On June 6, 2016 Kyowa Hakko Kirin Co., Ltd. (Tokyo; 4151 President and CEO: Nobuo Hanai; "Kyowa Hakko Kirin") reported the preliminary results today from the pivotal Phase 2 study of mogamulizumab (Code name: KW-0761) for the treatment of Adult T-cell Leukemia-Lymphoma (ATL) (Press release, Kyowa Hakko Kirin, JUN 5, 2016, View Source [SID:1234513141]).

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"We are very pleased to announce that we have completed the largest, prospective randomized clinical trial for relapsed/refractory ATL and that the preliminary results of this pivotal Phase 2 study showed potential of mogamulizumab for the treatment of relapsed/refractory ATL, where no standard of care exists" said Yoichi Sato, Managing Executive Officer, Vice President, Head of Research and Development Division of Kyowa Hakko Kirin.

Study Design
Patients from the USA, EU, and Latin America with aggressive relapsed or refractory ATL were randomized 2:1 to treatment with mogamulizumab or to 1 of 3 investigator choice (IC) regimens (Gem/Ox, DHAP or pralatrexate). Patients in the IC arm were permitted to cross-over to treatment with mogamulizumab after progression. Overall Response Rate (ORR; confirmed and unconfirmed) was assessed by the treating investigator (IA) and through blinded assessment by independent review (IR).

Study Results
71 patients were randomized (47 to mogamulizumab, 24 to IC). In the mogamulizumab treated group, unconfirmed ORR was 28% (13/47) by IR and 34% (16/47) by IA, while in the IC group, unconfirmed ORR was 8% (2/24) by IR and 0/24 by IA. Confirmed ORR (response maintained at successive evaluations approximately 8 weeks apart) for mogamulizumab was 11% by IR and 15% by IA, while there were no confirmed responses in the IC group. 18 out of 24 patients in the IC arm crossed over to mogamulizumab and 3 patients (17%) responded (1 of the responses was confirmed). The median duration of confirmed response for mogamulizumab was 5.0 months by IR and 5.5 months by IA. One patient had a response lasting more than 9 months. The frequently observed treatment-emergent, adverse events in the mogamulizumab arm included infusion reactions (46.8%), rash/drug eruption (19.1%) and infections (51.1%). The safety data collected from this study were similar to what has previously been documented.

These data from the study were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 5th, 2016.
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 Mogamulizumab
Mogamulizumab is a humanized mAb directed against CC chemokine receptor 4 (CCR4), which is frequently expressed on leukemic cells of certain hematologic malignancies including ATL. Mogamulizumab was produced using Kyowa Hakko Kirin’s proprietary POTELLIGENT platform, which is associated with enhanced antibody-dependent cellular cytotoxicity (ADCC), and was launched in Japan in May 2012 for the treatment of patients with relapsed or refractory CCR4-positive ATL under the trade name POTELIGEO. The drug was approved for indication expansion and was granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) in March 2014, and with chemotherapy-naive CCR4-positive ATL in December 2014.

About Adult T-cell Leukemia-Lymphoma (ATL)
ATL is a disease entity within the category of mature T- and NK-cell neoplasms, according to the classification by the World Health Organization. It is an extremely aggressive T lymphocytic malignancy that originates in T-cells infected with the human T-lymphotropic virus-1(HTLV-1). ATL has a very distinct epidemiology and geographic distribution, primarily involving areas of Japan, the Caribbean Basin, parts of South America, the Middle East and sub-Saharan Africa, where HTLV-1 infection is endemic. In non-endemic regions such as North America and Europe, HTLV-1 infection is mainly found in immigrants from endemic areas, their offspring or sexual contacts. Treatment regimens for ATL have not been standardized, especially in the relapsed/refractory setting, representing a large unmet medical need in this patient population.

On June 5, 2016 Johnson & Johnson reported that data from the Phase 3 MMY3004 (CASTOR) clinical trial show the immunotherapy daratumumab (DARZALEX) in combination with a standard of care therapy, bortezomib (a proteasome inhibitor [PI]) and dexamethasone (a corticosteroid), demonstrated a 61 percent reduction in the risk of disease progression or death (progression-free survival, or PFS) compared to bortezomib and dexamethasone alone in patients with multiple myeloma who received a median of two prior lines of therapy (Hazard Ratio (HR)=0.39; 95 percent CI (0.28-0.53), p<0.0001) (Press release, Johnson & Johnson, JUN 5, 2016, View Source [SID:1234513094]).1

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According to results Janssen-Cilag International NV announced today, daratumumab also significantly increased the overall response rate (ORR) [83 percent vs. 63 percent, p<0.0001]. The median PFS in the daratumumab arm has not been reached, compared with a median PFS of 7.16 months for patients who received bortezomib and dexamethasone alone.1

These data will be presented in full today at 3:10 – 3:25 p.m. CDT during the "Plenary Session: Including the Science of Oncology Award and Lecture" at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. They have also been selected for inclusion in the ASCO (Free ASCO Whitepaper) Press Programme. In addition, these results will also be featured in an encore, oral presentation at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) on Sunday 12 June at 12:00 – 12:15 p.m. CEST (Abstract #LB2236).

"We saw clinically meaningful improvements in progression-free survival and overall response rates with daratumumab when combined with standard of care," said Antonio Palumbo, M.D., Myeloma Unit Chief, Department of Oncology, Division of Haematology, University of Torino, Italy. "These compelling Phase 3 results demonstrate that a regimen built on daratumumab deepens clinical responses and help to underscore its potential for multiple myeloma patients who have been previously treated."

In addition to meeting the primary endpoint of improved PFS at a median follow-up of 7.4 months and significantly increasing the ORR compared to bortezomib and dexamethasone alone, daratumumab doubled rates of complete response (CR) or better [19 percent vs. 9 percent, p=0.0012], including doubling rates of very good partial response (VGPR) [59 percent vs. 29 percent, p<0.0001]. The median PFS has not been reached, compared with a median PFS of 7.16 months for patients who received bortezomib and dexamethasone alone. The treatment benefit of the daratumumab combination regimen was maintained across clinically relevant subgroups.1

"At Janssen we are committed to redefining the impact cancer has on patients, through delivering innovative research and solutions. We’re therefore extremely encouraged by the remarkable interim results of this study. The findings provide an important insight into the effect daratumumab can have in combination with established regimens, and illustrate the promise of this immunotherapy in earlier lines of treatment," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. "We’re dedicated to exploring the full treatment value of daratumumab for multiple myeloma patients and look forward to the difference we can make with data like these."

Overall, the safety of the daratumumab combination therapy was consistent with the known safety profile of daratumumab monotherapy (D) and bortezomib plus dexamethasone (Vd), respectively. The most common (>25 percent) adverse events (AEs) [DVd/Vd] were thrombocytopenia (59 percent/44 percent), peripheral sensory neuropathy (47 percent/38 percent), diarrhea (32 percent/22 percent) and anaemia (26 percent/31 percent). Most common grade 3 or 4 AEs (>10 percent) were thrombocytopenia (45 percent/33 percent), anaemia (14 percent/16 percent) and neutropenia (13 percent/4 percent). The rate of Grade 3/4 infections/infestations was 21 percent in the DVd group and 19 percent in the Vd group. The most common Grade 3/4 infections/infestations treatment-emergent AEs, or TEAEs (≥5 percent) was pneumonia (8 percent/10 percent). The number of patients with Grade 3 or 4 bleeding events (3 patients in DVd group, 2 patients in Vd group) was low in both treatment groups. Few (7 percent/9 percent) patients discontinued therapy due to a TEAE.1

About the MMY3004 (CASTOR) Trial

The Phase 3, multinational, open-label, randomised, multicentre, active-controlled MMY3004 study has included 498 patients with multiple myeloma who received a median of two prior lines of therapy. Sixty-six percent of patients received prior treatment with bortezomib; 76 percent received prior treatment with an immunomodulatory agent; and 48 percent received prior treatment with a PI and immunomodulatory agent. Thirty-three percent of patients were refractory to an immunomodulatory agent, and 32 percent were refractory to their last line of prior therapy. Patients were randomised to receive either daratumumab combined with subcutaneous bortezomib and dexamethasone (n=251) or bortezomib and dexamethasone alone (n=247). Participants were treated with daratumumab until disease progression, unacceptable toxicity, or if they had other reasons to discontinue the study.1

On March 30, 2016, the MMY3004 (CASTOR) trial was unblinded after meeting its primary endpoint of improved PFS in a pre-planned interim analysis (HR = 0.39, p<0.0001). Based on the recommendation of an Independent Data Monitoring Committee (IDMC), patients in the standard of care treatment arm were offered the option to receive daratumumab following confirmed disease progression.2

Janssen will initiate discussions with regulatory authorities about the potential for a regulatory submission for this indication based on the results of this study. A comprehensive clinical study report is being prepared for submission to global health authorities.

Additional Combination Data

The Phase 3 MMY3003 (POLLUX) study, comparing daratumumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with multiple myeloma who received at least one prior line of therapy, was also unblinded in May 2016. Based on the results at the pre-planned interim analysis conducted by an IDMC, the study met its primary endpoint of improved PFS.3 The POLLUX data have been selected for inclusion in the Presidential Symposium at EHA (Free EHA Whitepaper) on Friday 10 June 2016 at 4:47 p.m. CEST (Abstract #LB2238).

About Daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.4-6 Daratumumab induces rapid tumour cell death through apoptosis (programmed cell death)7,8 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).7,9,10 Daratumumab has also demonstrated immunomodulatory effects that contribute to tumour cell death via a decrease in immune suppressive cells including T-regs, B-regs and myeloid-derived suppressor cells.7,11 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed. For more information, please see www.clinicaltrials.gov.

In May 2016, daratumumab was approved by the European Commission (EC) for monotherapy of adult patients with relapsed and refractory multiple myeloma (MM), whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. Daratumumab was approved under an accelerated assessment, a process reserved for medicinal products expected to be of major public health interest, particularly from the point of view of therapeutic innovation.12

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialise daratumumab.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.13,14 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, patients progress within 60 days of their last therapy.15,16 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.17 Accounting for approximately one percent of all cancers and 15 percent to 20 percent of haematologic malignancies worldwide,18 multiple myeloma is designated as an orphan disease in both Europe and the US. Globally, it is estimated that 124,225 people were diagnosed, and 87,084 died from the disease in 2015.19,20 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone fracture or pain, low red blood counts, fatigue, calcium elevation, kidney problems or infections.14 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.21

On June 5, 2016 Tyrogenex, a privately held biopharmaceutical company, reported that data from its Phase I study of X-82, an oral dual anti-VEGFR/PDGFR tyrosine kinase inhibitor, with everolimus in solid tumors were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2016 held in Chicago, Illinois (Press release, Tyrogenex, JUN 5, 2016, View Source [SID:1234513093]).

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The data presented were from the Phase I study in which X-82 was combined with full dose everolimus in solid tumors to determine the dose limiting toxicities and recommended Phase II dose for pNET and RCC. Results were presented by Dr. Benjamin R. Tan, MD, Washington University School of Medicine, in a poster titled "Phase I study of X-82, an oral dual anti-VEGFR/PDGFR tyrosine kinase inhibitor, with everolimus in solid tumors."

"The results from this study provide critical information for moving forward with the development of X-82 in solid tumors," said Dr. Tan. "We have also seen favorable responses in renal cell carcinoma (RCC) and prolonged stable diseases (SD) in neuroendocrine tumors (NET) patients, which warrant further investigations in these tumor types. Tyrogenex continued to advances this program with the goal of providing patients suffering from a variety of solid tumors with a safe and effective treatment option."

About the Phase I Study

A 3+3 dose escalation design was utilized to determine the dose limiting toxicities and the recommended Phase II dose of daily oral X-82 plus everolimus at 10 mg PO daily for patients with solid malignancies. Key eligibility criteria included PS 0-1, measurable disease adequate organ function and normal LVEF.

Key conclusions from the study include:

Recommended Phase II dose is X-82 at 300 mg PO daily plus everolimus at 10 mg PO daily
Dose limiting toxicities include Grade 3 fatigue, mucositis and hypophosphatemia
Encouraging responses and prolonged stable disease seen in RCC and NETs
An expansion cohort for RCC and PNET are ongoing at Washington University and Vanderbilt University
About X-82

Tyrogenex’s lead compound is X-82. X-82 inhibits both VEGF and PDGFR. Tyrogenex believes X-82 targets the basic mechanisms of neovascular eye diseases, including angiogenesis, fibrosis and inflammation. X-82 is currently being evaluated for wet Age-Related Macular Degeneration (AMD) and solid tumors.

On June 5, 2016 Xcovery, a developer of targeted therapeutics for cancer, reported that results from an expansion cohort in the ongoing Phase I/II clinical study of its investigational tyrosine kinase inhibitor (TKI), ensartinib (X-396), in patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2016 held in Chicago, Illinois (Press release, Xcovery, JUN 5, 2016, View Source [SID:1234513092]).

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Results from this multicenter expansion study demonstrated that ensartinib is well-tolerated and induces response in both crizotinib-naive and crizotinib-resistant ALK-positive NSCLC patients, as well as patients with CNS disease. The results also showed that plasma NGS with the Resolution ctDxTM blood-based platform may be used to detect ALK kinase domain mutations to select patients for therapy and monitor changes in response to treatment in a non-invasive manner. Results were presented by Dr. Leora Horn, MD, MSc, Vanderbilt University Medical Center, in a poster titled "Plasma genotyping of patients in the eXalt2 trial: ensartinib+ (X-396) in ALK-positive non-small cell lung cancer (NSCLC)."

"Ensartinib has shown promising activity in ALK-positive NSCLC patients with durable responses observed in patients who are crizotinib-naïve and patients with resistance to crizotinib and second generation ALK tyrosine kinase inhibitors," said Dr. Horn. "The plasma sequencing of patients in the expansion study have identified a potential way to identify and select patients for therapy and to monitor for response and the development of acquired resistance."

About the Expansion Cohort of the Phase I/II "eXalt2" Study

In this multicenter study, 38 patients with ALK-positive (via FISH or IHC) advanced or recurrent NSCLC were treated with at least 200mg of ensartinib on 28-day cycles with plasma samples collected on the first day of each cycle. Major inclusion criteria for the expansion cohort included: ALK-positive (via FISH or IHC) advanced or recurrent NSCLC, measurable disease and ECOG performance status (PS) 0-1. Asymptomatic treated or untreated brain metastases (CNS) and leptomeningeal disease were allowed.

Key conclusions from the study include:

Ensartinib has shown promising activity in ALK-positive NSCLC patients with durable responses observed in patients who are crizotinib-naïve and patients with resistance to crizotinib and second generation ALK TKIs.
Plasma NGS can be used to detect ALK kinase domain mutations and monitor changes in response to treatment in a non-invasive manner.
In this study, ALK kinase domain mutations were detected in 4/11 patients who had prior crizotinib and 2/4 patients who had prior crizotinib and ceritinib. G1202R was found in both of the latter cases.
1/2 patients whose plasma detected the G1202R mutation prior to start of the trial responded to ensartinib.
Further study of this methodology is ongoing to correlate the presence of ALK kinase domain mutations with response and resistance to ALK TKI therapy.
A Phase III trial is ongoing comparing ensartinib to crizotinib in TKI naïve ALK-positive NSCLC patients.
About Ensartinib (X-396)

Xcovery’s lead asset is X-396, a small molecule, anaplastic lymphoma kinase (ALK) inhibitor. It is being studied in the Xalt2 Study, a phase II trial for the treatment of ALK-positive non-small cell lung cancer (NSCLC). The Xalt2 Study is currently enrolling patients. To learn more, visit: www.xalt2study.com or ClinicalTrials.gov under trial identifier NCT01625234.

About NSCLC and ALK

Lung cancer is the second most common type of cancer identified in the United States with an estimated 221,000 new diagnoses expected in 2015. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for an estimated 85-90% of the lung cancer cases. The anaplastic lymphoma kinase (ALK) gene is located on chromosome 2 and rearrangement of the ALK gene can lead to its activation or expression, therefore increasing a person’s chance of developing certain types of cancer, including NSCLC. Between three and seven percent of patients with NSCLC have the ALK rearrangement, making this a molecular target warranting investigation for NSCLC patients.

On June 5, 2016 Leap Therapeutics, a company developing immuno-oncology therapeutics, reported results of a Phase 1 clinical trial of TRX518, an aglycosylated monoclonal agonist antibody targeting glucocorticoid-induced TNFR-related (GITR) protein (Press release, Leap Therapeutics, JUN 5, 2016, View Source [SID:1234513091]). The Phase 1 trial demonstrated that a single dose of TRX518 in patients with advanced solid tumors was safe and well-tolerated. There were no autoimmune treatment-related adverse events. Saturation of TRX518 on GITR on T cells in peripheral blood was observed, and exposures demonstrating efficacy in preclinical models were safely reached. Henry Koon, M.D., of the University Hospitals, presented the data at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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"The safety and pharmacokinetic results from this clinical study have allowed us to further develop the drug in a repeat-dose study. We look forward to the exploring the activity of TRX518 as a single-agent and in combinations," commented Dr. Koon.

Leap is enrolling patients in two clinical studies in patients with advanced solid tumors to assess the safety, pharmacokinetics, pharmacodynamics, and efficacy of TRX518 when dosed at various dose levels and frequencies.

"GITR is emerging as an important target in regulating anti-tumor immune responses. Preclinical studies have shown that agonist anti-GITR antibodies can modulate inhibitory and stimulatory signals, which may potentiate anti-cancer immune responses," commented Jedd Wolchok, M.D., Ph.D., Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center and the principal investigator in Leap’s TRX518 study.

About TRX518

TRX518 is a humanized aglycosyl IgG1 monoclonal antibody with agonist activity targeting GITR. TRX518 has been shown to bind and activate GITR through bivalent binding to the receptor. TRX518 was engineered to remove Fc-receptor interactions to prevent complement-mediated cytolysis and antibody-mediated depletion of leukocytes expressing GITR. TRX518 surrogate antibodies have been effective in preclinical animal models, prolonging survival or enhancing immune responses when combined with chemotherapeutics and checkpoint inhibitors.