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LYNPARZA™ approved by the US food and drug administration for the treatment of advanced ovarian cancer in patients with germline BRCA-mutations

On December 19, 2014 AstraZeneca reported that the US Food and Drug Administration (FDA) has approved LYNPARZA (olaparib) capsules (400mg twice daily) as the first monotherapy for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer, who have been treated with three or more prior lines of chemotherapy (Press release, AstraZeneca, DEC 18, 2014, View Source;lynparza-approved [SID:1234502431]). Olaparib has been approved under the FDA’s Accelerated Approval programme, based on existing objective response rate and duration of response data. Continued approval for this indication is contingent upon verification of clinical benefit in ongoing confirmatory Phase III trials.

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Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. It is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, as detected by an FDA approved companion diagnostic test, BRACAnalysis CDx.

Dr. Briggs Morrison, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said "LYNPARZA is an excellent example of how advances in the understanding of cancer biology can be used to develop the next generation of targeted medicines. It is a much-needed new therapeutic option for patients with germline BRCA-mutated advanced ovarian cancer. Today’s approval also marks the first of what we hope will be a number of indications in which this medicine has the potential to improve the lives of cancer patients."

AstraZeneca filed a US regulatory submission for olaparib in February 2014, based on data from a Phase II maintenance study1 of olaparib compared to placebo in platinum-sensitive relapsed high grade serous ovarian cancer patients. Following the FDA Oncologic Drugs Advisory Committee recommendation on 25 June 2014 and in response to an FDA request for additional data, AstraZeneca submitted a major amendment to the olaparib New Drug Application on 24 July 2014. The FDA approval is therefore based on efficacy data from a single-arm, open-label, Phase II study2 of olaparib in patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers, as well as safety data from several other olaparib studies, including the placebo-controlled study.

The efficacy of olaparib is based on analysis of 137 patients with measurable, germline BRCA mutated advanced ovarian cancer treated with three or more prior lines of chemotherapy. The trial results demonstrated an overall response rate of 34% (95% Confidence Interval: 26%, 42%). The median response duration was 7.9 months (95% Confidence Interval: 5.6, 9.6 months). The most common adverse events associated with olaparib monotherapy to date have been generally mild to moderate and have included nausea, vomiting, fatigue and anaemia.

Dr. Ursula Matulonis, Associate Professor of Medicine, Harvard Medical School and Director of the Gynaecological Oncology Programme at the Dana-Farber Cancer Institute, Boston said: "Ovarian cancer is diagnosed in nearly 22,000 women per year. The long-term survival rate in patients with advanced ovarian cancer is 10% to 30%. The FDA approval of LYNPARZA is a significant milestone for our patients as currently there are only limited treatment options available to women with ovarian cancer who carry the BRCA mutation."

A full review of data from either of two ongoing studies under the SOLO Phase III clinical programme will be required for the accelerated approval of olaparib in BRCA-mutated advanced ovarian cancer to be converted to a full approval: SOLO2 is evaluating olaparib compared to placebo as a maintenance therapy and SOLO3 is evaluating olaparib compared to standard chemotherapy for relapsed disease. Data from the SOLO2 study is expected in 2015 and data from SOLO3 is expected in 2019.

The FDA’s approval follows the announcement on 18 December of the approval of olaparib in the European Union, as the first therapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated serous ovarian cancer.

1 Ledermann J et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncology. 2014. View Source(14)70228-1

2 Kaufman B, Shapira-Frommer R, Schmultzler RK et al. Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation. Journal of Clinical Oncology 2014. View Source

Anti-Cancer Agent “Xeloda®” Application for Approval of Additional Indication of “Postoperative Adjuvant Chemotherapy for Gastric Cancer”

On December 19, 2014 Chugai Pharmaceutical reported that it filed an application with the Japanese Ministry of Health, Labour and Welfare (hereafter, MHLW) for the approval of an additional indication of "postoperative adjuvant chemotherapy for gastric cancer," for the anti-cancer agent, capecitabine (brand name: Xeloda Tablet 300) (hereafter, "Xeloda) (Press release Chugai, DEC 19, 2014, View Source [SID:1234501214]). In Japan, Xeloda is currently marketed for these indications of "inoperable or recurrent breast cancer," "postoperative adjuvant chemotherapy for colon cancer," "advanced or refractory colorectal cancer, which is not amenable to curative resection" and "advanced or recurrent gastric cancer, which is not amenable to curative resection."

Chugai filed an application for approval with the MHLW based on the results of two studies: One is a Phase III study MO17527/L9570 (The CLASSIC study) conducted in foreign countries. Another is a Japanese Phase II study (MO28223/LOHP-PII-06) that was co-developed by Chugai and Yakult Honsha Co., Ltd. (Main Office: Minato-ku, Tokyo. President COO: Takashige Negishi).
In The CLASSIC study, patients were randomized to receive either combination therapy of Xeloda and oxaliplatin after curative gastrectomy (combination group) or surgery alone with follow-up (follow-up group). Disease-free survival (DFS) was evaluated as the primary endpoint.
As a result, the 3-year DFS rate was 74% in the combination group and 59% in the follow-up group, demonstrating statistically significant prolongation of DFS in the combination group (hazard ratio: 0.56, 95% confidence interval: 0.44 to 0.72, P<0.0001). Also, for overall survival, a secondary endpoint, 5-year survival was 78% in the combination group and 69% in the follow-up group, showing significant prolongation in the combination group (hazard ratio: 0.66, 95% confidence interval: 0.51 to 0.85, P=0.0015). The safety profile shown in the combination group was the same as those which have been reported for the two drugs.
The Japanese Phase II study investigated dose intensity (DI: cumulative dose of each drug actually administered / cumulative dose when 8 cycles were completed without treatment interruption or dose reduction) of Xeloda and oxaliplatin combination therapy as the primary endpoint. The results of the Japanese Phase II study will be presented at academic conferences and through other means.

Xeloda was developed by Nippon Roche K.K. (currently Chugai) and approved in 1998 for the first time in the US, Switzerland and Canada, in 2001 in the EU and has been approved in more than 100 countries worldwide. It has been authorized for the indication of "gastric cancer" in more than 95 countries.

Gastric cancer is prevalent in Asian countries including Japan, South Korea and China as well as in South America. In Japan, the number of patients newly diagnosed with gastric cancer continues to rise each year and is estimated to become, on annual average, approximately 133,900 during 2010-2014.

Chugai strongly believes that Xeloda will make a contribution to patients as a treatment option for "postoperative adjuvant chemotherapy for gastric cancer." In order Xeloda to be accessible for patients and healthcare professionals sooner, Chugai will continue its effort to receive an approval as soon as possible.

Seattle Genetics Initiates Phase 1b Trial of SGN-CD33A in Combination with Frontline Standard of Care and as Consolidation Therapy for Acute Myeloid Leukemia

On December 18, 2014 Seattle Genetics reported the initiation of a phase 1b clinical trial of SGN-CD33A in combination with standard of care chemotherapy, including cytarabine and daunorubicin, for patients with newly diagnosed acute myeloid leukemia (AML) (Press release Seattle Genetics, DEC 18, 2014, View Source;p=RssLanding&cat=news&id=2000668 [SID:1234501213]). The trial will also evaluate SGN-CD33A in the consolidation setting for AML, both in combination with cytarabine and as a single-agent maintenance regimen. SGN-CD33A is a novel antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology. CD33 is expressed on most AML cells regardless of subtype, cytogenetic abnormality or underlying mutational heterogeneity. SGN-CD33A is also under evaluation in an ongoing phase 1 dose escalation trial as a single-agent or in combination with hypomethylating agents for the treatment of patients who have relapsed AML or have declined intensive frontline therapy.

"There have been few therapeutic advances for the treatment of AML in the past three decades, and there is a significant need to identify more efficacious treatment options that result in durable remissions for patients," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We are encouraged by the single-agent activity of SGN-CD33A in AML patients from our ongoing phase 1 trial, as well as the preclinical data in AML models supporting combination regimens, both of which were recently presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Based on these data, we are expanding the evaluation of SGN-CD33A to include combination with standard of care chemotherapy in frontline and consolidation AML settings."

The study is a phase 1b, open-label, multi-center, dose-escalation clinical trial designed to evaluate SGN-CD33A administered in combination with frontline standard of care regimens for induction (cytarabine and daunorubicin) and/or consolidation (cytarabine). In addition, the study will evaluate single-agent SGN-CD33A as a maintenance regimen. The primary endpoints are determination of the maximum tolerated dose and safety profile of SGN-CD33A in these settings. In addition, the trial will evaluate anti-leukemic activity, pharmacokinetics, progression-free survival and overall survival. The phase 1b trial will enroll approximately 90 patients at multiple centers in the United States.

Clinical data from an ongoing phase 1 trial of SGN-CD33A in AML were presented in an oral session at the 2014 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #623). In this dose-escalation study, 56 patients had been enrolled. Patients were primarily older (median age 75 years) with relapsed AML, predominantly with intermediate or adverse cytogenetic risk and 55 percent had underlying myelodysplasia. Single-agent SGN-CD33A induced bone marrow blast clearance in 44 percent of evaluable patients treated across all dose levels, including 21 percent with a complete remission or complete remission with incomplete recovery (CR/CRi). A dose-response relationship is evolving, with 77 percent of patients treated at doses greater than or equal to 40 micrograms per kilogram achieving at least 50 percent blast reduction. Adverse events were generally manageable and associated with underlying myelosuppression.

ADCs are monoclonal antibodies that are designed to selectively deliver cell-killing agents to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

SGN-CD33A is comprised of three parts: A cysteine-engineered anti-CD33 antibody enabling uniform site-specific conjugation, a cleavable dipeptide linker that is highly stable in circulation, and a pyrrolobenzodiazepine (PBD) dimer that binds DNA with high intrinsic affinity. PBD dimers are a class of DNA-crosslinking agents significantly more potent than systemic chemotherapeutic drugs. Seattle Genetics has selected and optimized specific PBD molecules for its proprietary use in ADCs. In addition, SGN-CD33A employs a novel linker system and proprietary, site-specific conjugation technology (EC-mAb) that allows uniform drug-loading of the cell-killing PBD dimer to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its cytotoxic agent upon internalization into CD33-expressing cells.

For more information about the trial, including enrolling centers, please visit www.clinicaltrials.gov.

Inovio Pharmaceuticals Initiates DNA Immunotherapy Trial for Breast, Lung and Pancreatic Cancers

On December 18, 2014 Inovio Pharmaceuticals reported that it has initiated a phase I trial of its hTERT DNA immunotherapy (INO-1400) alone or in combination with Inovio’s IL-12 immune activator (INO-9012) in adults with breast, lung, or pancreatic cancer at high risk of relapse after surgery and other cancer treatments (Press release Inovio, DEC 18, 2014, View Source [SID:1234501211]). Because high levels of hTERT (human telomerase reverse transcriptase) expression are found in 85% of human cancers, Inovio’s cancer candidate holds the potential as a broad spectrum cancer therapeutic.

A previously published study of this product showed that administration in monkeys, whose TERT is 96% similar to human TERT, generated strong and broad TERT-specific immune responses and demonstrated the potential to eliminate tumor cells. Mice immunized with Inovio’s DNA immunotherapy experienced delayed tumor growth, tumor shrinkage, and longer overall survival compared with non-immunized mice.

This human trial is an open label, dose escalation study in subjects with breast, lung, or pancreatic cancer at high risk of relapse after surgery and other treatments including chemotherapy and radiation. Approximately 54 subjects will be enrolled into one of six treatment groups and receive INO-1400 alone or in combination with INO-9012, Inovio’s immune activator. The study will be conducted at the University of Pennsylvania’s Abramson Cancer Center, which will fund all site-specific clinical study costs.

Lung, breast, and pancreatic cancer mortality rates are ranked first, third, and fourth, respectively, among cancer types in the United States, despite improvement in detection and treatment. In each of these three cancer types, significant numbers of patients undergo surgical resection and adjuvant therapy with an attempt at cure, but only a fraction remain in remission. This study will evaluate Inovio’s novel immunotherapy with the ultimate goal of reducing the risk of relapse in these patients.

Robert Vonderheide, MD, DPhil, said, "The next great wave of oncology advancements will be treatments which empower the patient’s own immune system to seek and destroy cancer. In this study we will evaluate a new immunotherapy targeting the hTERT gene found in numerous cancers." Dr. Vonderheide is Professor of Medicine; Hanna Wise Professor in Cancer Research; Associate Director for Translational Research, Abramson Cancer Center; Vice Chief for Research, Hematology-Oncology Division, Department of Medicine.

Dr. J. Joseph Kim, President and CEO, said, "We are enthusiastic about the potential use of INO-1400 cancer immunotherapy in multiple major cancers, given that hTERT is expressed in the vast majority of cancer types yet is rare in normal cells. INO-1400 therapy adds to Inovio’s growing oncology franchise led by our phase III candidate, VGX-3100, for treating HPV-related pre-cancers and cancers."

The primary objective of this study is to evaluate the safety and tolerability of INO-1400 alone or in combination with INO-9012, delivered intramuscularly in subjects with high-risk breast, lung, or pancreatic cancer with no evidence of disease after surgery and adjuvant therapy. The secondary objectives are to evaluate cellular and humoral immune responses, measure time to disease progression, and evaluate immunotherapy-induced changes in subjects.

Approval for Additional Indication for Chemotherapy-Native CCR4-positive ATL of Mogamulizumab

On December 18, 2014 Kyowa Hakko Kirin Co, Ltd. (Tokyo: 4151, President and CEO: Nobuo Hanai, "Kyowa Hakko Kirin") reported that it has received approval for additional indication for chemotherapy-native CCR4-positive adult T-cell leukemia-lymphoma (ATL) of Mogamulizumab (brand name: POTELIGEO Injection 20 mg) from Japan’s Ministry of Health, Labour and Welfare ("MHLW") (Press release Kyowa Hakko Kirin, DEC 18, 2014, View Source [SID1234501205]).

Mogamulizumab was launched in Japan with the brand name "POTELIGEO Injection 20 mg" on May 29, 2012 for the treatment of patients with relapsed or refractory CCR4-positive ATL. On March 17, 2014, Kyowa Hakko Kirin has received approval for additional indication for relapsed or refractory CCR4-positive peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL).
Mogamulizumab was also granted orphan drug designations for the treatment of CCR4-positive ATL in August 2010 and PTCL/CTCL in March 2013 by the MHLW.

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.

State of Development of Mogamulizumab for Cancer conducted by Kyowa Hakko Kirin
Indication Status Applicable Locations
Relapsed or refractory CCR4-positive ATL, PTCL and CTCL Launched Japan
Chemotherapy-native CCR4-positive ATL Now approved Japan
Relapsed or refractory ATL Phase 2 trial United States, Europe, Others
Relapsed or refractory CTCL Phase 3 trial United States, Europe, Japan
Relapsed or refractory CCR4-positive PTCL Phase 2 trial Europe

About CC chemokine receptor 4 (CCR4)
CCR4 is one of the chemokine receptors involved in leukocyte migration, selectively expressed in type 2 helper T (Th2) cells and regulatory T (Treg) cells. CCR4 is also shown to be over-expressed in certain hematological malignancies.

About adult T-cell leukemia-lymphoma (ATL)
ATL is a peripheral T-cell malignancy and the retrovirus HTLV-1 is thought to be involved in its onset. Estimates show that around 1,150 new cases occur every year in Japan. In Japan ATL is generally treated with combination chemotherapy, such as mLSG15, but there are currently no therapeutic methods with the potential of providing a cure for ATL, although researchers are actively looking into other methods than transplantation. For relapsed/refractory cases, various chemotherapy regimens based on malignant lymphoma therapies are currently used, but an effective treatment method has yet to be established.

About peripheral T-cell lymphoma (PTCL)
Non-Hodgkin lymphomas account for the majority of malignant lymphoma cases and can be broadly divided into disease of B-cell origin and disease of T/natural killer (NK)-cell origin. Disease of T/NK-cell origin can be classified according to the main lesion site into nodal, extranodal, cutaneous, and leukemic disease. PTCL is a general term describing nodal and extranodal disease of T/NK-cell origin.

About cutaneous T-cell lymphoma (CTCL)
CTCL is a rare, low grade type of non-Hodgkin’s lymphoma. CTCL is one of the most common forms of T-cell lymphoma. The two most common types of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS). MF does not look the same in all patients and may present as skin patches, plaques, and tumors. SS in an advanced form of MF and includes the presence of malignant lymphocytes in the blood.

About orphan drug designation
A drug must meet the following three conditions in order to be granted an orphan drug designation in Japan.
1) The number of patients with severe disease who may use the drug is less than 50,000 in Japan.
2) There are high medical needs for the drug (There is no appropriate alternative drug/treatment, or high efficacy or safety is expected compared with existing products).
3) There is high possibility of development (There should be a theoretical rationale for the use of the drug for the target disease, and the development plan should be appropriate). For designated orphan drugs, measures to support the research and development activities are taken (The orphan drug and orphan medical device research and development promotion program by the MHLW).