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Aldoxorubicin Continues To Demonstrate Positive Clinical Activity In Phase 2 Glioblastoma Trial

On November 23, 2015 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that it has achieved its target enrollment of 28 patients with unresectable glioblastoma multiforme (GBM), a deadly form of brain cancer, in its Phase 2 trial with aldoxorubicin (Press release, CytRx, NOV 23, 2015, View Source [SID:1234508321]).

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To date, aldoxorubicin has shown evidence of tumor shrinkage, and overall survival has not yet been reached. Additionally, an advisory board of neuro-oncologists recently met to review the updated Phase 2 results and concluded that aldoxorubicin should be evaluated in combination with Avastin in what could potentially be a pivotal trial in patients with late-stage GBM.

"The initial findings strongly indicate that aldoxorubicin has significant anti-tumor activity in patients with GBM," said Morris D. Groves, M.D., Neuro-Oncologist, Texas Oncology-Austin Brain Tumor Center and co-principal investigator of the trial. "Pseudo-progression prevented us from determining the true efficacy of this agent since subjects may have been removed from aldoxorubicin treatment prematurely. Adding Avastin to aldoxorubicin may increase the uptake of this drug into tumors leading to improved efficacy. "

The open-label, multisite single-arm trial is investigating the preliminary efficacy and safety of aldoxorubicin in patients whose tumors have progressed following prior treatment with surgery, radiation and temozolomide. Patients to date received from 1 to 20 cycles of either 350 mg/m2 (260 mg/m2 doxorubicin equivalents) (n=6) or 250 mg/m2 (185 mg/m2 doxorubicin equivalents) (n=22) of aldoxorubicin intravenously on Day 1, and every 21 days thereafter until discontinuation. Median overall survival (range: 1 to 16+ months) has not yet been reached. Fifty-seven percent (16 of 28) of patients continue to be followed for survival with six patients still receiving aldoxorubicin treatment. Clear evidence of pseudo-progression was demonstrated in the tumor lesions of at least 4 subjects either after surgical debulking or by Dynamic Susceptibility Contrast MRI. Other subjects demonstrated extensive tumor necrosis on pathology with small amounts of residual tumor. Pseudo-progression refers to post-treatment imaging changes in the tumor where the tumor appears larger compared to the pre-treatment baseline images. These changes can be misleading in that the tumor appears to get worse (true progression), when in fact the changes may be the result of tumor destruction and related swelling around the tumor bed.

Aldoxorubicin was well tolerated at both dose levels, with all adverse events consistent with known doxorubicin toxicities. No subject has had a decrease in their cardiac function. At the 250 mg/m2 dose, the most common grade 3 or 4 adverse events included neutropenia, fatigue, thrombocytopenia and mucositis. All adverse events resolved prior to the subsequent dose of aldoxorubicin. Only four patients have had aldoxorubicin-related serious adverse events and all have been resolved successfully.

An Advisory Board of neuro-oncology experts recently reviewed the data from this trial. They concluded that aldoxorubicin clearly demonstrated anti-tumor activity with a favorable safety profile and that a randomized, comparative pivotal trial combining aldoxorubicin with Avastin compared to Avastin in patients who have relapsed after initial therapy was warranted.

"By adding Avastin to a treatment regimen with aldoxorubicin, we may be able to improve upon the activity of the agents in these very needy patients," said Daniel Levitt, M.D., Ph.D., CytRx Executive Vice President and Chief Medical Officer. "We plan to develop a protocol for a comparative potential pivotal trial based on the positive feedback from our advisors. We look forward to discussing the protocol with regulatory agencies, like the FDA, once we have the final data from the Phase 2 trial."

This Phase 2 study follows positive confirmatory results reported in 2013 from a preclinical study in which aldoxorubicin demonstrated statistically significant efficacy (p<.0001) in the treatment of rapidly growing human brain (glioblastoma) cancer in the brains of animals. In that study, animals treated with aldoxorubicin had median survival of more than 63 days, compared with approximately 25 days for animals treated with doxorubicin or saline. In addition, because aldoxorubicin uptake was confined to the tumor in the brain rather than normal brain tissue, the principal investigator concluded that aldoxorubicin has the potential to safely shrink glioblastoma tumors, which could dramatically prolong patient survival.

About Glioblastoma Multiforme

Glioblastoma is the most common and most malignant primary brain tumor in adults and afflicts more than 12,000 new patients in the U.S. annually. The median survival after diagnosis is approximately 14 months, despite patients subsequently receiving surgical resection, radiotherapy and chemotherapy. Limited efficacy of chemotherapeutic agents has been attributed to several contributing factors including insufficient drug delivery to the tumor site through the blood-brain barrier.

About Aldoxorubicin

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 ½ to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

Baxalta Receives Positive CHMP Opinion for Use of ONCASPAR (pegaspargase) in European Union as a Component of Combination Therapy in Acute Lymphoblastic Leukaemia (ALL)

On November 23, 2015 Baxalta Incorporated (NYSE:BXLT), a global biopharmaceutical leader dedicated to delivering transformative therapies to patients with orphan diseases and underserved conditions, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending marketing authorization for use of ONCASPAR as a component of antineoplastic combination therapy in acute lymphoblastic leukaemia (ALL) in paediatric patients from birth to 18 years, and adult patients (Press release, Baxalta, NOV 23, 2015, View Source [SID:1234508319]).

The CHMP’s positive opinion will now be referred to the European Commission (EC), which grants marketing authorization for medicines in the European Union. Pending EC approval, Baxalta will be authorized to market ONCASPAR in the 28 member countries of the European Union (EU), as well as Iceland, Liechtenstein and Norway.

Pending EC approval, ONCASPAR will provide an important treatment option for more European patients with this rapidly progressing cancer of the white blood cells responsible for more than 80 percent of childhood leukaemia cases2 – the most common type of childhood cancer.

"We are pleased to receive a positive CHMP opinion for ONCASPAR as part of a multi-agent chemotherapy regimen in paediatric and adult populations; this is a significant milestone in increasing patient access to this important biologic treatment for patients impacted by ALL," said John Orloff, M.D., head of Research & Development and chief scientific officer, Baxalta. "At Baxalta, we are committed to expanding the availability of ONCASPAR globally, and this decision makes a curative treatment available to more patients across the world."

Today, children in the U.S. diagnosed with ALL have a survival rate of more than 90 percent – a direct result of multi-agent chemotherapy treatments. ONCASPAR is a key component of these curative therapies. Currently, there have been national licenses granted to market ONCASPAR in Argentina, Belarus, Germany, Kazakhstan, Poland, Russia, Ukraine and the United States.

About ONCASPAR (pegaspargase)

In the U.S., ONCASPAR (pegaspargase) is indicated as a component of a multi-agent chemotherapeutic regimen for the first–line treatment of patients with acute lymphoblastic leukaemia (ALL) and for the treatment of patients with ALL and hypersensitivity to native forms of L-asparaginase.

Important Safety Information for ONCASPAR

ONCASPAR is contraindicated in patients with a history of serious allergic reactions to pegaspargase, and in patients with a history of pancreatitis, serious thrombosis, or serious hemorrhagic events with prior L-asparaginase therapy.

The most common adverse reactions with ONCASPAR (=2%) are allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system (CNS) events, thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) has been reported in patients exposed to ONCASPAR.

Patients should be observed for one hour after administration as anaphylaxis or serious allergic reactions can occur. Discontinue ONCASPAR in patients that develop pancreatitis, serious allergic reactions, or serious thrombotic events. Patients with abdominal pain should be evaluated for evidence of pancreatitis.

Serum glucose should be monitored as irreversible glucose intolerance can occur in some cases. Coagulopathy and hepatotoxicity can occur; appropriate monitoring should be performed.

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About Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukaemia (ALL) is a rare, fast-growing cancer of the white blood cells, and each year there are approximately 4,000-5,000 new cases in Europe and the United States, respectively. The disease is the most common childhood cancer and is responsible for more than 80 percent of childhood leukaemia cases. The five-year paediatric survival rate has climbed to 90 percent with modern therapies.

Aduro Biotech Receives Orphan Drug Designation in the European Union for CRS-207 for the Treatment of Mesothelioma

On November 23, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that the European Medicines Agency (EMA) granted Orphan Drug Designation to CRS-207 for the treatment of malignant pleural mesothelioma (MPM) (Press release, Aduro BioTech, NOV 23, 2015, View Source [SID:1234508317]).

"The receipt of Orphan Drug Designation in the European Union (EU) for CRS-207 for the treatment of MPM marks a significant regulatory milestone for Aduro, as we expand our operations in Europe and advance our therapies closer to the commercial marketplace," said Stephen T. Isaacs, chairman, president and chief executive officer of Aduro. "We look forward to working with the EMA to expeditiously advance CRS-207 through development with the goal of bringing this potential therapy to patients throughout Europe suffering from mesothelioma."

To receive Orphan Drug Designation from the EMA, a therapy must be intended for the treatment of a life-threatening or chronically debilitating rare condition with a prevalence of less than five in 10,000 in the European Union. Orphan Drug Designation provides incentives designed to facilitate development, including protocol assistance and scientific advice and importantly, may provide up to ten years of market exclusivity in the EU following product approval.

Aduro is conducting a Phase 1b study of CRS-207 in combination with standard of care chemotherapy in patients with unresectable malignant pleural mesothelioma. The company plans to advance directly to a Phase 3 clinical trial with CRS-207 in combination with standard-of-care chemotherapy in patients with unresectable MPM in the first half of 2016. In addition to the newly granted Orphan Drug Designation from the EMA, CRS-207 received Orphan Status for the treatment of mesothelioma from the U.S. Food and Drug Administration in March 2015.

About CRS-207

CRS-207 is one of a family of product candidates based on Aduro’s live-attenuated, double-deleted (LADD) Listeria monocytogenes immunotherapy platform that induces a potent innate and T cell-mediated adaptive immune response. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

Roche presents early data on investigational cancer immunotherapy atezolizumab in combination with Zelboraf in patients with BRAFV600 mutant-positive metastatic melanoma

On November 23, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from a phase Ib study of the investigational cancer immunotherapy atezolizumab (MPDL3280A), used in combination with the BRAF inhibitor Zelboraf (vemurafenib) for previously untreated BRAFV600 mutation-positive unresectable or metastatic melanoma (Press release, Hoffmann-La Roche , NOV 23, 2015, View Source [SID:1234508314]).

Adverse events (AEs) were manageable and generally reversible. The study also showed that the combination resulted in an objective response rate [ORR] of 76% (95% confidence interval [CI:] 50.1%–93.2%) of people (n=17), including three complete responders (CR). The data were presented at the Society of Melanoma Research (SMR) 2015 International Congress.1

"These early efficacy results encourage us to further evaluate combination strategies of atezolizumab and targeted therapies like Zelboraf in people living with advanced melanoma, a disease which is still associated with a poor prognosis", Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development.

Roche is also investigating a triplet regimen with atezolizumab plus the established targeted therapy combination of Zelboraf and Cotellic (cobimetinib), a selective MEK inhibitor, in a phase Ib study.

About the phase Ib study of atezolizumab in combination with Zelboraf

This phase Ib, open-label study aimed to evaluate the safety and pharmacology of atezolizumab in combination with Zelboraf in patients with previously untreated BRAFV600 mutation-positive metastatic melanoma
17 patients were evaluable for safety and efficacy at the time of this data cut
Patients received atezolizumab combined with Zelboraf concurrently (Cohort 1 [C1], n=3) or after a run-in period with Zelboraf alone of 56 days (Cohort 2 [C2]; n=8) or 28 days (Cohort 3 [C3]; n=6)
Patients were given atezolizumab intravenously every 3 weeks at 20 mg/kg (C1) or 15 mg/kg (or 1,200 mg fixed; C2/C3). Oral Zelboraf was given twice daily at 960 mg during the run-in period and at 720 mg during atezolizumab and Zelboraf combined treatment

PD-L1 expression was centrally assayed using immunohistochemistry (IHC; SP142 assay)

About BRAFV600 mutation-positive metastatic melanoma
Melanoma is less common, but more aggressive and deadlier, than other forms of skin cancer.2,3 A mutation of the BRAF protein occurs in approximately half of melanomas, and a test can be used to determine who can be treated with a BRAF-inhibitor.4 When melanoma is diagnosed early, it is generally a curable disease,5,6 but most people with advanced melanoma have a poor prognosis.3 More than 232,000 people worldwide are currently diagnosed with melanoma each year.7 In recent years, there have been significant advances in treatment for metastatic melanoma, and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.8

About atezolizumab
Atezolizumab (also known as MPDL3280A) 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, restoring their ability to effectively detect and attack tumour cells.

About Zelboraf
Zelboraf was the first approved treatment for patients with unresectable or metastatic melanoma with BRAFV600 mutation as detected by a validated test, such as Roche’s cobas 4800 BRAF Mutation Test. Zelboraf is not indicated for use in patients with wild-type BRAF melanoma.

About Cotellic plus Zelboraf
Cotellic and Zelboraf are used in combination to treat unresectable or metastatic melanoma with BRAFV600 mutation. Found in approximately half of melanomas, mutated BRAF causes abnormal signalling inside certain cancer cells leading to tumour growth. Zelboraf binds to mutant BRAF, to interrupt abnormal signalling that can cause tumours to grow.9,10 Cotellic is designed to inhibit some forms of MEK. Both BRAF and MEK are proteins in a cell signalling pathway that help control cell growth and survival. When used in combination, Cotellic and Zelboraf are thought to reduce cancer cell growth longer than Zelboraf alone. A patient’s healthcare provider will perform a test to make sure Cotellic and Zelboraf are right for the patient. It is not known if Cotellic and Zelboraf are safe and effective in children under 18 years of age.

Cotellic was approved in Switzerland in August 2015 and in the US in November 2015. In September, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) issued a positive opinion for Roche’s marketing authorisation application for Cotellic in the European Union. A decision from the European Commission is expected before the end of 2015.

Updated data showed Cotellic in combination with Zelboraf helped people with a specific type of advanced melanoma live significantly longer than with Zelboraf alone

On November 23, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported data from the pivotal coBRIM study, which showed that Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib) helped people with BRAF V600E and V600K mutation-positive unresectable or metastatic melanoma live significantly longer (overall survival; OS) than with Zelboraf alone (Press release, Hoffmann-La Roche , NOV 23, 2015, View Source [SID:1234508313]).1

Cotellic plus Zelboraf reduced the risk of death by 30 percent compared to Zelboraf alone and helped people live a median of nearly two years (median OS 22.3 months vs. 17.4 months, hazard ratio [HR]=0.70, 95 percent CI: 0.55–0.90, p=0.005).1 Ongoing study monitoring did not identify any new safety signals. The final coBRIM OS results were presented during the 12th International Congress of the Society for Melanoma Research (SMR) held in San Francisco, California from 18 – 21 November.

"With about half of the people taking Cotellic and Zelboraf alive after two years, these data underscore the progress being made in cancer research towards better patient outcomes." said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "Five years ago, the survival rate for BRAF mutation-positive advanced melanoma was measured in months, and now we are measuring it in years."

This final analysis of the OS data from coBRIM showed that with the combination of Cotellic and Zelboraf, 74.5 percent of people with BRAF V600 mutation-positive advanced melanoma in the study were alive at one year and 48.3 percent were alive at two years.

The data were presented in an oral session presentation by Dr. Victoria Atkinson, Medical Oncologist at Princess Alexandra Hospital, Queensland, Australia on 21 November.

The announcement follows the U.S. Food and Drug Administration (FDA) approval of Cotellic for the treatment of people with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma in combination with Zelboraf. A decision from the European Commission is expected before the end of 2015. The final OS results are being submitted to both of these health authorities for consideration.

About the coBRIM study
CoBRIM is an international, randomised, double-blind, placebo-controlled Phase III study evaluating the safety and efficacy of 60 mg once daily of Cotellic plus 960 mg twice daily of Zelboraf compared to 960 mg twice daily of Zelboraf alone. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomised to receive Zelboraf every day on a 28-day cycle plus either Cotellic or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS is the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.2

About Cotellic plus Zelboraf
Cotellic and Zelboraf are prescription medicines used in combination to treat melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene. Found in approximately half of melanomas3, mutated BRAF causes abnormal signaling inside cancer cells leading to tumor growth4,5. Zelboraf is designed to inhibit some mutated forms of BRAF and Cotellic is designed to inhibit some forms of MEK6. Both BRAF and MEK are proteins in a cell signaling pathway that help control cell growth and survivals7. When used in combination, Cotellic and Zelboraf are thought to reduce cancer cell growth longer than with Zelboraf alone. A patient’s healthcare provider will perform a test to make sure Cotellic and Zelboraf are right for the patient. Cotellic and Zelboraf are not used to treat melanoma with a normal BRAF gene. It is not known if Cotellic and Zelboraf are safe and effective in children under 18 years of age.

Cotellic is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumour types such as non-small cell lung cancer and colorectal cancer. Cotellic was discovered by Exelixis Inc. and is being developed by Roche in collaboration with Exelixis.

About melanoma
Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer.8,9 When melanoma is diagnosed early, it is generally a curable disease,10,11 but most people with advanced melanoma have a poor prognosis.8 More than 232,000 people worldwide are currently diagnosed with melanoma each year12 In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years.13