On September 6, 2016 (GLOBE NEWSWIRE) — OGD2 Pharma SAS, a biotechnology company developing innovative anti-cancer therapies targeting the O-acetylated form of the GD2 ganglioside (OAcGD2), reported a collaboration with Syndivia SAS, a biotechnology company that provides best-in-class bioconjugation technologies for the development of Antibody-Drug Conjugates (ADC) (Press release, OGD2 Pharma, SEP 6, 2016, View Source [SID1234519567]). Schedule your 30 min Free 1stOncology Demo! This collaboration agreement will explore the potential of targeting chemotherapeutic drugs using anti-OAcGD2 ADCs in the treatment of difficult-to-treat solid tumors. The ADCs will be designed to release the cytotoxic drug both within tumor cells and in the tumor microenvironment.
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"Thanks to this collaboration, OGD2 Pharma accelerates the development of its anti-OAcGD2 ADC platform. Syndivia’s versatile linker technology will allow depicting the best way to specifically deliver ADC payloads to tumors using the unique cellular biology of the OAcGD2 membrane glycolipid" said Jean-Marc Le Doussal, President at OGD2 Pharma. "Syndivia’s technology should result in ADCs that are highly stable in patient’s blood, in line with our strategy to develop safer anti-cancer therapies leveraging the highly tumor-specific tissue distribution of the OAcGD2 antigen. OGD2 Pharma will continue building such strategic partnerships with academic groups and private companies in other ADC technologies." he added.
Oleksandr Koniev, Chief Executive Officer of Syndivia commented "We are excited by this synergy between Syndivia’s stable payloads for intracellular and tumor microenvironment specific drug release and OGD2 Pharma’s innovative immunotherapy agents targeting OAcGD2 antigen. We believe this collaboration will result in the development and future commercialization of a brand-new class of efficient ADC for unmet clinical needs in both pediatric and adult cancers".
About Syndivia: www.syndivia.com
Syndivia SAS, headquartered in Illkirch, France, is a biotechnology company providing best-in-class bioconjugation technologies for the development of Antibody-Drug Conjugates (ADC). With a strong portfolio of patented ADC payloads and know-how in ADC preparation and characterization Syndivia is building up a strong partnered pipeline of ADCs for a broad range of oncology indications.
About OGD2 Pharma: www.ogd2pharma.com
OGD2 Pharma SAS, headquartered in Nantes, France, is a pre-clinical stage privately-held biotechnology company. Our mission is to research, develop and commercialize, with pharmaceutical partners, safe and efficacious cancer immunotherapies targeting the O-acetylated form of the GD2 ganglioside (OAcGD2). Pipeline includes OGD201 humanized monoclonal antibody (EMA Orphan Drug Designation for neuroblastoma), chimeric antigen receptors (CAR), antibody drug conjugates and companion diagnostic products.
About O-acetylated-GD2
As its first cousin GD2, the OAcGD2 glycolipid is expressed at high copy numbers in the membrane of tumor cells in many types of pediatric cancers (such as neuroblastoma) and adult cancers (such as glioblastoma, melanoma, sarcoma, breast cancer, etc.) and on cancer stem cells. Remarkably, and by contrast to GD2, OAcGD2 is not expressed by normal nerves and brain tissues.
About APN and C&R Technology
Syndivia’s APN technology enable the preparation of ADCs having increased stability in blood circulation. This stability is of crucial importance for oncology applications as it widens the therapeutic index of the conjugates. The C&R technology allows for tumor-specific release of the cytotoxic payload both inside cancer cells and in tumor microenvironment. This tumor-specific release contributes further to the improvement of the efficacy and toxicity profile of Syndivia’s ADCs.
Peloton Therapeutics, Inc. Announces Dual Publications of HIF-2α Antagonism in Kidney Cancer in the Journal Nature
On September 6, 2016 Peloton Therapeutics, Inc., a drug discovery and development company focused on advancing first-in-class, small molecule cancer therapies targeting unexploited molecular vulnerabilities, reported two publications in the journal Nature that describe the application of Peloton-invented antagonists to advance the understanding of hypoxia-inducible factor-2α (HIF-2α) and its role in kidney cancer (Press release, Peloton Therapeutics, SEP 6, 2016, View Source [SID:1234514959]). Schedule your 30 min Free 1stOncology Demo! The first paper titled "On-target efficacy of a HIF2α antagonist in preclinical kidney cancer models" (Cho et al., Nature, Advanced Online Publication, September 2016, View Source) characterizes PT2399, an analogue of PT2385, Peloton’s first-in-class small molecule antagonist of HIF-2α that is in clinical development for the treatment of clear cell renal cell carcinoma (ccRCC). Using multiple techniques, the researchers demonstrated the high specificity of PT2399 for HIF-2α and its efficacy in orthotopic, metastatic, and patient-derived models of ccRCC. Their work also raises the possibility that sensitivity of ccRCC tumors to HIF-2α antagonism may depend on the status of the tumor suppressor protein p53.
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In the second paper titled "Targeting renal cell carcinoma with a HIF-2 antagonist (Chen et al., Nature, Advanced Online Publication, September 2016, View Source), PT2399 was found to be more potent, active in a greater number of models, and less toxic than sunitinib in a large panel of patient-derived ccRCC xenografts. Additionally, a number of tumors that were completely insensitive to sunitinib regressed when transferred to PT2399. Importantly, genetic biomarkers that correlated with sensitivity to Peloton’s HIF-2α antagonists were identified.
"The work reported demonstrates the exquisite selectivity of Peloton’s antagonists that then enabled the further elucidation of the role of HIF-2α in kidney cancer and the potential value of our compounds in treating this disease," said John A. Josey, Ph.D., Peloton’s Chief Executive Officer. "By causing regression in tumors that are resistant to standard-of-care drugs while minimizing cardiovascular and other toxicities, our hope is to provide patients with more attractive drug treatment options. Genetic biomarker development may also enable identification of patients best able to benefit from treatment with our HIF-2α antagonists. These biomarkers may also be particularly important as we expand indications beyond kidney cancer."
About PT2385
PT2385 is a first-in-class small molecule antagonist of hypoxia-inducible factor-2α (HIF-2α), a transcription factor implicated in the development and progression of kidney cancer. It is currently being investigated in a Phase 1 clinical trial for the treatment of advanced or metastatic clear cell renal cell carcinoma (ccRCC) as monotherapy and in combination with the immuno-oncology agent nivolumab. Loss of the von Hippel-Lindau tumor suppressor (VHL) is the key oncogenic event in up to 95 percent of patients with ccRCC. With the loss of the VHL protein (pVHL), the transcription factor HIF-2α accumulates and drives the unbalanced expression of numerous gene products. Preclinical data indicate that orally bioavailable PT2385 disrupts HIF-2α activity in ccRCC and thereby blocks the expression of multiple tumorigenic factors. Clinical data in patients with advanced ccRCC has shown PT2385 to have encouraging efficacy, including a number of responses and a favorable tolerability profile, with no dose-limiting toxicities nor evidence of cardiovascular adverse events.
About Kidney Cancer
The American Cancer Society estimates that more than 62,000 new cases of kidney cancer will be diagnosed and more than 14,000 people will die from this disease this year. The National Cancer Institute reports that the prognosis for any treated renal cell cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage.
GlycoMimetics Initiates Dosing in Phase 1 Clinical Trial of GMI-1359
On September 6, 2016 GlycoMimetics, Inc. (NASDAQ: GLYC) reported dosing of the first healthy volunteers in a new Phase 1 clinical trial evaluating its novel combined E-selectin and CXCR4 antagonist GMI-1359 (Press release, GlycoMimetics, SEP 6, 2016, View Source [SID:1234514958]). In this first-in-humans trial, volunteer participants will receive a single injection of GMI-1359, which will be evaluated for safety, tolerability, pharmacokinetics and pharmacodynamics. GlycoMimetics intends to develop GMI-1359 as a potential treatment for hematologic malignancies. Schedule your 30 min Free 1stOncology Demo! "Our preclinical data points to the potential of GMI-1359 to inhibit the growth and metastasis of a variety of cancers. We believe this is due to a novel mechanism of action provided by inhibiting both E-selectin and CXCR4 simultaneously," said Helen Thackray, M.D., Chief Medical Officer of GlycoMimetics. "This first clinical trial will position the program for further development in hematologic malignancies and other cancers."
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The randomized, double-blind escalating dose study is being conducted at a single site in the United States. Each volunteer will receive a single dose of GMI-1359, and participate for 16 days of evaluation during the trial.
Previous preclinical research has been shared via oral and poster presentations at the annual meetings of both the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual and the American Society of Hematology (ASH) (Free ASH Whitepaper). Data presented have demonstrated activity in models of acute myelogenous leukemia (AML), prostate cancer and pancreatic cancer.
Exelixis Announces Outcome from First Planned Interim Analysis of the Phase 3 CELESTIAL Trial of Cabozantinib in Patients with Advanced Hepatocellular Carcinoma
On September 6, 2016 Exelixis, Inc. (NASDAQ:EXEL) reported the outcome from the first planned interim analysis of CELESTIAL, a randomized global phase 3 trial of cabozantinib compared with placebo in patients with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Press release, Exelixis, SEP 6, 2016, View Source [SID:1234514957]). Following this interim analysis, which was scheduled to take place when 50 percent of the events for the primary endpoint of overall survival (OS) had occurred, the trial’s Independent Data Monitoring Committee (IDMC) determined that the study should continue without modifications per the study protocol. The trial protocol calls for a second interim analysis to take place once 75 percent of events have been observed. Schedule your 30 min Free 1stOncology Demo! HCC is the most common form of liver cancer and the third-leading cause of cancer deaths worldwide.1 The disease originates in cells called hepatocytes, which make up the majority of the liver.2 Without treatment, patients with advanced disease usually survive less than 6 months.3 During 2003-2012, deaths in the U.S. from liver cancer increased at the highest rate of all cancer sites.4 In 2016 it is estimated that over 39,000 new cases and over 27,000 deaths occurred in the U.S. due to liver cancer.5 Across the U.S., EU5 (Italy, France, Germany, Spain, and United Kingdom), and Japan, it is estimated that approximately 117,000 new cases will be diagnosed in 2017.4,6-8 Liver cancer is a leading cause of cancer-related mortality worldwide, accounting for more than 700,000 deaths each year. 9
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Cabozantinib is not approved for the treatment of HCC.
About the CELESTIAL Study
CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial is designed to enroll 760 patients with advanced HCC who received prior sorafenib. Patients are randomized 2:1 to receive 60 mg of cabozantinib daily or placebo.
The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.
Based on available clinical trial data from various published trials conducted in the second line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in OS (HR = 0.76) at the final analysis. Two interim analyses were planned to be conducted at 50 percent and 75 percent of the planned 621 events.
Please see Important Safety Information below and full U.S. prescribing information at View Source
About CABOMETYX (cabozantinib)
CABOMETYX is the tablet formulation of cabozantinib. CABOMETYX targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance.
CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
On April 25, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.
On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. On January 28, 2016, the European Medicines Agency (EMA) validated Exelixis’ Marketing Authorization Application (MAA) for cabozantinib as a treatment for patients with advanced RCC who have received one prior therapy. The MAA has been granted accelerated assessment, making it eligible for a 150-day review, versus the standard 210 days. On July 22, 2016, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion of the MAA for cabozantinib for the treatment of adult patients with advanced RCC who have received at least one prior VEGF receptor tyrosine kinase inhibitor therapy. The CHMP’s positive opinion is under review by the European Commission (EC), which has the authority to approve medicines for the European Union.
Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.
Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.
Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.
Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.
Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Please see full Prescribing Information at View Source
Karyopharm Reports Positive Top-Line Phase 2b STORM Results and Reviews the Planned Development Path for Selinexor in Multiple Myeloma
On September 6, 2016 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported positive top-line results from its Phase 2b STORM study evaluating the activity of selinexor (KPT-330) in multiple myeloma (MM) (Press release, Karyopharm, SEP 6, 2016, View Source [SID:1234514955]). Selinexor, the Company’s lead, novel, oral Selective Inhibitor of Nuclear Export / SINE compound, is being developed for the treatment of a variety of malignancies, including MM. Karyopharm also provided an overview of the planned development path for selinexor in MM.
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The Phase 2b STORM study is a single-arm clinical trial evaluating selinexor in combination with low-dose dexamethasone in heavily pretreated MM patients, meaning patients with quad-refractory disease or penta-refractory disease. Patients with quad-refractory disease have previously received two proteasome inhibitors (PIs) (bortezomib (Velcade) and carfilzomib (Kyprolis)) and two immunomodulatory agents (IMiDs) (lenalidomide (Revlimid) and pomalidomide (Pomalyst)), and their disease is refractory to at least one PI, at least one IMiD, and has progressed following their most recent therapy. Patients with penta-refractory myeloma have quad-refractory disease that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (Darzalex) or isatuximab.
Among the 78 evaluable patients (median seven prior treatment regimens), the overall response rate (ORR) was 20.5% based on Independent Review Committee adjudication, including very good partial responses (VGPR) and partial responses (PR). Among the 48 patients in the quad-refractory group, the ORR was 20.8%. For comparison, in a similar quad-refractory patient population, Darzalex had an ORR of 21% and isatuximab had an ORR of 20%. Among the 30 patients in the penta-refractory group, the ORR was 20.0%. Several patients remain on study, including those with VGPRs, PRs and minor responses. To the Company’s knowledge, no agent has previously shown activity in this penta-refractory population. The side effect profile for selinexor was consistent with previous trials, and no new safety signals were identified. Additional data will be presented later this year.
Keith Stewart, MB. ChB., Anna Maria and Vasek Polack Professor of Cancer Research at the Mayo Clinic and lead investigator of the STORM study, said, "Although treatment of multiple myeloma has improved dramatically, eventually many patients will develop refractory disease, no longer responding to any of the immunomodulatory agents and proteasome inhibitors commonly used (quad-refractory). These patients will also eventually progress on anti-CD38 monoclonal antibodies, which we refer to as penta-refractory disease. These are clearly the patients with the highest unmet need, as they have no remaining viable treatment options. The STORM data are compelling because they demonstrate that oral selinexor achieves a 20.8% response rate in the quad-refractory group, similar to recently reported intravenous anti-CD38 therapy results in the same patient population. Selinexor also achieves an equally notable 20.0% response rate in the penta-refractory group, with the significant advantage of oral administration. We are currently unaware of any other therapy, oral or intravenous, reporting such activity in these difficult-to-treat patients who have exhausted all available therapies."
In addition to the STORM study, Karyopharm initiated the Phase 1b/2 STOMP (Selinexor and Backbone Treatments of Multiple Myeloma Patients) study to evaluate selinexor in combination with existing therapies across the broader population in MM. In the arm evaluating the combination of selinexor, bortezomib and dexamethasone, dose escalation has been completed and the recommended dose has been determined, providing a basis for the randomized Phase 3 "BOSTON" study described below.
Sagar Lonial, MD, Professor and Chair, Department of Hematology and Medical Oncology, Emory University School of Medicine and Chief Medical Officer, Winship Cancer Institute of Emory University, commented, "Myeloma continues to be an incurable blood cancer in most patients and our main goal in treating refractory disease is to induce responses and maintain them as long as possible. In addition to these new data with oral selinexor and low-dose dexamethasone, the emerging clinical data from selinexor in combination with bortezomib, including in proteasome-inhibitor refractory disease, suggests a synergistic effect and favorable safety profile. These data are quite exciting and will form the basis for future studies."
Selinexor: Multiple Myeloma Clinical Development Plans and Timelines
Based on these positive top-line STORM data and existing unmet medical need, Karyopharm plans to implement the following clinical development initiatives focusing on obtaining regulatory approval of selinexor in MM:
Karyopharm is expanding the STORM study to include approximately 120 additional patients with penta-refractory MM. To the Company’s knowledge, this will be the largest study ever undertaken in this patient population. Assuming a positive outcome and remaining unmet medical need, Karyopharm intends to use the data from the expanded STORM study to support a request that the FDA consider granting accelerated approval for selinexor in MM. The Company anticipates reporting top-line data from the expanded cohort in early 2018.
The FDA instituted its Accelerated Approval Program to allow for expedited approval of drugs that treat serious conditions and that fill an unmet medical need based on a surrogate endpoint or an intermediate clinical endpoint thought to predict clinical benefit, like ORR. Accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments at the time of consideration of the application for accelerated approval, which the FDA has reiterated in its feedback to the Company. Particularly in disease areas with multiple available and potential new therapies, such as MM, accelerated approval carries a high regulatory threshold. Drugs approved under the Accelerated Approval Program are also typically required to be studied in randomized confirmatory trials on a post-approval basis to confirm clinical benefit. Given the number of approved and experimental therapies in development to treat MM, and consistent with its standard guidance, the FDA has recommended that the Company conduct a randomized study geared towards full approval, which the Company is planning with the BOSTON study discussed below. In addition, to the Company’s knowledge, no other studies are currently being conducted in the penta-refractory patient population and no agents have shown activity in these patients. In light of this unmet medical need, the Company believes that positive data in this patient population could support accelerated approval. The FDA has stated to the Company that other therapies in MM may receive full approval prior to the potential action date on any accelerated approval request for selinexor that the Company may submit, which may prevent accelerated approval for selinexor if the FDA deems that such therapies constitute earlier lines of therapy in MM that were not administered to patients in the STORM study. Also, while the FDA has previously indicated its preference for studies that isolate the effects of individual drugs, steroids like dexamethasone are part of nearly every myeloma treatment regimen, and low-dose dexamethasone is not a single-agent treatment for MM. Other available therapies for MM, such as pomalidomide (Pomalyst), have received accelerated approval based on studies that were conducted in combination with dexamethasone or a similar steroid. Based on these factors, the Company believes that the STORM study design and the planned expansion in the penta-refractory patient group present an opportunity for the Company to request that the FDA grant accelerated approval if data from the expansion confirm the data presented today.
The Company also plans to initiate a pivotal randomized Phase 3 study, known as the BOSTON (Bortezomib, Selinexor and dexamethasone) study, which will evaluate selinexor in combination with bortezomib (Velcade) and low-dose dexamethasone (SVd) compared to bortezomib and low-dose dexamethasone (Vd) in patients with MM who have had one to three prior lines of therapy. Based on data from the Phase 1b portion of the STOMP study, which was most recently presented at the 2016 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting, the Company has identified the combination dose to be used in the BOSTON study. Karyopharm expects that the study will enroll approximately 360 patients. The Company intends to seek additional FDA input on the protocol for the BOSTON study prior to commencing the trial in early 2017.
Based in part on its plans to conduct the pivotal randomized BOSTON study to support full regulatory approval of selinexor for patients with previously-treated MM and the Company’s planned expansion of STORM to support potential accelerated approval, Karyopharm will not pursue the SCORE study at this time. The SCORE study was designed to assess the combination of selinexor with carfilzomib (Kyprolis) and low-dose dexamethasone. The ongoing Phase 1/2 investigator sponsored study evaluating selinexor in combination with carfilzomib and dexamethasone in refractory MM, including carfilzomib-refractory MM, continues to enroll patients, and updated data from this study is expected to be presented later this year.
"Our updated clinical development plan for selinexor in myeloma reflects the strong foundation of clinical data from both the STORM and STOMP studies," said Michael G. Kauffman, MD, PhD, Chief Executive Officer of Karyopharm. Dr. Kauffman was instrumental in the clinical development and regulatory approvals of Velcade and Kyprolis in MM. "We believe this development plan provides a path to potential FDA and EMA filings for oral selinexor in MM, with the potential to support accelerated or conditional approval if the FDA or EMA, respectively, agree. We look forward to sharing the additional data from both STORM and STOMP later this year. We believe selinexor has the potential to be a much-needed oral treatment option for patients suffering with this incurable disease."
More About the Phase 2b STORM Study
The Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) (NCT02336815) study is a multi-center, single-arm clinical trial evaluating selinexor in combination with low-dose dexamethasone in patients with heavily-pretreated multiple myeloma (MM), which the Company refers to as having at least quad-refractory MM. These are patients who have received bortezomib (Velcade) and carfilzomib (Kyprolis), each of which is a proteasome inhibitor (PI), and lenalidomide (Revlimid) and pomalidomide (Pomalyst), each of which is an immunomodulatory agent (IMiD), and whose disease is refractory to at least one PI, at least one IMiD, and is refractory to their most recent therapy. Prior treatment regimens must have also included an alkylating agent and a glucocorticoid. In the original version of the protocol, at least 25% of patients in this study must have had MM that is also refractory to an anti-CD38 monoclonal antibody, such as daratumumab (DarzalexTM), which the Company refers to as having penta-refractory MM. Of the 79 patients enrolled in the first cohort, 78 had measurable disease at baseline, with 48 (62%) patients classified as having quad-refractory and 30 (38%) patients classified as having penta-refractory MM.
The primary endpoint of the STORM study is overall response rate (ORR). The original trial had several secondary endpoints, including ORR in patients whose disease is relapsed/refractory to an anti-CD38 monoclonal antibody, duration of response (DOR) and clinical benefit rate (CBR). Karyopharm is now expanding the STORM study to include additional sites in the United States and Europe to enroll approximately 120 additional patients with penta-refractory MM to further evaluate the safety and efficacy of selinexor as a basis for potential regulatory submission requesting accelerated (FDA) or conditional (EMA) approval, based on ORR.
More About the Phase 1b/2 STOMP Study
The Phase 1b/2 STOMP (NCT02343042) study is a multi-arm clinical trial evaluating selinexor and low-dose dexamethasone in combination with backbone therapies bortezomib (Velcade), pomalidomide (Pomalyst) or lenalidomide (Revlimid) in patients with heavily pretreated relapsed/refractory MM. Each combination is evaluated on a separate arm of the STOMP study and, within each combination, each of two treatment cohorts will receive either once weekly or twice weekly dosing of selinexor.
Data from the STOMP study was initially reported at the European Hematology Association (EHA) (Free EHA Whitepaper) 2016 annual meeting. As of June 8, 2016, of the 16 patients treated in the SVd combination arm, all of whom are evaluable, 11 responded (1 patient with a complete response (CR), 3 with VGPRs and 7 with PRs for an ORR of 69%). An additional three patients achieved a minor response (MR), for a CBR of 88%. Several of the patients on this selinexor, Velcade and low-dose dexamethasone (SVd) combination arm had high-risk haplotypes, including deletion of chromosome 17p, and 10 of the 16 evaluable patients had MM previously refractory to a proteasome inhibitor. Seven of these 10 patients responded (1 CR, 1 VGPR, and 5 PRs) for an ORR of 70%. An additional patient achieved an MR for a CBR of 80% in this subgroup. Overall, side effects reported in the SVd arm were similar to, or less severe than, those observed with single-agent selinexor. Karyopharm plans to submit updated data from the STOMP study for presentation at a medical conference later this year. The Company is also planning to add two additional arms to the STOMP study — one to evaluate selinexor in combination with daratumumab (Darzalex) and the other to evaluate selinexor in combination with Pomalyst, Velcade and low-dose dexamethasone.
About Selinexor
Selinexor (KPT-330) 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. Over 1,600 patients have been treated with selinexor in company- and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Selinexor is currently being evaluated in several mid- and later-stage clinical trials, including a Phase 2b single-arm trial of selinexor and low-dose dexamethasone in multiple myeloma (STORM), a Phase 1b/2 trial in combination with backbone therapies in multiple myeloma (STOMP), a Phase 2 trial in older patients with acute myeloid leukemia (SOPRA), a Phase 2b trial in diffuse large B-cell lymphoma (SADAL), and a Phase 2/3 trial in liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. The latest clinical trial information for selinexor is available at www.clinicaltrials.gov.
About Multiple Myeloma
Multiple myeloma (MM) is form of blood cancer that develops in the bone marrow. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal protein or M protein. The monoclonal protein produced by myeloma cells interferes with normal blood cell production. In addition, the levels of functional immunoglobulins are depressed in individuals with multiple myeloma. Although the process is not completely understood, it appears that the functional immunoglobulins made by existing, healthy plasma cells breaks down more quickly in patients with multiple myeloma than in healthy individuals. MM is the second most commonly diagnosed blood cancer after Non-Hodgkin’s Lymphoma (NHL). According to SEER data from the National Cancer Institute, in the United States in 2016 approximately 30,000 new cases of MM will be diagnosed, and approximately 12,500 patients will die from the disease. Approximately 100,000 people in the United States were living with MM in 2013. According to GlobalData, the 2015 MM market was valued at approximately $11 billion and the size of the myeloma market is projected to increase to over $22 billion by 2023.