On December 23, 2019 Seattle Genetics, Inc. (Nasdaq:SGEN) reported it has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tucatinib (Press release, Seattle Genetics, DEC 23, 2019, View Source [SID1234552587]). This NDA requests FDA approval of tucatinib in combination with trastuzumab and capecitabine for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. The submission is based on the results of HER2CLIMB, a randomized pivotal trial comparing tucatinib added to trastuzumab and capecitabine versus trastuzumab and capecitabine alone. HER2CLIMB trial results were presented on December 11, 2019 at the 2019 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine.Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

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Tucatinib was recently granted Breakthrough Therapy designation by the FDA in combination with trastuzumab and capecitabine, for treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and T-DM1. This designation was based on data from the HER2CLIMB trial.

"Today’s submission marks another important milestone for Seattle Genetics and tucatinib, and a potential advance for patients with either locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. "We look forward to working with the FDA on the review of this application."

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About HER2CLIMB

HER2CLIMB is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab, and T-DM1. The primary endpoint of the trial was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review (BICR) in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival, PFS per BICR in patients with brain metastases at baseline, and confirmed objective response rate. Safety data were evaluated throughout the study.

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab.1, 2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal, and gastric cancers. HER2 mediates cell growth, differentiation, and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival per RECIST criteria. Secondary endpoints include overall survival, objective response rate, and duration of response. The trial is being conducted in North America and is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, which is evaluating tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic, or unresectable colorectal cancer. The primary endpoint of the trial is objective response rate by RECIST criteria. Progression-free survival, duration of response, overall survival, and safety and tolerability of the combination regimen are secondary objectives. Results for 26 patients were evaluated in an analysis and presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress. Enrollment is ongoing. More information about the MOUNTAINEER trial, including enrolling centers, is available at www.clinicaltrials.gov.

On December 23, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, as a new treatment for patients with relapsed or refractory diffuse large B-Cell lymphoma (DLBCL) after at least two prior multi-agent therapies and who are ineligible for stem cell transplantation, including CAR-T (chimeric antigen receptor modified T cell) therapy (Press release, Karyopharm, DEC 23, 2019, View Source [SID1234552571]). XPOVIO has received both Orphan Drug and Fast Track designations from the FDA for this indication.

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"Earlier this year we reported compelling results from the Phase 2b SADAL study investigating XPOVIO in patients with relapsed or refractory DLBCL. The updated results submitted in the NDA demonstrate a 28.3% overall response rate, including an 11.8% complete response rate, and a median duration of response of over 9 months," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "These data highlight XPOVIO’s potential as a new, first-in-class oral therapy for patients whose DLBCL has progressed following two prior treatments and who have extremely limited treatment options available. The submission of this second NDA is a significant achievement for Karyopharm and brings XPOVIO one step closer to serving an entirely new group of patients. We are sincerely grateful to all of the patients, caregivers and physicians who have contributed to the XPOVIO DLBCL program, and we look forward to providing future updates on the status of this NDA. If approved, XPOVIO would represent the first and only oral regimen to treat patients with relapsed or refractory diffuse large B-cell lymphoma."

Karyopharm also expects to submit a marketing authorization application (MAA) to the European Medicines Agency in 2020 requesting conditional approval for XPOVIO in this same indication.

About XPOVIO (selinexor)

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

IMPORTANT SAFETY INFORMATION IN APPROVED MULTIPLE MYELOMA INDICATION

Thrombocytopenia

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

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

Neutropenia

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

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

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

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

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

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

Diarrhea

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

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

Anorexia/Weight Loss

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

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

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

Hyponatremia

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

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

Infections

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

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

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

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

Embryo-Fetal Toxicity

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

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

ADVERSE REACTIONS IN APPROVED MULTIPLE MYELOMA INDICATION

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

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

Please see XPOVIO Full Prescribing Information available at www.XPOVIO.com.

Further Information About Potential Accelerated Approval for XPOVIO in DLBCL

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 overall response rate (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 DLBCL, accelerated approval carries a high regulatory threshold. Consistent with its general guidance, the FDA has noted to the Company its preference for randomized studies geared toward full approval, and has reminded the Company that accelerated approval requires patients to have exhausted all available approved therapies. FDA’s Fast Track designation is available to therapeutics treating an unmet medical need in a serious condition; the Company has received Fast Track designation from the FDA specifically for the population treated in the SADAL study. In light of this recognition that the SADAL patient population represents an unmet medical need and the positive clinical results reported in December 2018 at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, and then updated results resented in June 2019 at the International Conference on Malignant Lymphoma, the Company believes that the SADAL study should support its request to the FDA for accelerated approval.

On December 23, 2019 Gilead Sciences, Inc. (Nasdaq: GILD) reported that Daniel O’Day, Gilead’s Chairman and Chief Executive Officer, will provide an overview of the company at the 38th Annual J.P. Morgan Healthcare Conference in San Francisco on Monday, January 13 at 9:30 a.m. Pacific Time (Press release, Gilead Sciences, DEC 23, 2019, View Source [SID1234552588]).

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The live webcast can be accessed at the company’s Investors page at View Source Please connect to the company’s website at least 15 minutes prior to the start of the presentation to ensure adequate time for any software download that may be required to listen to the webcast. The replay will be available for 14 days following the presentation.

On December 23, 2019 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a biotechnology company focused on developing cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that both batches of the company’s manufactured clinical trial product have now passed 7 of the 10 completed "release tests" per batch required by the U.S. Food and Drug Administration (FDA), including the test for "enzymatic activity" on both batches (Press release, PharmaCyte Biotech, DEC 23, 2019, View Source [SID1234552589]).

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PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner, said, "As we expected, each batch of our clinical trial product is performing well during ‘release testing.’ There are 10 tests in total being performed on each batch that was manufactured by Austrianova. These tests will provide essential data for us to complete our Investigational New Drug application (IND). This data, together with other information and data we are developing, will enable us to submit the IND to the FDA to request approval for our planned clinical trial in locally advanced, inoperable pancreatic cancer (LAPC). There are 3 tests that remain outstanding on each batch before we are completely done with release testing."

PharmaCyte’s partner, Austrianova Singapore (Austrianova), is conducting release tests related to the "functionality" of the encapsulated cells, while third-party laboratories are conducting release tests related to the "safety" of the company’s clinical trial product.

To learn more about PharmaCyte’s pancreatic cancer treatment and how it works inside the body to treat locally advanced inoperable pancreatic cancer, we encourage you to watch the company’s documentary video complete with medical animations at: View Source

On December 23, 2019 Rubius Therapeutics, Inc. (Nasdaq:RUBY), a clinical-stage biopharmaceutical company that is genetically engineering red blood cells to create an entirely new class of cellular medicines, reported the appointment of Christina Coughlin, M.D., Ph.D., as the Company’s chief medical officer, effective January 6, 2020 (Filing, 8-K, Rubius Therapeutics, DEC 23, 2019, View Source [SID1234552573]). With Dr. Coughlin’s appointment, Chris Carpenter, M.D., Ph.D., Rubius’ previous chief medical officer, is transitioning to a scientific advisory role.

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"As Rubius begins its next chapter as a clinical-stage organization, we are excited to welcome Christina to Rubius, as our chief medical officer. Christina brings extensive experience leading clinical development and translational medicine teams and has a track record of building successful drug development organizations, with a particular focus in cellular therapy and oncology. We look forward to having her clinical and scientific leadership as we advance our pipeline of Red Cell Therapeutics for the potential treatment of rare diseases, cancer and autoimmune diseases," said Pablo J. Cagnoni, M.D., chief executive officer. "I would like to thank Chris for his many contributions to Rubius and look forward to his continued guidance through his scientific advisory role."

A trained oncologist and immunologist, Dr. Coughlin joins Rubius from Tmunity Therapeutics, Inc., where she served as chief medical officer and was responsible for the development of Tmunity’s CAR-T and TCR-T cellular therapy pipeline across preclinical, regulatory and clinical development activities. Prior to Tmunity, Ltd., Dr. Coughlin served as chief medical officer at Immunocore, where she led the development of the preclinical and clinical pipeline of soluble T cell receptor product candidates recognizing multiple tumor targets, including advancing the lead program from Phase 1 to dual pivotal clinical trials. Earlier, she held positions at several pharmaceutical companies, including executive director of oncology clinical development at Novartis; international project team leader, early development at Morphotek, Inc.; and was an asset team leader in early clinical development at Pfizer’s Oncology Business Unit. Before entering the pharmaceutical industry, Dr. Coughlin was an instructor in pediatrics at the University of Pennsylvania School of Medicine; completed her postdoctoral research fellowship in the Translational Research Group of the Abramson Family Cancer Research Institute under the direction of CAR-T cell therapy pioneer Carl June, M.D.; and was an attending physician and instructor in the Department of Pediatrics and Division of Oncology at The Children’s Hospital of Philadelphia. She holds an M.D. and Ph.D. from the University of Pennsylvania School of Medicine and a B.S. in mathematics and biology from Temple University.

"I have dedicated my career to leading the development of potentially transformative, novel cellular therapies for the treatment of patients with cancer," said Christina Coughlin, M.D., Ph.D., chief medical officer of Rubius Therapeutics. "I believe the Rubius Therapeutics’ RED PLATFORM represents the next forefront in cellular therapy innovation and with it the potential to help patients across multiple therapeutic areas. I am excited to join the team during such a pivotal time for the company."