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Seattle Genetics Completes Enrollment in Phase 3 ALCANZA Clinical Trial Evaluating ADCETRIS® (Brentuximab Vedotin) in CD30-Expressing Cutaneous T-Cell Lymphoma (CTCL)

On September 9, 2015 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that the company and its collaborator, Takeda Pharmaceutical Company Limited (Takeda), completed patient enrollment in the phase 3 ALCANZA clinical trial (Press release, Seattle Genetics, SEP 9, 2015, View Source [SID:1234507425]). ALCANZA is a randomized trial evaluating ADCETRIS (brentuximab vedotin) versus investigator’s choice of methotrexate or bexarotene in 132 patients with CD30-expressing cutaneous T-cell lymphoma (CTCL) who received prior systemic therapy.

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ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on skin lesions in at least 50 percent of patients with CTCL. The ALCANZA trial is being conducted under a Special Protocol Assessment (SPA) agreement from the U.S. Food and Drug Administration (FDA). In addition, Takeda received European Medicines Agency (EMA) scientific advice. In 2012, the FDA granted ADCETRIS orphan drug designation for the treatment of mycosis fungoides (MF), which is the most common type of CTCL. ADCETRIS is currently not approved for the treatment of CTCL.

Data from two investigator-sponsored phase 2 clinical trials evaluating ADCETRIS in relapsed CTCL were recently published in the Journal of Clinical Oncology (JCO) by physicians at Stanford University and the University of Texas MD Anderson Cancer Center. The results of these two clinical trials demonstrated objective response rates of 70 and 73 percent, respectively, in relapsed CTCL patients having variable levels of CD30 expression treated with ADCETRIS. This compares to objective response rates of 30 to 45 percent from published trials utilizing standard of care treatments in this disease setting. The most common adverse events in these trials were peripheral neuropathy, fatigue, nausea, skin rash, hair loss, diarrhea, muscle pain and neutropenia.

"We are pleased to announce the completion of patient enrollment in the phase 3 ALCANZA clinical trial evaluating ADCETRIS as a potential treatment for CD30-expressing CTCL," said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "We look forward to reporting results from the ALCANZA trial in the second half of 2016 to potentially support an ADCETRIS supplemental Biologics License Application seeking a label expansion for use in this setting."

The following highlights data summaries from the JCO publications.

Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project (Published on July 20, 2015)

The phase 2 investigator-sponsored trial enrolled CTCL patients with MF or Sézary syndrome, which are types of CTCL. Of the 32 patients enrolled in the study, 30 were evaluable for efficacy and more than half had received three or more prior systemic therapies. The primary endpoint of the trial was objective clinical response rate. The study was led by principle investigator Dr. Youn H. Kim from Stanford University School of Medicine in Stanford, CA. Key findings include:

Twenty-one of 30 patients (70 percent) achieved an objective response across all stages of disease, including Stage IB, Stage IIB and Stage IV/SS. Overall, one patient had a complete response, 20 patients had a partial response, four patients had stable disease and five patients had progressive disease. Two patients were not evaluable for response. Of the patients who had partial responses, seven had near complete responses with over 90 percent skin improvement as measured by modified Severity-Weighted Assessment Tool (mSWAT) scores and eight were still responding to therapy.

Responses appeared to be durable; six- and 12-month Kaplan-Meier estimates indicated continuing responses in 90 percent and 79 percent of patients, respectively.

The most common related adverse events of any grade were peripheral neuropathy (66 percent), fatigue (47 percent), nausea (28 percent), hair loss (22 percent) and neutropenia (19 percent).

The most common Grade 3 or 4 related adverse events were neutropenia (four patients), rash (three patients) and peripheral neuropathy (one patient).

Results of a Phase II Trial of Brentuximab Vedotin (SGN-35) for CD30+ Cutaneous T-Cell Lymphomas and Lymphoproliferative Disorders (Published on August 10, 2015)

Data were published from a phase 2 investigator-sponsored trial evaluating the use of ADCETRIS in CD30-positive CTCL patients, including lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL) or MF. The study was conducted by Dr. Madeleine Duvic from the University of Texas MD Anderson Cancer Center in Houston, TX. Among 54 patients enrolled, 48 patients were evaluable at the time of analysis. The primary endpoint of the trial was to evaluate the safety and efficacy of ADCETRIS in CD30-positive CTCL. The key findings include:

Thirty-five of 48 patients (73 percent) achieved an objective response, including 20 of 20 (100 percent) with LyP and/or pcALCL and 15 of 28 (54 percent) with MF. Seventeen patients (35 percent) achieved a complete response.
The most common adverse events were peripheral neuropathy (67 percent), fatigue (35 percent), skin rash (24 percent), diarrhea (15 percent), muscle pain (17 percent), localized skin infection (15 percent), neutropenia (15 percent) and hair loss (11 percent).
The most common Grade 3 or 4 adverse events were neutropenia (three patients), nausea (two patients), unstable angina or myocardial infarction (two patients), infection (two patients), joint pain (two patients), fatigue (one patient), deep vein thrombosis (one patient), pulmonary embolism (one patient), aminotransferase elevation (one patient) and dehydration (one patient).
ALCANZA Trial design

ALCANZA is a randomized, open-label, phase 3 trial of single agent ADCETRIS versus investigator’s choice of methotrexate or bexarotene in patients with CD30-positive CTCL, including those with pcALCL or MF. The primary endpoint of the study is overall response rate lasting at least 4 months in patients with CD30-expressing MF or pcALCL. Key secondary endpoints are complete response, progression-free survival and burden of symptoms during treatment.

For more information about the trial, please visit www.clinicaltrials.gov.

About CTCL

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 (HL) and non-Hodgkin lymphoma (NHL). Cutaneous lymphomas are a category of non-Hodgkin lymphomas that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement is variable and may be accompanied by tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. According to published literature, CD30 is expressed on skin lesions in at least 50 percent of CTCL patients.

The standard treatment for systemically pretreated CTCL includes skin-directed therapies, radiation and systemic therapies. The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.

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.

BIND Therapeutics Initiates Multicenter iNSITE 2 Trial with BIND-014 in Four Tumor Histologies

On September 9, 2015 BIND Therapeutics, Inc. (NASDAQ: BIND), a clinical-stage nanomedicine company developing targeted and programmable therapeutics called AccurinsTM, treported that patient dosing is underway in the iNSITE 2 trial, a global, phase 2, two-stage clinical trial of BIND-014 in patients with four tumor histologies (Press release, BIND Therapeutics, SEP 9, 2015, View Source [SID:1234507417]).

These diseases (cholangiocarcinoma [bile duct cancer], advanced cervical cancer, advanced bladder cancer, and advanced squamous cancer of the head and neck) each affect fewer than 200,000 patients in the U.S., making investigational drugs for these diseases candidates for orphan drug designation by the U.S. Food and Drug Administration. Stage 1 data readout for the iNSITE 2 trial is expected in the first half of 2016.

"The dosing of the first patient in the iNSITE 2 trial further expands the clinical development opportunities of BIND-014," said Hagop Youssoufian, M.Sc., M.D., chief medical officer at BIND Therapeutics. "It also represents a new milestone for the first targeted nanoparticle to enter the clinic by utilizing a rigorous biomarker program that can become a useful aid for more reliable patient selection in the future. The orphan tumor types that we have chosen for iNSITE 2 are all cancers with high unmet need and limited treatment options, representing potential opportunities for rapid development. Our choice was also guided by the activity seen with BIND-014 in our phase 1 trial and the historical role of docetaxel in treating these tumors."

The open-label, phase 2, multi-center two-stage iNSITE 2 clinical trial is designed to determine the activity, safety and tolerability of BIND-014 and will enroll up to 160 patients. In addition, an imaging and biomarker program that can potentially inform the future clinical utility of BIND-014 is also planned. Additional information on this study can be found at: View Source

Kancera evaluates immuno-oncology drug candidate

On September 8, 2015 Kancera reported it has entered into an agreement with Acturum Life Science AB in order to evaluate and further develop the unique Fractalkine inhibitor AZD8797 (Press release, Kancera, SEP 8, 2015, View Source [SID:1234511323]). Published research points to that Fractalkine signaling probably contributes to the growth and spread of tumors and the pain that often affects cancer patients. In addition, the presence of Fractalkine has been proposed to be associated with a lack of efficacy of immuno-oncology drugs. Taken together, these findings provide a new perspective of Fractalkine signaling as a target for cancer drug development. Kancera will now evaluate how efficiently the Fractalkine inhibitor AZD8797 may stop tumor growth and relieve severe pain.

Originally, the candidate drug AZD8797 was successfully developed by AstraZeneca in Södertälje as an effective inhibitor of Fractalkine signaling. The present documentation of AZD8797 includes drug properties, safety, toxicology, and production. Kancera’s assessment is that this documentation is likely to meet requirements for an application to undertake clinical trials against cancer. AstraZeneca originally developed AZD8797 against multiple sclerosis and showed effect of AZD8797 in a preclinical model of the disease (see the publication in PNAS April 8, 2014 vol. 111, no. 14, p 5409). Acturum Life Science acquired the rights to the Fractalkine project from AstraZeneca as part of Acturum’s acquisition of the research facility in Södertälje. However, AstraZeneca has retained the rights to develop Fractalkine inhibitors against respiratory diseases.

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. Accordingly, the two companies share the risk in the product development through the first study in man. Kancera intends to apply for orphan drug designation, covering the Fractalkine inhibitor, in order to ensure at least 10 years of exclusivity on the market in Europe and 7 years in the United States.

Since AZD8797 already meets the pharmaceutical properties Kancera considers necessary for the biological evaluation of the effect against cancer, the project can be run without significantly affecting the resource allocation to Kancera’s other projects.

"The agreement with Acturum provides Kancera with a technically strong candidate drug in an dynamic field of drug discovery. We are thereby set to evaluate how the promising research on Fractalkine can be translated into a new effective immune-oncology treatment" says Thomas Olin, CEO of Kancera.

Peter Sjöstrand, representing Acturum Life Science AB and its main shareholder FAM (the Wallenberg Foundations’ investment company) continues, "the agreement with Kancera provides the best conditions for a professional evaluation and further development of the Fractalkine project in a very important medical area. Since Acturum is committed to keep the Kancera shares received as payment for the project for at least five years, the agreement is also the start of a long-term commitment in Kancera. "

About the Fractalkine project
Fractalkine is an immune regulatory factor that sends signals via the CX3CR1 receptor, also called G-protein coupled receptor 13 (GPCR13). In the healthy individual, Fractalkine and its receptor regulate migration of immune cells from the blood capillary wall into areas where the immune system is needed. Animal studies show that Fractalkine and its receptor are not essential for survival and that important immune functions remain intact indicating that inhibition of the Fractalkine signaling by a drug probably will be tolerated without significant adverse effects. Fractalkine and its receptor have been linked to the growth and proliferation of pancreatic, breast and prostate cancer. Also, cancer cells that have the Fractalkine receptor on their surface migrate towards nerve ends that have Fractalkine on their surface. Thus, cancer cells are led to surround and apply pressure on nerves and thereby cancer pain may arise. Another proposed mechanism for how Fractalkine and its receptor affect the development of tumors is that they contribute to the transformation of the body’s macrophages from being a threat against the cancer (the M1 form) to supporting the cancer (the M2 form). This mechanism is also suggested as a predictive factor for responsiveness to the new immuno-oncology drugs that act through PD-1 and PD-L1 such as nivolumab, pembrolizumab and pidilizumab. During 2014 and 2015 studies have been published demonstrating that the absence of Fractalkine in tumor cells is a significant marker for how successful the immuno-oncology treatment is expected to be (see e.g. the publication in Nature on November 27, 2014, Vol. 515, pp 563). In the light of these observations, there are good reasons to further study if inhibition of the Fractalkine signaling with AZD8797 has the potential to increase the proportion of patients responding to the new immuno-oncology drugs that act through PD-1 and PD-L1.

Aduro Biotech Completes Enrollment in Phase 2b ECLIPSE Trial in Metastatic Pancreatic Cancer

On September 8, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that it has completed enrollment in the Phase 2b ECLIPSE trial of its novel LADD and GVAX immunotherapies being developed for the treatment of metastatic pancreatic cancer. The randomized, controlled three-arm trial enrolled 303 patients in the United States and Canada (Press release, Aduro BioTech, SEP 8, 2015, View Source;p=RssLanding&cat=news&id=2085917 [SID:1234507460]). Top line results are expected in the first half of 2016.

ECLIPSE was designed to evaluate the safety, immune response and efficacy of the combination immunotherapy of CRS-207 and GVAX Pancreas compared to chemotherapy. The trial also included a treatment arm to evaluate CRS-207 as a monotherapy. The primary endpoint of the trial is overall survival in the primary cohort of patients who have received two or more prior therapies for metastatic disease. A second cohort of patients who received one prior therapy for metastatic disease is also being evaluated.

"This is a significant clinical trial in the pancreatic cancer field which has the potential to yield important information on the role of Aduro’s immunotherapy combination in this indication," said Vincent Picozzi, M.D., director of the Pancreatic Center of Excellence at the Virginia Mason Clinic. "Very few therapeutic options exist for metastatic pancreatic cancer patients, especially after initial chemotherapy, and this field could benefit greatly from more varied and attractive therapy options."

"The fight against metastatic pancreatic cancer continues to be arduous," said Dirk G. Brockstedt, Ph.D., senior vice president of research and development at Aduro. "We are encouraged by data from long-term survivors in our Phase 2a clinical trial and look forward to results from our Phase 2b ECLIPSE trial. We would like to thank our investigators, and more importantly the patients and their families, for their participation and support in our trials and development of our technologies in this indication."

The ECLIPSE trial was initiated following a Phase 2a trial which demonstrated efficacy of the immunotherapy combination with CRS-207 and GVAX Pancreas compared to GVAX Pancreas alone in a randomized, controlled, multi-center trial in metastatic pancreatic cancer patients. Results of the Phase 2a clinical trial, published in the Journal of Clinical Oncology (JCO), indicated the median overall survival of Arm A patients receiving the combination regimen of CRS-207 and GVAX Pancreas was 6.1 months compared to 3.9 months for Arm B patients receiving GVAX monotherapy (HR=0.5930, one-sided p=0.0172).

Overall, the combination immunotherapy was well-tolerated. Of the 93 patients enrolled, the most common Grade 3 adverse events were transient lymphopenia, fevers, elevated liver enzymes and fatigue.

In 2014, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for Aduro’s pancreatic cancer combination treatment consisting of CRS-207 and GVAX Pancreas based on results from the Phase 2a clinical trial of patients with metastatic pancreatic cancer. According to the FDA, Breakthrough Therapy designation is for a drug candidate that treats a serious or life-threatening condition for which preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

About CRS-207

CRS-207 is one of a family of product candidates based on Aduro’s live-attenuated, double-deleted (LADD) Listeria monocytogenes immuno-oncology platform that are designed to induce potent innate and adaptive immune responses. 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 and gastric cancers.

About GVAX Pancreas

GVAX Pancreas is one of a family of GVAX immunotherapies derived from human cancer cell lines that are genetically modified to express granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune system-stimulating cytokine. GVAX Pancreas is derived from human pancreatic cancer cell lines and is designed to activate specific T cell immunity to pancreatic cancer antigens, including mesothelin.

Five Prime Therapeutics Initiates Patient Dosing in Phase 1a/1b Trial Evaluating the Immunotherapy Combination of FPA008 and OPDIVO (nivolumab) in Six Tumor Types

On September 8, 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 it has initiated patient dosing in the Phase 1a/1b clinical trial evaluating the immunotherapy combination of FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R), with OPDIVO (nivolumab), Bristol-Myers Squibb’s PD-1 immune checkpoint inhibitor, in six tumor types (Press release, Five Prime Therapeutics, SEP 8, 2015, View Source [SID:1234507422]).

FPA008 and OPDIVO are part of a new class of cancer treatments known as immunotherapies that are designed to harness the body’s own immune system to fight cancer. FPA008 targets macrophages and monocytes, which are activated or elevated in multiple disease settings. In cancer, tumor-associated macrophages suppress the immune system’s ability to kill cancer cells. OPDIVO is approved in the United States, Japan and the European Union for metastatic melanoma, and in the United States and European Union for squamous non-small cell lung cancer. OPDIVO is being evaluated as a mono therapy, as well as in combination with other agents, across multiple tumor types in more than 50 clinical trials. Preclinical data suggest that combining antibodies targeting PD-1 and CSF1R may lead to an enhanced anti-tumor immune response compared to either drug alone.

"We hope that targeting tumor suppressing macrophages in addition to a known immune checkpoint will allow us to harness more of the immune system’s anticancer activity, and will make durable responses a reality for more of our patients," said Julie Brahmer, M.D., Associate Professor of Oncology and Interim Director at the Sidney Kimmel Comprehensive Cancer Center (Johns Hopkins Bayview campus) and a Principal Investigator for the trial. "We look forward to participating in this trial, which will generate important information about the potential of this immunotherapy combination across a number of tumor types, including many where patients have few effective treatments."

"We are excited about the potential of FPA008 as a novel immuno-oncology therapeutic and about combining it with OPDIVO in this clinical collaboration with Bristol-Myers Squibb. We believe that targeting the CSF1R and PD-1 pathways in tandem may produce a synergistic treatment effect against a variety of tumors," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "Five Prime looks forward to enrolling this study, as it will provide us a wealth of information about this novel therapeutic combination and will further guide our development of FPA008 in oncology."

During Phase 1a, Five Prime will evaluate the safety, pharmacokinetics and biomarkers of escalating doses of FPA008 as a monotherapy, as well as in combination with the approved 3 mg/kg dose of nivolumab. Approximately 30 patients with advanced cancers are expected to be enrolled during the Phase 1a part of the study and both drugs will be administered every two weeks. In the Phase 1b part of the study, Five Prime will evaluate the safety, tolerability and preliminary efficacy of the selected dose of FPA008 in combination with nivolumab in approximately 240 patients, as a front-line therapy for melanoma; as second-line therapy for squamous cell carcinoma of the head and neck, pancreatic cancer, and malignant glioma; as a second- or third-line therapy for non-small cell lung cancer (NSCLC); and as a third-line therapy for colorectal cancer. Tumor biopsies will be obtained both pre-treatment and one month post-treatment in a subset of patients to analyze the immune response within the tumor microenvironment, and Five Prime will use this analysis to further guide FPA008’s development in oncology.

Under the terms of the clinical collaboration, BMS made a one-time payment of $30 million to Five Prime and is responsible for external study costs, the costs for OPDIVO, and half of the costs for FPA008 used in the Phase 1b part of the trial. The study design will be described in further detail in a trial-in-progress presentation at the International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper), to be held September 16-19, 2015 in New York City. Five Prime expects to complete Phase 1a dose escalation and expand into Phase 1b with the selected dose of FPA008 in late 2015 or early 2016.

About FPA008

FPA008, Five Prime’s antibody that inhibits colony stimulating factor-1 receptor (CSF1R), targets macrophages and monocytes, which are activated or elevated in multiple disease settings. In cancer, tumor-associated macrophages suppress the immune system’s ability to kill cancer cells. In joint diseases, such as PVNS and RA, synovial macrophages play a central role in the disease process. Five Prime is evaluating the immunotherapy combination of FPA008 and OPDIVO (nivolumab), Bristol-Myers Squibb’s investigational PD-1 immune checkpoint inhibitor, in six tumor types in a Phase 1a/1b clinical trial. Five Prime is also conducting a Phase 1/2 trial of FPA008 in pigmented villonodular synovitis (PVNS), a joint tumor driven by the CSF1 pathway and an orphan disease, and a Phase 1 study in rheumatoid arthritis.