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DelMar Pharmaceuticals Receives Approval from China’s Human Genetic Resources Administration to Initiate Phase 2 Clinical Trial in Newly Diagnosed GBM

On July 24, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) ("DelMar" and "the Company"), a biopharmaceutical company focused on the development of new cancer therapies, reported that the Human Genetic Resources Administration of China (HGRAC), has approved the Company’s application to initiate a Phase 2 safety and efficacy study of its lead product candidate VAL-083 in newly diagnosed MGMT-unmethylated glioblastoma multiforme (GBM) (Press release, DelMar Pharmaceuticals, JUL 24, 2017, View Source [SID1234519857]). DelMar was required to obtain HGRAC approval because the trial involves analysis of patient’s MGMT status as a biomarker for patient selection and enrollment.

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"Our clinical trials to date have been focused on recurrent GBM for patients whose tumors have recurred following currently approved therapies. Obtaining HGRAC approval represents a significant step toward maximizing the potential benefit of VAL-083 in newly diagnosed GBM for patients whose tumors exhibit features, such as high expression of MGMT, which render them resistant to the current standard-of-care chemotherapy," said Jeffrey Bacha, Chief Executive Officer of DelMar Pharmaceuticals. "Success of VAL-083 as a front-line treatment would be a major turning point for the brain tumor community and this area of science."

Up to 30 newly diagnosed GBM patients whose tumors exhibit high-expression of the DNA-repair enzyme O6-methylguanine methyltransferase (MGMT) will be treated with VAL-083 in combination with radiotherapy to examine the safety and efficacy of VAL-083 in this population. MGMT methylation status will be used as a biomarker for
patient selection and only patients whose tumors are MGMT-unmethylated will be enrolled.

Results of the trial will be used to guide design of global randomized trials, which if successful, would position VAL-083 as a potential replacement for the current standard-of-care (chemoradiation with temozolomide) for the approximately 2/3 of newly diagnosed GBM patients whose tumors feature MGMT-unmethylated GBM.
GBM patients with MGMT-unmethylated tumors exhibit a high expression of the MGMT enzyme, which is directly correlated to resistance to temozolomide, the current front-line chemotherapy used in the treatment of GBM. MGMT-unmethylated patients have particularly poor patient outcomes and significantly reduced survival compared to MGMT-methylated patients.

DelMar has demonstrated that VAL-083’s anti-cancer activity is independent of MGMT expression against multiple GBM cell lines in vitro. VAL-083’s clinical activity against GBM has been established by DelMar’s recent Phase 2 clinical trials in refractory GBM and historical trials conducted by the US National Cancer Institute (NCI). Results of prior NCI-sponsored trials of VAL-083 combined with radiotherapy in newly diagnosed GBM suggest a potential superior benefit of chemoradiation with VAL-083 versus radiotherapy alone (+8.3 months) in comparison to similar studies involving temozolomide or nitrosoureas (+1.2 – 2.5 months).

Mr. Bacha continued, "GBM has been largely left behind in the recent advancements made in the fight against cancer and new therapies improving median survival have been lacking. We strongly believe that VAL-083 represents a potential paradigm shift in the treatment of GBM, particularly for the 2/3 of newly diagnosed GBM patients whose tumors exhibit high expression of MGMT."

The trial is expected to open for enrollment in the coming weeks at Sun Yat-sen University Cancer Center (SYUCC) in Guangzhou, China under the direction of Professor Zhong-ping Chen, M.D., Ph.D., who serves as chair of the Department of NeuroSurgery/Neuro-Oncology at SYUCC. Prof. Chen has authored dozens of publications and been involved in numerous international brain tumor trials. He also currently serves as president of the Chinese Society for NeuroOncology and as editor-in-chief of the Chinese Journal of NeuroOncology. Kun Tuo, a subsidiary of QuintilesIMS, has been retained to monitor and oversee the conduct of the trial. Funding support for the trial will be provided by Guangxi Wuzhou Pharmaceutical Group Co. Ltd. (Guangxi Wuzhou Pharma), under the terms of DelMar’s collaboration with Guangxi Wuzhou Pharma. Further details of the trial can be found at clinicaltrials.gov (Identifier Number: NCT03050736)

About VAL-083
VAL-083 (dianhydrogalactitol) is a "first-in-class", DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institute.

VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas.
DelMar has demonstrated that VAL-083’s anti-tumor activity against GBM is unaffected by the expression of MGMT in vitro. Further details regarding these studies can be found at View Source

The Company’s recent outcomes in Phase 1-2 clinical trials suggest that VAL-083 may offer a clinically meaningful survival benefit for patients with recurrent GBM following treatment with both TMZ and bevacizumab. A well-tolerated dosing regimen of 40mg/m2/day on days 1, 2, and 3 of a 21-day cycle was selected for study in subsequent GBM clinical trials.

Based on these results, DelMar has embarked on human clinical trials for VAL-083 across multiple lines of GBM therapy. These trials include, i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab, improves overall survival, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962); ii) a pivotal, controlled Phase 3 study in temozolomide-Avastin Recurrent GBM ("STAR-3") to evaluate overall survival versus salvage chemotherapy (clinicaltrials.gov identifier: NCT03149575); and iii) a single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels (clinicaltrials.gov identifier: NCT03050736). DelMar believes that the results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM.

About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer. GBM has an incidence of two to three per 100,000 adults per year, and accounts for 52 percent of all primary brain tumors. In the US alone, approximately 18,000 people are diagnosed with GBM every year. GBM accounts for 13,000 cancer deaths in the US annually. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%.

U.S. Food and Drug Administration Expands Approval of Yervoy® (ipilimumab) to Include Pediatric Patients 12 Years and Older with Unresectable or Metastatic Melanoma

On July 24, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) has expanded the indication for Yervoy (ipilimumab) injection for intravenous use to now include the treatment of unresectable or metastatic melanoma in pediatric patients 12 years of age and older (Press release, Bristol-Myers Squibb, JUL 24, 2017, View Source [SID1234519856]).

Yervoy was evaluated in two trials of pediatric patients: a dose-finding study in 33 patients aged two to 21 years with relapsed or refractory solid tumors and an open-label, single-arm trial in 12 adolescents (ages ranging from 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. The overall safety profile of Yervoy in children and adolescents was consistent with the safety profile in adults, and similarities in disease between adult and pediatric patients 12 years and older allow for extrapolation of data. Based on a population pharmacokinetic analysis, exposure in adolescents 12 years and older is comparable to that in adults for the approved dose of 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.1

Yervoy is associated with a Boxed Warning and can result in severe to fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Please see below for additional Important Safety Information, including Boxed Warning regarding immune-mediated adverse reactions.

"When my daughter was diagnosed with melanoma, our entire family was devastated," said Brenda Busby, mother to a 12-year-old patient and pediatric program coordinator, Melanoma Research Foundation. "As someone who has lived with the many challenges of pediatric cancer, I know how important it is for patients and their families who face metastatic melanoma to have access to new therapies."

"Metastatic melanoma is extremely rare in children and adolescents, which makes it particularly difficult to investigate in clinical trials. Though designing clinical trials in small pediatric populations can be challenging, this group of investigators committed to bringing a new therapy to those in need," said Lia Gore, MD, University of Colorado School of Medicine and Children’s Hospital of Colorado. "Ipilimumab’s approval represents the culmination of a long effort and gives physicians the ability to expand immuno-oncology – one of the most exciting areas of medicine2 – for the treatment of young adults with metastatic melanoma."

The U.S. FDA approval for Yervoy in patients 12 years and older with metastatic melanoma marks Bristol-Myers Squibb’s first pediatric indication for an immuno-oncology medicine. The expanded indication builds upon six years of experience with Yervoy, which has been used to treat more than 38,000 adult patients with metastatic melanoma since its first approval.3

"Despite significant advancements in oncology research for adults in recent years, treatment options continue to be limited for pediatric patients with metastatic melanoma," said Chris Boerner, PhD, president and head of U.S. commercial operations, Bristol-Myers Squibb. "At Bristol-Myers Squibb, we are committed to providing meaningful support to the pediatric oncology community. This latest approval of Yervoy exemplifies our ongoing effort to expand the availability of therapies for younger cancer patients."

As part of its commitment to children and adolescents with cancer, Bristol-Myers Squibb continues to explore pediatric applications for investigational oncology agents within its broad development program. In addition, Bristol-Myers Squibb supports organizations and initiatives focused on pediatric patients and their families.

About the Yervoy Studies in Pediatric Patients
Yervoy has been evaluated in a total of 45 pediatric patients across two clinical trials. The safety and effectiveness of Yervoy have been established in pediatric patients 12 years and older. The use of Yervoy in this age group is supported by evidence from adequate and well-controlled studies of Yervoy in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the pediatric and adult populations is comparable. In addition, the tumor biology and the course of advanced melanoma is sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.

In a dose-finding trial, Yervoy was evaluated in 33 pediatric patients with relapsed or refractory solid tumors. Patients enrolled in the study ranged from two to 21 years of age, with a median age of 13 years, and 20 of the patients were 12 years of age or older. Yervoy was administered at doses of 1, 3, 5 and 10 mg/kg intravenously over 90 minutes every three weeks for four doses and then every 12 weeks thereafter until progression or treatment discontinuation.1

Yervoy was also evaluated in an open-label, single-arm trial in 12 pediatric patients 12 years and older with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. Patients received Yervoy 3 mg/kg (four patients) or 10 mg/kg (eight patients) intravenously over 90 minutes every three weeks for four doses.1

Of the 17 patients 12 years of age and older with melanoma treated with Yervoy across both studies, two patients experienced objective responses, including one partial response that was sustained for 16 months.1

The approved dose for Yervoy in pediatric patients with unresectable or metastatic melanoma is 3 mg/kg, administered intravenously over 90 minutes every three weeks for a total of four doses.
About the Population Pharmacokinetic Analysis
Based on a population pharmacokinetic analysis using available pooled data from 565 patients from four phase 2 adult studies (N=521) and two pediatric studies (N=44), body weight normalized clearance of Yervoy is comparable between adult and pediatric subjects.
Indications and Important Safety Information for YERVOY (ipilimumab)

Indications
YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older).
YERVOY (ipilimumab) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Important Safety Information
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests, at baseline and before each dose.
Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Recommended Dose Modifications
Endocrine: Withhold YERVOY for symptomatic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.
Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment.

All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Immune-mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY- treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune- mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life- threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life- threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%).
There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. In Trial 2, the following clinically significant immune- mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

Embryo-fetal Toxicity
Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY.

Lactation
It is not known whether YERVOY is secreted in human milk. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Common Adverse Reactions
The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

Please see U.S. Full Prescribing Information for YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions.

MorphoSys Announces That Its Partner Bayer Reports On Phase 2 Study of Investigational Anetumab Ravtansine in Second-Line Mesothelioma

On July 21, 2017 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported that its partner Bayer AG has reported that a phase 2 clinical study examining anetumab ravtansine as monotherapy in patients with recurrent malignant pleural mesothelioma did not meet the primary endpoint of progression-free survival (Press release, MorphoSys, JUL 21, 2017, View Source [SID1234556342]). Anetumab ravtansine is an antibody-drug conjugate (ADC) directed against mesothelin, comprising an antibody made using MorphoSys’s HuCAL technology. Malignant pleural mesothelioma is a rare cancer and is commonly caused by occupational or environmental exposure to asbestos.

"The outcome of this phase 2 study with anetumab ravtansine in recurrent malignant pleural mesothelioma is disappointing, in particular for the patients suffering from this serious and extremely difficult to treat disease", said Dr. Markus Enzelberger, Interim Chief Scientific Officer of MorphoSys AG. "Nevertheless, Bayer remains committed to further evaluating the potential of this compound across multiple tumor types with significant unmet medical need. We are proud of our long-standing relationship with Bayer, and we look forward to further updates about the development program with anetumab ravtansine going forward."

The phase 2 clinical trial is a randomized, open-label, active-controlled, multicenter superiority study evaluating the safety and efficacy of anetumab ravtansine as second-line treatment in 248 patients with advanced or metastatic mesothelin-positive malignant pleural mesothelioma whose disease had progressed after treatment with first-line platinum/pemetrexed-based chemotherapy.

Bayer reported further that anetumab ravtansine is currently being investigated, as monotherapy and in combination, in additional studies, including a Phase Ib multi-indication study in six different types of advanced solid tumors, as well as a Phase Ib combination-study in patients with recurrent platinum-resistant ovarian cancer. According to Bayer, based on the available data, Bayer remains committed to further evaluating the utility and safety of anetumab ravtansine across multiple tumor types with significant unmet medical need. Bayer further announced that, in the trial reported, the safety and tolerability of anetumab ravtansine were consistent with earlier clinical findings and that detailed study results are expected to be presented at an upcoming medical meeting.

Further detailed information about mesothelioma and the clinical study can be found in a press release issued by Bayer or at clinicaltrials.gov.

There is no change to MorphoSys’s financial guidance for Fiscal Year 2017.

About anetumab ravtansine
Anetumab ravtansine is an antibody-drug conjugate (ADC) that specifically targets mesothelin, a surface marker protein overexpressed in many cancers. After binding to mesothelin, anetumab ravtansine is taken up inside the tumor cells, where degrading enzymes release cytotoxic DM4, a maytansinoid tubulin inhibitor, which induces cell cycle arrest and apoptosis in dividing cells. Anetumab ravtansine comprises an antibody made using MorphoSys’s HuCAL technology.

LIDDS signs research agreement with major European pharma company

LIDDS has entered into a research agreement with Ferring Pharmaceuticals which has an exclusive option right to leverage the NanoZolid technology for the development of an injectable, controlled-release formulation for cancer treatment (Press release, Lidds, JUL 21, 2017, View Source [SID1234555959]).

Under the terms of the agreement, LIDDS will conduct feasibility studies fully funded by the other party. Upon completion of the development work, the right to exercise its option and enter into an exclusive agreement with LIDDS to further develop the novel formulation based on NanoZolid.

– LIDDS is committed to provide the NanoZolid technology to enhance the performance of drugs by either reducing its side effects or facilitate longer acting pharmaceuticals to improve compliance and quality of life for patients. We are very pleased with the new agreement which adds another exciting project that does not compete with LIDDS own development portfolio, says Monica Wallter, CEO of LIDDS.

LIDDS has several ongoing development projects in oncology. The prostate cancer project is currently in Phase IIb and there are several promising preclinical projects where NanoZolid is combined with cytotoxic drugs and with immuno active substances such as antibodies.

Syros Publishes Foundational Data Supporting Ongoing Phase 2 Clinical Trial of SY-1425 for Genomically Defined AML and MDS Patients

On July 21, 2017 Syros Pharmaceuticals (NASDAQ: SYRS) reported that data providing the foundation of its clinical development strategy for SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist currently in a Phase 2 clinical trial in genomically defined subsets of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), were published online in Cancer Discovery, a peer-reviewed journal of the American Association of Cancer Research. Syros is on track to present initial data from the Phase 2 clinical trial this fall (Press release, Syros Pharmaceuticals, JUL 21, 2017, View Source [SID1234519876]).

The publication highlights Syros’ discovery of a subset of AML patients with a super-enhancer associated with the RARA gene, which was shown in preclinical studies to be predictive of response to SY-1425. Syros also found a subset of MDS patients with high expression of the RARA gene and demonstrated in ex vivo studies that RARA-high MDS had a similar response to SY-1425 as that seen in AML driven by the RARA super-enhancer.

"The publication of our work in Cancer Discovery is a demonstration of our pioneering approach for analyzing non-coding regulatory regions of the genome to identify disease-driving genes with the goal of developing new medicines that make a meaningful difference for patients," said Eric Olson, Ph.D., Chief Scientific Officer of Syros. "Although genetic mutations associated with AML and MDS in protein-coding regions of the genome are well known, there are limited targeted therapy options in these diseases and there remains a high unmet need. Our investigation of the regulatory genome adds a new dimension to the understanding of AML and MDS disease biology that offers the potential to address these underserved patient populations and improve their prognosis and treatment."

In collaboration with the Majeti lab at Stanford University School of Medicine, Syros used its gene control platform to analyze 66 AML patients’ tumor samples and identified six distinct patient subsets based on super-enhancer profiles, including one enriched for a super-enhancer associated with the RARA gene. The data show that:

· Super-enhancer profiles were strongly associated with survival outcomes, often independent of known genetic mutations in AML.

· The RARA super-enhancer was associated with high expression of the RARA gene, which codes for a transcription factor targeted by SY-1425.

· The RARA super-enhancer was predictive of response to SY-1425. In AML cells with high RARA expression, SY-1425 reduced proliferation and promoted differentiation. Moreover, SY-1425 decreased tumor burden and prolonged survival in patient-derived xenograft (PDX) models of AML with high RARA expression, while no effect was found on AML cells or PDX models with low RARA expression. Notably, ATRA, a less potent and non-selective retinoid, produced no survival benefit in PDX models with high RARA expression.

· SY-1425 induced profound transcriptional changes promoting cell differentiation in AML cells with high RARA expression but little to no transcriptional changes in AML cells with low RARA expression.

· DHRS3 was the most strongly and rapidly induced gene in response to treatment with SY-1425, leading to the identification of DHRS3 induction as a pharmacodynamic marker for use in the ongoing Phase 2 clinical trial as an early indicator of whether SY-1425 is affecting the targeted biology in defined subsets of AML and MDS patients.

· SY-1425 induced transcriptional and epigenomic changes in AML cells with high RARA expression similar to those seen in acute promyelocytic leukemia (APL) cells treated with SY-1425. SY-1425 is approved in Japan as Amnolake (tamibarotene) to treat relapsed or refractory APL, a form of AML that is driven by fusions of the RARA gene, and has a well-established safety and efficacy profile in those patients.

The Phase 2 clinical trial of SY-1425 is assessing the safety and efficacy of SY-1425 as a single agent in four AML and MDS patient populations, as well as in combination with azacitidine, a standard-of-care therapy, in newly diagnosed AML patients who are not suitable candidates for standard chemotherapy. All patients in the trial are prospectively selected using biomarkers for high expression of RARA or IRF8, which are genes associated with the RARA pathway. Additional details about the trial can be found using the identifier NCT02807558 at www.clinicaltrials.gov