On December 8, 2019 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported new in vivo preclinical data for FT596, its off-the-shelf, multi-antigen targeting natural killer (NK) cell product candidate derived from a clonal master engineered induced pluripotent stem cell (iPSC) line (Press release, Fate Therapeutics, DEC 8, 2019, View Source [SID1234552041]). The data were featured during the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition as part of the organization’s CAR-T and Beyond press program, which spotlighted promising next-generation cancer immunotherapies having the potential to overcome the key limitations of patient-specific chimeric antigen receptor (CAR) T-cell therapy.

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"Current patient- and donor-specific CAR T-cell immunotherapies recognize only one antigen and fail to address the significant risk of relapse due to antigen escape. FT596 is ground-breaking in that it is designed to be available off-the-shelf for timely patient access and to promote deeper and more durable responses by targeting multiple tumor-associated antigens," said Bob Valamehr, Ph.D., Chief Development Officer of Fate Therapeutics. "Additionally, since FT596 is manufactured from a renewable master engineered iPSC line, the complexities of patient-by-patient genetic engineering and production are greatly reduced and, for the first time, we are able to mass produce multi-functional cellular immunotherapies in a uniform and cost-effective manner."

FT596 is the first cellular immunotherapy engineered with three active anti-tumor components to be cleared for clinical investigation by the FDA. In addition to a proprietary CAR targeting CD19, FT596 expresses a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor that has been modified to augment antibody-dependent cellular cytotoxicity, enabling coincident targeting of CD19 and additional tumor-associated antigens such as CD20. FT596 also expresses an interleukin-15 receptor fusion (IL-15RF), a potent cytokine complex that promotes survival, proliferation and trans-activation of NK cells and CD8 T cells without the need for systemic cytokine support. Together, these features of FT596 are intended to maximize potency and minimize toxicity in treated patients. The Company plans to initiate enrollment of a first-in-human clinical trial of FT596 in early 2020.

New preclinical data presented at ASH (Free ASH Whitepaper) showed that FT596 administered as a monotherapy exhibited durable tumor clearance and extended survival in vivo similar to primary CAR T cells in a humanized mouse model of CD19+ lymphoma. Additionally, when combined with the anti-CD20 monoclonal antibody rituximab, FT596 showed enhanced killing of CD20+ lymphoma cells in vivo as compared to rituximab alone. These data confirm previously presented in vitro findings that demonstrate the unique multi-antigen targeting functionality of FT596, and the product candidate’s potential to effectively overcome CD19 antigen escape.

The Company also announced that, in preparation for Phase 1 initiation, it had recently completed GMP production of FT596. In a single small-scale manufacturing campaign, the Company produced over 300 cryopreserved, infusion-ready doses of FT596 at a cost of approximately $2,500 per dose. The Company’s iPSC product platform unites stem cell biology and precision genetic engineering to create renewable master engineered iPSC lines that can be repeatedly used to mass produce cancer-fighting immune cells, replacing the high production costs, weeks of manufacturing time, and complex manufacturing processes required for current-generation CAR T-cell immunotherapies with a lower-cost, easier-to-manufacture, well-characterized, off-the-shelf product that has the potential to reach many more patients.

FT596 is the third off-the-shelf, iPSC-derived NK cell product candidate from the Company’s proprietary iPSC product platform cleared for clinical investigation by the FDA in the past twelve months. On Saturday, the Company announced that the first patient treated for acute myeloid leukemia in its Phase 1 clinical trial of FT516, an off-the-shelf, iPSC-derived NK cell cancer immunotherapy engineered to express hnCD16, showed no morphologic evidence of leukemia, chimerism of FT516 in the bone marrow, and hematopoietic recovery, including complete neutrophil recovery without growth factor support (>1,000 per µL), after receiving three once-weekly doses of FT516 and IL-2 cytokine support.

On December 8, 2019 Innate Pharma SA (Euronext Paris: IPH – ISIN: FR0010331421; Nasdaq: IPHA) ("Innate" or the "Company") shared new, reported that long-term data from the pivotal Phase III trial of Lumoxiti (moxetumomab pasudotox-tdfk) at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Orlando, USA, which expands on the efficacy results and affirms the manageable safety profile of the medicine (Press release, Innate Pharma, DEC 8, 2019, View Source [SID1234552026]).

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The final analysis showed that 36 percent (29/80) of the relapsed or refractory hairy cell leukemia patients achieved durable complete response (CR) with Lumoxiti at Day 181 of patients’ respective evaluation, compared to the primary analysis in which 30 percent durable CR rate was reported. In addition, there was a 61 percent probability that patients who achieved a CR would maintain it after five years.

"Lumoxiti is a first-in-class medicine and the only treatment approved in the US for relapsed or refractory hairy cell leukemia in more than twenty years; therefore, it is important for the hematology-oncology community to receive additional analysis of its long-term efficacy," commented Pierre Dodion, MD, Executive Vice President and Chief Medical Officer of Innate Pharma. "We are grateful to the patients and health care professionals who participated in the clinical development of Lumoxiti and we are passionate about continuing to address the unmet need in this rare form of cancer."

The single-arm, multi-center, open-label Phase III ‘1053’ clinical trial assessed the efficacy, safety, immunogenicity and pharmacokinetics of Lumoxiti monotherapy in 80 patients with relapsed or refractory hairy cell leukemia who had received at least two prior therapies, including one purine nucleoside analog. The primary endpoint of durable CR was defined as CR with hematologic remission (HR) for >180 days.

Findings from the final analysis of the Lumoxiti Phase III trial include:

Efficacy measure

Result* (n=80, 95% Confidence Interval)

Durable CR (CR with HR > 180 days)

36.3% (25.8 to 47.8)

CR with HR ≥ 360 days

32.5% (22.4 to 43.9)

CR rate

41.3% (30.4 to 52.8)

CR with MRD-negative status

33.8% (23.6 to 45.2)

Partial Response Rate

33.8%

Hematologic Remission Rate

80.0%

Median duration of CR

62.8 months (0.0+ to 62.8)

Median Progression-Free Survival

41.5 months (range 0.0+ to 71.7)

* BICR = blinded independent central review

"A key treatment goal for patients with relapsed or refractory hairy cell leukemia is to achieve sustained remission, which can be particularly challenging in patients in whom prior therapies have failed. This long-term analysis demonstrates that Lumoxiti achieved a high rate of durable efficacy, while maintaining the benefit risk profile we saw in the primary analysis," said Robert J. Kreitman, MD, Senior Investigator, Head of Clinical Immunotherapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, and Principal Investigator of the Phase III clinical trial.

The final analysis shows that the risk-benefit profile of Lumoxiti is maintained. There were no new serious adverse events and no change in hemolytic uremic syndrome or capillary leak syndrome. Per the primary analysis on the 1053 study, the most frequent treatment-related adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), headache (33%), and pyrexia (31%). Treatment-related grade 3/4 AEs were reported in 24 patients (30%) and treatment-related serious AEs in 14 patients (18%). Grade 3/4 CLS events occurred in two patients (2.5%) and any grade of HUS occurred in six patients (7.5%). CLS and HUS events were manageable and reversible with appropriate supportive care and monitoring.

Treatment-emergent AEs led to study drug discontinuation in eight patients (10.0%): hemolytic uremic syndrome (HUS), n = 4 (5.0%); capillary leak syndrome (CLS), n = 2 (2.5%); increased blood creatinine, n = 2 (2.5%); renal failure, n =1 (1.3%); vomiting, n =1 (1.3%); and chills, n =1 (1.3%). There were four deaths reported (including the three reported during the primary analysis): two due to disease progression and two due to an AE (1 each of pneumonia and septic shock). No death was considered treatment related.

On December 8, 2019 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company focused on the development of precision medicines for the treatment of cancer, reported clinical and regulatory updates for its lead drug candidate, tipifarnib, in angioimmunoblastic T-cell lymphoma (AITL), including data from the Company’s ongoing Phase 2 clinical trial of tipifarnib in relapsed or refractory peripheral T-cell lymphoma (PTCL) (Press release, Kura Oncology, DEC 8, 2019, View Source [SID1234552042]). The updated interim data are being presented during an oral session today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual meeting in Orlando. A copy of the presentation is available on the Company’s website at www.kuraoncology.com.

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"Tipifarnib continues to demonstrate clinically meaningful activity in advanced PTCL, including patients with AITL for whom there are few treatment options," said Thomas Witzig, M.D., a Hematologist at Mayo Clinic and a principal investigator in the trial. "The high level of clinical activity of tipifarnib, including complete responses, in third- and fourth-line patients, coupled with the fact that tipifarnib is an oral medication means it could be another treatment option for a patient population with high unmet need."

In June 2019, Kura reported that the primary efficacy endpoint was achieved in each of the expansion cohorts in its Phase 2 trial of tipifarnib in relapsed or refractory PTCL: 1) patients with AITL, an aggressive form of T-cell lymphoma often characterized by high levels of CXCL12 expression, and 2) patients with PTCL who lack a single nucleotide variation in the 3’-untranslated region of the CXCL12 gene. Given the high level of activity observed among AITL patients, Kura continued to enroll patients to acquire more experience regarding safety and tolerability in this population. Based upon the 2016 revision of the World Health Organization classification of lymphoid neoplasms1, AITL and AITL-like histologies represent approximately one-third of all PTCL cases.

As of the November 11, 2019 data cutoff date, a total of 26 patients with relapsed or refractory AITL were enrolled in all stages of the trial. Among the 20 patients evaluable for efficacy, five achieved a complete response (CR) and five achieved a partial response (PR), for an objective response rate (ORR) of 50% on an evaluable basis and 38% on an intent-to-treat basis. In addition, three patients experienced disease stabilization. Patients had a median of three prior regimens (range 1-7).

Next-generation sequencing of 19 available patient biopsies showed that 10 (53%) carried C336R/Q386E variants in the killer-cell immunoglobulin-like receptor (KIR) 3DL2, an immune checkpoint receptor. Four of the 10 patients with KIR3DL2 variants achieved a CR and three achieved a PR, for a CR rate of 40% and an ORR of 70%. This compares to a CR rate of 11% and an ORR of 22% among the nine AITL patients with KIR3DL2 wild type.

Tipifarnib was generally well-tolerated in this Phase 2 trial, with adverse events consistent with its known safety profile. The most frequently observed treatment-related adverse events (grade ≥ 3) were hematology-related, including thrombocytopenia, neutropenia, leukopenia, anemia, febrile neutropenia and lymphopenia.

"We are encouraged by our growing body of data for tipifarnib in AITL," said Antonio Gualberto, M.D., Ph.D., Head of Development and Chief Medical Officer of Kura Oncology. "We believe these data support our efforts to expand the development of tipifarnib beyond our initial focus in HRAS mutant solid tumors and could enable registrational strategies in multiple CXCL12-dependent hematologic and solid tumor indications."

Regulatory Update

Following FDA feedback from an end-of-Phase 2 (EOP2) meeting, Kura plans to initiate a Phase 2 registration-directed trial of tipifarnib in patients with relapsed or refractory AITL and related lymphomas in 2020. The multi-center, single-arm trial will target enrollment of 128 patients with AITL and AITL-like histologies who are relapsed or refractory to at least one prior systemic cytotoxic therapy.

The trial has two independent primary objectives: 1) Efficacy in terms of ORR in all patients enrolled and 2) Efficacy in terms of ORR in patients who carry KIR3DL2 variants. Patients will be enrolled on the basis of a pathological diagnosis of AITL and AITL-like histologies, and KIR3DL2 mutational status will be determined retrospectively. Each of the two primary objectives has a null hypothesis of 9%, and each one can be met independently. FDA EOP2 meeting minutes indicate that the trial, as designed, may be adequate to support an NDA seeking accelerated approval of tipifarnib in AITL and AITL-like histologies, and/or AITL and AITL-like histologies with KIR3DL2 mutations.

"We are grateful for the regulatory feedback from the FDA on our single-arm trial design, providing an opportunity for a potential path for accelerated approval for tipifarnib in AITL and AITL-like histologies, an indication of significant unmet need and one for which they are no FDA approved therapies," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "Consistent with our development strategy in HRAS mutant solid tumors, we have chosen to focus initially on AITL and AITL-like histologies, an indication that can be pursued with small, single-arm, registration-directed study. Once we establish a foothold there, we expect to see a clear path to expand the potential commercial opportunity by moving both to earlier lines of therapy and expanding to additional CXCL12-driven hematologic malignancies and solid tumor indications."

About Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive form of T-cell lymphoma frequently characterized by high levels of CXCL12 expression. Significant advances in the genetic landscape of T-cell and NK-cell neoplasms as the result of genomic studies, as well as the introduction of more powerful diagnostic technologies have led to revisions in the classification and introduction of new entities. Many of the same genetic changes observed in AITL are also observed in cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) that manifest a T follicular helper (TFH) phenotype. This common genotype/phenotype has led to follicular T-cell lymphoma (FTCL) and AITL being unified under a common heading. Cases of nodal PTCL with TFH phenotype are now included in the same grouping as well. As a result, patients with the PTCL-NOS phenotype are increasingly being characterized as having AITL and/or AITL-like histologies.

About Tipifarnib

Kura Oncology’s lead drug candidate, tipifarnib, is a potent, selective and orally bioavailable inhibitor of farnesyl transferase in-licensed from Janssen in December 2014. Previously, tipifarnib was studied in more than 5,000 cancer patients and showed compelling and durable anti-cancer activity in certain patient subsets; however, no molecular mechanism of action had been determined that could explain its clinical activity across a range of solid tumor and hematologic indications. Leveraging advances in next generation sequencing as well as emerging information about cancer genetics and tumor biology, Kura is seeking to identify those patients most likely to benefit from tipifarnib. Kura initiated its first Phase 2 registration-directed trial of tipifarnib in patients with recurrent or metastatic HRAS mutant head and neck squamous cell carcinoma (HNSCC) in November 2018. Later that month, the U.S. Patent and Trademark Office issued a new patent for tipifarnib as a method of treating patients with AITL, providing exclusivity in the United States to 2037.

On December 8, 2019 Eli Lilly and Company (NYSE: LLY) reported interim clinical data from the LOXO-305 global Phase 1/2 BRUIN dose escalation trial. LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor (Press release, Eli Lilly, DEC 8, 2019, View Source [SID1234552043]). These data were presented today at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando (abstract 501). At all doses studied, LOXO-305 delivered objective responses in patients who had received diverse prior therapies and had exhibited varied molecular mechanisms of acquired resistance.

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"We are excited to report that LOXO-305 is active in patients resistant and intolerant to covalent BTK inhibitors, as well as in patients resistant to BCL2 inhibition," said Anthony Mato, M.D., director of the CLL Program at Memorial Sloan Kettering Cancer Center and the presenting author. "We observed compelling response rates in both CLL and MCL. Interestingly, we reported responses regardless of C481 status, a putative mechanism of resistance to the covalent BTK class. We saw objective responses in dose cohort 1 and have not identified a maximum tolerated dose. These data suggest that LOXO-305 has the required selectivity profile and human target coverage to maximize the full potential of this molecular target, combine well with other agents, and perhaps, even move to earlier lines of therapy."

"Put simply, LOXO-305 has exceeded our expectations," said Jacob Van Naarden, chief operating officer of Loxo Oncology at Lilly. "LOXO-305’s wide therapeutic index allows us to plan and implement an ambitious comprehensive development program, one that includes combination regimens that exploit the drug’s selectivity profile. We look forward to working closely with global regulators to position LOXO-305 in the most appropriate patient populations. It will be exciting to combine Lilly’s resources and talent with Loxo’s focus and agility for the benefit of this program within Loxo Oncology at Lilly."

Trial Background
The BRUIN Phase 1/2 trial, which began enrolling patients in March 2019, contains a dose escalation phase and a dose expansion phase. The dose escalation phase follows a "3+3" design. LOXO-305 is dosed orally in 28-day cycles. As dose cohorts are cleared, additional patients can enroll in cleared cohorts and intra-patient dose escalation is permitted. The primary endpoint of the trial is the determination of the maximum tolerated dose (MTD) or recommended dose for further study. Secondary endpoints include safety, overall response rate (by disease-specific criteria) and duration of response. The dose expansion phase is designed to further characterize the overall response rate, durability of response, and safety of LOXO-305 in predefined groups of patients with B-cell leukemias and lymphomas.

Key Data Presented at ASH (Free ASH Whitepaper)
The data presented at ASH (Free ASH Whitepaper) were based on patients treated as of September 27, 2019, with follow-up as of November 5, 2019. Twenty-eight total patients had been enrolled to five dose escalation cohorts: 25 mg QD (n=5), 50 mg QD (n=6), 100 mg QD (n=9), 150 mg QD (n=5), and 200 mg QD (n=3). There were 16 patients with CLL, eight patients with MCL, two patients with Waldenstrom macroglobulinemia, one patient with diffuse large B-cell lymphoma (DLBCL), and one patient with marginal zone lymphoma (MZL). The CLL patients had received a median of four prior systemic therapy regimens and 75% had received at least one prior BTK inhibitor. The MCL patients had received a median of three prior systemic therapy regimens and 88% had received at least one prior BTK inhibitor.

Pharmacokinetic analyses during the dose escalation phase demonstrated dose-dependent and linear increases in LOXO-305 exposure with increasing dose. Starting at the 50 mg QD dose, LOXO-305 delivered >IC90 target coverage for wild-type and C481S-mutated BTK, based on estimates from cell-based potencies.

The efficacy data presented at ASH (Free ASH Whitepaper) are based on investigator response assessments. Responses were observed across all dose levels.

Of 16 CLL patients enrolled, there were 10 responders (8 partial responses, 2 partial response with ongoing lymphocytosis) among 13 patients eligible for response assessment, resulting in a 77% ORR. All patients with CLL have demonstrated tumor reduction, with evidence of deepening response over time. Responses were observed in patients with acquired resistance to prior BTK therapy (those with and without C481S mutations), in patients who were intolerant to prior BTK therapy, and in patients with acquired resistance to prior BCL2 therapy (including one with a known BCL G101V mutation). As expected, LOXO-305 treatment causes acute lymphocytosis, which resolves over time—a well described pharmacodynamic response associated with effective BTK inhibition. Of the three CLL patients not yet eligible for response assessment (one with the BTK C481S mutation), all three have demonstrated lymphocytosis early in cycle 1. All CLL responding patients remain in response and all CLL patients remain on study.
Of eight MCL patients enrolled, there were three responses (1 complete response, 2 partial responses) among six patients eligible for response assessment, resulting in a 50% ORR. Two of the responders had progressed on prior BTK therapy (but without a documented C481x mutation). All MCL responding patients remain in response and on study. Three MCL patients discontinued therapy in cycle 1 due to progressive disease.
Most treatment-emergent adverse events were Grade 1 in severity with the most commonly reported events, regardless of attribution, being fatigue (25% total: 21% Grade 1, 4% Grade 2) and diarrhea (18% total: 14% Grade 1, 4% Grade 2). Two adverse events ≥Grade 3 were attributed to LOXO-305 (Grade 3 leukocytosis and Grade 3 transient neutropenia). No dose limiting toxicities were reported and an MTD had not been reached.

About LOXO-305
LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies has been limited by acquired resistance, most commonly through BTK C481 mutations, and intolerance, due to off target inhibition of other cellular targets. LOXO-305 was designed to reversibly bind BTK, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the Loxo Oncology Physician and Patient BTK Clinical Trial Hotline at 1-855-LOXO-305 or email [email protected].

About the BRUIN Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates LOXO-305 as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL). The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose or recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate and Duration of Response, as determined by appropriate histology-specific response criteria). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. In the Phase 2 dose expansion phase, six cohorts are planned to allow for the characterization of the preliminary anti-tumor activity of LOXO-305: 1) CLL/SLL failed prior BTK inhibitor with BTK C481 mutation; 2) CLL/SLL failed prior BTK inhibitor without BTK C481 mutation; 3) Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL) failed prior BTK inhibitor with BTK C481 mutation; 4) WM, MCL or MZL failed prior BTK inhibitor without BTK C481 mutation; 5) CLL/SLL, WM, MCL or MZL intolerant to prior BTK inhibitor; 6) CLL/SLL, WM, MCL or MZL failed prior BTK inhibitor with unknown BTK C481 mutation status and other CLL/SLL, WM, CML, MZL or other NHL patients not meeting the definitions of Cohorts 1 through 5.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world. To learn more about Lilly’s commitment to people with cancer, please visit www.LillyOncology.com.

On December 7, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported that two presentations highlighting new and updated data relating to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, will be given 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 7, 2019, View Source [SID1234552028]). The first study, which will be featured in an oral presentation, describes updated data from the Phase 1b/2 STOMP study evaluating the all oral regimen of selinexor in combination with Pomalyst (pomalidomide) and low-dose dexamethasone (dex) (SPd) in patients with relapsed or refractory multiple myeloma. The second abstract, which will be featured in a poster presentation, describes new data on the use of selinexor and dexamethasone, either alone or in combination with standard approved therapies, in patients with multiple myeloma whose disease has progressed following experimental chimeric antigen receptor T-cell (CAR-T) therapy.

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"We continue to be pleased with the efficacy and safety observed in the all oral selinexor plus Pomalyst arm of the Phase 1b/2 STOMP study, where patients with Pomalyst-naïve and Revlimid (lenalidomide)-relapsed or -refractory myeloma achieved a 56% overall response rate (ORR) and a 12-month progression free survival (PFS)," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "Another key study this year is the presentation of new data from patients treated with selinexor-based regimens after their myeloma had progressed following experimental CAR-T therapy. Although these data are early, six of seven patients whose disease relapsed after CAR-T achieved a response when treated with selinexor and dexamethasone alone or in combination with either Velcade (bortezomib) or Kyprolis (carfilzomib). There is currently very limited data regarding treatment options for patients whose disease has progressed following experimental CAR-T therapy, and we believe these encouraging results further reinforce the therapeutic activity of selinexor in patients with relapsed or refractory disease."

Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In this arm of the Phase 1b/2 STOMP study, oral selinexor is being evaluated in combination with Pomalyst (3 or 4mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or patients with myeloma refractory to both a PI and an IMiD. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 1-Oct-20192
Prior Therapy Status N3 ORR VGPR4 PR Median PFS
Pomalyst-naïve and Revlimid refractory or relapsed 32 18 (56%) 6 (19%) 12 (38%) 12.2 months
Pomalyst Treated and Revlimid refractory 14 5 (36%) 1 (7%) 4 (29%) 5.6 months
Key: ORR=Overall Response Rate (VGPR+PR); 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
3 Five patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, one withdrawal of consent before disease follow up, one death related to progressive disease (PD), one PD before C2D1
4 One unconfirmed VGPR

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 (52%), fatigue (52%) and weight loss (39%). As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (58%), thrombocytopenia (27%) and anemia (27%).

Based on these Phase 2 results, a Phase 3 study investigating the SPd combination is planned.

In parallel with the ongoing Phase 1b/2 STOMP study, Karyopharm is conducting the pivotal, randomized Phase 3 BOSTON study evaluating once-weekly selinexor in combination with the PI Velcade and dexamethasone (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. Enrollment in the BOSTON study is complete and top-line data are expected in early 2020 contingent upon the occurrence of PFS events, the primary endpoint of the study. Data from the BOSTON study, if positive, are expected to be used to support regulatory submissions to the U.S. Food and Drug Administration and the European Medicines Agency requesting the use of selinexor in combination with Velcade and dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

New Data from Study Evaluating Selinexor in Patients with Multiple Myeloma Following CAR-T Therapy

In this study, seven patients were identified from selinexor myeloma trials who had received an active dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) as treatment for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. One patient was treated with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice weekly), one patient was treated with the regimen currently being investigated in the ongoing Phase 3 BOSTON study, a combination of selinexor (100 mg once-weekly), Velcade (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly), and five patients were treated with a combination of selinexor (100 mg once-weekly), Kyprolis (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once weekly or 20 mg twice weekly). Patients had a median of ten prior therapeutic regimens (range: 5-15), all had high-risk cytogenetics, and six of the seven had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days).

The following table is a summary of the efficacy results:

Best Responses1 in Evaluable Patients2
N ORR sCR VGPR PR
All patients 7 6 (86%) 1 (14%) 3 (43%) 2 (29%)
Key: ORR=Overall Response Rate (CR+VGPR+PR); sCR=Stringent Complete Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data

Of the six patients who responded (≥PR), the duration of response ranged from 1.4 months to 7.4 months, with two patients still on therapy and responding. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia.

These preliminary data suggest that selinexor-dexamethasone alone or in combination with Velcade or Kyprolis may offer a therapeutic option for patients who have exhausted other available treatments, have rapidly progressing disease, and who have progressed after CAR-T therapy.

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

Oral Presentation

Title: Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Presenter: Christine Chen, Princess Margaret Cancer Centre
Abstract #: 141
Session: 653. Myeloma: Therapy, excluding Transplantation: New Approaches in the Treatment of Relapsed/Refractory Plasma Cell Discrasias
Date and Time: Saturday, December 7, 2019; 9:30-11:00 AM ET
Location: Orange County Convention Center, Hall E1
Poster Presentation – Company-Sponsored Studies

Title: Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Presenter: Ajai Chari, Icahn School of Medicine at Mount Sinai
Abstract #: 1854
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30 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 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%.