On September 3, 2015 Sandoz, a Novartis company, reported that ZarxioTM (filgrastim-sndz) is now available in the United States (Press release, Sandoz, NOV 20, 2015, View Source [SID:1234508310]). Zarxio is the first biosimilar approved by the US Food and Drug Administration (FDA) and the first to launch in the US."

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As the pioneer and global leader in biosimilars, Sandoz has maintained a commitment to bringing high-quality biosimilar medicines to patients and healthcare professionals around the world," said Richard Francis, Global Head, Sandoz. "With the launch of Zarxio, we look forward to increasing patient, prescriber and payor access to filgrastim in the US by offering a high-quality, more affordable version of this important oncology medicine."

"While biologics have had a significant impact on how diseases are treated, their cost and co-pays are difficult for many patients and the healthcare budget in general. Biosimilars can help to fill an unmet need by providing expanded options, greater affordability and increased patient access to life-saving therapies," said Dr. Ralph Boccia, Medical Director of the Center for Cancer and Blood Disorders, and Chief Medical Officer for the International Oncology Network (ION).

Sandoz understands the importance of providing comprehensive patient support services in the oncology setting. With the launch of Zarxio, Sandoz is also proud to offer Sandoz One SourceTM a patient services center, providing support that connects the patient to the information and resources they need.

The launch follows the FDA approval of Zarxio on March 6, 2015. The approval, via the new biosimilars pathway established under the Biologics Price Competition and Innovation Act, was based on a comprehensive package of analytical, nonclinical, and clinical data, which confirmed that Zarxio is highly similar with no clinically meaningful differences to the US-licensed reference product. The successful Sandoz pivotal head-to-head PIONEER study was the final piece of data contributing to the totality of evidence used by FDA to approve Zarxio as biosimilar to the reference product. Importantly, the data demonstrating high similarity was sufficient to allow extrapolation of use of Zarxio to five indications of the reference product.

Sandoz has an unwavering commitment to increasing patient access to high-quality, life-enhancing biosimilars. Sandoz is the global market leader and currently markets three biosimilars outside the US. Sandoz has a leading pipeline with several biosimilars across the various stages of development, including five programs in Phase III clinical trials/filing preparation.

For more information on Zarxio, please visit www.zarxio.com.INDICATIONS

Patients with Cancer Receiving Myelosuppressive Chemotherapy: to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe neutropenia with fever.

Patients with Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy: to reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia (AML).

Patients with Cancer Undergoing Bone Marrow Transplantation: to reduce the duration of neutropenia and neutropenia-related clinical sequelae, e.g., febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation.

Patients Undergoing Autologous Peripheral Blood Progenitor Cell Collection and Therapy: for the mobilization of autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis.

Patients with Severe Chronic Neutropenia: for chronic administration to reduce the incidence and duration of sequelae of neutropenia (e.g, fever, infections, oropharyngeal ulcers) in symptomatic patients with congenital neutropenia, cyclic neutropenia, or idiopathic neutropenia.

IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONS
ZARXIO is contraindicated in patients with a history of serious allergic reactions to human granulocyte colony-stimulating factors such as filgrastim or pegfilgrastim.

WARNINGS AND PRECAUTIONS

Splenic rupture, including fatal cases, has been reported following the administration of filgrastim products. Patients who report left upper abdominal or shoulder pain should be evaluated.
Acute respiratory distress syndrome (ARDS) has been reported in patients receiving filgrastim products. Patients who develop fever and lung infiltrates or respiratory distress should be evaluated. Discontinue ZARXIO in patients with ARDS.

Serious allergic reactions, including anaphylaxis, have been reported in patients receiving filgrastim products. The majority of reported events occurred upon initial exposure. Provide symptomatic treatment for allergic reactions. Allergic reactions, including anaphylaxis, in patients receiving filgrastim products can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue ZARXIO in patients with serious allergic reactions.

Sickle cell crisis, in some cases fatal, has been reported with the use of filgrastim products in patients with sickle cell trait or sickle cell disease.
Glomerulonephritis has occurred in patients receiving filgrastim products. The diagnoses were based upon azotemia,hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of filgrastim. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of ZARXIO.
Alveolar hemorrhage manifesting as pulmonary infiltrates and hemoptysis requiring hospitalization have been reported in healthy donors treated with filgrastim undergoing peripheral blood progenitor cell (PBPC) collection mobilization. Hemoptysis resolved with discontinuation of filgrastim. The use of ZARXIO for PBPC mobilization in healthy donors is not an approved indication.
Capillary leak syndrome (CLS) has been reported after G-CSF administration, including filgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive appropriate treatment.
Confirm the diagnosis of severe chronic neutropenia (SCN) before initiating ZARXIO therapy. Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported to occur in the natural history of congenital neutropenia without cytokine therapy. Cytogenetic abnormalities, transformation to MDS, and AML have also been observed in patients treated with filgrastim for SCN. Abnormal cytogenetics and MDS have been associated with the eventual development of myeloid leukemia. The effect of filgrastim products on the development of abnormal cytogenetics and the effect of continued filgrastim administration in patients with abnormal cytogenetics or MDS are unknown. If a patient with SCN develops abnormal cytogenetics or myelodysplasia‚ the risks and benefits of continuing ZARXIO should be carefully considered.

Thrombocytopenia has been reported in patients receiving filgrastim products. Monitor platelet counts.

Leukocytosis:

Patients with Cancer Receiving Myelosuppressive Chemotherapy: White blood cell counts of 100‚000/mm3 or greater were observed in approximately 2% of patients receiving filgrastim at dosages above 5 mcg/kg/day. In patients with cancer receiving ZARXIO as an adjunct to myelosuppressive chemotherapy‚ to avoid the potential risks of excessive leukocytosis‚ it is recommended that ZARXIO therapy be discontinued if the ANC surpasses 10‚000/mm3 after the chemotherapy-induced ANC nadir has occurred. Monitor CBCs at least twice weekly during therapy.

Peripheral Blood Progenitor Cell (PBPC) Collection and Therapy: During the period of administration of ZARXIO for PBPC mobilization in patients with cancer, discontinue ZARXIO if the leukocyte count rises to >100,000/3.

Cutaneous vasculitis has been reported in patients treated with filgrastim products. In most cases‚ the severity of cutaneous vasculitis was moderate or severe. Most of the reports involved patients with SCN receiving long-term filgrastim therapy. Hold ZARXIO therapy in patients with cutaneous vasculitis. ZARXIO may be started at a reduced dose when the symptoms resolve and the ANC has decreased.

The possibility that filgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which filgrastim is not approved, cannot be excluded. The safety of filgrastim products in chronic myeloid leukemia (CML) and myelodysplasia has not been established. When ZARXIO is used to mobilize PBPC‚ tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. Available data is limited and inconclusive.

The safety and efficacy of filgrastim products given simultaneously with cytotoxic chemotherapy have not been established. Do not use ZARXIO in the period 24 hours before through 24 hours after the administration of cytotoxic chemotherapy. The safety and efficacy of filgrastim products have not been evaluated in patients receiving concurrent radiation therapy. Avoid the simultaneous use of ZARXIO with chemotherapy and radiation therapy.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging changes on nuclear imaging.

ADVERSE REACTIONSMost common adverse reactions in patients:

With nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs (≥ 5% difference in incidence compared to placebo) are thrombocytopenia, nausea, pyrexia, chest pain, pain, fatigue, back pain, arthralgia, bone pain, pain in extremity, dizziness, cough, dyspnea, rash, blood lactate dehydrogenase increased and blood alkaline phosphatase increased

With AML (≥ 2% difference in incidence) are epistaxis, back pain, pain in extremity, erythema, and rash maculo-papular
With nonmyeloid malignancies undergoing myeloablative chemotherapy followed by BMT (≥ 5% difference in incidence) are rash and hypersensitivity

Undergoing peripheral blood progenitor cell mobilization and collection (≥ 5% incidence) are bone pain, pyrexia, blood alkaline phosphatase increased and headache

With severe chronic neutropenia (SCN) (≥ 5% difference in incidence) are arthralgia, bone pain, back pain, muscle spasms, musculoskeletal pain, pain in extremity, splenomegaly, anemia, upper respiratory tract infection, urinary tract infection, epistaxis, chest pain, diarrhea, hypoesthesia, and alopecia

On November 20, 2015 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) (Aptose or the Company), a clinical-stage company developing new therapeutics and molecular diagnostics that target the underlying mechanisms of cancer, reported that the Food and Drug Administration (FDA), following a voluntary suspension of dosing by the Company and discussions with the Company, placed the Phase Ib clinical trial of APTO-253 in patients with hematologic cancers on clinical hold (Press release, Aptose Biosciences, NOV 20, 2015, View Source;p=RssLanding&cat=news&id=2114349 [SID:1234508462]). This hold is intended to ensure patient safety on the trial and to ensure manufacturing and dosing procedures are consistent with the appropriate documented quality standards.

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The voluntary suspension of dosing by the Company was initiated as a result of a planned preliminary review, which was accelerated to evaluate manufacturing processes and procedures upon the report of an operational difficulty with an IV infusion pump at a clinical site. The pump experienced back pressure during IV patient dosing at the point of the filter. Further review discovered preliminary concerns regarding the documentation records of the manufacturing procedures of the drug product associated with APTO-253.

The Company stated that a complete safety review of all patient files had been completed prior to initial discovery of the manufacturing documentation irregularities, and there have been no drug-related serious adverse events (SAEs) reported. The observed pharmacokinetic levels in the patients treated were within the expected range.

"We are disappointed by these events and have engaged an independent third party review. Importantly, this finding does not undermine the positive safety profile that APTO-253 has demonstrated in clinical development, and we remain confident in its potential as a promising therapeutic option for patients with acute myeloid leukemia and other hematologic malignancies," said William G. Rice, Ph.D., Chairman, President and CEO. "While we expect some delay in the clinical trial, we are committed to ensuring that upon re-initiation of clinical dosing the drug product is of the highest standards. We plan to provide updated timeline guidance as soon as practical."

Key Points:

An internal review identified potential documentation irregularities and the Company voluntarily and immediately suspended dosing of patients out of an abundance of caution to ensure safety.

Aptose currently possesses a sufficient supply of API to create fresh batches of drug product for the resumption of clinical dosing upon FDA approval and guidance.

New contract manufacture organizations have been identified to manufacture fresh batches of cGMP clinical supply upon completion of investigation and in coordination with FDA guidance.

Overall effect to the Phase Ib trial timeline is expected to be partially mitigated by initiation of the new trial sites and updated timeline will be reported as soon as determined.

On November 20, 2015 Kancera reported its Interim Report for Kancera AB (publ) Q3 2015 (Press release, Kancera, NOV 20, 2015, View Source;releaseID=1076341 [SID:1234508315]). January 1 – September 30, 2015.

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The period January to September 2015 and the third quarter 2015 in brief

R&D expenses for the period amounted to SEK 12.1m (SEK 9.6m) of which the third quarter constituted SEK 3.2m (SEK 2.7m).

Operating income for the period amounted to SEK -13.8m (SEK -11.0m) of which the third quarter constituted SEK -3.4m (SEK -3.1m).

Income after financial items for the period amounted to SEK -13.7m (SEK -10.9m) of which the third quarter constituted SEK -3.4m (SEK -3.0m).

Earnings per share for the period were SEK -0.14 (SEK -0.13) of which the third quarter constituted SEK -0.03 (SEK -0.03).

Cash flow from operating activities for the period amounted to SEK -16.0m (SEK -11.6m) of which the third quarter constituted SEK -5.1m (SEK -4.4m).

Equity as of September 30, 2015 amounted to SEK 27.8m (SEK 31.6m) or SEK 0.27 (SEK 0.32) per share. The equity/assets ratio as of September 30, 2015 was 74 percent (77 percent).

Cash and cash equivalents as of September 30, 2015 amounted to SEK 20.2m (SEK 27.5m).
Significant events during the period

Kancera reported that a second efficacy study of the drug candidate KAN0439834 has been completed in an animal model of an advanced stage of chronic lymphocytic leukemia characterized by a genetic change which makes the disease more difficult to treat. The results show that KAN0439834 reduces the number of ROR expressing leukemia cells in the lymphatic system (spleen) after 14 days of treatment. Further, Kancera reported that a second patent application EP15153394.0 has been filed covering small-molecule ROR inhibitors, including the drug candidate KAN0439834.

Kancera reported that the patent WO 2011/079902 concerning monoclonal antibodies against ROR1 has been approved in China. Kancera has acquired partial rights to this patent from Bioinvent under an agreement that does not involve any financial burden for Kancera (except patent expenses) before revenues are generated. Kancera through the company’s co-founder Professor Håkan Mellstedt has been involved in the development of these antibodies. These antibodies have mainly been used to identify and validate new indications for a future ROR-inhibiting drug. Any further development of the ROR-targeted monoclonal antibodies for therapeutic purposes will only be done in a partnership that provides funding and access to expertise in development of antibody-based drugs.

Kancera reported an operational update of the cancer projects ROR, PFKFB3, and HDAC6.

The ROR project reported that that Kancera’s candidate drug KAN0439834 is effective against both leukemic cells circulating in the blood and leukemic cells that have invaded the lymph nodes in humans.

Recent studies of clinical samples from leukemia patients underscore that ROR inhibitors mainly target the white blood cells causing cancer while the healthy white blood cells, including T cells, are spared. These results are of significance for the possibility to combine ROR inhibitors with the new generation of immuno-stimulating cancer drugs that have been developed since the effect of those requires functional T-cells.

A new generation of ROR inhibitors is being developed against solid tumors.

The PFKFB3 project reported a new discovery showing that Kancera’s PFKFB3 inhibitor KAN0438757 kills cancer cells by preventing them to repair their DNA. The discovery indicates that KAN0438757 could be an efficient complement to radiation for the treatment of advanced cancer.

The HDAC6 project reported that Kancera’s HDAC6 inhibitors counteract the migration of cancer-associated fibroblast cells and that an international patent application was filed in May.

Kancera’s Annual General Meeting on May 28, 2015 decided to re-elect the current Board of Directors and auditor (Ernst & Young). The General Meeting also decided to authorize the Board, on one or more occasions until the next Annual General Meeting, to issue new shares. A new share issue may be made with or without preferential rights and against cash payment and / or in kind or set-off. The purpose of the authorization and the reason for the deviation from shareholders’ preferential rights is to enable the acquisition of capital for corporate acquisitions and the company’s operation. If the share issue is made against cash payment and without preferential rights for the shareholders, the number of shares issued may not exceed ten percent of the total number of shares outstanding at the time the authorization is exercised.

Kancera announced that a new share issue, with the authorization of the Annual General Meeting in 2014, was closed on May 27, 2015. The issue comprised a maximum of 4,927,386 shares. In total 25,926,793 shares were signed, of which 4,644,304 with preferential rights (with the support of subscription rights) and 21,282,489 without preferential rights. The share issue was thus oversubscribed to about 500 percent. This issue raised Kancera AB approximately SEK 12.3m before issue costs.

Kancera announced that the first subscription period for the exercise of the employee warrants was closed in June 2015. In total 450,246 new shares were signed giving Kancera SEK 1.7m before issue costs. There remain 2,349,754 warrants, of which 560,000 are held by Kancera to cover social security costs that are part of the employee warrants program.

Kancera announced that the company’s HDAC6 project has been awarded a grant totaling SEK 2m from the Swedish innovation agency VINNOVA. The grant is directed to projects that can develop into new strong innovations in a range of common diseases, including cancer. The grant is paid on four occasions during the two-year project. The project will be implemented in collaboration with the Cancer Center Karolinska (CCK), and is also planned to involve Swedish companies such as SARomics Biostructures, MetaSafe and Adlego Biomedical.

Kancera announced that the company has entered into an agreement with Acturum Life Science AB in order to evaluate and further develop the unique Fractalkine receptor antagonist AZD8797. Based on published research that supports that the Fractalkine receptor antagonist may have a central role in different cancer forms, Kancera will evaluate how efficiently the Fractalkine receptor antagonist AZD8797 may stop tumor growth and relieve severe cancer pain. The agreement with Acturum Life Science gives Kancera right to evaluate AZD8797 in preclinical studies and then to acquire the project. This agreement entails no expenses for Kancera apart from investments in the patent portfolio and in the scientific evaluation. If Kancera chooses to acquire the Fractalkine project, following the preclinical evaluation phase, the total payment to Acturum will consist of 6 million Kancera shares divided into three tranches, which are due at pre-defined success-milestones.

Kancera provided an operational update on the ROR and Fractalkine projects:

In the ROR project, Kancera reported that follow-up studies of the pharmaceutical properties of KAN0439834 show that they probably are better than previously assumed with respect to uptake and penetration of the substance to the cancer. The new studies indicate that dosing 2-3 times a day at 65-300 mg gives a concentration in the body that may be sufficient to exert an effect on solid tumors. Against this background, ROR inhibitors will be tested in animal models of solid tumors. It was further reported that ROR inhibitors have shown effect against leukemic cells from bone marrow which is a capacity wanted since the existing drugs are not sufficiently effective against cancer cells in the bone marrow.

In the Fractalkine project, Kancera reported that a network of leading cancer and pain scientists that has been established that will evaluate the drug candidate KAN0440567 (AZD8797) in an advanced animal model closely resembling the human form of pancreatic cancer. Kancera has synthesized and quality controlled the salt form of the drug candidate that will be used in this study and has conducted a successful peroral dosing study in mice.

Significant events after the end of the reporting period

Kancera provided an operational update for the PFKFB3 and HDAC6 projects as well as the EU-funded epigenetically targeted parasitic project A PARADDISE.

After the end of the period, Kancera reported from the collaboration with Prof. Thomas Helleday that Kancera’s PFKFB3 inhibitor significantly reduces the size of a tumor formed by aggressive human breast cancer cells (called triple negative breast cancer cells) transplanted into zebrafish. The results from the study support that Kancera’s PFKFB3 inhibitor is effective against these aggressive cancer cells if the substance reaches the tumor at a sufficient concentration, which is easier to achieve in zebrafish compared to e.g. in mice.

Kancera has developed several chemical families of potent and selective HDAC6 inhibitors based on a common scaffold, and it is now reported that Kancera has decided to withdraw the original patent from 2014 in order to postpone the publication of the structures at least 12 months. This is done in order to prevent that Kancera’s existing patent application becomes an obstacle to a new supplementary patent application that will include the newly developed HDAC6 inhibitors.

In June 2015, Vinnova announced that a grant was awarded to Kancera to support the further development of HDAC6 inhibitors against cancer. The first installment of the grant was then paid in July. Vinnova has now decided to bring forward the second installment (SEK 750, 000) to the HDAC6 project.

In February 2014 Kancera received an initial payment from the EU amounting to € 523,655 for the execution of the A-PARADDISE project. The project has now issued an interim report which has been approved by the EU. This means that a further installment of the grant will be paid to Kancera at year-end according to plan. This installment amounts to € 285,000.

Statement from the CEO

On November 11, Kancera appeared on the front page of the international trade journal "Bioworld" (View Source). The news item concerned Kancera’s new Fractalkine project that aims to help the immune system to attack the cancer. The study is performed using a drug candidate that was originally developed by AstraZeneca against the autoimmune disease multiple sclerosis (MS). The effect of this drug candidate against an MS-like disease in animals has convinced us that it is effective. The question we are now asking in the ongoing studies is if the same mechanism of action that is effective against MS also can help against intractable cancers. The risk in this cancer project is high as usual, but the scientific literature suggests that there is a realistic chance of success. The study is performed in collaboration with the FAM-owned Acturum Life Science AB which through an agreement has given Kancera an exclusive right to evaluate and later acquire this drug candidate.

In the ROR project, we have learnt more about how the first drug candidate KAN0439834 is expected to work in humans. The results of these calculations, partly based on animal studies and partly on comparative studies of chemically similar drugs, suggest that we can achieve a concentration in the blood that is effective against leukemia and possibly also against solid tumors. As is often the case in drug development, a problem encountered is that even if the drug candidate appears to have good properties in humans, efficacy has to be shown in a rodent disease model before clinical studies and in rodents drugs are often broken down too quickly. We are now testing two ways past this challenge; one where we stop the breakdown of the compound in the rodent by means of a drug-like substance, and one where we study the effect on tumors in zebra fish where it is possible to set the concentration of the drug to the level that is expected to be achieved in humans. In the autumn’s big biotech meeting "Bio Europe", which this year took place in Munich in November, it was clear that several large pharmaceutical companies now are using the zebra fish model as a step between cell studies and studies in rodents and humans.

We have also conducted the first cancer study with a PFKFB3 inhibitor in zebrafish in collaboration with Prof. Thomas Helleday. The study was performed using human tumor cells from a treatment-resistant breast cancer (so called triple negative breast cancer) and showed that Kancera’s PFKFB3 inhibitor significantly slows the development of tumor cells. These results are currently particularly relevant since this effect is coupled to this year’s Nobel Prize in chemistry, where one recipient was Tomas Lindahl for his discoveries about how cells are able to repair their DNA. It is thanks to the discoveries behind this Nobel Prize that Kancera in collaboration with Prof. Thomas Helleday’s group at the Karolinska Institute has been able to show that our PFKFB3 inhibitors can beat the cancer by preventing the repair of its genome.

During the Bio Europe meeting in Munich, Kancera presented the project portfolio during a session dedicated to cancer companies and had individual meetings with pharmaceutical companies from Europe, USA and Japan. At these meetings, we received a positive response regarding the progress in the company’s portfolio of cancer projects.

On November 19, 2015 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new cancer immunotherapies, reported that the Company is presenting initial results from an ongoing Phase 1 dose-escalation study of Ad-RTS-hIL-12 + orally administered veledimex in recurrent or progressive glioblastoma or grade III malignant glioma (Press release, Ziopharm, NOV 19, 2015, View Source [SID:1234508288]). The presentation, titled "Intratumoral Regulated Expression of IL-12 as a Gene Therapy Approach to Treatment of Glioma," will be delivered at 5:15 pm CT, Saturday, November 21, 2015 at the 20th Annual Society for Neuro-Oncology (SNO) Annual Scientific Meeting in San Antonio, Texas. Ad-RTS-hIL-12 + the oral activator veledimex is a novel viral gene therapy candidate for the controlled expression of IL-12, a critical protein for stimulating an anti-cancer T-cell immune response.

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"Immunotherapy is an attractive approach for the treatment of glioma, an aggressive cancer with few treatment options," said Nino Chiocca, MD, PhD, Harvey W. Cushing Professor of Neurosurgery, Department of Surgery, Harvard Medical School, Surgical Director, Center for Neuro-oncology, Dana-Farber Cancer Institute, Chairman, Neurosurgery, Brigham And Women’s Hospital and Co-Director, Institute for the Neurosciences, Brigham And Women’s Hospital. "IL-12 is among the most potent anti-cancer immune cytokines, yet carries equally significant potential for immune-mediated toxicities. The ability to turn IL-12 expression on and off using an orally activated gene switch, particularly in the brain’s immune privileged environment, is a tremendous advancement in the potential of this therapeutic approach. We look forward to enrolling additional patients and follow up from this study to evaluate Ad-RTS-IL-12’s potential in this challenging, rapidly advancing and lethal disease."

The ongoing multi-center Phase 1 trial of Ad-RTS-hIL-12 + veledimex examines a gene therapy strategy for recurrent high grade gliomas, with the goal of generating a localized anti-tumor immune response. The primary objective of the study is to determine the safety and tolerability of a single intra-tumoral Ad-RTS-hIL-12 injection activated upon dosing with oral veledimex. Secondary objectives are to determine the Ad-RTS-hIL-12 + veledimex maximum tolerated dose, the immune responses elicited by Ad-RTS-hIL-12 + veledimex, and assessment of biologic response. The study is expected to enroll up to 72 subjects.

Preclinically, the effects of Ad-RTS-mIL-12 + veledimex were studied in orthotopic glioma animal models, demonstrating veledimex crossed the blood-brain-barrier. In a standard orthotopic glioma mouse model that evaluated dexamethasone, bevacizumab, temozolamide and a PD-1 inhibitor, Ad-RTS-mIL-12 + veledimex demonstrated a dramatic dose-related increase in survival, without significant adverse events, that was superior to all other treatments.

In the current, on-going Phase 1 study, five patients are available for initial assessment, two with recurrent grade III malignant glioma and three with grade IV. Results show IL-12 was detectable in peripheral blood along with downstream IFNg, indicating that veledimex crossed the blood brain barrier activating IL-12 expression from intra-tumorally administered Ad-RTS-hIL-12. Ad-RTS-hIL-12 + veledimex was well tolerated with minimal neurologic toxicity. The most common adverse events were headache, fever, hyponatremia and nausea/vomiting. Related serious adverse events were aseptic meningitis, neutropenia, thrombocytopenia, leukopenia, with all toxicity to date consistent with the "on-target" effects of immunotherapy.

"Observing that veledimex can cross the blood brain barrier and that IL-12 expression can be regulated in the brain, demonstrates a clear translation of results from the laboratory to the clinic," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "We look forward to follow-up of the current recipients and to further enrollment in this multi-center gene therapy study."

On November 19, 2015 Five Prime Therapeutics, Inc. (Nasdaq:FPRX), a clinical-stage biotechnology company focused on discovering and developing novel protein therapeutics for cancer and inflammatory diseases, reported that the dose escalation part of the ongoing Phase 1 trial of FPA144 has been completed and that dose expansion has begun at a selected dose in new cohorts of gastric cancer patients whose tumors overexpress FGFR2b (Press release, Five Prime Therapeutics, NOV 19, 2015, View Source [SID:1234508293]). FPA144 is an isoform-selective antibody in development as a targeted therapy for tumors that over-express FGFR2b, and has been engineered for enhanced ADCC, increasing direct tumor cell killing by recruiting natural killer (NK) cells. FGFR2 gene amplification is found in a number of tumors, including approximately 5% of gastric cancers, and is associated with poor prognosis.

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Part 1 of the Phase 1 study evaluated the safety and pharmacokinetics (PK) of escalating doses of FPA144 in 27 patients with solid tumors, including unselected gastric cancer patients. Data from Part 1 will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) 2016 Gastrointestinal Cancers Symposium in San Francisco. The poster entitled, "FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors," is scheduled during the session entitled, "Cancers of the Esophagus and Stomach," on Thursday, January 21, 2016 from 12:30-2:00 and 5:30-7:00 Pacific Time. Abstracts are expected to be posted on the meeting website on Tuesday, January 19, 2016.

Enrollment has begun in Part 2 of the trial, evaluating the efficacy of biweekly infusions of FPA144 in approximately 70 metastatic gastric cancer patients, with the aim of exploring the correlation between efficacy and FGFR2b overexpression. Tumor testing for FGFR2b overexpression is being conducted centrally, using a proprietary immunohistochemistry assay. Tumors are also being assessed for FGFR2 gene amplification by FISH analysis. Trial endpoints include safety, pharmacokinetics, response rate and duration of response.

"We are really pleased with the progress we are making in this study and to now be moving into our target population of gastric cancer patients," said Julie Hambleton, M.D., Executive Vice President and Chief Medical Officer of Five Prime. "This is an orphan indication in the U.S. and given the unmet need in this disease and the potential for patients to benefit greatly from new treatment options, we aspire to develop the program expeditiously. In the Phase 1 study, we are already enrolling at global sites, including in Asia where gastric cancer is most prevalent. We are also running preclinical studies to evaluate therapeutic combinations with FPA144 for future testing in gastric cancer patients and to identify other indications that may be suitable for FPA144 therapy."

About FPA144

FPA144 is an anti-FGF receptor 2b (FGFR2b) humanized monoclonal antibody in clinical development as a targeted therapy for tumors that over-express FGFR2b, as determined by a proprietary immunohistochemistry (IHC) diagnostic assay. FPA144 binds specifically to FGFR2b and prevents the binding of certain fibroblast growth factors that promote tumor growth. Additionally, FPA144 has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), increasing direct tumor cell killing by recruiting natural killer (NK) cells. FGFR2 gene amplification (as identified by FISH) is found in a number of tumors, including in approximately 5% of gastric cancer patients, and is associated with poor prognosis.