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Onxeo Announces 9th Positive DSMB Recommendation to Continue Livatag® ReLive Phase III Trial in HCC

On November 21, 2016 Onxeo S.A. (Euronext Paris, Nasdaq Copenhagen: ONXEO), a biopharmaceutical company specializing in the development of innovative drugs for the treatment of orphan diseases, in particular in oncology, reported that the company has received the 9th unanimous recommendation from the Data Safety Monitoring Board (DSMB), an independent European board of experts that monitors the safety of the Livatag Phase III trial, "ReLive", to continue the study without modification (Press release, Onxeo, NOV 21, 2016, View Source [SID1234516731]).

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The nine consecutive positive DSMB recommendations reinforce the acceptable safety profile of Livatag. The ReLive study is an ongoing international, randomized Phase III trial designed to evaluate the efficacy of intravenous (IV) administration of Livatag in patients with advanced hepatocellular carcinoma (HCC) after failure or intolerance to sorafenib. The study plans to enroll a total of 400 patients across approximately 90 sites. To date, more than 90% of the patients have been randomized in the study. The DSMB reviews the safety data of the treated patients in the study, totaling more than 900 infusions of Livatag.

"As we are approaching complete randomization in the ReLive study, we are, once again, encouraged by the DSMB’s positive recommendation which confirmed the acceptable safety profile of Livatag as regards to unexpected safety events. Enrolment is well on track and we should reach the 400 patients in the coming weeks, which comforts us in our planning of preliminary data announcement mid-2017. Livatag’s potential to address the unmet medical need for HCC patients combined with the drug’s favorable safety profile is a significant cornerstone in Onxeo’s mission to develop innovative medicines for patients, providing patients with new therapeutic options, and a significant catalyst for the company value," said Judith Greciet, CEO of Onxeo.

As per study protocol, the DSMB meets twice a year since study initiation to review the safety data of the ReLive trial and subsequently issues recommendations on the conduct of the study.

Celyad announces the approval to initiate its NKR-2 CAR-T Clinical Trial in Belgium

On November 21,2016 Celyad (Euronext Brussels and Paris, and NASDAQ: CYAD), a leader in the discovery and development of engineered cell therapies, reported the approval in Belgium to initiate the THINK clinical trial (Press release, Celyad, NOV 21, 2016, View Source [SID1234516730]). THINK is the second clinical trial of its NKR-2 product candidate, a CAR-T cell therapy using NKG2D ligands as a target, to evaluate safety and efficacy in seven cancer indications including both solid and hematological malignancies.

THINK (THerapeutic Immunotherapy with NKR-2) is a multinational open-label Phase Ib study to assess the safety and clinical activity of multiple administrations of autologous NKR-2 T-cells in seven, refractory cancers including five solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and two hematological tumors (acute myeloid leukemia and multiple myeloma).

This trial will be conducted in the US and in Europe. It contains a dose escalation and an extension stage. The dose escalation will be conducted in parallel in the solid tumor and in the liquid cancer groups, while the extension phase will evaluate in parallel each tumor independently.

The dose escalation design will include three dose levels adjusted to body weight: up to 3×108, 1×109 and 3×109 NKR-2 T-cells. At each dose, the patients will receive three successive administrations, two weeks apart, of NKR-2 T-cells at the specified dose. The dose escalation part of the study will enroll up to 24 patients while the extension phase would enroll 86 additional patients.

The seven indications evaluated in the THINK trial were selected based on evidence generated in the pre-clinical settings and in the first study recently completed (a Phase I single injection, dose escalation study evaluating NKR-2 T-cells in 12 patients suffering from Acute Myeloid Leukemia (AML) or Multiple Myeloma (MM) at Dana Farber Cancer Institute in Boston, MA, USA).

Dr. Christian Homsy, CEO of Celyad commented: "We are extremely happy to be able to start this next phase of the clinical development program of NKR-2, building on the successful outcome of the single dose, dose escalation trial, to be presented at ASH (Free ASH Whitepaper). We now look forward to treating the first patients in Belgium, and to receiving FDA clearance to initiate the trial at our US-based sites."

Dr. Frédéric Lehmann, VP Clinical Development and Medical Affairs at Celyad added: "We are excited to initiate this multiple tumor study with key cancer institutions in Belgium. While immunotherapy is rapidly transforming the treatment of patients with cancer, there remains a significant unmet medical need for more effective therapies. It is our hope that Celyad’s NKR-2 T-cells have the potential to be truly disruptive in the way we treat cancer and this study is one more step towards that goal."

CEL-SCI SUBMITS RESPONSE TO FDA IN CONNECTION WITH PARTIAL CLINICAL HOLD ON PHASE 3 CLINICAL TRIAL

On November 21, 2016 -CEL-SCI Corporation (NYSE MKT: CVM) reported that it has submitted its response to the U.S. Food and Drug Administration (FDA) regarding the previously announced partial clinical hold of CEL-SCI’s Phase 3 clinical trial of its investigational drug Multikine* (Leukocyte Interleukin, Injection) in patients with squamous cell carcinoma of the head and neck (Press release, Cel-Sci, NOV 21, 2016, View Source [SID1234516728]).

Aeglea BioTherapeutics Announces Publication in Nature Medicine Demonstrating that Targeting Tumor Oxidative Stress with AEB3103 Suppresses Cancer Growth in Preclinical Models

On November 21, 2016 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat genetic rare diseases and cancer, reported results of preclinical studies demonstrating that its product candidate AEB3103 suppressed the growth of tumors in models of prostate and breast cancer and extended survival in a model of chronic lymphocytic leukemia (CLL) (Press release, Aeglea BioTherapeutics, NOV 21, 2016, View Source [SID1234516727]). The article entitled "Systemic depletion of serum L-Cyst(e)ine with an engineered human enzyme induces production of reactive oxygen species and suppresses tumor growth in mice" was published online today in Nature Medicine.

In these preclinical models, AEB3103 deprived tumors of a key ingredient for cysteine-dependent anti-oxidant pathways, such as in the production of glutathione, which are involved in protecting tumors from oxidative stress due to reactive oxygen species (ROS). AEB3103 systemically degraded serum L-cysteine and its oxidized form L-cystine resulting in increased oxidative stress and cancer cell death.

"These preclinical results suggest that the use of AEB3103 to deplete the amino acid L-cysteine has the potential to be a well-tolerated approach for treating tumors with high levels of ROS. The idea of targeting cancer with an enzyme that degrades L-cysteine was first proposed in 1961. Since then, the evidence that this is an important and unexploited vulnerability of cancer has been widely described but not effectively applied for therapeutic benefit," said David G. Lowe, Ph.D., president and chief executive officer of Aeglea. "Our results with AEB3103 also provide support for our broader cancer strategy of using well established amino acid biology to target tumor metabolism."

"Preclinical findings showed that AEB3103 had a potent anti-tumor effect in multiple solid tumor models, including prostate and breast cancer, and was well tolerated for more than five months. This suggests AEB3103 could be a safe and effective alternative to experimental drugs targeting oxidative stress that are currently under clinical evaluation," said study co-author George Georgiou, Ph.D., co-founder of Aeglea and Laura Jennings Turner Chair in Engineering at the University of Texas at Austin. "As many other chemotherapeutic agents are also known to oxidatively stress cancer cells, we are looking forward to exploring AEB3103 in combination with ROS-inducing drugs as a potential cancer treatment."

"In these preclinical studies, treatment with AEB3103 demonstrated significantly longer survival in a CLL animal model compared to treatment with the standard of care alone, indicating that AEB3103 has potential as a treatment for hematological malignancies as well as solid tumors," said Peng Huang, M.D., Ph.D., co-author of the published paper and professor, Department of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center in Houston. "Of particular interest, AEB3103 was effective at treating CLL patient samples with 17p deletions, a mutation associated with more aggressive disease that can be resistant to treatment with standard of care drugs such as fludarabine."

Rationale for Preclinical Studies

Tumors cells experience an abnormally high level of oxidative stress through ROS and, as a result, require elevated levels of anti-oxidant compounds for their survival and growth. Oxidative stress is one of the hallmarks of cancer and occurs in numerous tumor types. It had been suspected for several decades that the levels of ROS stress and the ensuing increased demand for anti-oxidants may represent an opportunity for the development of therapeutics that selectively increase the oxidative stress of cancer cells but do not impact normal tissues. However, earlier efforts to develop therapeutics that block the synthesis of glutathione, one of the major cellular anti-oxidants, or to inhibit other cellular pathways that serve to protect cancer cells from ROS had not been successful.

The defense of tumor cells against ROS is critically dependent on the absorption of L-cysteine and its oxidized form L-cystine from the blood. L-cysteine is used to make glutathione and plays a central role in other cellular anti-oxidant mechanisms. The requirement for extracellular L-cysteine to support cancer cell growth is well established in hematological malignancies such as myeloma, acute myelogenous leukemia and CLL, and solid tumors such as glioblastoma, triple negative breast cancer, esophageal squamous cell carcinoma, small cell lung cancer and prostate carcinoma. AEB3103, an engineered human enzyme that in these preclinical studies efficiently degraded L-cysteine in serum into non-toxic metabolites, was developed to exploit this metabolic vulnerability, killing tumor cells by depriving them of a key anti-oxidant precursor.

Results of Preclinical Studies

Results showed that administration of AEB3103 significantly reduced L-cysteine/cystine in the serum, depleting intracellular glutathione and elevating ROS, resulting in cell cycle arrest/death in cancer cells. When tested in mouse tumor models, AEB3103 suppressed the growth of human prostate cancer cells, and reduced the growth of mouse prostate and breast cancer cells. Additionally, AEB3103 had an improved therapeutic effect over the standard of care drug fludarabine in a mouse genetic model of CLL, doubling the median survival time from 3.5 to 7 months. AEB3103 was also effective in treating CLL patient samples with 17p deletions. This genetic deletion is a hallmark for the loss of the tumor suppressor gene p53, the most commonly mutated gene in human cancers. Patients with these deletions often develop more aggressive disease and are typically resistant to standard of care drugs such as fludarabine.

AEB3103 in CLL Models

The effect of AEB3103 was studied both alone and in combination with fludarabine, a standard of care for CLL, in leukemic cells from an animal model of CLL. Results showed that the leukemic cells were moderately affected by fludarabine but were killed by treatment with AEB3103. A separate long-term survival study conducted in the mouse genetic model of CLL treated with either fludarabine, AEB3103 or the combination showed that the median survival time in untreated animals was 3.5 months compared with a median survival time of 5.3 months for fludarabine treated animals (p<0.001). Those treated with AEB3103 exhibited a significantly longer median survival time of 7 months (p<0.0001). The combination of fludarabine and AEB3103 showed a slight but not statistically significant improvement in median survival (p=0.092, 7.4 months vs. 7 months) compared with AEB3103 alone. AEB3103 was well tolerated with the longest surviving animals treated twice a week for over 5 months.

A separate study evaluated the efficacy of AEB3103, fludarabine or the combination against primary leukemia cells isolated from CLL patients with or without 17p deletions (17p- CLL cells and 17p wt CLL cells, respectively). Treatment for 48 hours with AEB3103 alone or in combination with fludarabine was efficacious in killing both p17 wt CLL cells and 17p- CLL cells. In contrast, fludarabine treatment alone only moderately impacted p17 wt CLL cells in the presence of stromal cells that provide trophic support for the cancer cells, and was even less effective against 17p- CLL samples, consistent with the known chemotherapeutic resistance arising from 17p deletions. Both patient-derived CLL cells and CLL cells from the mouse genetic model showed a marked reduction in glutathione levels following treatment with AEB3103 for 24 hours and a concomitant increase in ROS levels. Collectively, the results suggest that treatment with AEB3103 induces death in cancer cells that depend on an exogenous supply of L-cysteine/cystine for survival.

Teva Secures European Approval of Trisenox® for First Line Treatment of Low to Intermediate Risk Acute Promyelocytic Leukemia (APL)

On November 21, 2016 Teva Pharmaceutical Industries Ltd., (NYSE and TASE:TEVA) reported it has obtained approval from the European Commission for an indication extension of Trisenox (arsenic trioxide) (Press release, Teva, NOV 21, 2016, View Source [SID1234516724]). This marks an important advancement in treatment for Acute Promyelocytic Leukemia (APL) patients in Europe, as it is the first time that a form of acute leukemia can be effectively treated with a regimen that is entirely chemotherapy-free. APL is a rare and aggressive type of acute leukemia that can kill within hours or days if left untreated2. Trisenox, in combination with retinoic acid, has shown a 99% overall survival rate with almost no relapses after more than four years (50 months) of median follow-up1.

"Teva is committed to providing wider access to high-quality medicines to ensure more people can benefit from the treatments they need. We’re very pleased by this decision of the European Commission, and we look forward to offering a chemotherapy-free treatment option for all newly diagnosed APL patients," said Rob Koremans, MD, President & CEO, Teva Global Specialty Medicines.
The decision by the European Commission, which follows a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on October 13, grants marketing authorization for first line use of Trisenox in the 28 countries of the European Union. The indication extension is for newly diagnosed low to intermediate risk Acute Promyelocytic Leukemia (APL) in combination with retinoic acid. Today’s announcement points to a recognition by the European Commission that treating low to intermediate risk APL with a chemo-free regimen of Trisenox plus retinoic acid can increase survival rates, dramatically reduce the risk of relapse, and help avoid chemotherapy-related side effects, such as the risk of life-threatening infections.

Welcoming the approval, Francesco Lo-Coco, Professor of Haematology and Head of the Laboratory of Integrated Diagnosis of Oncohematologic Diseases, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy said, "This approval by the European Commission is good news for APL patients as we now have access to a cure for an acute leukemia without using chemotherapy. Moreover, this decision is a very positive endorsement by the European Commission, as it was made based solely on published academic research and studies. From now on, APL patients with non-high risk disease will have access to this chemotherapy-free regimen of Trisenox plus retinoic acid at diagnosis, which has the potential to increase survival rates while minimizing side effects associated with chemotherapy."
In Europe, approximately 1,500 to 2,000 people are diagnosed with APL each year3. APL, a life-threatening form of leukemia, can cause uncontrollable bleeding leading rapidly to death if left untreated2. The rapid progression of APL leading to early mortality is a substantial problem, affecting up to 30% of patients4. Rapid diagnosis and commencement of treatment is essential to avoid early mortality2,5.

About Acute Promyelocytic Leukemia
Acute Promyelocytic Leukemia is a form of acute myeloid leukemia (AML), a cancer of the blood-forming tissue (bone marrow). Approximately 5% to 10% of patients initially diagnosed with AML present with the aggressive sub-type of the condition, APL6.
In normal bone marrow, hematopoietic stem cells produce red blood cells (erythrocytes) that carry oxygen, white blood cells (leukocytes) that protect the body from infection, and platelets (thrombocytes) that are involved in blood clotting. In APL, immature white blood cells called promyelocytes accumulate in the bone marrow. The overgrowth of promyelocytes leads to a shortage of normal white and red blood cells and platelets in the body, which causes many of the signs and symptoms of the condition.

People with APL are especially susceptible to developing bruises, small red dots under the skin (petechiae), nosebleeds, bleeding from the gums, blood in the urine (hematuria), or excessive menstrual bleeding. The most important lethal bleeding sites are pulmonary (35%) and intracranial (65%)7. The abnormal bleeding and bruising occur because leukemic blasts produce anticoagulant factors and substances are released that cause excessive blood clotting, leading as a consequence to a low number of platelets in the blood (thrombocytopenia). The low number of red blood cells (anemia) can cause people with acute promyelocytic leukemia to have pale skin (pallor) or excessive tiredness (fatigue). In addition, affected individuals may heal slowly from injuries or have frequent infections due to the decrease of normal white blood cells that fight infection. Furthermore, the leukemic cells can expand into the bones and joints, which may cause pain in those areas. Other general signs and symptoms may occur as well, such as fever, loss of appetite, and weight loss.

APL is generally diagnosed in much younger patients than in AML (the median age is approximately mid-408,9 for APL patients and 67 for AML patients10), and can be diagnosed in patients of any age.

About Trisenox
On 5 March 2002, the European Commission granted approval for the Marketing Authorization Application (MAA) for Trisenox. The authorization, which was valid throughout the European Union (EU), was granted to treat patients with relapsed or refractory acute promyelocytic leukemia (APL) and characterized by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptoralpha (PML/(RARα) gene. Trisenox, a targeted drug, degrades the PML- RARα fusion protein. Trisenox received marketing authorization in 2000 by the U.S. Food and Drug Administration.

The marketing approval for Trisenox was granted based on results from a multicenter study in which 40 relapsed APL patients were treated with Trisenox 0.15 mg/kg until bone marrow remission or a maximum of 60 days. Thirty-four patients (85 percent) achieved complete remission after two cycles. When the results for these 40 patients were combined with those for the 12 patients in a pilot trial, an overall response rate of 87 percent was observed11.

1mL of Trisenox contains 1mg of arsenic trioxide. Trisenox is a concentrate for solution for infusion. It is a sterile, clear, colorless, aqueous solution. Trisenox must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and special monitoring procedures must be followed.
Study Results
The APL0406 Intergroup GIMEMA-AMLSG-SAL study was a prospective, randomized, multicenter, open-label, phase III non-inferiority study1. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, genetically proven low- or intermediate-risk APL (WBC at diagnosis ≤ 103 x 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3%v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P , .001, P = .0013, and P = .0073, respectively).
Post-induction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm.
References:
1. Journal of Clinical Oncology, July 11, 2016 as 10.1200/JCO.2016.67.1982.Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non–High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. Professor Uwe Platzbecker et al. View Source
2. Coombs CC, et al. Blood Cancer J. 2015;5,e304.
3. Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116(19):3724-34.
4. Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011;25:1128–34
5. Lo-Coco F. Blood. 2011;118:1188-9
6. Cicconi L, Lo-Coco F. Ann Oncol. 2016;27:1847-81
7. De la Serna J, et al. Blood. 2008;111:3395-402
8. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD. View Source, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed June 8, 2016.
9. Lo-Coco F, Cicconi L, Breccia M. Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol. 2015. doi.10.1111.bjh.13890.
10. National Cancer Institute SEER Stat Factsheet Acute Promyelocytic Leukemia View Source accessed 16 Nov 2016
11. Soignet SL, et al. J Clin Oncol. 2001;19:3852-3860.