On December 10, 2017 Seattle Genetics, Inc. (Nasdaq: SGEN) reported final five-year survival results from a phase 1 clinical trial evaluating ADCETRIS (brentuximab vedotin) in mature T-cell lymphoma (MTCL) at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Atlanta, Georgia, December 9-12, 2017 (Press release, Seattle Genetics, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321959 [SID1234522496]). The presentation highlighted durability data from a phase 1 clinical trial of ADCETRIS in combination with chemotherapy for the treatment of patients with newly diagnosed MTCL, also known as peripheral T-cell lymphoma (PTCL). ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma. ADCETRIS is currently not approved for the frontline treatment of MTCL.

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"Approximately 4,000 patients are diagnosed with MTCL each year. The current standard of care for frontline MTCL treatment has not changed for several decades and there remains a significant need for improved therapeutic options. The results of this phase 1 trial support the ongoing phase 3 ECHELON-2 clinical trial and our goal to redefine frontline MTCL treatment with a novel ADCETRIS combination regimen," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "The final results from the phase 1 study were presented today, with five-year progression-free survival and overall survival rates of 52 and 80 percent, respectively. No patients have experienced any disease progression events since the three-year follow-up results. Importantly, after more than five years of follow-up, patients who remain in remission have the potential to be cured. These data continue to support the phase 3 ECHELON-2 trial, from which we anticipate reporting data in 2018."

Five-Year Survival Results: Frontline Brentuximab Vedotin in Combination with CHP in Patients with CD30-Expressing Peripheral T-Cell Lymphomas (Abstract #2790, poster presentation on Sunday, December 10, 2017)

Data were reported from 26 frontline MTCL patients who received the combination regimen of ADCETRIS plus cyclophosphamide, doxorubicin and prednisone (CHP). Patients who achieved at least a partial remission with combination therapy following six cycles of ADCETRIS plus CHP were eligible to receive up to ten additional cycles of single-agent ADCETRIS treatment. The median age of patients was 56 years. Nineteen patients (73 percent) had a subtype of MTCL called systemic anaplastic large cell lymphoma (sALCL), including 16 patients with anaplastic lymphoma kinase (ALK)-negative disease, which is typically associated with a poor prognosis. Seven patients (27 percent) had a diagnosis of other types of MTCL. The majority of patients had advanced stage disease and were considered high risk. All patients on the trial achieved an objective response, including 92 percent with a complete response and eight percent with a partial response.

Updated key findings based on a median observation time of 60 months from first dose of therapy include:

At five-year follow-up, there have been no progression events or deaths in this trial since the three-year follow up.
The estimated five-year progression-free survival rate was 52 percent, with no patients receiving a consolidative stem cell transplant in first remission. The median progression-free survival has not yet been reached.
The estimated five-year overall survival rate was 80 percent. The median overall survival has not yet been reached.
Seventy-three percent of patients (19 of 26) experienced peripheral neuropathy, the majority of which was Grade 1 or 2. Ninety-five percent of these patients had complete resolution or some improvement of their symptoms at last follow-up with a median time to resolution of 4.2 months and median time to improvement of symptoms was 2.6 months.
A global phase 3 study called ECHELON-2 completed enrollment in November 2016. The ECHELON-2 trial is a randomized, double-blind, placebo-controlled, multi-center trial designed to investigate ADCETRIS plus CHP versus CHOP as frontline therapy in patients with CD30-expressing MTCL. The trial enrolled 452 patients (approximately 225 patients per treatment arm) randomized to receive ADCETRIS plus CHP or CHOP every three weeks for six to eight cycles. Data from the ECHELON-2 trial are expected in 2018.

About T-Cell Lymphomas

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphomas are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B-lymphocytes, and T-cell lymphomas, which develop from abnormal T-lymphocytes. T-cell lymphomas account for approximately 15 percent of all non-Hodgkin lymphoma in the United States. There are many different forms of T-cell lymphomas, some of which are extremely rare. T-cell lymphomas can be aggressive (fast-growing) or indolent (slow-growing). Almost all types of T-cell lymphoma fall under the category of mature T-cell lymphoma, also known as peripheral T-cell lymphoma. According to the American Cancer Society and analysis of literature sources, approximately 4,300 patients will be diagnosed with CD30-expressing mature T-cell lymphoma in the United States during 2017.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 70 clinical trials, including three phase 3 studies: the completed ECHELON-1 trial in frontline classical Hodgkin lymphoma that supported the recent FDA Breakthrough Therapy Designation and submission of the supplemental Biologics License Application (BLA) for use in this setting, the ongoing ECHELON-2 trial in frontline mature T-cell lymphomas, and the ongoing CHECKMATE 812 trial of ADCETRIS in combination with Opdivo (nivolumab) for relapsed/refractory Hodgkin lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS injection for intravenous infusion has received FDA approval for four indications: (1) regular approval for adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, (2) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (3) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (4) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL in 2013, and non-conditional approval for post-ASCT consolidation treatment of Hodgkin lymphoma patients at increased risk of relapse or progression.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. The European Commission extended the current conditional marketing authorization of ADCETRIS and approved ADCETRIS for the treatment of adult patients with CD30-positive Hodgkin lymphoma at increased risk of relapse or progression following ASCT.

ADCETRIS has received marketing authorization by regulatory authorities in 69 countries for relapsed or refractory Hodgkin lymphoma and sALCL. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

On December 10, 2017 Novartis reported updated results from the JULIET clinical trial demonstrating sustained responses with KymriahTM (tisagenlecleucel) suspension for intravenous infusion, formerly CTL019, in adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) (Press release, Novartis, DEC 10, 2017, View Source [SID1234522495]). The data from this pivotal trial, led by researchers from the University of Pennsylvania (Penn), show an overall response rate (ORR) of 53% (95% confidence interval [CI], 42% – 64%; p<0.0001), with 40% achieving a complete response (CR) and 14% achieving a partial response (PR) among 81 infused patients with three or more months of follow-up or earlier discontinuation. At six months from infusion, the ORR was 37% with a CR rate of 30%. The median duration of response was not reached. Results from this study of Kymriah, the first-ever FDA-approved chimeric antigen receptor T cell (CAR-T) therapy, were included in the US and EU regulatory filings for Kymriah in r/r DLBCL and will be presented in an oral presentation at the 59th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting (Abstract #577; Monday, December 11, 7:00 AM EST)[1].

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"At the time of trial enrollment, these patients with DLBCL had been through multiple rounds of chemotherapy and many had unsuccessful stem cell transplants, leaving them with few options and a poor prognosis," said the study’s principal investigator Stephen J. Schuster, MD, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research in the University of Pennsylvania’s (Penn) Perelman School of Medicine and director of the Lymphoma Program at the Abramson Cancer Center. "With tisagenlecleucel, we have been able to significantly increase their chance of achieving and maintaining a sustained response without stem cell transplant, demonstrating the therapy’s benefit in the treatment of this lethal blood cancer."

At month three, the CR rate was 32% and the PR rate was 6%, which remained consistent to month six (30% CR, 7% PR). Response rates were also consistent among prognostic subgroups, including patients who received prior autologous stem cell transplant (ASCT) and those with a subtype of DLBCL known as double-hit lymphoma, who historically have poor outcomes. No patients in response following treatment with Kymriah proceeded to stem cell transplant[1].

In the JULIET study, the relapse-free probability at six months after first response was 74% (95% CI, 52%-87%), and median duration of response was not reached. Median overall survival was also not reached (95% CI: 6.5 months to NE [not estimable]), and the median time from infusion to data cutoff was 5.6 months[1].

"While immediate response to treatment is a marker for efficacy, patients and physicians need treatment options that provide sustained responses over time with a consistent safety profile," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We look forward to continuing to work with health authorities to bring Kymriah to patients with relapsed or refractory DLBCL."

In the JULIET study, cytokine release syndrome (CRS) occurred in 58% of all treated patients, with 23% of patients experiencing grade 3/4 CRS (15% grade 3; 8% grade 4) using the Penn Grading Scale, a rigorous scale for grading CRS. CRS is a known complication of CAR-T therapy that may occur when the engineered cells become activated in the patient’s body. CRS was managed globally using prior site education on implementation of the CRS treatment algorithm[1].

Twenty one percent of patients experienced any grade neurologic events, and 12% of patients had grade 3/4 neurologic adverse events, which were managed with supportive care. Grade 3/4 cytopenias lasting more than 28 days, grade 3/4 infections and grade 3/4 febrile neutropenia occurred in 27%, 20% and 13% of patients, respectively. Three patients died from disease progression within 30 days of infusion. There were no deaths attributed to Kymriah, CRS or neurological events. No cerebral edema events were reported[1].

In the JULIET trial, 26 patients (26%) were infused in the outpatient setting; of those, 20 patients (77%) remained outpatient for three or more days after infusion. Forty-three patients discontinued before infusion and the majority did so due to rapid progression of their disease or deterioration in their clinical status. This reflects the acute and progressive nature of relapsed or refractory DLBCL. Only 9 of 147 (6.1%) enrolled patients could not be infused due to inability to manufacture an adequate dose of CAR-T cells. Over the course of JULIET, with continuous process improvements, manufacturing success rate improved to 97% for the last 30 patients.

JULIET is the first multi-center global registration study for Kymriah in adult patients with r/r DLBCL and the second global CAR-T cell therapy trial, following the Novartis ELIANA study of Kymriah in children and young adults with r/r B-cell acute lymphoblastic leukemia (ALL). JULIET was conducted in collaboration with Penn and enrolled patients from 27 sites in 10 countries across the US, Canada, Europe, Australia and Japan. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

The results from JULIET build upon a pilot study of Kymriah in r/r DLBCL and follicular lymphoma published online today in the New England Journal of Medicine, which was led by and conducted at Penn and supported by Novartis and grants from the National Institutes of Health, as well as through philanthropic support. Among patients with r/r DLBCL, the study demonstrated an ORR and safety profile similar to results seen in JULIET. The study demonstrated sustained remissions at a follow up of 28.6 months among patients who responded at six months[2].

In April 2017, the US Food and Drug Administration (FDA) granted Breakthrough Therapy designation to Kymriah based on data from the JULIET study. In October 2017, Novartis submitted an application to the FDA for Kymriah in adult patients with r/r DLBCL who are ineligible for or relapse after ASCT, followed shortly by an application to the European Medicines Agency (EMA) in November for Kymriah for the treatment of adult patients with r/r DLBCL who are ineligible for ASCT, and for children and young adults with r/r B-cell ALL. Additional filings beyond the US and EU are anticipated in 2018.

Economic and Societal Value of Kymriah in ALL Presented at ASH (Free ASH Whitepaper)
Results of a cost-effectiveness analysis of Kymriah for the treatment of r/r B-cell ALL in the US will be presented in an oral presentation at the meeting (Abstract #609; Monday, December 11, 7:30 AM EST).

The analysis showed that, based on the current US list price of $475,000, Kymriah is cost-effective compared to standard of care. The analysis compared the life years and quality-adjusted life years gained with Kymriah compared to clofarabine monotherapy, clofarabine combination therapy, blinatumomab, other salvage chemotherapies and allogeneic stem cell transplant. Quality-adjusted life years is a measure of value of health outcomes based on disease burden, including both the quality and quantity of life lived[3].

In addition, results of another analysis to determine the potential societal value of Kymriah to patients with r/r ALL in the United Kingdom were presented in a poster presentation at the meeting (Abstract #1330; Saturday, December 9, 5:30 PM EST).

To quantify the societal value of Kymriah, the analysis looked at the economic value of the incremental quality adjusted life years gained along with the patient’s expected productivity using nationally representative data on employment rates and earnings. Results show that therapies such as Kymriah have the potential to provide benefit to patients and society, particularly through gains in survival, contributing to productivity[4].

About Kymriah
In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

About Kymriah Manufacturing
Kymriah will be manufactured for each individual patient using their own cells at the Novartis Morris Plains, New Jersey facility. Novartis has successfully demonstrated a 22-day turnaround time for manufacturing Kymriah in the commercial setting, and this will continue to be the target. The reliable and integrated manufacturing and supply chain platform for Kymriah allows for an individualized treatment approach on a global scale. The process includes cryopreservation of a patient’s harvested (or leukapheresed) cells, giving treating physicians and centers the flexibility to initiate therapy with Kymriah based on the individual patient’s condition. Building on the company’s experience, having manufactured CAR-T cells for over 250 patients from 11 countries across various indications in clinical trials, it has demonstrated a high-quality and reproducible product. Novartis continues to advance its CAR-T manufacturing expertise and make investments to support the anticipated demand to meet the needs of patients.

About DLBCL
DLBCL is the most common form of non-Hodgkin lymphoma, a cancer of the lymphatic system, with an estimated 27,650 new cases diagnosed in 2016[5],[6]. Ten to 15% of DLBCL patients fail to respond to initial therapy or relapse within three months of treatment, and an additional 20% to 25% relapse after initial response to therapy[5]. Nearly 40% of patients with DLBCL will die of relapsed or refractory disease[7].

KymriahTM (tisagenlecleucel) Important Safety information (for pediatric and young adult patients with B-cell precursor acute lymphoblastic leukemia)
The full prescribing information, including Boxed WARNING, for Kymriah can be found at:
View Source

Kymriah may cause side effects that are severe or life-threatening, such as Cytokine Release Syndrome (CRS) or Neurological Toxicities. Patients with CRS may experience symptoms including high fever, difficulty breathing, chills/shaking chills, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, or dizziness/lightheadedness. Patients may be admitted to the hospital for CRS and treated with other medications.

Patients with neurological toxicities may experience symptoms such as altered or decreased consciousness, headaches, delirium, confusion, agitation, anxiety, seizures, difficulty speaking and understanding, or loss of balance. Patients should be advised to call their health care provider or get emergency help right away if they experience any of these signs and symptoms of CRS or neurological toxicities.

Because of the risk of CRS and neurological toxicities, Kymriah is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) in the US called Kymriah REMS.

Serious allergic reactions, including anaphylaxis, may occur after Kymriah infusion.
Kymriah can increase the risk of life-threatening infections that may lead to death. Patients should be advised to tell their health care provider right away if they develop fever, chills, or any signs or symptoms of an infection.

Patients may experience prolonged low blood cell counts (cytopenia), where one or more types of blood cells (red blood cells, white blood cells, or platelets) are decreased. The patient’s health care provider will do blood tests to check all of their blood cell counts after treatment with Kymriah. Patients should be advised to tell their health care provider right away if they get a fever, are feeling tired, or have bruising or bleeding.

Patients may experience hypogammaglobulinemia, a condition in which the level of immunoglobulins (antibodies) in the blood is low and the risk of infection is increased. It is expected that patients may develop hypogammaglobulinemia with Kymriah, and may need to receive immunoglobulin replacement for an indefinite amount of time following treatment with Kymriah. Patients should tell their health care provider about their treatment with Kymriah before receiving a live virus vaccine.

After treatment with Kymriah, patients will be monitored life-long by their health care provider, as they may develop secondary cancers or recurrence of their leukemia.

Patients should not drive, operate heavy machinery, or do other dangerous activities for 8 weeks after receiving Kymriah because the treatment can cause temporary memory and coordination problems, including sleepiness, confusion, weakness, dizziness, and seizures.

Some of the most common side effects of Kymriah are difficulty breathing, fever (100.4°F/38°C or higher), chills/shaking chills, confusion, severe nausea, vomiting and diarrhea, severe muscle or joint pain, very low blood pressure, and dizziness/lightheadedness. However, these are not all of the possible side effects of Kymriah. Patients should talk to their health care provider for medical advice about side effects.

Prior to a female patient starting treatment with Kymriah, their health care provider may do a pregnancy test. There is no information available for Kymriah use in pregnant or breast-feeding women. Therefore, Kymriah is not recommended for women who are pregnant or breast feeding. If either sex partner has received Kymriah, patients should talk to their health care provider about birth control and pregnancy.

Patients should tell their health care provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

After receiving Kymriah, patients should be advised that some commercial HIV tests may cause a false positive test result. Patients should also be advised not to donate blood, organs, or tissues and cells for transplantation after receiving Kymriah.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for Kymriah, regarding our ability to scale and sustain commercial manufacturing for Kymriah, regarding our ability to build and sustain a network of treatment centers to offer Kymriah, or regarding potential future revenues from Kymriah. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that Kymriah will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Neither can there be any guarantee that Novartis will successfully scale and sustain commercial manufacturing for Kymriah, or successfully build and sustain a network of treatment centers to offer Kymriah. Nor can there be any guarantee that Kymriah will be commercially successful in the future. In particular, our expectations regarding Kymriah could be affected by, among other things, our ability to successfully scale and sustain commercial manufacturing and build and sustain a network of treatment centers; the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

On December 10, 2017 Kyowa Hakko Kirin Co., Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") reported that the results of the Global Phase 3 study (MAVORIC: Mogamulizumab anti-CCR4 Antibody Versus ComparatOR In CTCL) investigating the use of mogamulizumab (KW-0761) in patients with cutaneous T-cell lymphoma (CTCL) will be presented at the Annual Meeting of American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 (Press release, Kyowa Hakko Kirin, DEC 10, 2017, View Source [SID1234522494]).

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The American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 Oral Presentation 817:

Title: Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study

MAVORIC is a phase 3 open-label, multi-centre, randomised study of mogamulizumab versus vorinostat in patients with CTCL who have failed at least one prior systemic treatment. The study was conducted in the US, Europe, Japan and Australia and randomised 372 patients to receive either the investigational monoclonal antibody, mogamulizumab, or vorinostat. The primary endpoint was investigator-assessed Progression-free Survival (PFS), and the key secondary endpoints included overall response rate (ORR).

In the study, the patients who received mogamulizumab had significantly better PFS compared to vorinostat with a median PFS of 7.7 months for mogamulizumab and 3.1 months for vorinostat (p<0.0001). Global ORR was significantly improved in the patients randomised to mogamulizumab at 28.0% vs 4.8% for vorinostat (p<0.0001). Patient-reported outcomes, as measured by the Skindex-29 and FACT-G, showed significantly greater symptom reduction and improved functional status in favor of mogamulizumab vs vorinostat (p<0.05).

The most common treatment-emergent adverse events (TEAEs) that were more frequent in the mogamulizumab arm included infusion-related reactions (33.2%, vs 0.5% in the vorinostat arm) and drug rash (23.9% vs 0.5%). Common TEAEs reported more often with vorinostat included diarrhoea (23.4%, vs 61.8% in the vorinostat arm) nausea (15.2% vs 42.5%), thrombocytopenia (11.4% vs 30.6%), dysgeusia (3.3% vs 29.0%), and increased blood creatinine (3.3% vs 28.0%).

In conclusion, mogamulizumab demonstrated significant PFS and ORR improvement compared to vorinostat in patients with previously treated CTCL.

"We are delighted with the finding from the MAVORIC study which is the largest, global randomised phase 3 clinical study ever conducted in patients with CTCL," said Jeffrey S. Humphrey, MD., Chief Medical Officer and President of Kyowa Kirin Pharmaceutical Development, Inc. "We look forward to having the data reviewed by regulatory agencies in the near future and to providing mogamulizumab to patients with CTCL if approved."

The Kyowa Hakko Kirin Group companies strive to contribute to the health and well-being of people around the world by creating new value through the pursuit of advances in life sciences and technologies.

About MAVORIC

MAVORIC is a Phase 3 open-label, multi-center, randomized study of mogamulizumab versus vorinostat, active comparator, in patients with mycosis fungoides (MF) and Sézary syndrome (SS) who have failed at least one prior systemic treatment. The study was the largest comparative trial in patients with MF and SS conducted in the US, Europe, Japan and Australia and randomised 372 patients.

About Mogamulizumab

Mogamulizumab is an investigational humanised monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4), which is frequently expressed on leukemic cells of certain haematologic malignancies including CTCL. Mogamulizumab was produced using Kyowa Hakko Kirin’s proprietary POTELLIGENT platform, which is associated with enhanced antibody-dependent cellular cytotoxicity (ADCC).

About Cutaneous T-cell Lymphoma (CTCL)

CTCL is a rare type of non-Hodgkin’s lymphoma which is characterised by localisation of malignant T lymphocytes to the skin. The two most common types of CTCL are mycosis MF and SS, and depending on the stage, the disease may involve skin, blood, lymph nodes, viscera and other organs.

On December 10, 2017 Kura Oncology, Inc., (Nasdaq:KURA) a clinical-stage biopharmaceutical company focused on the development of precision medicines for oncology, reported positive, preliminary results from a Phase 2 clinical study of its lead candidate tipifarnib in patients with chronic myelomonocytic leukemia (CMML) (Press release, Kura Oncology, DEC 10, 2017, View Source;p=RssLanding&cat=news&id=2321958 [SID1234522493]). The data were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta. A copy of the poster is now available on the company’s website at www.kuraoncology.com.

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The CMML study is one of four ongoing company-sponsored Phase 2 studies of tipifarnib. The open-label study is evaluating the anti-tumor activity of tipifarnib as a single agent in patients with CMML, retrospectively stratified based on RAS mutational status. In addition, patient samples are analyzed for the presence or absence of various biomarkers potentially relevant to the activity of tipifarnib.

As of the data cutoff date of November 7, 2017, all nine evaluable patients in the study with RAS wild-type CMML had achieved stable disease or better, including three objective responses as assessed using the MDS/MPN International Working Group criteria. The primary objective of the study was met with an overall response rate of 33% in patients with RAS wild-type CMML. The study has enrolled 24 patients of whom 16 were evaluable for response as of the data cutoff date. Nine patients had tumors with RAS wild-type status and seven were RAS mutant.

"CMML is an aggressive malignancy with few therapeutic options, particularly for those patients who have been treated with hypomethylating agents," said Eric Padron, M.D., of the Department of Hematologic Malignancies at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, a clinical investigator on this study. "These encouraging preliminary data indicate that tipifarnib has anti-tumor activity in a post-hypomethylating agent setting and support further study of tipifarnib for the treatment of CMML."

"Although the signal observed in RAS wild-type patients is encouraging, these data are still immature and time to event endpoints cannot be yet fully evaluated. We continue to follow these patients and evaluate biomarkers of activity, and look forward to reporting additional data from this study in the year ahead," said Antonio Gualberto, M.D., Ph.D., Chief Medical Officer of Kura Oncology.

Patients receive tipifarnib administered at a starting dose of 900 mg, orally, twice a day for 7 days in alternating weeks in 28-day cycles. Tipifarnib was generally well-tolerated in the study, with adverse events consistent with its known safety profile.

In addition to the CMML study, Kura Oncology is also conducting Phase 2 clinical trials in HRAS mutant head and neck squamous cell carcinomas (HNSCC), peripheral T-cell lymphoma (PTCL) and myelodysplastic syndrome (MDS). In September 2017, Kura Oncology reported that its Phase 2 trial of tipifarnib in patients with HRAS mutant HNSCC achieved its primary efficacy endpoint prior to the completion of patient enrollment. The company is now planning to initiate a registration-enabling study of tipifarnib in HRAS mutant HNSCC in 2018.

About Chronic Myelomonocytic Leukemia

CMML is a clonal disorder of bone marrow stem cells that shares characteristics of both myeloproliferative and myelodysplastic diseases. CMML is characterized by increased monocytes and blasts in the peripheral blood and bone marrow, as well as dysplasia in at least one type of blood cell. The prognosis of CMML is poor, with a median survival of 2 to 3 years, due in part to limited therapeutic options. Hypomethylating agents are the most commonly used therapeutic intervention in CMML.

About Tipifarnib

Kura Oncology’s lead candidate, tipifarnib, is a potent and selective inhibitor of farnesyl transferase, a key cell signaling process implicated in cancer initiation and development. In extensive clinical trials, tipifarnib has shown a well-established safety profile and compelling and durable anti-cancer activity in certain patient subsets. Leveraging advances in next-generation sequencing as well as emerging information about cancer genetics and tumor biology, the company is seeking to identify patients most likely to benefit from tipifarnib.

On December 10, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported the presentation of four posters highlighting clinical data from the ongoing Phase 1b/2 STOMP study at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2017 annual meeting held December 9-12, 2017 in Atlanta (Press release, Karyopharm, DEC 10, 2017, View Source [SID1234522492]). The STOMP study is evaluating selinexor, the Company’s lead, novel, oral SINE compound, in combination with backbone therapies for the treatment of patients with heavily pretreated multiple myeloma (MM). Two of the presentations feature updated data from the STOMP arms evaluating selinexor plus low dose dexamethasone (Sd) in combination with either Velcade (bortezomib) (SVd), or Pomalyst (pomalidomide) (SPd). The other two presentations feature new data from the STOMP arms evaluating Sd with Revlimid (lenalidomide) (SRd) and with Darzalex (daratumumab) (SDd).

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"The results from the SVd arm of the Phase 1b/2 STOMP study, particularly the high response rates of 83% in the same patient population eligible for the BOSTON study and 84% in proteasome inhibitor (PI)-naïve or PI-relapsed patients, together with prolonged progression-free survival (PFS), strongly support our ongoing, pivotal Phase 3 BOSTON study," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "Overall, the four presentations continue to highlight evidence of strong activity when oral selinexor is combined with the currently available "backbone" myeloma therapies, including PIs, immunomodulatory drugs (IMiDs) and anti-CD38 monoclonal antibodies. Oral selinexor continues to demonstrate an expected and manageable tolerability profile, particularly in the SVd regimen where the combination produced higher response rates, paired with lower rates of peripheral neuropathy (PN), compared to the commonly used regimen of Velcade plus dexamethasone. We are delighted to share the results of this research with the medical community at ASH (Free ASH Whitepaper) this year."

Selinexor in Combination with Velcade and Low-dose Dexamethasone (SVd)

In the poster presentation titled, "Selinexor in combination with weekly low dose bortezomib and dexamethasone (SVd) induces a high response rate with durable responses in patients with refractory multiple myeloma," (Abstract #3135) Nizar Bahlis, MD, Southern Alberta Cancer Research Institute, presented updated clinical data from the SVd arm of the STOMP study. The study included patients whose disease was PI naïve, exposed or refractory, provided their disease was not refractory to Velcade as a last therapy. In this study arm, oral selinexor was dose-escalated in once-weekly (80 or 100mg) or twice-weekly (60 or 80mg) regimens. Velcade (1.3mg/m2 subcutaneously) was administered once-weekly or twice-weekly. Dexamethasone (dex) was administered orally either 40mg once-weekly or 20mg twice-weekly. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SVd Patients as of 15-Nov-20172
Category N3 ORR (%) CR VGPR PR4 Median PFS
PI Relapsed/Naïve 19 16 (84%) 2 (11%) 5 (26%) 9 (47%) >13 months
PI Relapse/Naïve, ≤3 Prior Treatments (BOSTON5) 18 15 (83%) 2 (11%) 6 (33%) 7 (39%)
PI Refractory (Velcade, Kyprolis, Ninlaro) 21 9 (43%) 1 (5%) 4 (19%) 4 (19%) 6.4 months
All 40 25 (63%) 3 (8%) 9 (23%) 13 (33%) 9.0 months
Key: ORR=Overall Response Rate (CR+VGPR+PR), CR=Complete Response, VGPR=Very Good Partial Response, PR=Partial Response
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Two patients not evaluable for response: one death unrelated to myeloma and one withdrawal of consent before disease follow up
4One unconfirmed PR
5Patient population eligible for the ongoing Phase 3, randomized BOSTON study evaluating SVd versus Vd

The majority of patients had reductions in M-protein, including 33% with a ≥90% reduction. In the PI Relapsed/Naïve population (N=19), the ORR was 84% and the median PFS was >13 months with similar results in the "BOSTON" population (N=18). This compares favorably to standard Vd regimens (the control arm of the BOSTON study) with ORR 60-65% and PFS 7-9 months across many previous studies.

Adverse events were consistent with those reported previously from the SVd arm of the STOMP study with nausea, anorexia, fatigue, diarrhea and vomiting the most commonly reported for Grade 1/2. Importantly, the reported PN across all patients was Grade 1/2 and limited to six patients (14%), of which five had prior Velcade exposure. Grade ≥3 adverse events were also consistent with those reported previously with thrombocytopenia, neutropenia, fatigue and anemia being the most common. The recommended Phase 2 dose (RP2D) regimen for SVd is oral selinexor (100mg once weekly), Velcade (1.3mg/m2 once-weekly subcutaneously) and oral dex (40mg once weekly), which represents 40% less Velcade and 25% less dex compared to the approved standard Velcade + dex (Vd) regimen.

Dr. Bahlis commented, "These updated data continue to support the thesis that selinexor combined with once-weekly Velcade and low-dose dex is well tolerated and highly active in relapsed or refractory myeloma. The high response rates and durability observed with SVd are achieved with 40% less Velcade and 25% less dex, with no overt major organ toxicities. The SVd response rates in patients with PI non-refractory myeloma, together with the low rate of PN, compares favorably to the response rates and much higher PN reported from other late-stage Vd trials. In patients with PI refractory myeloma, the response rates reported here support prior preclinical findings suggesting selinexor’s potential to re-sensitize myeloma to PIs."

Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In the poster presentation titled, "Selinexor in Combination with Pomalidomide and Low Dose Dexamethasone in a Relapsed / Refractory Multiple Myeloma Patient Population with Prior Proteasome Inhibitor and Lenalidomide Exposure," (Abstract #3136) Christine Chen, MD, FRCP, University of Toronto, Princess Margaret Cancer Center, presented updated clinical data from the SPd arm of the STOMP study which includes MM patients who previously received Revlimid and a PI. In this study arm, selinexor was dosed orally either once weekly (60 or 80mg) or twice weekly (60 or 80mg) with Pomalyst (4mg orally, once daily) and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 15-Nov-20172
Category N3 ORR (%) VGPR PR4 Median PFS
Pomalyst Naïve and Revlimid Refractory or Relapsed 19 12 (63%) 2 (11%) 10 (53%) 11.6 months
Pomalyst and Revlimid Refractory 8 3 (38%) - 3 (38%) 4.8 months
All 27 15 (56%) 2 (7%) 13 (48%) 11.6 months
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Four patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, two withdrawals of consent before disease follow up
4One unconfirmed PR

Responses tended to occur rapidly with a median of one month to onset. Median PFS of 11.6 for SPd compares favorably with the PFS of ~4 months reported for Pomalyst-dex in the Revlimid refractory or relapsed population.

Among the 31 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (52%), anorexia (45%), fatigue (45%) and diarrhea (32%). The most common Grade ≥3 adverse events were neutropenia (55%), thrombocytopenia (32%) and anemia (29%). Gastrointestinal adverse events were generally manageable with antiemetics. There were two Grade 5 treatment-related events (febrile neutropenia and intracranial hemorrhage). Five DLTs (Grade 3 fatigue, neutropenia and febrile neutropenia) were observed in patients receiving selinexor 60mg twice weekly and 80mg once weekly. Based on the activity and tolerability observed in this study arm, 60-80mg of oral selinexor 60mg 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.

Dr. Chen commented, "Myeloma patients whose disease is refractory to a PI and an IMiD would typically move to the currently approved regimen of Pomalyst and dex, which carries an expected ORR of up to 30% and PFS of approximately four months in this patient population. The 56% ORR reported here shows the significant clinical activity of this novel, all oral, SPd regimen in patients with heavily pretreated myeloma. These data continue to build upon the body of clinical data suggesting that once-weekly selinexor is generally well tolerated and can rapidly induce durable responses when combined with Pomalyst and dex in patients with PI- and Revlimid-exposed myeloma, including patients whose disease was refractory to prior therapy with Pomalyst. This SPd regimen has the potential to provide a new therapeutic option for myeloma patients where a significant unmet need remains."

Selinexor in Combination with Revlimid and Low-dose Dexamethasone (SRd)

In the poster presentation titled, "A Phase Ib/II Trial of Selinexor Combined with Lenalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma," (Abstract #1861) Darrell White, MD, Dalhousie University and QEII Health Sciences Center, presented new clinical data from the SRd arm of the STOMP study evaluating patients who received at least one prior therapy, which may include prior Revlimid, as long as the patient’s MM was not refractory to prior Revlimid. Patients whose MM was refractory to Revlimid maintenance regimens were also allowed in this cohort. In this study arm, oral selinexor was dose-escalated starting at either 60mg once weekly or 60mg twice weekly, with Revlimid (25mg orally, once daily), and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SRd Patients as of 15-Nov-20172
Category N3 ORR VGPR PR4
Revlimid Naïve (All) 12 11 (92%) 3 (25%) 8 (67%)
Revlimid Naïve, ≤2 Prior Treatments 10 10 (100%) 3 (30%) 7 (70%)
Revlimid Relapsed or Refractory 4 2 (50%) - 2 (50%)
All 16 13 (81%) 3 (19%) 10 (63%)
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3Three patients not evaluable for response: two deaths unrelated to myeloma, one withdrawal of consent before disease follow up
4Three unconfirmed PRs

Median PFS for the overall study population and for patients with Revlimid-naïve disease was not reached. The median time on treatment for the overall study population was not reached.

Among the 19 patients evaluable for safety, the most common Grade 1/2 adverse events were nausea (68%), anorexia (42%), fatigue (42%), weight loss (42%), constipation (32%) and vomiting (32%). The most common Grade ≥3 adverse events were thrombocytopenia (68%) and neutropenia (58%). Gastrointestinal adverse events were generally manageable with antiemetics. Five DLTs (thrombocytopenia (n=4) and anorexia (n=1)) were observed in patients receiving selinexor 60mg twice weekly and 80mg once weekly. Thrombocytopenia and anorexia were reduced in the selinexor 60mg once weekly cohort versus the twice weekly groups. Based on the activity and tolerability observed in this study arm, the RP2D of the all-oral SRd is selinexor (60mg orally, once weekly), Revlimid (25mg orally, once daily) and dex (40mg orally, once weekly).

Dr. White commented, "These Phase 1 results suggest that selinexor can be safely combined with Revlimid and dex in an all oral regimen in patients with relapsed or refractory myeloma who have received at least one prior therapy. We were especially pleased to see an encouraging 81% response rate across all patients and a 92% response rate in patients with Revlimid-naïve disease, clear signals of clinical activity, with no new or unexpected toxicities observed. Importantly, this combination shows no evidence of cardiac, pulmonary, liver or renal toxicity. We look forward to continuing our evaluation of selinexor in this SRd regimen in patients with relapsed or refractory myeloma."

Selinexor in Combination with Darzalex and Low-dose Dexamethasone (SDd)

In the poster presentation titled, "A Phase 1b Study to Assess the Combination of Selinexor and Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma Previously Exposed to Proteasome Inhibitors (PI) and Immunomodulatory Drugs," (Abstract #3100) Cristina Gasparetto, MD, Duke University Cancer Center, presented new clinical data from the SDd arm of the STOMP study evaluating MM patients who received at least three prior lines of therapy, including a PI and an IMiD, or patients with MM refractory to both a PI and an IMiD. In this study arm, oral selinexor was dose escalated using either 100mg once weekly or 60mg twice weekly, with Darzalex (16mg/kg intravenously once weekly) and dex (orally, 40mg once weekly or 20mg twice weekly). The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SDd Patients as of 15-Nov-20172
Category N3 ORR VGPR PR4
Darzalex Naïve 6 5 (83%) 3 (50%) 2 (33%)
All 8 5 (63%) 3 (38%) 2 (25%)
Key: ORR=Overall Response Rate (VGPR+PR)
1Responses were adjudicated according to the International Myeloma Working Group criteria
2Based on interim unaudited data
3One patient not evaluable for response withdrew consent prior to disease follow up due to severe infusion reaction associated with Darzalex
4One unconfirmed PR

Four of nine patients remain on treatment. Responses tended to occur rapidly with a median of one month to onset. Among the nine patients evaluable for safety, the most common Grade 1/2 adverse events were fatigue (44%), nausea (33%) and neutropenia (33%). The most common Grade 3/4 adverse events were thrombocytopenia (56%), leukopenia (44%), anemia (44%) and neutropenia (33%). Gastrointestinal adverse events were generally manageable with antiemetics. The maximum tolerated dose was not reached. Two DLTs (Grade 3 thrombocytopenia and Grade 2 fatigue) were observed in patients receiving selinexor 60mg twice weekly; both patients showed responses. Based on the preliminary tolerability and efficacy data, the RP2D of SDd is selinexor (100mg orally, once weekly), Darzalex (16mg/kg, once weekly) and dex (40mg orally, once weekly).

"Preclinical results have shown that oral selinexor sensitizes patients’ myeloma cells to the anti-CD38 monoclonal antibody, Darzalex," stated Dr. Gasparetto. "These Phase 1b data are early but encouraging, and suggest that selinexor can be safely combined with Darzalex and low-dose dexamethasone in patients with heavily pretreated myeloma. The responses observed occur rapidly within a median one cycle of treatment. We look forward to further evaluating the SDd combination."

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. To date, over 2,200 patients have been treated with selinexor, and it is currently being evaluated in several 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), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and 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 Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.