On August 17, 2015 Seattle Genetics, Inc. (Nasdaq: SGEN) reported that the U.S. Food and Drug Administration (FDA) has approved ADCETRIS (brentuximab vedotin) for the treatment of patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation (Press release, Seattle Genetics, AUG 17, 2015, View Source [SID:1234507285]).

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The approval is based on a phase 3 clinical trial called AETHERA that was designed to compare up to 16 cycles (approximately one year) of ADCETRIS therapy administered every three weeks following auto-HSCT to placebo. The primary endpoint was met with a significant improvement in median progression-free survival (PFS) of 42.9 months (95% CI: 30.4, 42.9) for patients who received ADCETRIS versus 24.1 months (95% CI: 11.5, not estimable) for patients who received placebo, an improvement of 18.8 months (hazard ratio=0.57 [95% CI: 0.40, 0.81]; p-value=0.001). In addition, data from the AETHERA trial converted the U.S. accelerated approval of the relapsed classical HL indication to regular approval. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed in classical HL and systemic anaplastic large cell lymphoma (sALCL), as well as other lymphoma subtypes. This is the third indication for ADCETRIS, which was granted accelerated FDA approval in August 2011 for two other indications: (1) treatment of Hodgkin lymphoma patients who fail autologous transplant or who fail at least two prior multi-agent chemotherapy regimens and are not autologous transplant candidates, and (2) treatment of systemic ALCL patients who fail at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This Smart News Release features multimedia. View the full release here: View Source

ADCETRIS Product Photo (Photo: Business Wire)
ADCETRIS Product Photo (Photo: Business Wire)

Globally, there are more than 65,000 cases of HL diagnosed each year. Although frontline combination chemotherapy can result in durable responses, up to 30 percent of these patients fail frontline treatment. The standard for these patients is salvage therapy, followed by auto-HSCT; approximately half of all HL patients who undergo an auto-HSCT experience subsequent disease relapse.

"With this FDA approval, ADCETRIS is the first and only consolidation treatment option available to high risk classical Hodgkin lymphoma patients who undergo a transplant to preserve their post-auto-HSCT remissions," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "This represents a meaningful advance for cancer patients and an important milestone for the ADCETRIS development program. Together with our three ongoing phase 3 trials and more than 30 additional clinical trials, this approval supports our goal to broadly establish ADCETRIS as the foundation of therapy for classical Hodgkin lymphoma and CD30-expressing malignancies."

"The FDA approval of brentuximab vedotin for post-autologous hematopoietic transplantation consolidation treatment in classical Hodgkin lymphoma patients with high risk of relapse or progression is a significant milestone for patients and physicians," said Craig Moskowitz, M.D., lead investigator on the trial and Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center. "Approximately half of all Hodgkin lymphoma patients who undergo an autologous hematopoietic stem cell transplant will relapse, representing a significant need for additional treatment options to improve progression free survival."

AETHERA Phase 3 Trial Demonstrates Significant Progression-Free Survival Benefit with ADCETRIS as Post-Transplant Consolidation in Hodgkin Lymphoma

The positive results from the phase 3 AETHERA trial were published in The Lancet in March 2015 and presented at the 56th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2014. A total of 329 HL patients at risk of relapse or progression were enrolled, including 165 on the ADCETRIS arm and 164 on the placebo arm. Patients eligible for enrollment in the AETHERA trial must have had a history of primary refractory HL, have relapsed within one year from receiving frontline chemotherapy and/or have had disease outside of the lymph nodes at the time of pre-auto-HSCT relapse. Results included:

The trial achieved its primary endpoint and demonstrated a significant increase in PFS per independent review facility, with a hazard ratio of 0.57 (95% CI: 0.40, 0.81) and a p-value of 0.001. Median PFS was 43 months (95% CI: 30.4, 42.9) for patients who received ADCETRIS versus 24 months (95% CI: 11.5, not estimable) for patients who received placebo.

The most common adverse events (≥20 percent), of any grade and regardless of causality, in the ADCETRIS arm were neutropenia (78 percent), peripheral sensory neuropathy (56 percent), thrombocytopenia (41 percent), anemia (27 percent), upper respiratory tract infection (26 percent), fatigue (24 percent), peripheral motor neuropathy (23 percent), nausea (22 percent), cough (21 percent) and diarrhea (20 percent). The most common adverse events (≥20 percent), of any grade and regardless of causality, in the placebo arm were neutropenia (34 percent), upper respiratory tract infection (23 percent) and thrombocytopenia (20 percent). Sixty-seven percent of patients on the ADCETRIS arm experienced peripheral neuropathy. Of those patients, 85 percent had resolution (59 percent) or partial improvement (26 percent) in symptoms at the time of their last evaluation, with a median time to improvement of 23 weeks (range 0.1-138).

There are no post-marketing requirements as part of the U.S. approval. The AETHERA data have also been submitted to both the European Medicines Agency (EMA) and Health Canada requesting marketing authorization.

As part of a broad clinical development program, ADCETRIS is also being evaluated in three additional phase 3 clinical trials, referred to as ECHELON-1, ECHELON-2 and ALCANZA. Enrollment is expected to be completed in ECHELON-1 and ALCANZA during 2015 and in ECHELON-2 during 2016.

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including three additional phase 3 studies, in earlier lines of its approved classical HL and sALCL indications as well as in many additional types of CD30-positive malignancies, including cutaneous T-cell lymphoma, B-cell lymphomas and mature T-cell lymphomas.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical HL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical HL patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory HL and sALCL.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive HL following ASCT, or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS (brentuximab vedotin).

Contraindication

ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

Anaphylaxis and infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion-related reaction occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy.

Hematologic toxicities: Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS. Febrile neutropenia has been reported with ADCETRIS. Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Closely monitor patients during treatment for the emergence of possible bacterial, fungal or viral infections.

Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with severe renal impairment.

Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment.

Hepatotoxicity: Serious cases of hepatotoxicity, including fatal outcomes, have occurred with ADCETRIS. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first dose of ADCETRIS or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk. Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

Pulmonary Toxicity: Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, some with fatal outcomes, have been reported. Monitor patients for signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.

Serious dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal outcomes, have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Embryo-fetal toxicity: Fetal harm can occur. Advise pregnant women of the potential hazard to the fetus.

Most Common Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients with relapsed classical HL and sALCL in two uncontrolled single-arm trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-auto-HSCT in a placebo-controlled randomized trial. The most common adverse reactions (≥20%) in the ADCETRIS-treatment arm (167 patients), regardless of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea.

Drug Interactions:

Concomitant use of strong CYP3A4 inhibitors or inducers, or P-gp inhibitors, has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations:

MMAE exposure and adverse reactions are increased in patients with moderate or severe hepatic impairment or severe renal impairment. Avoid use.

For additional Important Safety Information, including Boxed WARNING, please see the full Prescribing Information for ADCETRIS at View Source

About Classical Hodgkin Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system and is the most common type of blood cancer. There are two major categories of lymphoma: HL and non-Hodgkin lymphoma. Classical HL is distinguished from other lymphomas by the characteristic presence of CD30-positive Reed-Sternberg cells. The Reed-Sternberg cell generally expresses CD30.

According to the American Cancer Society, approximately 9,050 cases of HL will be diagnosed in the United States during 2015 and more than 1,150 will die from the disease.

On August 17, 2015 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations and a primary focus in Hematology and Oncology, reported that the company has reached agreement with the U.S. Food and Drug Administration (FDA) on the Special Protocol Assessment (SPA) of the planned Phase 3 clinical trial of its novel, potent pro-drug, apaziquone (Press release, Spectrum Pharmaceuticals, AUG 17, 2015, View Source [SID:1234507284]). This trial will further evaluate the intravesical use of apaziquone for the treatment of patients with non-muscle invasive bladder cancer (NMIBC) as one or two instillations, immediately following transurethral resection of bladder tumor (TURBT).

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"Spectrum’s agreement with the FDA on the SPA represents a significant milestone for bladder cancer patients," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "The learnings from previous Phase 3 studies and comments from the FDA have been incorporated in the new protocol to improve the chances of success. We look forward to initiating this trial and filing the apaziquone NDA by year-end. This NDA is based on data from the previously completed program that included two Phase 3 studies with a total of 1,615 patients. We believe there continues to be a significant unmet need for these patients, as no drugs have been approved in the U.S. for more than 40 years for the treatment of low-grade NMIBC. Due to the high rate of recurrence, the overall cost of the treatment of bladder cancer in the U.S. is a staggering $3.4 billion annually, most of which is related to direct treatment of the disease. We endeavor to bring this much needed therapy for patients and help reduce overall medical costs at the same time."

In accordance with the SPA, the Phase 3 trial will be a randomized, double-blind, placebo-controlled, multicenter trial that will enroll patients with Ta G1 or G2 NMIBC. The patients will be randomized to receive either one instillation of apaziquone, two instillations of apaziquone, or placebo. The primary endpoint is Time to Recurrence. Since apaziquone is known to be inactivated in presence of blood, the new protocol includes a 30-60 minute waiting period post-TURBT, before apaziquone instillation. Patients that receive two instillations of apaziquone, will receive the second dose approximately two weeks after surgery minimizing the potential for drug inactivation due to bleeding. Further, it is recommended that patients with significant post-operative bleeding not receive apaziquone.

Apaziquone is an anticancer pro-drug that is activated by bio-reductive enzymes that are over-expressed in bladder cancer cells, rendering it into a highly cytotoxic alkylating agent. Spectrum has conducted two multi-center, international Phase 3 trials of a single intravesical instillation of apaziquone (4 mg) into the bladder in the immediate post-operative period after surgical resection of low-grade NMIBC. Pooled data from the two studies (n=1,615) showed a statistically significant treatment effect for the primary study endpoint, 2-Year Recurrence Rates, in favor of apaziquone (p-value = 0.0218) and in a key secondary endpoint, Time to Recurrence (p-value = 0.0096).

About Bladder Cancer

According to the National Cancer Institute, bladder cancer is the fifth most common malignancy in the US with 74,000 new cases of bladder cancer expected in 2015, and currently over 500,000 patients living with the disease. Due to high recurrence rates, intensive surveillance strategies, and expensive annual treatment costs, bladder cancer has the highest per patient costs, and an overall cost estimated at around $3.4 billion. Non-muscle invasive bladder cancer (NMIBC) is a form of bladder cancer that is localized in the surface layers of the bladder and has not invaded or spread to the deeper muscle layer. Approximately 70% of all patients newly diagnosed with bladder cancer have NMIBC. Urologists treat the disease predominantly by transurethral resection of the bladder tumor(s) (TURBT); in the U.S., there are approximately 300,000 TURBT procedures every year to treat bladder cancer. Because of the high recurrence rates, both professional urology associations and NCCN Guidelines recommend instillation of a cytotoxic agent following TURBT for NMIBC, although in the U.S., there are no FDA-approved agents for this indication.

On August 17, 2015 Kite Pharma, Inc. (Kite) (Nasdaq:KITE) treported an update from the Company’s ongoing Phase 1/2 clinical trial of KTE-C19 in patients with refractory aggressive non-Hodgkin’s lymphoma (NHL) who have failed prior chemotherapy treatments and have a poor prognosis (Press release, Kite Pharma, AUG 17, 2015, View Source [SID:1234507281]). KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a Chimeric Antigen Receptor (CAR) designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias.

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In May, Kite announced that the first patient was treated with KTE-C19 in the Phase 1 portion of the trial and we have since treated multiple patients. Complete responses have been observed by investigators. The responses happened shortly after treatment was administered and Kite is monitoring these patients to determine durability of treatment. To date, toxicities associated with treatment have been similar to those observed in the National Cancer Institute’s study of anti-CD19 CAR T cell therapy. There was one patient death early in the study, which was determined to be unrelated to KTE-C19 by the study investigator. After appropriate discussions with the U.S. Food and Drug Administration (FDA), Kite continued to enroll and treat patients in its study and the study was never placed on clinical hold. Kite has submitted an abstract and plans to present top-line data from the Phase 1 portion of the trial at the upcoming 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, to take place in Orlando, FL, December 5-8, 2015.

"We are encouraged by the progress of the KTE-C19 clinical trial and excited by the responses we have seen so far. We believe the KTE-C19 clinical findings are in line with previous results demonstrating the potential of this promising therapeutic approach," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer of Kite. "In agreement with ASH (Free ASH Whitepaper), we have taken this exceptional step of providing an update on the trial in order to address recent misinformation in the market related to our clinical program. We are on track to transition to the Phase 2 portion of the trial and plan to present Phase 1 data at ASH (Free ASH Whitepaper) later this year."

Kite’s Phase 1/2 clinical trial of KTE-C19 is a single arm, open-label, multi-center study, designed to determine the safety and efficacy of KTE-C19 in patients with refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). Upon completion of the Phase 1 portion of the study, Kite expects to proceed with the Phase 2 portion that will include a total of approximately 112 patients. Additional information about Kite’s Phase 1/2 study may be found at ClinicalTrials.gov, using Identifier NCT: 02348216.

On August 17, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on developing and commercializing proven cancer therapies in new orphan drug indications, reported an increase in funding of up to CDN$287,000 from the National Research Council of Canada Industrial Research Assistance Program (NRC-IRAP) to support an ongoing research project (Press release, DelMar Pharmaceuticals, AUG 17, 2015, View Source [SID:1234507280]).

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With the increase, NRC-IRAP’s total non-refundable financial contributions to DelMar total CDN$420,000 to date.

"We are very pleased with the continued support to accelerate and expand our non-clinical research to further establish the competitive differentiation of our lead product candidate VAL-083," said Jeffrey Bacha, president & CEO of DelMar Pharmaceuticals. "We have made tremendous progress this year executing on our clinical development strategy with VAL-083. These additional funds, along with support from the technological expertise and advisory services provided by NRC-IRAP, will be invaluable as we continue to advance VAL-083 in refractory glioblastoma multiforme (GBM) and expand its utility in other tumor types."

This most recent funding builds upon previous non-repayable contributions from NRC-IRAP totaling CDN$133,000 that supported research conducted in collaboration with University of British Columbia, the Vancouver Prostate Centre and the B.C. Cancer Agency. The increase in funding reflects the success of this research program to date. The results of the collaborative project, funded in part by the NRC-IRAP, support differentiation of the anti-cancer mechanism of VAL-083 and its potential as a treatment for other tumor types beyond its current Phase II GBM clinical trial into non-small cell lung cancer (NSCLC) and other solid tumors.

DelMar’s drug development program leverages numerous preclinical and clinical Phase I/Phase II historical research studies in which VAL-083 demonstrated activity, safety and efficacy in treating a wide range of tumor types including lung, brain, cervical and ovarian cancers. The Company intends to expand its clinical development program for VAL-083 into NSCLC and other solid tumors to target specific unmet medical needs in major cancer indications.

DelMar recently presented interim data of its ongoing Phase I/II clinical trial in patients with recurrent GBM at the American Association of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual meeting. The Company confirmed the completion of the Phase I dose-escalation portion of the trial and presented data supporting a dose response trend: Patients receiving a dose greater than or equal to 30mg/m2 had a median survival of 9.0 months vs. 4.4 months at doses less than 10mg/m2. DelMar also confirmed the initiation of a 14-patient Phase II expansion cohort at a dose of 40mg/m2. The purpose of the Phase II expansion cohort is to gain additional information about the safety and efficacy of VAL-083 at the 40mg/m2 dose prior to advancement into registration-directed Phase II/III clinical trials.

About VAL-083
VAL-083 is a "first-in-class", small-molecule chemotherapeutic. In more than 40 Phase 1 and 2 clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated safety and efficacy in treating a number of cancers including lung, brain, cervical, ovarian tumors and leukemia. VAL-083 is approved in China for the treatment of chronic myelogenous leukemia and lung cancer and has received orphan drug designation in Europe and the U.S. for the treatment of gliomas.

DelMar is currently studying VAL-083 in a multi-center Phase I/II clinical trial for patients with refractory glioblastoma multiforme (GBM) in accordance with the protocol that has been filed with the U.S. Food and Drug Administration (FDA). As a potential treatment for glioblastoma, VAL-083’s mechanism of action appears to be unaffected by the expression of MGMT, a DNA repair enzyme that causes chemotherapy resistance to front-line treatment with Temodar (temozolomide).

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.
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