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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.