On October 19, 2015 Seattle Genetics, Inc. (NASDAQ: SGEN) reported the initiation of a randomized phase 2 clinical trial of Rituxan (rituximab) and bendamustine with or without ADCETRIS (brentuximab vedotin) in relapsed or refractory patients with CD30-expressing diffuse large B-cell lymphoma (DLBCL) (Press release, Seattle Genetics, OCT 19, 2015, View Source [SID:1234507736]). The study is intended to evaluate the activity and safety of the combination regimen. ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, a protein found on the surface of certain types of cells. CD30 is expressed in several types of non-Hodgkin lymphoma, including at least 25 percent of patients with DLBCL. ADCETRIS is currently not approved for the treatment of DLBCL.

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"Diffuse large B-cell lymphoma, or DLBCL, is the most common type of aggressive non-Hodgkin lymphoma. DLBCL patients who relapse following initial treatment often receive salvage therapy sometimes followed by an autologous stem cell transplant, after which most patients will eventually relapse," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "This trial is designed to build on the single-agent activity we have observed with ADCETRIS in CD30-expressing DLBCL, including both relapsed and refractory status. Our goal is to improve long-term outcomes for relapsed and refractory DLBCL patients who express CD30 at detectable levels by combining ADCETRIS with Rituxan and bendamustine, two agents that are commonly used in this disease setting."

In this phase 2 randomized, open-label, multi-center clinical trial, approximately 110 relapsed/refractory CD30-expressing DLBCL patients will receive Rituxan and bendamustine either with or without ADCETRIS every three weeks for six cycles. Patients in the ADCETRIS combination arm who respond to treatment with a manageable safety profile may continue to receive single-agent ADCETRIS treatment for up to 10 additional cycles. The primary endpoint is to compare the objective response rates between the two study arms. Secondary endpoints include progression-free survival, complete remission rate, duration of response and overall survival. The study is being conducted at approximately 50 sites across North America and Europe.

At the 2015 International Conference on Malignant Lymphoma (ICML), data were presented from an ongoing phase 2 trial for relapsed/refractory CD30-positive non-Hodgkin lymphoma that included DLBCL patients who received single-agent ADCETRIS or in combination with Rituxan every three weeks. Of the 48 patients treated in the single-agent arm, the objective response rate was 44 percent, including 19 percent complete remissions and 25 percent partial remissions. Of the 13 patients treated in the combination arm, the objective response rate was 46 percent, including 15 percent complete remissions and 31 percent partial remissions. The most common treatment-emergent adverse events of any grade occurring in more than 15 percent of all patients enrolled were fatigue, nausea, neutropenia, diarrhea, peripheral sensory neuropathy, fever and vomiting. The most common treatment-emergent adverse event Grade 3 or higher was neutropenia.

Seattle Genetics is also evaluating ADCETRIS in newly diagnosed DLBCL patients through an ongoing phase 2 clinical trial evaluating ADCETRIS in combination with RCHP (rituximab, cyclophosphamide, doxorubicin and prednisone). For more information about the DLBCL clinical trials, including enrolling centers, visit www.clinicaltrials.gov.

About Lymphoma

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma represents a diverse group of cancers that develop in the lymphatic system and are characterized by uncontrolled growth and accumulation of abnormal lymphocytes. Lymphocytes are a type of blood cells that are responsible for defending the body against infection. The most common forms of non-Hodgkin lymphoma are diffuse large B-cell lymphoma (an aggressive subtype) and follicular lymphoma (an indolent subtype).

About ADCETRIS

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, one in frontline classical HL and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-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 autologous hematopoietic stem cell transplantation (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 systemic anaplastic large cell lymphoma (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 autologous stem cell transplant (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.

About Seattle Genetics

Seattle Genetics is a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer. Seattle Genetics is leading the field in developing antibody-drug conjugates (ADCs), a technology designed to harness the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. The company’s lead product, ADCETRIS (brentuximab vedotin), is a CD30-targeted ADC that, in collaboration with Takeda Pharmaceutical Company Limited, is commercially available in more than 55 countries, including the U.S., Canada, Japan and members of the European Union. Additionally, ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials in CD30-expressing malignancies. Seattle Genetics is also advancing a robust pipeline of clinical-stage programs, including SGN-CD19A, SGN-CD33A, SGN-LIV1A, SGN-CD70A, ASG-22ME, ASG-15ME and SEA-CD40. Seattle Genetics has collaborations for its ADC technology with a number of leading biotechnology and pharmaceutical companies, including AbbVie, Agensys (an affiliate of Astellas), Bayer, Genentech, GlaxoSmithKline and Pfizer. More information can be found at www.seattlegenetics.com.

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.

On October 19, 2015 Pfizer Inc. reported that investigational antibody-drug conjugate (ADC) inotuzumab ozogamicin received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for acute lymphoblastic leukemia (ALL) (Press release, Pfizer, OCT 19, 2015, View Source [SID:1234507735]).

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The Breakthrough Therapy designation was based on the results of the Phase 3 INO-VATE ALL trial, which enrolled 326 adult patients with relapsed or refractory CD22-positive ALL and compared inotuzumab ozogamicin to standard of care chemotherapy. Topline results from the trial were announced in April 2015 and also presented at the 20th Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

"Inotuzumab ozogamicin is the third Pfizer oncology medicine to be granted Breakthrough Therapy designation by the FDA, underscoring our commitment to innovative research and development that addresses significant unmet needs. Breakthrough Therapy designation will allow us to work more closely with the FDA to bring this important therapy to patients as rapidly as possible," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "Advancing therapies for patients with adult acute lymphoblastic leukemia is crucial as only 10 percent of adults with ALL who relapse after first-line therapy survive five years or more with current treatment options."1

Enacted as part of the 2012 FDA Safety and Innovation Act (FDASIA), Breakthrough Therapy designation is intended to expedite the development and review of a potential new medicine if it is "intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies."2 The Breakthrough Therapy designation is distinct from the FDA’s other mechanisms to expedite drug development and review.3

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with high unmet need and a poor prognosis in adults.4The current standard treatment is intensive, long-term chemotherapy.5 In 2015, it is estimated that 6,250 cases of ALL will be diagnosed in the United States6, with about 1 in 3 cases in adults. Only approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.7 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.8

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22,9 a cell surface antigen expressed on approximately 90 percent of B-cell malignancies,10 linked to a cytotoxic agent. When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.11

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing, clinical development and commercialization activities for this molecule.

On October 19, 2015 OXiGENE, Inc. (Nasdaq:OXGN), a biopharmaceutical company developing novel cancer therapeutics, reported the presentation of interim phase 2 data for the company’s lead investigational drug, CA4P (also known as fosbretabulin) (Press release, OXiGENE, OCT 19, 2015, View Source [SID:1234507734]). The data were presented in a poster session on October 16 at the North American Neuroendocrine Tumor Society (NANETS) Annual Symposium in Austin, Texas.

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Interim data from the first nine subjects in the study suggested that CA4P monotherapy may improve biomarkers and quality of life (QOL) measures. Additionally, CA4P appears to be relatively well tolerated by subjects. The poster also notes that results are preliminary, due to the small number of subjects analyzed at this point.

"The encouraging interim results seen in this Phase 2 study add to the body of evidence showing that CA4P has a positive effect in the treatment of solid tumors," said William D. Schwieterman, MD, OXiGENE’s President and CEO. "We look forward to full results from this trial anticipated in the second half of 2016, as we simultaneously move to advance CA4P in later-stage trials in our core programs for ovarian cancer and glioblastoma multiforme, which will evaluate CA4P in combination with complementary, approved anti-angiogenic agents."

The poster presentation, entitled "Phase 2 study (OX4218s) of fosbretabulin tromethamine (CA4P) for the treatment of well-differentiated, low-to-intermediate-grade unresectable, recurrent or metastatic pancreatic or gastrointestinal neuroendocrine tumors/carcinoid (PNETs or GI-NETs) with elevated biomarkers," was authored by Steven K. Libutti, MD1, Lowell Anthony, MD2, Julie Ann Sosa, MD3, Pamela Kunz, MD4, James Thomas, MD, PhD5, Susan A. Cruikshank6, Alice Varga6, David J. Chaplin, PhD6, James Burke, MD6, and Edward M. Wolin, MD2. A copy has been posted to the company’s website under "Presentations."

About CA4P

CA4P (also known as fosbretabulin), is a vascular disrupting agent (VDA) and is OXiGENE’s lead investigational drug. CA4P exerts its anti-tumor effects by targeting an established tumor’s immature endothelial cells within the tumor’s blood vessels, compromising the tumor vasculature and leading to widespread ischemia and necrosis of the cells within the central core of the tumor. OXiGENE plans to advance CA4P in clinical development in combination with approved anti-angiogenic agents which prevent the growth of new tumor blood vessels. Following an extensive clinical review, OXiGENE recently announced its plans to focus on initiation of two late-stage clinical programs for CA4P in 2016. These planned programs would combine CA4P with standard-of-care in platinum-resistant ovarian cancer and in glioblastoma multiforme. CA4P is also being evaluated in ongoing studies in neuroendocrine tumors and in recurrent ovarian cancer.

On October 19, 2015 Galectin Therapeutics, Inc. (Nasdaq: GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, reported that Providence Cancer Center has filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to study GR-MD-02 in combination with Keytruda (pembrolizumab), an immune checkpoint inhibitor, in a Phase 1b study of patients with advanced refractory metastatic melanoma (Filing, 8-K, Galectin Therapeutics, OCT 19, 2015, View Source [SID:1234507733]). GR-MD-02 binds to and inhibits galectin proteins, predominantly galectin-3 (Gal-3). Galectin will provide GR-MD-02 to the investigators, who are funding the costs of this study.

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The IND filing was prompted by findings from preclinical studies led by tumor immunology expert William L. Redmond, Ph.D. of the Providence Cancer Center’s Earle A. Chiles Research Institute. That study found that GR-MD-02 increased tumor shrinkage and enhanced survival in immune competent mice with multiple types of cancers when combined with one of the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD-1. Pembrolizumab (anti-PD-1) was approved by the FDA in September 2014 to treat patients whose melanoma had progressed after treatment with Yervoy (ipilimumab) or targeted therapy in melanomas that have a BRAF mutation. GR-MD-02 is also the subject of an ongoing Phase 1b study in combination with Yervoy in patients with malignant melanoma, also by Providence Cancer Center. Details of the study design can be found at clinicaltrials.gov: here

"This proposed study will be the second involving a checkpoint inhibitor in combination with GR-MD-02, and we are very pleased to reach this milestone with the investigators at the Portland Cancer Center," said Peter G. Traber, M.D., president, chief executive officer and chief medical officer of Galectin Therapeutics. "Preclinical data show that GR-MD-02 holds potential to increase the effectiveness of other therapies and represents a promising approach to enhance cancer immunotherapy."

Pending FDA review of the IND, the Phase 1b study will be conducted by the Providence Cancer Center under principal investigator Brendan D. Curti, M.D., director of the Providence Biotherapy Program. Providence Cancer Center researchers have been leaders in immunotherapy research and translational clinical trials in melanoma and other cancers.

"Clinical research has shown that therapeutic combinations involving checkpoint inhibitors have improved outcomes in patient survival. The Phase 1b study will determine if GR-MD-02 enhances the probability of melanoma response with pembrolizumab by inducing proliferation, activation and memory function of CD8+ T cells," said Dr. Curti. "The combination of GR-MD-02 and pembrolizumab has a strong scientific rationale based on Dr. Redmond’s laboratory work. This study represents a novel approach for patients with metastatic melanoma and complements our similar study of GR-MD-02 in combination with Yervoy."

Study Design
The proposed Phase 1b study is expected to enroll 16 to 22 patients with advanced melanoma whose disease has progressed after treatment with ipilimumab and/or BRAF-targeted therapy in melanomas with a BRAF mutation, and is designed to determine a safe dose of GR-MD-02 in combination with the approved dose of pembrolizumab (2 mg/kg). The study will employ a 3+3 Phase 1 design with dose escalation of GR-MD-02 beginning with 2 mg/kg in the first cohort and increasing to 8 mg/kg, depending on toxicity. In addition to monitoring for toxicity and clinical response, blood samples will be obtained to assess immunologic measures relevant to galectin biology and pembrolizumab T-cell checkpoint inhibition. Galectin Therapeutics will supply researchers with supporting analysis of the pharmacokinetics of GR-MD-02 and the right to reference the Company’s open IND on GR-MD-02.
Yervoy is a registered trademark of Bristol-Myers Squibb. Keytruda is a registered trademark of Merck.

About Metastatic Melanoma
Melanoma, the most dangerous form of skin cancer, is one of the most widespread cancers among young adults. Metastatic melanoma occurs when the cancer cells spread (or metastasize) through the lymph nodes to other parts of the body. The liver, lungs, bones and brain are most often affected by these metastases. The American Cancer Society estimates that there were more than 76,000 new diagnoses and 9,100 deaths from melanoma in the United States in 2012.

On October 19, 2015 DelMar Pharmaceuticals, Inc. (OTCQX: DMPI) ("DelMar" and the "Company"), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, reported that yesterday it presented positive preclinical data demonstrating the promising potential of its lead product candidate VAL-083 (dianhydrogalactitol) as a treatment for ovarian cancer (Press release, DelMar Pharmaceuticals, OCT 19, 2015, View Source [SID:1234507732]).

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The Company presented data from its collaboration with researchers at MD Anderson Cancer Center in a poster entitled, "A Comparison of the Mechanisms and Cytotoxic Activity of Dianhydrogalactitol (VAL-083) to Cisplatin in Ovarian Tumor Models Harboring Wild-type and Mutant p53," at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Conference.

The data demonstrate the effectiveness of VAL-083 against cisplatin-resistant ovarian cancers and raise the potential for VAL-083 as a treatment for ovarian cancers as a single-agent against platinum-resistant tumors or in combination with platinum-based chemotherapeutic regimens.

VAL-083 is a bi-functional alkylating agent, whose cytotoxic activity is due to the formation of DNA cross links at the N7 position of guanine. Unlike platinum-based chemotherapies such as cisplatin, carboplatin and oxaliplatin, which predominantly form intrastrand DNA cross-links, VAL-083 is believed to derive its anti-cancer activity via interstrand DNA cross-links, which leads to a distinct downstream of biological events within the tumor leading to apoptosis and cancer cell death. In prior NCI-sponsored clinical studies, VAL-083 demonstrated clinical activity against a range of tumor types, including ovarian cancer.

"These data represent another success in our strategy to leverage VAL-083’s historical clinical data with contemporary biological research to address significant unmet medical needs in the modern treatment of cancer," stated Jeffrey Bacha, president & CEO of DelMar Pharmaceuticals.

"Onset of drug resistance is a major factor limiting the clinical utility of platinum-based therapeutic regimens. Such regimens form the basis of ovarian cancer treatment and produce an initial 70% response rate. Unfortunately, many patients experience relapse as their cancer becomes resistant to currently available chemotherapy. The average duration of survival after recurrence of ovarian cancer is about 12 to 18 months with fewer than one in ten patients surviving beyond five years following standard salvage chemotherapy treatment," added Mr. Bacha. "We believe that these data, coupled with evidence of historical clinical activity against ovarian cancer, represent the promise of VAL-083 to address a major modern unmet medical need by providing a potential new treatment option for ovarian cancer patients whose tumors exhibit resistance to platinum-based therapy."

Platinum drug resistance is normally ascribed to several mechanisms. The current study investigated the activity of VAL-083 in multiple ovarian cancer models including both cisplatin-sensitive (A2780); and cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) phenotypes in vitro. The data support the potential of VAL-083 to circumvent drug-resistance in the treatment of ovarian cancer.

DelMar previously reported that the combination of VAL-083 and cisplatin demonstrated significant super-additivity (p<0.05) in animal models of non-small cell lung cancer (NSCLC) and synergy (CI < 1) in vitro.

Mr. Bacha continued, "We have a growing body of evidence indicating that, in comparison to platinum-based chemotherapy, the anti-cancer mechanism of VAL-083 is less dependent on, or independent of, wild-type p53. The current ovarian study provides additional proof that there is a lack of cross-resistance between cisplatin and VAL-083 further suggesting distinct modes of action for the two drugs. Importantly, the non-overlapping mechanisms of action support the potential of VAL-083 in the treatment of platinum-resistant cancers as well as the potential for therapeutic benefit in combining VAL-083 with platinum-based chemotherapy regimens."

HIGHLIGHTS OF DELMAR’S PRESENTATION

VAL-083 demonstrated cytotoxic activity in all tested ovarian cancer cell lines, including cisplatin-resistant cell lines, in vitro;
VAL-083 is significantly less dependent on wild-type p53 for its activity than both cisplatin and oxaliplatin, and appears to have a distinct mode of action;
VAL-083 exhibits significantly different cytotoxic-related cell-signaling patterns against resistant tumor phenotypes in comparison to platinum-based chemotherapy, in vitro;
VAL-083 displays significant synergy with cisplatin in vitro; and
Taken together, these results support VAL-083 as a viable treatment option for ovarian cancer patients failing platinum-based therapy, and suggests a potential benefit of a VAL-083 + platinum combination therapy.

SUMMARY

VAL-083 activity in five wild-type p53 ovarian cancer cell lines
The activity of VAL-083 was examined in five ovarian cancer cell lines: including one cisplatin-sensitive (A2780), and four cisplatin-resistant (2780CP-16, OVCAR-10, Hey and OVCA-433) tumors in vitro. The relative tumor-killing effect (IC50) was compared in cisplatin-sensitive versus cisplatin-resistant cell-lines. VAL-083 maintained significantly greater cytotoxic activity in comparison to cisplatin. These results demonstrate a lack of significant cross-resistance between cisplatin and VAL-083, further suggesting distinct modes of action for VAL-083.

Limited dependence of VAL-083 on p53 status
The dependence on p53 status was investigated in isogenic models with (HCT-116p53-/-) or without (HCT-116p53+/+) p53 knockout. Loss of p53 increased resistance to cisplatin and oxaliplatin by 3- and 6-fold, respectively, whereas the increase in resistance to VAL-083 was <2-fold. These data suggest that the cytotoxic a mechanism of VAL-083 that is much less dependent on, or independent of, p53.

VAL-083 signaling is distinct from platinum-based chemotherapy in drug-resistant ovarian tumors
Resistance to platinum-based chemotherapy can also arise in tumors bearing wild-type (non-mutant) p53 due to other factors effecting p53 function, such failure to induce downstream regulation of checkpoint proteins or activation via phosphorylation of p53 itself. VAL-083 and cisplatin demonstrate similar effects on p53 induction and activation via phosphorylation and CHK2-related p21 induction in p53 wild-type cisplatin-sensitive (A2780) ovarian cancer cells. However, in cisplatin-resistant (2780CP-16) ovarian cancer cells, only VAL-083 caused significant activation of p53 and p21, and induced greater Ser-15 and Ser-20 phosphorylation of p53, all of which are hallmarks of cytotoxic DNA damage. This further supports the conclusion of distinct modes of action for VAL-083 versus platinum-based chemotherapy and activity against platinum-resistant cancer phenotypes.

Combination of VAL-083 with platinum-based chemotherapy in p53 mutant H1975 NSCLC
The combination of VAL-083 with either cisplatin or oxaliplatin in the human H1975 model demonstrated significant super-additivity (p<0.05) and synergy (CI<1). These results suggest non-overlapping mechanism of action between the platinum drugs and VAL-083, and support the potential for synergistic benefit for a combination of VAL-083 and platinum-based therapies in the treatment of cisplatin resistant cancers.

The Company’s poster presentation from AACR (Free AACR Whitepaper) Advances in Ovarian Cancer Research and other VAL-083 posters and scientific publications may be found on DelMar’s website under View Source