On December 3, 2018 Tiziana Life Sciences plc (Nasdaq: TLSA / AIM: TILS), a biotechnology company focusing on the discovery and development of innovative therapeutics for inflammation and oncology indications, reported that patient enrollment in the ongoing Phase 2a clinical trial (CDKO-125A-010) is completed (Press release, Tiziana Life Sciences, DEC 3, 2018, View Source [SID1234531836]). This is a single-arm, repeated-dose, 6-month duration study to evaluate safety, tolerability and anti-tumor activity of Milciclib in Sorafenib-refractory or -intolerant patients with unresectable or metastatic HCC. Topline data from this multi-center trial, being conducted in Italy, Greece and Israel, will be available in the second quarter of 2019.

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Previously we reported interim analysis data from the first 10 patients, following 6 months of treatment, showing that Milciclib (100 mg once daily; 4 days on/3 days off every 4 weeks defining each cycle) was well-tolerated in this HCC patient population. It was concluded by an Independent Data Monitoring Committee (IDMC) that there were no major signals of tolerability concerns, and the IDMC allowed continuation of patient enrollment in the trial. Following completion of 6 months of treatment, three patients opted to continue treatment under the compassionate use program. Notably, one patient is still continuing treatment in the 14th month and the other two patients received treatment until 9th month and 13th month, respectively.

About HCC

HCC is the 5th most common cancer and the 3rd cause of cancer mortality worldwide. In 2007 the approval by the European Medical Agency (EMA) and Food and Drug Administration (FDA) of Sorafenib (Nexavar), an inhibitor of several receptor tyrosine kinases, in HCC represented the first systemic therapy for improving outcome in patients unsuitable for loco-regional and surgical therapies and created a new standard of treatment for the disease. However, although significant in respect to placebo, the benefits of Sorafenib are modest; the response rate is less than 3%, the improvement in median survival is 2-3 months and the drug-related symptoms are not ordinary. The complex multi-factorial etiology of HCC warrants a need for systemic therapies that target different signaling cascades to provide improved efficacy and safety for both naive patients presenting with unresectable, advanced stage and those who suffer recurrence after curative treatments (resection, ablation and transplantation).

About Milciclib

Milciclib (PHA-848125AC) is a small molecule inhibitor of several cyclin dependent kinases such as CDK1, CDK4, CDK5 and CDK7. CDKs are serine threonine kinases that play crucial roles in progression of the cell cycle from G1 to S phase. Overexpression of CDKs and other downstream signaling pathways that regulate cell cycles have been frequently associated with development of resistance towards chemotherapies. In a Phase 1 study, oral treatment with Milciclib was well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in NSCLC, pancreatic and colon cancer, thymic carcinoma and thymoma. Additionally, milciclib met its primary endpoint in two separate Phase 2 multi-center clinical trials (CDKO-125A-006: 72 patients and CDKO-125A-007: 30 patients) in thymic carcinoma and thymoma patients.

About Sorafenib

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) is a small molecular multi-tyrosine kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), HCC, and radioactive iodine resistant advanced thyroid carcinoma. Treatment with Sorafenib induces autophagy, which may suppress tumor growth. However, autophagy can also cause drug resistance.

On December 3, 2018 Takeda Pharmaceutical Company Limited (TSE: 4502) reported the presentation of results from the randomized Phase 3 study TOURMALINE-MM3 to evaluate the efficacy of oral monotherapy with NINLARO (Ixazomib) as a maintenance treatment in adult multiple myeloma patients previously responding to high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), Sunday, December 2, 2018 in San Diego, California (Press release, Takeda, DEC 3, 2018, View Source [SID1234531834]).

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The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in progression-free survival (PFS) compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, with assessment by an independent review panel (Independent Review Panel) Review Committee, IRC) (HR 0.72, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and a 39 percent improvement in NINLARO PFS compared to placebo. The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.

"The evidence that multiple myeloma maintenance therapy may extend the duration of disease control is increasing," said Meletios Dimopoulos, MD, professor and chair of the Department of Clinical Therapeutics at the Faculty of Medicine, University of Athens, Athens, Greece. "Because there are currently limited treatment options and no proteasome inhibitor among them, there is a need for additional maintenance therapies that can prolong remission and have an acceptable safety profile. Data from the TOURMALINE-MM3 clinical trial suggest monotherapy with NINLARO as a potential oral treatment option for maintenance therapy with an ASCT proteasome inhibitor. "

"The positive results of this pivotal trial, which is the first and only placebo-controlled Phase 3 trial to test a proteasome inhibitor in this setting, support the use of NINLARO as a potential maintenance therapy in patients undergoing stem cell transplantation," said Jesús Gómez Navarro, MD, Vice President, Head of Oncology Clinical Research and Development, Takeda. "It is imperative that we continue to assist patients with the development of treatment options that support and deepen remission and delay disease progression. NINLARO-treated patients showed an improvement in progression-free survival compared to the control arm,

"Continuing research efforts are constantly evolving treatment options for multiple myeloma. This message is encouraging for anyone dealing with multiple myeloma, but further efforts are needed to bring us closer to our goal of meeting patients’ unmet medical needs, "said Brian Durie, MD, Chairman of the Board Board, International Myeloma Foundation. "This requires the development of additional safe and effective maintenance therapies."

Maintenance therapy with oral proteasome inhibitor (PI) Ixazomib causes significant progression-free survival (PFS) after autologous stem cell transplantation (ASC) in patients with newly diagnosed multiple myeloma (NDMM): the TOURMALINE-MM3 phase 3 study Sunday, 2. December 2018, 7:30 am – 9:00 am, Marriott Marquis San Diego Marina, Grand Ballroom 7

Among the main results, by Dr. med. Meletios Dimopoulos are presented include:

The study reached its primary endpoint with NINLARO leading to a statistically significant improvement in PFS compared to placebo in adult patients with multiple myeloma who responded to HDT and ASCT, assessed by an independent review panel (IRC) (HR 0.72, 95% CI: 0.582, 0.890, p-value = 0.002). This equates to a 28 percent reduction in the risk of disease progression or death and 39 percent improvement in PFS under NINLARO.
According to the IRC assessment, median PFS for patients in the NINLARO arm was 26.5 months compared to 21.3 months for the placebo arm.
The conversion of documented positive finding for minimal residual disease (MRD) at study to MRD negativity was more common in NINLARO-treated patients compared to placebo (12 percent versus 7 percent).
Maintenance therapy with NINLARO resulted in higher rates of deep remission compared to placebo (relative risk 1.41, 95 percent CI: 1.10, 1.80, p = 0.0042).
PFS benefits were broadly distributed across subgroups, including ISS III (HR 0.661), PI pretreated (HR 0.750), PI naive (HR 0.497), and patients with high-risk cytogenetic signs (HR 0.625).
The secondary endpoints, including median PFS2 and OS, have not been reached in either arm. The median follow-up time was 31 months.
Overall quality of life scores (EORTC QLQ-C30) were similar in NINLARO-treated patients compared to the placebo group.
The safety profile of NINLARO maintenance therapy is in line with the already published results on the use of NINLARO as monotherapy.
The discontinuation of treatment due to adverse events (AEs) was low and was 7 percent in the NINLARO arm compared to 5 percent in the placebo arm.
A third or higher grade of AEs occurred in 42 percent of patients in the NINLARO arm compared with 26 percent in the placebo arm.
In the NINLARO arm, severe AEs were found in 27 percent of the cases compared to 20 percent in the placebo arm.
Common AEs 3 or higher included infections (15 vs. 8 percent) in both the NINLARO and placebo arm, including pneumonia (6 vs. 4 percent), gastrointestinal disorders (6 vs. 1 percent ), Neutropenia (5 vs. 3 percent), and thrombocytopenia (5 vs. <1 percent).
In the NINLARO arm, peripheral neuropathy was observed in 19 percent of patients compared to 15 percent in the placebo arm. In the NINLARO arm, less than 1 percent of the incidence of peripheral neuropathy was Grade 3 AEs compared to 0 percent in the placebo arm.
The second tumor rate was 3 percent in both arms.
One patient in the NINLARO arm died during the study, whereas no death occurred in the placebo arm. The only death in the study was classified as a treatment-related event and was the result of pneumonia.
About the study TOURMALINE-MM3

TOURMALINE-MM3 is a randomized, placebo-controlled, double-blind Phase 3 study in 656 patients to determine the effect of NINLARO (Ixazomib) maintenance therapy on progression-free survival (PFS) versus placebo in patients with multiple myeloma who have a history of disease Remission (complete remission [CR], very good partial remission [VGPR] or partial remission [PR]) on induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) The primary endpoint is progression-free survival (PFS) An important secondary endpoint includes overall survival (OS). For more information, seeView Source .

About NINLARO (ixazomib) capsules

NINLARO (Ixazomib) is an oral proteasome inhibitor that is also being studied in the multiple myeloma therapy continuum and in systemic light chain amyloidosis (AL), the first oral proteasome inhibitor tested in Phase 3 clinical trials and approved. NINLARO was approved by the US Food and Drug Administration (FDA) in November 2015 after a Priority Review and by the European Commission in November 2016. In the US and Europe, NINLARO is used in combination with lenalidomide and dexamethasone in the treatment of patients with multiple myeloma NINLARO has received marketing approval from regulators in more than 60 countries.

In 2011, Ixazomib was granted orphan drug status in multiple myeloma in the US and Europe, and AL amyloidosis in the US and Europe in 2012. In 2014, Ixazomib received breakthrough therapy from the FDA for relapsed or refractory systemic light chain amyloidosis (AL), a related extremely rare disease. The Japanese Ministry of Health, Labor and Social Affairs granted Ixazomib orphan drug status in 2016.

TOURMALINE, the comprehensive Ixazomib clinical development program, includes a total of six ongoing regulatory trials – five investigating all major groups of multiple myeloma patients and one dealing with light chain amyloidosis:

TOURMALINE-MM1 for testing ixazomib over placebo in combination with lenalidomide and dexamethasone in relapsed and / or refractory multiple myeloma
TOURMALINE-MM2 for the testing of ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
TOURMALINE-MM3 for testing ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma after induction therapy and autologous stem cell transplantation (ASCT)
TOURMALINE-MM4 for the testing of ixazomib versus placebo as a maintenance treatment in patients with newly diagnosed multiple myeloma who have not undergone autologous stem cell transplantation (ASCT)
TOURMALINE-AL1 for the testing of ixazomib plus dexamethasone for a physician on the basis of a selection of therapies in patients with relapsed or refractory AL amyloidosis. Patients are currently enrolled in this study.
TOURMALINE-MM5 for the testing of ixazomib plus dexamethasone versus pomalidomide plus dexamethasone in patients with relapsed and / or refractory multiple myeloma who have become resistant to lenalidomide. Patients are currently enrolled in this study.
For more information on actively recruiting Phase 3 studies, visit View Source

In addition to the TOURMALINE study program, Ixazomib is currently being evaluated in several therapeutic combinations in various patient populations worldwide through investigator-initiated studies (IIT).

NINLARO Ixazomib) Capsules: Important Safety Information Worldwide

SPECIAL WARNINGS AND PRECAUTIONS

Thrombocytopenia has been reported with the use of NINLARO (28% vs. 14% with the NINLARO or placebo regimen). Platelets reached their lowest point between the 14th and 21st day of the 28-day treatment cycle and recovered to baseline by the start of the next cycle. This did not lead to increased bleeding events or platelet transfusions. During treatment with NINLARO, the platelet count should be monitored at least monthly and more frequent monitoring should be considered during the first three cycles. Thrombocytopenia should be treated with dose adjustment and platelet transfusions according to the recommendations of the standard guidelines.

Gastrointestinal toxicities have been reported in the NINLARO and placebo regimens, for example, diarrhea (42% vs. 36%), constipation (34% vs. 25%), nausea (26% vs. 21%), and vomiting (22% vs 11%). These occasionally required the use of medication for vomiting and diarrhea, as well as supportive therapy.

Peripheral neuropathy has been reported in NINLARO (28% vs. 21% with the NINLARO or placebo regimen). The most commonly reported adverse reaction was peripheral sensory neuropathy (19% and 14% in the NINLARO or placebo regimen). Peripheral motor neuropathy has not been reported in any of the two regimens (<1%). Patients should be monitored for signs of peripheral neuropathy and dosing adjusted if necessary.

Peripheral edema has been reported in NINLARO (25% vs. 18% with the NINLARO or placebo regimen). The underlying causes should be clarified. If necessary, patients should receive supportive care. Dose adjustment should be made with dexamethasone according to the SPC or with NINLARO if severe symptoms occur.

Skin reactions occurred in 19 percent of patients with the NINLARO regimen compared to 11 percent of patients on the placebo regimen. The most common form of rash on both schemes was a maculopapular and macular rash. Rashes should be treated with supportive therapy, dose adjustment or discontinuation of the drug.

Hepatotoxicity, drug-induced liver damage, hepatocellular damage, fatty liver, and cholestatic hepatitis have not been reported commonly in NINLARO-treated patients. Liver values ​​should be monitored regularly and dose adjustments should be made for symptoms of Grade 3 and 4.

Pregnancy – NINLARO can lead to harm to unborn life. For fertile men and women of childbearing potential, contraceptive methods should be used during treatment and for a further 90 days after the last dose of NINLARO. Due to the possible risk to the unborn child, women of childbearing age should be prevented from taking pregnancy while being treated with NINLARO. Women who use hormonal contraceptives should also use a barrier method for contraception.

Breastfeeding – It is not known whether NINLARO or its breakdown products are excreted in breast milk. Due to possible adverse events in breast-fed infants, NINLARO-treated patients should abstain.

SPECIAL PATIENT POPULATIONS

Hepatic impairment: The starting dose of NINLARO should be reduced to 3 mg in patients with moderate or severe hepatic impairment.

Renal impairment: In patients with severe renal impairment or dialysis-dependent patients with end stage renal disease (ESRD), the starting dose of NINLARO should be reduced to 3 mg. NINLARO is not dialyzable and can therefore be administered independently of the dialysis schedule.

INTERACTIONS WITH OTHER MEDICINAL PRODUCTS

Simultaneous use of NINLARO and strong CYP3A inducers is foreseeable.

SIDE EFFECTS

The most common adverse reactions reported in at least 20% of NINLARO regimens or more frequently than placebo were diarrhea (42% vs. 36%), constipation (34% vs. 25%), thrombocytopenia (28% vs. 14%), peripheral neuropathy (28% vs. 21%), nausea (26% vs. 21%), peripheral edema (25% vs. 18%), vomiting (22% vs. 11%) and back pain (21% vs. 16%). Serious side effects that occurred in at least 2 percent of patients included thrombocytopenia (2%) and diarrhea (2%). For each adverse reaction, one or more of the three drugs was discontinued in ≤ 1 percent of patients on NINLARO regimen.

On December 3, 2018 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported presentations highlighting updated data from the Phase 2b STORM study evaluating selinexor, the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, in patients with penta-refractory multiple myeloma, and from two arms of the Phase 1b/2 STOMP study evaluating selinexor and dexamethasone in combination with standard approved therapies, Pomalyst (pomalidomide) or Darzalex (daratumumab), in patients with previously treated multiple myeloma (Press release, Karyopharm, DEC 3, 2018, View Source [SID1234531833]). The data were featured in oral and poster presentations at American Society of Hematology (ASH) (Free ASH Whitepaper) 2018 Annual Meeting taking place December 1-4, 2018 in San Diego. A New Drug Application (NDA) seeking accelerated approval for oral selinexor with low dose dexamethasone as a treatment for patients with penta-refractory multiple myeloma is under Priority Review by the U.S. Food and Drug Administration (FDA) with an action date of April 6, 2019, under the Prescription Drug User-Fee Act (PDUFA).

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"As an increasing number of myeloma patients experience progressive disease despite treatment with combination regimens, there is a growing need for new therapies, particularly those with novel mechanisms, to help treat patients with relapsed and/or refractory myeloma. The 26.2% ORR determined by the Independent Review Committee (IRC) in the STORM study is highly compelling and reinforces the potential of selinexor in this difficult to treat patient population," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "Additionally, the Phase 1b/2 STOMP study continues to generate encouraging efficacy and safety data from multiple ongoing arms evaluating once weekly oral selinexor and dexamethasone (dex) in combination with the standard approved therapies in patients with newly diagnosed and relapsed/refractory multiple myeloma. The data presented at this year’s ASH (Free ASH Whitepaper) annual meeting show impressive response rates across several high unmet need patient subgroups, including Darzalex-naïve or Pomalyst-naïve and Revlimid (lenalidomide)-relapsed or -refractory myeloma. Given the synergistic activity observed to date with once weekly oral selinexor plus these approved myeloma therapies, we continue to believe that selinexor holds tremendous potential as a future combination backbone therapy in myeloma."

Updated Phase 2b STORM Results

These clinical results are from Part 2 of the international, multi-center, single-arm Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) study, which enrolled 122 heavily pretreated patients (median of seven prior treatment regiments) with penta-refractory myeloma. Patients with penta-refractory myeloma have previously received the two proteasome inhibitors (PIs), Velcade (bortezomib) and Kyprolis (carfilzomib), the two immunomodulatory drugs (IMiDs), Revlimid and Pomalyst, and the anti-CD38 monoclonal antibody Darzalex, as well as alkylating agents, and their disease is refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex and their most recent therapy. Each patient started 80mg oral selinexor twice weekly in combination with low-dose dexamethasone (dex; 20mg twice weekly).

For the STORM study’s primary objective, oral selinexor achieved a 26.2% ORR, which included two stringent complete responses (sCRs), six very good partial responses (VGPRs) and 24 partial responses (PRs). The two sCRs were negative for minimal residual disease, one at the level of 1×10-6 and one at 1×10-4; this is particularly significant in this penta-refractory population. Both patients who had relapsed after CAR-T therapy achieved PRs. The ORR in patients who had previously received Darzalex combination therapy (n=86) was 29.1%. The disease control rate for patients who had achieved stable disease or better was 78.7%. All responses were confirmed by an IRC. Median progression-free survival (PFS) was 3.7 months and the median duration of response (DOR) was 4.4 months. Median overall survival (OS) across the study was 8.6 months. Median OS in the approximately 40% of patients with at least a minimum response (MR) on selinexor + dex was 15.6 months compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable (p<0.0001). The short median OS of patients with no response to selinexor is consistent with the lack of available effective therapies for the very heavily pretreated population who entered the study. Real world OS data were also obtained from the Flatiron Health Analytic Database (FHAD). These results further highlight the limited life-expectancy in patients with highly refractory multiple myeloma. OS data from the FHAD indicate that patients with triple-class refractory myeloma (n=69) had a median OS of 3.5 months, also consistent with previously reported data from the literature.

The most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms and were consistent with those previously reported from Part 1 of this study (Vogl et al., J Clin Oncol, 2018) and from other selinexor studies. Most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (69%), fatigue (56%), anorexia (52%), and weight loss (47%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 treatment-related AEs were thrombocytopenia (54%), anemia (29%), neutropenia (19%) and fatigue (19%). No significant major organ toxicities were observed, and bleeding and infection rates were low.

Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. A NDA seeking accelerated approval for oral selinexor with low dose dexamethasone as a new treatment for patients with penta-refractory multiple myeloma was accepted and filed with Priority Review by the U.S. FDA. The FDA assigned an action date of April 6, 2019 under the Prescription Drug User-Fee Act (PDUFA). Provided marketing approval is granted by the FDA, Karyopharm plans to commercialize selinexor in the U.S. in the first half of 2019. The Company also plans to submit a Marketing Authorization Application to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval.

Updated Phase 1b/2 STOMP Study (Selinexor plus Darzalex and Low-dose Dexamethasone (SDd))

In this arm of the Phase 1b/2 STOMP (Selinexor and Backbone Treatments of Multiple Myeloma Patients) study, oral selinexor (dose escalated using either 100mg once weekly or 60mg twice weekly) is being evaluated in combination with Darzalex (16mg/kg intravenously once weekly) and low dose dexamethasone (dex; 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 PI and an 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 SDd Patients as of 15-Nov-20182
Category N3 ORR VGPR PR4
Darzalex naïve 24 19 (79%) 7 (29%) 12 (50%)
All 26 19 (73%) 7 (27%) 12 (46%)
Key: ORR=Overall Response Rate (VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Two patients were not evaluable for response withdrew consent prior to disease follow up
4 Two unconfirmed PR

Despite the heavily pretreated nature of the patients in the study, with 100% of the patients having dual- (PI and IMID) refractory disease, only 19% of patients did not respond (≤stable disease). Median PFS and DOR have not been reached. Based on published data the expected ORR for Darzalex therapy without selinexor in the Darzalex-naïve population is ~30%. Thus, the ORR of 79% provides a basis for further evaluation of the SDd combination.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (60%), fatigue (48%), diarrhea (32%), vomiting (24%) and anorexia (28%) and mostly Grade 1 and 2 events. As expected, the most common Grade 3 and 4 treatment-related AEs were thrombocytopenia (44%), anemia (28%), leukopenia (28%) and neutropenia (24%). No Grade 5 AEs were reported. The maximum tolerated dose was not reached. Two dose-limiting toxicities (DLTs) (Grade 3 thrombocytopenia and Grade 2 fatigue) were observed in patients receiving selinexor 60mg twice weekly. No DLTs were reported in the 100mg once weekly cohort. The longest duration of therapy is over 60 weeks. Based on these preliminary tolerability and efficacy data, the RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dex (40mg orally, weekly).

Updated Phase 1b/2 STOMP Study (Selinexor plus 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 dex (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 PI and an 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 15-Nov-20182
Prior Therapy Status N3 ORR VGPR PR4 Median PFS
Pomalyst-naïve and Revlimid refractory or relapsed 26 14 (54%) 5 (19%) 9 (35%) 12.2 months
Pomalyst and Revlimid refractory 8 3 (38%) - 3 (38%) 5.5 months
All 34 17 (50%) 5 (15%) 12 (35%) 12.2 months
Key: ORR=Overall Response Rate (VGPR+PR)
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Four patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, two withdrawal of consent before disease follow up
4 One unconfirmed PR

Responses tended to occur rapidly with a median of one month to onset. Median PFS among all evaluable patients was 12.2 months, with a follow up of 9.4 months. Median PFS in Pomalyst and Revlimid-refractory myeloma was 5.5 months. Among patients with a PR or better (n=17), the median time on treatment was 9.4 months.

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (53%), fatigue (50%) and weight decreased (34%). As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (55%), thrombocytopenia (34%), anemia (29%) and leukopenia (18%). There were three Grade 5 treatment-related events (febrile neutropenia, intracranial hemorrhage and pneumonia). Based on these tolerability and efficacy data, doses of oral selinexor 60-80mg once weekly are being evaluated in combination with Pomalyst (3mg orally, once daily) and low dose dex to determine the RP2D for this combination regimen.

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 proteasome inhibitor Velcade and dex (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. The Company expects to complete enrollment in the BOSTON study by the end of 2018, with top-line data anticipated at the end of 2019. Assuming a positive outcome, Karyopharm plans to use the results from the BOSTON study to support an application for full approval of selinexor in relapsed/refractory multiple myeloma.

Details for the ASH (Free ASH Whitepaper) 2018 presentations highlighting the STORM and STOMP studies are as follows:

Title: Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta-Refractory MM
Presenter: Ajai Chari, Icahn School of Medicine at Mount Sinai, New York, New York
Abstract Number/Publication ID: 598
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Date and Time: Monday, December 3, 2018; 7:45 AM PT
Location: San Diego Convention Center, Room 6F

Title: Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasone (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of SDd
Presenter: Cristina Gasparetto, Duke University Cancer Center, Durham, North Carolina
Abstract Number/Publication ID: 599
Session: 653. Myeloma: Therapy, excluding Transplantation: Antibodies and Targeted Therapies
Date and Time: Monday, December 3, 2018; 8:00 AM PT
Location: San Diego Convention Center, Room 6F

Title: Selinexor Plus Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Presenter: Christine Chen, Princess Margaret Cancer Center, Toronto, Ontario
Abstract Number/Publication ID: 1993
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 1, 2018; 6:15-8:15 PM PT
Location: San Diego Convention Center, Hall GH

About Selinexor

Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,800 patients have been treated with selinexor. In April and September 2018, Karyopharm reported positive data from the Phase 2b STORM study evaluating selinexor in combination with low-dose dexamethasone in patients with penta-refractory multiple myeloma. Selinexor has been granted Orphan Drug Designation in multiple myeloma and Fast Track designation for the patient population evaluated in the STORM study. Karyopharm’s New Drug Application (NDA) has been accepted for filing and granted Priority Review by the FDA, and oral selinexor is currently under review by the FDA as a possible new treatment for patients with penta-refractory multiple myeloma. The Company also plans to submit a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in early 2019 with a request for conditional approval. 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 diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an investigator-sponsored study 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.

On December 3, 2018 NantKwest Inc. (Nasdaq:NK), a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of our immune system using natural killer (NK) cells to treat cancer, infectious diseases and inflammatory diseases, reported an abstract/poster presentations will be given at the upcoming 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, CA, which runs from December 1-4, 2018 (Press release, NantKwest, DEC 3, 2018, https://ir.nantkwest.com/news-releases/news-release-details/nantkwest-present-updated-preclinical-data-60th-annual-meeting [SID1234531832]).

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Presentation Title: Providing a Homing Receptor for CAR Engineered NK Cells – Improving Cellular Immunotherapy for B-Cell Lymphoma

Abstract: #4547

Presenter:Nathan Thomas Schomer, Laurent Boissel, Karen Jiang, Hans Klingemann, John Lee, and Patrick Soon-Shiong, NantKwest, Inc., Culver City, CA

Date:Monday, December 3, 2018, 6:00-8:00pm

Location:San Diego Convention Center, Hall GH

Presentation Highlights

NantKwest’s proprietary natural killer (NK) therapy is based on an activated natural killer cell platform (aNK) derived from a novel cell line with potent cytotoxicity. With over 400 doses safely administered to over 80 patients across multiple Phase I/II clinical trials, NantKwest’s off-the-shelf therapies have demonstrated encouraging clinical responses across a broad range of cancer cell types.

The company’s haNK cells, currently in multiple human clinical trials, have been engineered to carry a high-affinity version of the CD16/FcγRIII receptor that binds to the Fc portion of a monoclonal antibody to enhance the cancer cell killing effect when used in combination with haNK cell therapy.

As part of our next-generation NK cell therapy program, we further enhanced the potential targeting and homing efficiency of haNK cell therapy by incorporating both a CD19-targeting CAR, together with the chemokine-homing receptor, C-C Chemokine Receptor Type 7 (CCR7), which targets both Chemokine (C-C motif) ligand CCL19 (CCL19) and Chemokine (C-C motif) ligand 21 (CCL21), key signaling molecules expressed in lymph nodes to guide homing to these tissues. This tri-targeting NK cell therapy is designed to maximize NK cell activity by increasing NK cell migration to tumor sites and enhance cancer cell killing activity through both CD19-targeted, CAR-mediated killing, together with antibody mediated killing when combined with monoclonal clonal antibodies such as Rituximab.

Dr. Patrick Soon-Shiong, Chairman and CEO of NantKwest commented, "We look forward to reporting preclinical data on this novel tri-specific, off-the-shelf, homing CD19.t-haNK cell therapy. By engineering a novel chemokine-based CAR, into our off-the-shelf NK cell platform, we show that we can increase NK cell migration to target cancer cells and this enhanced homing can potentially maximize NK cell-driven immunogenic cell death. Representing what we believe will be an attractive treatment option, we are now focused on transitioning this next-generation NK cell therapy program to human clinical trials as rapidly as possible."

On December 3, 2018 Syndax Pharmaceuticals, Inc. ("Syndax," the "Company" or "we") (Nasdaq: SNDX), a clinical stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported the presentation of preclinical data from the Company’s Menin-Mixed Lineage Leukemia (MLL) inhibitor program at the 60thAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California (Press release, Syndax, DEC 3, 2018, View Source [SID1234531831]).

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"Acute leukemias characterized by MLL-rearrangements (MLL-r) and nucleophosmin (NPM1) mutations represent areas of high unmet medical need, with 5-year survival rates falling below 50%," said Briggs W. Morrison, M.D., Chief Executive Officer of Syndax. "Data presented on VTP-50469, a Syndax Menin-MLL inhibitor, provides further support for developing this class of molecules for specific, genetically-defined acute leukemias. The robustness and consistency of the accumulated preclinical data seen with our Menin-MLL inhibitors provide support for an anticipated IND filing on our lead compound, SNDX-5613, in the second quarter of 2019."

In an oral presentation at ASH (Free ASH Whitepaper), Hannah Uckelmann, Ph.D., Dana-Farber Cancer Institute, presented new preclinical data demonstrating that NPM1 mutant progenitor cells can act as drivers of leukemic transformation, and that VTP-50469 can block their pathological capacity by disrupting the menin-MLL interaction. In addition, data generated using a mouse PDX model of NPM1 mutant acute myeloid leukemia (AML) demonstrated that single agent treatment with VTP-50469 eradicated pre-leukemic NPM1 mutant cells and prevented leukemia development, resulting in a marked survival benefit. These data lend further support to the potential therapeutic utility of menin inhibitors in the setting of NPM1 mutant AML.

Furthermore, during a Scientific Spotlight Session at ASH (Free ASH Whitepaper), Scott Armstrong, M.D., Ph.D., Dana-Farber Cancer Institute, provided an overview of the multiple complexes that influence gene expression in MLL-r leukemias and NPM1 AML. Additional preclinical data generated in his laboratory further substantiate that inhibition of the Menin-MLL interaction can decrease leukemic burden and prolong survival in mouse PDX models of both MLL-r and NPM1 mutant leukemias. These data build on prior encouraging preclinical results presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April, and further underscore the potential therapeutic utility of menin inhibitors as modulators of critical epigenetic mechanisms in acute human leukemias, including subsets of both acute lymphoblastic leukemia (ALL) and AML.

Oral Presentation:

Title: MLL-Menin Inhibition Reverses Pre-Leukemic Progenitor Self-Renewal Induced By NPM1 Mutations and Prevents AML Development
Presenter: Hannah Uckelmann, Ph.D., Research Fellow at the Dana-Farber Cancer Institute
Publication Number: 546

Scientific Spotlight Session:

Title: Targeting Chromatin Complexes in MLL Rearranged Leukemia
Presenter: Scott Armstrong, M.D., Ph.D., Chairman of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute, Associate Chief of the Division Hematology/Oncology at Boston Children’s Hospital, and the David G. Nathan Professor of Pediatrics at Harvard Medical School

Both presentations are available in the Publications section of the Company’s website, www.syndax.com.

About MLL Rearranged Leukemias

Rearrangements of the MLL gene give rise to an acute leukemia, MLL-r. MLL-r occurs in ~80% of infant acute leukemias and up to 10% of adult acute leukemias. It is associated with a poor prognosis, with less than 50% of infants with MLL-r surviving past 5 years. MLL rearrangements produce fusion proteins that require interaction with a protein called Menin in order to drive leukemic cancer growth. Disruption of the Menin-MLL-r interaction has been shown to halt the growth of MLL-r leukemic cells. MLL-r leukemias are routinely diagnosed through currently available cytogenetic screening techniques in leukemic cells, but there are currently no approved therapies indicated for MLL-r leukemias.

About NPM1c Acute Myeloid Leukemia

NPM1c represents another discrete form of acute myeloid leukemia (AML) distinguished by point mutations in the NPM1 gene that drives the leukemic phenotype. NPM1c is the most common type of cytogenetically normal AML and represents ~30% of all diagnosed AML. This subtype of AML has a poor prognosis, with a 5-year overall survival rate of ~50%. Similar to MLL-r leukemias, NPM1c AML is highly dependent on the expression of specific developmental genes, shown to be negatively impacted by inhibitors of the menin-MLL1 interaction. NPM1c AML is routinely diagnosed through currently available screening techniques in leukemic cells, but there are currently no approved therapies indicated for NPM1c AML.