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Loxo Oncology Announces First Patient Enrolled in LOXO-101 Phase 2 Basket Trial in Patients With Solid Tumors Harboring TRK Fusions

On October 14, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported the enrollment of the first patient in its Phase 2 basket trial of LOXO-101 in adult cancer patients whose tumors harbor tropomyosin receptor kinase (TRK) fusions (Press release, Loxo Oncology, OCT 14, 2015, View Source [SID:1234507715]). A basket trial is a new clinical trial design that enrolls patients based on a common, defining genetic feature of their cancer, rather than based on an anatomic definition. LOXO-101 is the only selective TRK inhibitor in clinical development.

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"The emergence of highly selective cancer therapies designed to fully exploit the genetic drivers of disease represents an important shift in oncology, one that demands new trial designs and cooperation among clinical investigators and molecular testing labs," said David Hyman, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center and the global principal investigator for the Phase 2 trial. "Results from the ongoing Phase 1 trial of LOXO-101 suggest that it is a very selective drug, which we believe will allow it to maximally inhibit TRK signaling. I believe the Phase 2 trial we have launched will provide important data to further substantiate the role of TRK fusion biology across solid tumors."

"We are proud to have advanced LOXO-101 from a preclinical package to a Phase 2 clinical trial so quickly," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "I am grateful to our Phase 1 investigators who have positioned us so well for this milestone, and I am glad they will have the opportunity to share their work publicly next month in Boston. As we move forward, we are excited to work with leading medical centers, as well as their favored molecular testing partners, who understand the value of genetic testing in the care of patients with cancer."

LOXO-101 Phase 2 Basket Trial in Patients with Solid Tumors Harboring TRK Fusions

The Phase 2 clinical trial is a global, multi-center, single-arm, open-label basket trial in adult patients with solid tumors that harbor a TRK fusion, as determined by any Clinical Laboratory Improvement Amendments (CLIA) certified or equivalently-accredited test, the choice of which will be guided by the treating physician’s routine clinical laboratory practice. Loxo Oncology plans to open 20-30 clinical sites worldwide.

LOXO-101 is administered orally as a single agent at 100 mg twice-daily continuously in 28-day cycles. This dose has been shown to achieve systemic drug exposures anticipated to inhibit TRK signaling by over 90%. The primary endpoint of the trial is the overall response rate (ORR) to LOXO-101, as measured by the proportion of subjects with best overall confirmed response of complete response or partial response by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate. Secondary endpoints include duration of response, the proportion of subjects that have any tumor regression as a best response, progression-free survival, overall survival, safety and tolerability.

As a basket trial, the Phase 2 trial will enroll patients with diverse tumor types but common genetic features. Patients may still be analyzed statistically by anatomic subgroups that are prospectively defined (e.g. non-small cell lung cancer, thyroid cancer, etc.), but all patients share common genetic features, in this case TRK fusions. The LOXO-101 Phase 2 basket trial will enroll patients with TRK fusions into one of eight cohorts: non-small cell lung cancer, thyroid cancer, sarcoma, colorectal cancer, salivary gland cancer, biliary cancer, primary central nervous system tumors and all other solid tumor histologies. Available scientific evidence suggests that TRK fusions behave similarly across tumor types, but this approach allows for independent statistical analyses of each cohort for the purposes of evaluating efficacy or futility. The total size of the trial is not expected to exceed approximately 150 patients. In order to meet the criteria for enrollment, patients must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy. Loxo Oncology has plans in place to collaborate with the clinical, laboratory, and molecular pathology communities in both academia and industry to ensure that that TRK fusion patients and their treating physicians are alerted to the LOXO-101 Phase 2 clinical trial, integrating trial recruitment into routine clinical practice.

The Phase 1 trial will remain open, as it may contribute to a deeper pharmacokinetic understanding of the 100 mg twice-daily dose, as well as provide an open protocol for the study of TRK biology outside of gene fusions, such as TRK mutations, amplifications and overexpression.

For additional information about both the Phase 1 and Phase 2 trials of LOXO-101, please refer to www.clinicaltrials.gov.

Phase 1 Trial Update at AACR (Free AACR Whitepaper)-NCI-EORTC Meeting

New data from the Phase 1 study of LOXO-101 has been accepted for an oral, late-breaking presentation at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) on November 8, 2015 in Boston. Abstracts will be available online on October 26, 2015.

About LOXO-101

LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions. For additional information about both the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

Innate Pharma receives development milestone payment from Bristol-Myers Squibb

On October 14, 2015 Innate Pharma SA (the "Company" – Euronext Paris: FR0010331421 – IPH) reported that it has received a US$5 million milestone payment from Bristol-Myers Squibb as part of the lirilumab licencing agreement (Press release, Innate Pharma, OCT 14, 2015, View Source [SID:1234507714]).

This payment was triggered by the dosing of a first patient in a Phase II trial of lirilumab in combination with rituximab in patients with relapsed/ refractory or high-risk untreated Chronic Lymphocytic Leukemia.

Hervé Brailly, CEO and co-founder of Innate Pharma, said: "This milestone marks the start of a new Phase II trial of lirilumab in hemato-oncology outside of Acute Meloid Leukemia. We are pleased with the broad clinical program for lirilumab, and expect that results will begin to be delivered in 2016".

In total, 6 trials are currently being performed with lirilumab, testing a range of solid and hematological cancer indications, multiple rationales and combinations with cytotoxic antibodies, checkpoint inhibitors and chemotherapy.

MacroGenics Highlights Progress at 2015 R&D Day

On October 13, 2015 MacroGenics, Inc. (NASDAQ:MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, as well as autoimmune disorders and infectious diseases, reported that it held its first R&D Day and provided an in-depth review of the Company’s broad portfolio of product candidates and technology platforms (Press release, MacroGenics, OCT 13, 2015, View Source [SID:1234507712]). Special guest speakers included Charles Drake, M.D., Ph.D., Professor of Oncology, Urology and Immunology, Johns Hopkins School of Medicine, and Holbrook Kohrt, M.D., Ph.D., Assistant Professor of Medicine (Oncology) at Stanford University Medical Center.

"The team at MacroGenics continues to make significant advances in realizing our mission to create breakthrough biologics and life-changing medicines," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "Our growing and advancing pipeline now includes eight product candidates in clinical development across a wide range of indications in solid and hematological malignancies, as well as autoimmune disorders. Today’s R&D Day allowed us to provide an update on our Fc-optimized antibodies, margetuximab and enoblituzumab, our five DART molecules in the clinic, additional programs that we have not previously disclosed and the evolution of our multi-specific targeting platforms."

Program Updates and Highlights:

Margetuximab. MacroGenics today provided details about its ongoing SOPHIA Phase 3 clinical study of margetuximab, the company’s Fc-optimized, HER2-directed monoclonal antibody in patients with metastatic breast cancer. The Company also highlighted activity of margetuximab as single agent in patients with gastric cancer from its recently completed Phase 1 study, and a planned Phase 1b/2 study evaluating the combination of margetuximab with an anti-PD-1 antibody.

B7-H3 Franchise. MacroGenics highlighted its industry-leading franchise related to therapeutic targeting of B7-H3, a member of the B7 family of molecules involved in immune regulation. The Company is developing three product candidates that engage this target through complementary mechanisms of action and take advantage of this target’s broad expression pattern in multiple solid tumors.

Enoblituzumab (MGA271). The Company provided an overview of initial data from its ongoing Phase 1 monotherapy clinical study of enoblituzumab, an Fc-optimized monoclonal antibody. To date, enoblituzumab has been well tolerated in patients and has shown encouraging, initial single-agent activity, including tumor regression in multiple, heavily pre-treated patients. In addition, evidence of T-cell immunomodulatory function has been observed in patients treated with enoblituzumab. The Company continues to enroll patients in additional monotherapy Phase 1 study cohorts as well as in two combination studies with either ipilimumab or pembrolizumab. Data from the ongoing monotherapy study will be presented in a late-breaking abstract session at the 2015 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting on November 7, 2015.

MGD009. MacroGenics disclosed that MGD009, a Dual-Affinity Re-Targeting (DART) molecule targeting B7-H3 and CD3, has entered into a Phase 1 study in patients and is being evaluated across multiple solid tumor types. MGD009 is designed to target tumors expressing B7-H3 as well as recruit and expand T cells at the tumor site. MacroGenics retains worldwide development and commercialization rights to MGD009.

B7-H3 Antibody-Drug Conjugate. MacroGenics also presented pre-clinical data on an antibody-drug conjugate (ADC) program targeting B7-H3. The Company is evaluating several toxin/linker combinations to induce direct killing of B7-H3-positive tumor cells.

DART Platform. MacroGenics provided an overview of the advantages and versatility of its DART platform for bispecific targeting. The Company also provided a summary of the five DART molecules currently in clinical development, including MGD006 (CD123 x CD3), MGD007 (gpA33 x CD3), MGD011 (CD19 x CD3), MGD010 (CD32B x CD79B) and MGD009 (B7-H3 x CD3). In addition, the Company disclosed for the first time two DART molecules that it expects to advance into clinical development in the first half of 2017. These two product candidates include the following:

MGD013. MacroGenics is developing MGD013 to provide co-blockade of two immune checkpoint molecules co-expressed on T cells, PD-1 and LAG-3, for treatment of diseases spanning a wide range of solid tumors and hematological malignancies. The Company presented pre-clinical data on an Fc-bearing DART molecule directed against these targets. In addition to MGD013, MacroGenics is generating and evaluating multiple other candidates that target a range of immune regulators using its DART and Trident platforms.
MGD014. MacroGenics presented pre-clinical data on MGD014, an Fc-bearing DART molecule that targets HIV-infected cells and CD3. MGD014 is being developed to eliminate latent HIV infection in patients treated with continuous anti-retroviral therapy (cART) alone or in combination with latency-reversing agents. MGD014 will be developed under a contract recently awarded by the National Institute of Allergy and Infectious Diseases for up to $24.5 million. This is the first infectious disease DART program planned for clinical testing.

Trident Platform

MacroGenics presented its Trident tri-specific platform, extending the Company’s leadership position in multi-specific antibody-based targeting. Trident molecules have an antibody-like structure with three specificities that enable novel mechanisms of action by recognizing up to three separate antigens in different, customizable conformations.

Pfizer and the Union for International Cancer Control Award 20 Grants Totaling $760,000 to Address the Needs of Metastatic Breast Cancer Patients Worldwide

On October 13, 2015 Pfizer reported that this Breast Cancer Awareness Month, it and the Union for International Cancer Control (UICC) are proud to announce the recipients from the Seeding Progress and Resources for theCancer Community: Metastatic Breast Cancer Challenge (SPARC MBC Challenge), a first-of-its-kind initiative to address the unique challenges facing women with metastatic breast cancer worldwide (Press release, Pfizer, OCT 13, 2015, View Source [SID:1234507711]). In total, 20 organizations from 18 countries have been selected to receive grants amounting to $760,000 (USD) in funding provided by Pfizer.

Launched on World Cancer Day in February 2015, the SPARC MBC Challenge received significant interest with over 80 applications submitted by organizations in 46 countries, reflecting the urgent need for improved services and support for women with metastatic breast cancer. Due to this high level of interest, Pfizer increased its funding of the initiative from $500,000 (USD) to $760,000 (USD) to support additional projects.

The SPARC MBC Challenge aims to empower advocacy groups, hospital networks, support groups and other organizations worldwide as they initiate projects to close the gap in information, support, awareness and policy between metastatic breast cancer and early disease, as well as help reduce the number of women diagnosed at the metastatic stage of breast cancer.

"Globally, there are wide disparities in the diagnosis, management and care of metastatic breast cancer, a disease that is clinically complex, emotionally burdensome and socially misunderstood," said Professor Sanchia Aranda, president-elect, UICC. "We are hopeful this program will help us to fulfill our mission of promoting greater equity in access to comprehensive breast cancer services, and we are thrilled with the community’s response to the SPARC MBC Challenge and the number of applications submitted to support projects that can greatly impact the lives of women living with this diagnosis."

Awardees were selected through a competitive application process overseen by an external, multidisciplinary selection committee formed by UICC and chaired by Dr. Fatima Cardoso, director of the Breast Unit of the Champalimaud Cancer Center in Lisbon, Portugal.

Each awardee will receive either a campaign grant ($20,000 USD) or a network grant ($60,000 USD). These grants will be used to fund projects in support of women with metastatic breast cancer worldwide, including projects in low-income countries, such as Uganda and Haiti, where women are frequently diagnosed at a more advanced stage of breast cancer than women in developed nations.1,2

"Our partnership with UICC on this initiative represents our commitment to the hundreds of thousands of women worldwide who are living with metastatic breast cancer," said Liz Barrett, global president and general manager, Pfizer Oncology. "This initiative helps bring us one step closer to the day when metastatic breast cancer patients around the world may have access to the care and support they need, regardless of their location or socio-economic status."

"One particularly valuable component of the SPARC MBC Challenge is that it will also provide mentorship support to the awardees and enable networking and sharing of best practices among the organizations," said Professor Aranda. "We look forward to following the progress and results of all awarded projects that were selected to address the challenges facing the MBC community globally."

Among the awardees is Associação Mama Help, an organization based in Portugal that will be creating an online resource center in the Portuguese language to provide information and support to women living with metastatic breast cancer. Additionally, Uganda Women’s Cancer Support Organisation (UWOCAO), will implement a project in partnership with the Uganda Cancer Institute to identify the challenges faced by women with advanced breast cancer in Uganda and help increase awareness of their unique needs among advocates, caregivers and policymakers. Based on this understanding, the organization will seek to develop new tools, services and policies to address their needs and to ultimately help increase access to supportive care and improve quality of life for women with metastatic breast cancer.

New Study Published in Cell Reports Highlights Indoximod, Demonstrates the Key Role of IDO in Both Local and Systemic Immunosuppression

On October 13, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of developing and commercializing novel immuno-oncology product candidates to improve the lives of patients with cancer, reported that a peer-reviewed article in Cell Reports offers new insight demonstrating that the tumor indoleamine 2,3-dioxygenase (IDO) pathway is a central regulator of both local and systemic immunosuppression and resistance to immunotherapy in melanoma (Press release, NewLink Genetics, OCT 13, 2015, View Source [SID:1234507710]).

The paper also reports that indoximod, NewLink Genetics’ wholly owned IDO pathway inhibitor, reversed tumor-associated immunosuppression in pre-clinical melanoma models and that there is a "strong rationale" for therapeutic targeting of IDO as one of the central regulators of immune suppression. The paper, titled Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner and authored by Rikke B. Holmgaard, Dmitriy Zamarin, Yanyun Li, Billel Gasmi, David H. Munn, James P. Allison, Taha Merghoub, and Jedd D. Wolchok, was published on line and appears today in the October 13, 2015 issue of Cell Reports.

Rikke B. Holmgaard, Ph.D., lead author of the paper and Research Associate, Memorial Sloan Kettering Cancer Center, said, "We learned that IDO mediates local and systemic immune suppression in murine tumor models by means of other immunosuppressive cells, such as MDSCs and Tregs, and by upregulating other immunosuppressive mechanisms mediated by MDSCs, such as arginase 1, iNOS, and immunosuppressive cytokines. In so doing, IDO makes tumors grow faster and become less responsive to immune checkpoint therapy, such as PD1/CTLA4. Thus, adding IDO inhibition may be one of the key elements of combination therapies for strong, durable anti-tumor responses."

Jedd D. Wolchok, M.D., Ph.D., Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, Associate Professor of Immunology and Microbial Pathogenesis at Weill Cornell Medical College, and co-author of the article, added, "This data further demonstrate IDO as one of the key immune checkpoint targets and show that indoximod can block the expansion of suppressive myeloid cells and recruitment of MDSCs to the tumor microenvironment that mediate local immune suppression. It prevents activation of Tregs that mediate systemic immune suppression in a mouse model and enhances the antitumor activity of combination anti-CTLA4 and anti-PD1."

David H. Munn, M.D., Professor of Pediatric Hematology and Oncology at Georgia Regents University and co-author of the article in Cell Reports, added, "This research not only sheds additional light on the mechanism of IDO expression in tumors but also shows how indoximod can enhance anti-tumor responses when combined with other checkpoint inhibitors."

"This important work, both in animal studies and in analyses of human melanoma samples, by leading scientists in immuno-oncology validates our view of the central role IDO inhibition and indoximod may play in tumor immunosuppression," said Charles Link, M.D., CEO and Chief Scientific Officer of NewLink Genetics. "It also points to the potential for IDO inhibitors like indoximod to overcome that immunosuppression and enhance anti-tumor responses."

Indoximod is in Phase 2 clinical trials for breast cancer, prostate cancer, melanoma and glioblastoma multiforme as well as in Phase 1b/2 clinical trials for pancreatic cancer.

The authors’ analysis of tumor samples from 36 melanoma patients found that myeloid-derived suppressor cells (MDSCs) were increased in IDO+ tumors. This suggests that IDO recruits and activates such cells through activation of regulatory T cells (Tregs). The authors found greater tumor growth, as well as resistance to immune checkpoint blockade, in the tumors overexpressing IDO. Treatment of the mice bearing tumors overexpressing IDO with the IDO pathway inhibitor indoximod reversed this tumor-associated immunosuppression by decreasing the number of MDSCs and Tregs and stopping their suppressive capability.