induction appeared to reduce venetoclax TLS risk, with no patients remaining as TLS high-risk following 3 cycles of U2
13 patients treated for >7 cycles and 9 patients for > 12 cycles:
° 100% ORR (13/13) after cycle 7 for the triple combination
° 100% ORR (9/9) including 44% Complete Response (CR) after cycle 12 for the combination
° 100% (9/9) of patients had undetectable minimal residual disease (MRD) (<0.01%) in peripheral blood after 12 cycles of therapy; and
° 78% (7/9) of patients who completed 12 cycles of therapy had undetectable MRD in bone marrow and have stopped therapy
No patients (n = 27) have progressed to date with a median follow-up of 6.4 months
Triple combination was generally well tolerated with no events of TLS observed
An open-label, multicenter, Phase 2 study evaluating U2 plus venetoclax (ULTRA-V) in treatment naïve and previously treated CLL is now open for enrollment.

Remaining ASH (Free ASH Whitepaper) Presentation Details

Title: Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton’s Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies
° Publication Number: 4001
° Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III
° Date and Time: Monday, December 9, 2019; 6:00 PM – 8:00 PM ET
° Location: Orange County Convention Center, Hall B
° Presenter: Chan Cheah, MD, Sir Charles Gairdner Hospital, Hollywood Private Hospital, University of Western Australia, Blood Cancer Research Western Australia
Following the presentation, the data presented will be available on the Publications page of the Company’s website at View Source

On December 8, 2019 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported that it will present updated data from the ongoing Phase 2 ANCHOR (OP-104) triple combination study at the ASH (Free ASH Whitepaper) Annual Meeting 2019 (Press release, Oncopeptides, DEC 8, 2019, View Source [SID1234552040]). In the data presented, melflufen and dexamethasone demonstrated positive efficacy in combination with daratumumab or bortezomib in patients with relapsed/refractory multiple myeloma (RRMM). Preclinical data supporting clinical development of melflufen in AL amyloidosis will also be presented for the first time.

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Overall Conclusions – ANCHOR Poster Presentation

Patients in the ANCHOR study had a median of two prior lines of therapy. All patients were refractory to at least one agent.
For melflufen and dexamethasone in combination with daratumumab (n=33) the overall response rate (ORR) was 76% with a median progression-free survival (PFS) of 14.3 months.
70% of the patients were still progression-free at the time of the data cut.
For melflufen and dexamethasone in combination with bortezomib (n=6) the ORR was 67%.
Responses improved with continued therapy for both combinations.
Both combinations were well tolerated and the grade 3 and 4 Adverse Events (AE) were primarily hematologic.
Klaas Bakker, MD, and Chief Medical Officer comments on the ANCHOR data
"The ANCHOR data presented today are truly encouraging and support the future development of melflufen in triplet regimens. The ORR of 76% and median PFS of 14.3 months in the daratumumab arm, while immature, are among the highest reported in this patient population. This further validates the foundation for our next pivotal randomized Phase 3 study LIGHTHOUSE (OP-108), in which we will compare subcutaneous daratumumab with or without melflufen. We expect to enroll the first patient in early 2020 and are excited to embark on this next journey with melflufen in multiple myeloma."

Klaas Bakker, MD, and Chief Medical Officer comments on the AL amyloidosis data
"Based on our very positive preclinical data around AL amyloidosis and our experience of melflufen in a clinical setting, we are excited to initiate our first study with melflufen in patients with Immunoglobulin Light Chain (AL) amyloidosis. This lays the foundation for the use of melflufen in another indication with a high unmet medical need."

About the OP-104 ANCHOR study
ANCHOR is a phase 1/2 study where melflufen and dexamethasone is dosed in combination with either bortezomib or daratumumab. All patients enrolled must have had 1-4 prior lines of therapy and be refractory (or intolerant) to an immunomodulary agent (IMiD) or a proteasome inhibitor (PI) or both. The enrollment in the daratumumab regimen is completed while recruitment for the bortezomib arm is still ongoing.

More information about the study can be found at:

View Source;rank=4

About the OP-102 AL amyloidosis study
The AL amyloidosis study is an Open-label, Phase 1/2 dose-escalation and dose-expansion study of melflufen and dexamethasone in patients with immunoglobulin light chain (AL) amyloidosis following at least one prior line of therapy. The study will enroll approximately 45 patients. The primary endpoint in the phase 2 part is to study the Overall Response Rate (ORR).

More information about the study can be found at:

View Source;rank=4

About melflufen
Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.