On May 15, 2019 X4 Pharmaceuticals, Inc. (Nasdaq:XFOR), a clinical-stage biopharmaceutical company focused on the development of novel therapeutics for the treatment of rare diseases, and The Leukemia & Lymphoma Society (LLS) reported a collaboration to accelerate the development of X4’s lead product candidate, mavorixafor (X4P-001) for the treatment of Waldenström’s macroglobulinemia (WM), a rare form of non-Hodgkin lymphoma (Press release, X4 Pharmaceuticals, MAY 15, 2019, View Source [SID1234536349]).

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Mavorixafor was selected for LLS’s Therapy Acceleration Program (TAP), a strategic initiative where LLS builds business alliances and collaborations with biotechnology companies and academic researchers to speed the development of new therapies for blood cancers. Under the collaboration, X4 will conduct a multi-national Phase 1/2 clinical trial to evaluate the safety and assess the preliminary anti-tumor activity of mavorixafor in combination with ibrutinib in WM patients. The trial is planned to commence this year. Lee Greenberger, Ph.D., chief scientific officer of LLS, will also serve as a member of an advisory board to X4, providing important strategy and partnership guidance throughout the trial.

"LLS’s selection of mavorixafor for TAP collaboration and investment reinforces its potential as a novel therapy for Waldenström’s macroglobulinemia. Approximately 30 to 40 percent of WM patients have a CXCR4 mutation, and a number of these patients do not respond well to current therapies," said Paula Ragan, Ph.D., president and chief executive officer of X4 Pharmaceuticals. "We look forward to working closely with Dr. Greenberger and the LLS TAP team to gain valuable data and insights throughout the upcoming clinical trial as we work to bring a new therapeutic option to patients with this rare form of cancer."

Mavorixafor is a first-in-class, oral, small molecule allosteric antagonist of the chemokine receptor CXCR4 and is designed to address certain rare primary immunodeficiency diseases and certain cancers, including lymphomas, in which genetic mutations in CXCR4 create abnormal trafficking of white blood cells and play a role in disease process.

"Through TAP, LLS is committed to advancing the development of promising investigational therapies that we believe have potential to improve standards of care for patients, especially in disease areas with high unmet medical need, such as Waldenström’s macroglobulinemia," said Dr. Greenberger. "Mavorixafor has demonstrated early promise in other disease areas with CXCR4 mutations, including solid tumors, and its potential application among CXCR4-mutant WM patients makes it an excellent fit and an important asset within our program as we work with innovative companies like X4 to uncover and develop cutting-edge therapies for patients with blood cancers."

About Waldenström’s Macroglobulinemia
Waldenström’s macroglobulinemia (WM) is a rare form of non-Hodgkin lymphoma and B-cell lymphoproliferative disorder. According to the American Cancer Society, approximately three per one million people are diagnosed each year, including 1,400 new cases in the United States annually. Recent advancements in whole-genome sequencing have identified genetic mutations in the disease similar to WHIM syndrome, a rare congenital primary immunodeficiency characterized by warts, hypogammaglobulinemia, infection and myelokathexis. Approximately 30 to 40 percent of WM cases express mutations in the CXCR4 gene in the cancer cells. In WM, somatic mutations of CXCR4 are associated with active tumor cells and possible drug resistance, including resistance to anti-CD20 monoclonal antibodies and Burton tyrosine kinase (BTK) inhibitors, such as ibrutinib, the current standard of care. WM patients with this somatic mutation have a dramatically reduced median progression-free survival, or mPFS, of approximately two years, whereas patients without the mutation have a mPFS of well over five years.

About the Therapy Acceleration Program
The Leukemia & Lymphoma Society’s Therapy Acceleration Program (TAP) identifies and funds innovative projects related to therapies, supportive care or diagnostics that have the potential to change the standard of care for patients with blood cancer, especially in areas of high unmet medical need. TAP funding assists both clinical investigators and companies in gaining critical clinical proof of concept data that better enables them to obtain the resources they need or a partner to complete the testing, registration and marketing of new treatments, supportive care and diagnostics for leukemia, lymphoma and myeloma. TAP funding is different from the traditional grant at LLS. The TAP review process is separate from the grant process and LLS’s TAP staff play an active advisory role and closely monitor each approved project. To learn more about how TAP works, please click here.

On May 15, 2019 Bayer reported findings from new analyses and data for Vitrakvi (larotrectinib), which is approved for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic tropomyosin receptor kinase (NTRK) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment (Press release, Bayer, MAY 15, 2019, View Source [SID1234536366]).5 This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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In the analysis of children with TRK fusion cancer, there was an ORR of 94% as per investigator assessment using RECIST 1.1, with median DOR not reached at the time of data cut-off of July 30, 2018. In the analysis of adult patients with TRK fusion cancer, a response rate of 68% as per independent assessment and 76% as per investigator assessment was seen using RECIST 1.1, and with median follow up of 17.5 and 17.2 months, respectively, the median DOR had not been reached at time of data cut-off (July 30, 2018). New data on patients with primary central nervous system (CNS) tumors of various histologies or brain metastases will be presented as part of an oral presentation. An analysis on quality of life (QoL) with Vitrakvi treatment was also conducted in both children and adults with TRK fusion cancer. Adverse events seen with the new data for adults and children were mostly grade 1-2.1,2,3,4 The full data from these analyses will be presented at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019, taking place in Chicago, Illinois from May 31 – June 4, 2019.

"These data further confirm the efficacy and safety of larotrectinib in patients with TRK fusion cancer, regardless of tumor type and age, including those who present with brain metastases or primary CNS tumors," said Douglas S. Hawkins, M.D., hematology/oncology division chief at Seattle Children’s Hospital and professor of pediatrics at the University of Washington School of Medicine. "It underscores the urgency for widespread genomic testing to identify patients."

"These latest data add to the body of evidence for larotrectinib in patients with TRK fusion cancer," said Scott Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer’s Pharmaceutical Division. "With our commitment to developing treatments like larotrectinib as well as the investigational TRK inhibitor BAY 2731954, we are demonstrating our commitment to researching and advancing the future of cancer care, while providing true value for patients and physicians."

Vitrakvi Presentations and Posters

Data from pediatric patients from the expanded dataset show an ORR of 94% (n=32/34) with Vitrakvi as per investigator assessment using RECIST 1.1, including 12 complete responses (CR), 18 confirmed partial responses (PR) and 2 PR pending confirmation.1 At the time of data cut-off (July 30, 2018), the median DOR had not been reached (range 1.6+ to 26.7+ months). (Oral Presentation 10010, Session: Pediatric Oncology II; Sunday, June 2, 8:12AM – 8:24AM (CDT), Room: S504)

Data in adult patients from the expanded dataset show an ORR of 68% as per independent assessment (n=44/65), including a 17% CR and 51% PR, and 76% by investigator assessment (n=56/74) with a 9% CR, 57% confirmed PR, and 9% PR pending confirmation.2 At the time of data cut-off (July 30, 2018), the median DOR had not been reached. (Poster Presentation 3122, Session: Developmental Therapeutics and Tumor Biology (Nonimmuno); Saturday, June 1, 8:00AM – 11:00AM (CDT), Room: Hall A)

An analysis across clinical trials of TRK fusion cancer patients with evaluable brain metastases (n=5) shows an ORR of 60% per investigator assessment using RECIST 1.1.3 Additional data will be provided in an oral presentation at ASCO (Free ASCO Whitepaper) on June 3, 2019. (Oral Presentation 2006, Session: Central Nervous System Tumors; Monday, June 3, 3:15PM – 3:27PM (CDT), Room: S102)

An evaluation on patient-reported outcomes is also being presented.4 (Poster Presentation 6602, Session: Health Services Research, Clinical Informatics, and Quality of Care; Saturday, June 1, 1:15PM – 4:15PM (CDT), Room: Hall A)

About Vitrakvi (larotrectinib)
Vitrakvi is indicated for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.5 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Research suggests that the NTRK gene can become abnormally fused to other genes, producing a TRK fusion protein that can act as an oncogenic driver, promoting cell growth and survival in tumor cell lines.5

Important Safety Information for VITRAKVI (larotrectinib)

Neurotoxicity: Among the 176 patients who received VITRAKVI, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority (65%) of neurologic adverse reactions occurred within the first three months of treatment (range 1 day to 2.2 years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria (1%), dizziness (1%), gait disturbance (1%), and paresthesia (1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modification included dizziness (3%), gait disturbance (1%), delirium (1%), memory impairment (1%), and tremor (1%).5

Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dose when resumed.5

Hepatotoxicity: Among the 176 patients who received VITRAKVI, increased transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.5

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed.5

Embryo-Fetal Toxicity: VITRAKVI can cause fetal harm when administered to a pregnant woman. Larotrectinib resulted in malformations in rats and rabbits at maternal exposures that were approximately 11- and 0.7-times, respectively, those observed at the clinical dose of 100 mg twice daily.5

Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.5

Most Common Adverse Reactions (≥20%): The most common adverse reactions (≥20%) were: increased ALT (45%), increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%).5

Drug Interactions: Avoid coadministration of VITRAKVI with strong CYP3A4 inhibitors (including grapefruit or grapefruit juice), strong CYP3A4 inducers (including St. John’s wort), or sensitive CYP3A4 substrates. If coadministration of strong CYP3A4 inhibitors or inducers cannot be avoided, modify the VITRAKVI dose as recommended. If coadministration of sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.5

Lactation: Advise women not to breastfeed during treatment with VITRAKVI and for 1 week after the final dose.5

Please see the full Prescribing Information for VITRAKVI (larotrectinib).

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein.5 The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade.5 These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless to where it originates in the body.5 TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body.5 TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).5,6

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes five marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On May 15, 2019 Heat Biologics, Inc. (Nasdaq: HTBX), a biopharmaceutical company developing therapies designed to activate a patient’s immune system against cancer, reported financial and clinical updates for the first quarter ended March 31, 2019 (Press release, Heat Biologics, MAY 15, 2019, View Source [SID1234536304]).

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Jeff Wolf, Heat’s CEO, commented, "We are making progress with our Phase 2 clinical trial investigating HS-110 for advanced non-small cell lung cancer (NSCLC) in combination with Bristol-Myers Squibb’s anti-PD-1 checkpoint inhibitor, Opdivo (nivolumab) and Merck’s KEYTRUDA (pembrolizumab). Most notably, we announced positive interim Phase 2 data at the ASCO (Free ASCO Whitepaper)/SITC Clinical Immuno-Oncology Symposium where we observed a survival benefit in patients with low CD8+ "cold" tumors compared to high CD8+ patients. The Cohort B data was especially encouraging, as the addition of HS-110 to nivolumab may restore anti-tumor activity in patients whose disease has progressed after checkpoint inhibitor therapy."

"We anticipate filing two INDs early this summer: HS-130, the first dual-acting immunotherapy designed to deliver local T-cell activation and co-stimulation, as well as PTX-35, our first-in-class T cell costimulator antibody. We recently presented a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, in which we reported efficacy in a mouse model, demonstrating that the combination of HS-110 with OX40L co-stimulation has the potential to dramatically enhance anti-tumor immune responses via the activation and expansion of CD8+, tumor antigen-specific, T effector cells. We also remain encouraged by the preliminary pre-clinical efficacy and safety data of PTX-35, which show activity with a favorable safety profile across a wide range of doses."

"We ended the quarter with approximately $23.5 million of cash, cash equivalents and short-term investments. We expect to receive an additional $6.9 million in grant funds from Cancer Prevention Research Institute of Texas (CPRIT) after filing our IND for PTX-35."

First Quarter 2019 Financial Results

Recognized $0.7 million of grant revenue for qualified expenditures under the CPRIT grant.

Research and development expenses increased to $3.2 million for the quarter ended March 31, 2019 compared to $2.9 million for the quarter ended March 31, 2018. The $0.3 million increase is due to the increased enrollment in the Phase 2 portion of our multi-arm NSCLC clinical trial, stock-based compensation, and the PTX expense as we continue pre-clinical development of the PTX-35 program.

General and administrative expenses were approximately $3.3 million for the quarter ended March 31, 2019 compared to $1.8 million for the quarter ended March 31, 2018. The $1.6 million increase is primarily attributable to increased stock-based compensation expense.

Net loss attributable to Heat Biologics was approximately $5.7 million, or ($0.17) per basic and diluted share for the quarter ended March 31, 2019 compared to a net loss of approximately $3.3 million, or ($0.71) per basic and diluted share for the quarter ended March 31, 2018.

As of March 31, 2019, the Company had approximately $23.5 million in cash, cash equivalents and short-term investments.

On May 15, 2019 ArQule, Inc. (Nasdaq: ARQL) reported that Dr. Marc Schegerin, Chief Financial Officer and Head of Strategy, will present at the 20th Annual B. Riley FBR Institutional Investor Conference on May 22, 2019 at 9:30 a.m. PT at the Beverly Hilton in Beverly Hills, CA (Press release, ArQule, MAY 15, 2019, View Source [SID1234536334]).

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The live webcast of the presentation will be available via the "Investors & Media" section of ArQule’s website, www.arqule.com, under "Events & Presentations." A replay of the webcast will be available shortly after the conclusion of the presentation.

On May 15, 2019 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported positive data from the Phase I/II STARTRK-NG study, evaluating the investigational medicine entrectinib in children and adolescents with recurrent or refractory solid tumors with and without neurotrophic tyrosine receptor kinase (NTRK), ROS1 or anaplastic lymphoma kinase (ALK) gene fusions (Press release, Genentech, MAY 15, 2019, View Source [SID1234536351]). The study showed entrectinib shrank tumors (objective response rate; ORR) in all children and adolescents who had NTRK, ROS1 or ALK fusion-positive solid tumors (11 of 11 patients), including two patients achieving a complete response. Of the 11 patients, five patients with primary high-grade tumors in the central nervous system (CNS) had an objective response, including one patient with a complete response. The safety profile of entrectinib was consistent with that seen in previous analyses. Data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Sunday, June 2, 2019, from 8:00 – 8:12 a.m. CDT (Abstract 10009), and was part of today’s official ASCO (Free ASCO Whitepaper) presscast.

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"We are encouraged by the results we have seen with entrectinib in children with pediatric and adolescent cancers, including those with tumors in the brain," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "The STARTRK-NG study underscores the importance of combining comprehensive genomic profiling with targeted therapies and supports our approach to providing people with personalized medicines developed specifically for their type of cancer."

Additional data for entrectinib across different tumor types and patient populations will also be presented at ASCO (Free ASCO Whitepaper), highlighting the company’s unique approach to personalized healthcare through advances in targeted therapies, diagnostics and data analytics:

Initial results from an integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials evaluating the efficacy of entrectinib in adults with solid tumors and CNS metastases will be presented on Saturday, June 1, 2019, in a poster session from 3:00 – 4:30 p.m. CDT (Abstract 3017).

Results from a real-world data study evaluating time-to-treatment discontinuation and progression-free survival as endpoints for comparative efficacy analysis of clinical trials of entrectinib and crizotinib for the treatment of people with ROS1-positive non-small cell lung cancer (NSCLC) will be presented during a poster session on Sunday, June 2, 2019, from 8:00 – 11:00 a.m. CDT (Abstract 9070).

The FDA recently granted Priority Review for entrectinib for both the treatment of pediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of people with metastatic ROS1-positive NSCLC. These NDAs are based on results from the integrated analysis of the Phase II STARTRK-2, Phase I STARTRK-1 and Phase I ALKA-372-001 trials, and data from the STARTRK-NG study. The FDA is expected to make a decision on approval by August 18, 2019.

About the STARTRK-NG study

STARTRK-NG is a Phase I/II open-label dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary CNS tumors, with or without NTRK, ROS1 or ALK fusions. Response, assessed by Investigator, was classified as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) using Response Assessment in Neuro-Oncology (RANO) for CNS tumors, Response Evaluation Criteria in Solid Tumors (RECIST), and Curie score (CS) for neuroblastoma. The study enrolled 29 children and adolescents aged 4.9 months through 20 years (median age of 7 years) who had recurrent or refractory solid tumors, and 28 were evaluated for response. Of the 28 children and adolescents evaluated, 11 children were identified to have tumors with NTRK, ROS1 or ALK fusions and one with ALK F1174L-mutated neuroblastoma. A summary of the results are included below.

Complete responses were observed in two patients with tumors harboring NTRK and ALK fusions: one with an NTRK fusion-positive primary CNS tumor and one with an ALK fusion-positive inflammatory myofibroblastic tumor. Another complete response was observed in one neuroblastoma patient with an ALK F1174L mutation.
Partial responses were observed in nine patients, three unconfirmed at the time of the clinical cut-off date, across NTRK, ROS1 and ALK fusion-positive primary CNS (n=4) and extracranial (n=5) solid tumors.
Median duration of therapy for confirmed fusion-positive responders was 10.51 months (3.8 to 17.7 months), and median time to response was 1.89 months (1 to 1.9 months).
The safety profile of entrectinib was consistent with that seen in previous analyses. Treatment-related adverse events were most frequently National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or 2, leading to discontinuation in 6.9 percent of patients.

About NTRK fusion-positive cancer

Neurotrophic tyrosine receptor kinase (NTRK) fusion-positive cancer occurs when the NTRK1/2/3 genes fuse with other genes, resulting in altered TRK proteins (TRKA/TRKB/TRKC) that can activate signaling pathways involved in proliferation of certain types of cancer. NTRK gene fusions are tumor-agnostic, meaning they are present in tumors irrespective of site of origin. These fusions have been identified in a broad range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

About entrectinib

Entrectinib (RXDX-101) is an investigational, oral medicine in development for the treatment of locally advanced or metastatic solid tumors that harbor NTRK1/2/3 or ROS1 gene fusions. It is a selective tyrosine kinase inhibitor designed to inhibit the kinase activity of the TRK A/B/C and ROS1 proteins, whose activating fusions drive proliferation in certain types of cancer. Entrectinib can block ROS1 and NTRK kinase activity and may result in the death of cancer cells with ROS1 or NTRK gene fusions. Entrectinib is being investigated across a range of solid tumor types, including breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.