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European Commission Grants Marketing Authorisation for Unituxin™ (dinutuximab) for the Treatment of Paediatric High-Risk Neuroblastoma

On August 17, 2015 United Therapeutics Corporation (NASDAQ: UTHR) reported that the European Commission (EC) has granted Marketing Authorisation for Unituxin (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT) (Press release, United Therapeutics, AUG 17, 2015, View Source [SID:1234507276]).

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Unituxin is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin.

Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence in the European Union of approximately 1500 patients, of whom 50% are diagnosed as having high-risk disease.

The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children’s Oncology Group (COG).

Trial design and results

The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years).

The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030).

Frequently occurring adverse reactions

The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported – including anaphylactic reaction (18%) and bronchospasm (4%).

Posology and method of administration

Unituxin is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days).

The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses.

About Unituxin

Unituxin (dinutuximab) is a monoclonal chimeric antibody composed of murine variable heavy and light chain regions and the human constant region for the heavy chain kappa. Unituxin reacts specifically with the ganglioside GD2, which is highly expressed on the surface of the neuroblastoma cells and minimally expressed on the surface of normal human neurons, peripheral pain fibres, and skin melanocytes.

On 10 March 2015, Unituxin, in combination with GM-CSF, IL-2 and RA, became the first therapy to be approved by the US Food and Drug Administration for the treatment of paediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent multimodality therapy.

Unituxin carries a Boxed Warning alerting patients and health care professionals that Unituxin irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Unituxin may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression. Full prescribing information is available at: View Source

Important EU Safety Information for Unituxin

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
Contraindications
Hypersensitivity (Grade 4) to the active substance or to any of the excipients in Unituxin.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Allergic Reactions
Antihistamine premedication (e.g. hydroxyzine or diphenhydramine) should be administered by intravenous injection approximately 20 minutes before starting each Unituxin infusion.

It is recommended that antihistamine medicinal product be repeated every 4-6 hours as required during infusion of Unituxin. Patients should be monitored for signs and symptoms of infusion reactions for 4 hours after the completion of the Unituxin infusion.
Epinephrine (adrenaline) and hydrocortisone for intravenous administration should be immediately available at the bedside during administration of dinutuximab to manage life-threatening allergic reactions.

It is recommended that treatment for such reactions include hydrocortisone administered by intravenous bolus, and epinephrine administered by intravenous bolus once every 3-5 minutes as necessary according to clinical response.
Depending on the severity of the allergic reaction, the rate of infusion should be reduced or treatment discontinued.

Capillary Leak Syndrome
Capillary leak syndrome is more likely when dinutuximab is co-administered with IL-2. It is recommended to administer oral metolazone or intravenous furosemide every 6-12 hours as required. Supplemental oxygen, respiratory support, and albumin replacement therapy should be used as necessary according to clinical response.
Characteristic symptoms and signs include hypotension, generalized oedema, ascites, dyspnoea, pulmonary oedema and acute renal failure associated with hypoalbuminaemia and haemoconcentration.

Pain
Severe pain (Grade 3 or 4) occurs most frequently during the first 4-day course of Unituxin, often subsiding over time with subsequent courses.

For severe pain, the Unituxin infusion rate should be decreased to 0.875 mg/m2/hour. Unituxin should be discontinued if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures.
Paracetamol should be administered orally 20 minutes prior to starting each dinutuximab infusion, and repeated every 4-6 hours as needed. Regular dosing every 4-6 hours is recommended when IL-2 is coadministered. If required for persistent pain, ibuprofen should be administered orally every 6 hours between doses of paracetamol. Ibuprofen should not be administered if there is evidence of thrombocytopenia, bleeding, or renal dysfunction.

An opioid, such as morphine sulphate, is recommended to be administered by intravenous infusion prior to each dinutuximab infusion and continued as an intravenous infusion during and until 2 hours after completion of the treatment. It is recommended that additional intravenous bolus doses of an opioid are administered as needed for treatment of pain up to once every 2 hours during the dinutuximab infusion. If morphine is not tolerated, then fentanyl or hydromorphone may be utilised.
Lidocaine may be administered as an intravenous infusion (2 mg/kg in 50 mL of 0.9% sodium chloride) over 30 minutes prior to the start of each dinutuximab infusion and continued via intravenous infusion at 1 mg/kg/h up to 2 hours after completion of the treatment. Lidocaine infusion should be discontinued if the patient develops dizziness, perioral numbness, or tinnitus.
Gabapentin may be administered at the time of starting morphine premedication, at an oral dose of 10 mg/kg/day. The dose may be subsequently increased (up to a maximum of 60 mg/kg/day or 3600 mg/day) as needed for pain management.

Hypotension
Intravenous sodium chloride 9 mg/mL (0.9%) solution for injection (10 mL/kg) should be administered over one hour just prior to the dinutuximab infusion. If hypotension occurs, this can be repeated, or intravenous albumin or packed red blood cells can be administered as clinically indicated.
It is recommended that vasopressor therapy is also administered if necessary to restore an adequate perfusion pressure.

Neurological Disorders of the Eye
Eye disorders may occur, especially with repeated courses. These changes usually resolve over time. Patients should have an ophthalmic examination before initiating therapy and be monitored for visual changes.

Hepatic Dysfunction
Regular monitoring of liver function is recommended during dinutuximab immunotherapy.

Systemic Infections
Patients typically have a central venous catheter in situ and as a consequence of prior ASCT are likely to be immunocompromised during therapy, and therefore, at risk of developing systemic infection.
Patients should have no evidence of systemic infection and any identified infection should be under control before beginning therapy.

Laboratory Test Abnormalities
Electrolyte abnormalities occurring in at least 25% of patients who received Unituxin included hyponatraemia and hypokalaemia.

Atypical Haemolytic Uraemic Syndrome
Haemolytic uraemic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anaemia, and hypertension has been reported. Supportive measures should be instituted including control of hydration status, electrolyte abnormalities, hypertension, and anaemia.
For the Summary of Product Characteristics, and detailed information on this medicinal product, please visit www.ema.europa.eu.

Pivotal Phase II Study Showed Genentech’s Investigational Immunotherapy Atezolizumab Shrank Tumors in People with a Specific Type of Lung Cancer

On August 16, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that in the large pivotal Phase II study, BIRCH, the investigational cancer immunotherapy atezolizumab (MPDL3280A; anti-PDL1) met its primary endpoint and shrank tumors (objective response rate; ORR) in people with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease expressed PD-L1 (Programmed Death Ligand-1) (Press release, Genentech, AUG 16, 2015, View Source [SID:1234507278]). The study showed the amount of PD-L1 expressed by a person’s cancer correlated with their response to the medicine. Adverse events were consistent with what has been previously observed for atezolizumab.

"We are encouraged by the number of people who responded to atezolizumab and maintained their response during the study, which is particularly meaningful for people who had received several prior treatments," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We plan to present results at an upcoming medical meeting and will discuss these data as well as results from our other lung cancer studies with health authorities to bring this medicine to patients as quickly as possible."

Earlier this year, the FDA granted atezolizumab a Breakthrough Therapy Designation for the treatment of people whose NSCLC expresses PD-L1 and who progressed during or after standard treatments (e.g., platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease). This designation is designed to expedite the development and review of medicines intended to treat serious diseases. We have seven Phase III studies evaluating atezolizumab alone or in combination with other medicines as a potential new treatment for people with early and advanced stages of lung cancer.

About the BIRCH Study

BIRCH is an open-label, multicenter, single-arm Phase II study that evaluated the safety and efficacy of atezolizumab in 667 people with locally advanced or metastatic NSCLC whose disease expressed PD-L1. PD-L1 expression was assessed on both tumor cells (TC) and tumor-infiltrating immune cells (IC) with an investigational immunohistochemistry test (IHC) being developed by Roche Diagnostics. Eligibility criteria included people whose tumors were determined to express PD-L1 with an IHC score of TC2/3 or IC2/3. People in the study received a 1200-milligram intravenous dose of atezolizumab every three weeks. The primary endpoint of the study was ORR. Secondary endpoints included duration of response (DoR), overall survival (OS), progression-free survival (PFS) and safety. Results from BIRCH will be presented at an upcoming medical meeting.

About Lung Cancer

According to the American Cancer Society, it is estimated that more than 221,000 Americans will be diagnosed with lung cancer in 2015, and NSCLC accounts for 85 percent of all lung cancers. It is estimated that approximately 60 percent of lung cancer diagnoses in the United States are made when the disease is in the advanced stages.

About atezolizumab

Atezolizumab (also known as MPDL3280A; anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.

All studies of atezolizumab include the evaluation of an investigational IHC test that uses the antibody SP142 to measure PD-L1 expression on both tumor cells and infiltrating immune cells. The goal of PD-L1 as a biomarker is to identify those people most likely to benefit when treated with atezolizumab alone, and to determine which people may benefit most from a combination of atezolizumab and another medicine. There are 11 ongoing or planned Phase III studies of atezolizumab across certain kinds of lung, kidney, breast and bladder cancer.

Hospira Japan Receives Approval for New Generic Oncology Products

On August 16, 2015 Hospira Japan Co., Ltd. reported that two new generic oncology drugs have been approved by the Ministry of Health, Labour and Welfare (MHLW) in Japan (Press release, Hospira, AUG 16, 2015, View Source;p=RssLanding&cat=news&id=2079850 [SID:1234507271]).

Gemcitabine I.V. lnfusion[Hospira] is the pre-mixed solution and the additional dosage form to Gemcitabine for I.V. lnfusion[Hospira] with freeze-dried formulation. It is expected to contribute to reducing the medical preparation time and the risks of exposure to cytotoxic agents.
Oxaliplatin I.V. lnfusion 200mg/40mL [Hospira] is the additional presentation to the current Oxaliplatin lineup – 50mg/10mL, 100mg/20mL.

We are committed to launching a broad portfolio of high-quality generics in Japan to meet medical needs of patients across the country.

About the Products
[Product name]
Gemcitabine I.V. lnfusion 200mg/5.3mL [Hospira]
Gemcitabine I.V. lnfusion 1g/26.3mL [Hospira]
[Therapeutic category]
Metabolic antagonist malignant tumour drug
[Indications]
Non-small cell lung cancer, pancreatic cancer, biliary tract cancer, uroepithelial cancer, inoperable or recurrent breast cancer, ovarian cancer progressing after chemotherapy, recurrence or refractory malignant lymphoma

[Product name]
Oxaliplatin I.V. lnfusion 200mg/40mL [Hospira]
[Therapeutic category]
Anticancer drug
[Indications]
Unresectable advanced/recurrent colorectal cancer, Supplementary postoperative chemotherapy for colon cancer, Inoperable pancreatic cancer

Hospira Japan has a partnership co-promoting oncology generic products with Mochida Pharmaceuticals in Japan.

Pivotal Phase II study showed Roche's investigational immunotherapy atezolizumab shrank tumours in people with a specific type of lung cancer

On August 17, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that in the large pivotal Phase II study, BIRCH, the investigational cancer immunotherapy atezolizumab (MPDL3280A; anti-PDL1) met its primary endpoint and shrank tumours (objective response rate; ORR) in people with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease expressed PD-L1 (Programmed Death Ligand-1) (Press release, Hoffmann-La Roche , AUG 16, 2015, View Source [SID:1234507269]). The study showed the amount of PD-L1 expressed by a person’s cancer correlated with their response to the medicine. Adverse events were consistent with what has been previously observed for atezolizumab.

"We are encouraged by the number of people who responded to atezolizumab and maintained their response during the study, which is particularly meaningful for people who had received several prior treatments," said Sandra Horning, M.D., Chief Medical Officer and head of Global Product Development. "We plan to present results at an upcoming medical meeting and will discuss these data as well as results from our other lung cancer studies with health authorities to bring this medicine to patients as quickly as possible.’’

Earlier this year, the FDA granted atezolizumab a Breakthrough Therapy Designation for the treatment of people whose NSCLC expresses PD-L1 and who progressed during or after standard treatments (e.g. platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease). This designation is designed to expedite the development and review of medicines intended to treat serious diseases. Roche have seven Phase III studies evaluating atezolizumab alone or in combination with other medicines as a potential new treatment for people with early and advanced stages of lung cancer.

About the BIRCH Study
BIRCH is an open-label, multicentre, single-arm Phase II study that evaluated the safety and efficacy of atezolizumab in 667 people with locally advanced or metastatic NSCLC whose disease expressed PD-L1. PD-L1 expression was assessed on both tumour cells (TC) and tumour-infiltrating immune cells (IC) with an investigational immunohistochemistry test (IHC) being developed by Roche Diagnostics. Eligibility criteria included people whose tumours were determined to express PD-L1 with an IHC score of TC2/3 or IC2/3. People in the study received a 1200-milligram intravenous dose of atezolizumab every 3 weeks. The primary endpoint of the study was ORR. Secondary endpoints included duration of response (DoR), overall survival (OS), progression-free survival (PFS) and safety.

About non-small cell lung cancer
Lung cancer is the leading cause of cancer death globally. Each year, 1.59 million people die as a result of the disease, which means more than 4,350 deaths worldwide every day. Lung cancer can be broadly divided into two major types, NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.

About Roche in lung cancer
Lung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have three approved medicines to treat certain kinds of lung cancer and more than 10 medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.

About atezolizumab
Atezolizumab (also known as MPDL3280A; anti-PDL1) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, atezolizumab may enable the activation of T cells.
All studies of atezolizumab include the evaluation of an investigational IHC test that uses the antibody SP142 to measure PD-L1 expression on both tumour cells and infiltrating immune cells. The goal of PD-L1 as a biomarker is to identify those people most likely to benefit when treated with atezolizumab alone, and to determine which people may benefit most from a combination of atezolizumab and another medicine. There are 11 ongoing or planned Phase III studies of atezolizumab across certain kinds of lung, kidney, breast and bladder cancer.

10-Q – Quarterly report [Sections 13 or 15(d)]

(Filing, 10-Q, Vaccinogen, AUG 14, 2015, View Source [SID:1234507275])