On May 30, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported results from the Phase III GADOLIN study showing that Gazyva (obinutuzumab) plus bendamustine followed by Gazyva alone provided significant benefit for people with indolent non-Hodgkin’s lymphoma (NHL) that is refractory to Rituxan (rituximab)-based treatment (Press release, Genentech, MAY 30, 2015, View Source [SID:1234506560]). In the study, Gazyva plus bendamustine followed by Gazyva alone reduced the risk of disease worsening or death (progression-free survival, PFS) by 45 percent (HR=0.55, p=0.0001), compared to bendamustine alone. The study was stopped prior to its protocol-specified final analysis due to the high level of benefit seen in the Gazyva arm compared to the bendamustine arm. There were no unexpected safety signals identified with Gazyva.

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"Unfortunately, some people with indolent non-Hodgkin’s lymphoma have disease that is refractory to Rituxan-based therapy, a standard of care treatment. We’re excited by these data showing that Gazyva could help these people who have few treatment options remaining," said Sandra Horning, M.D., chief medical officer and head of Global Product Development.

The late-breaking data from the GADOLIN study will be featured in the official press program of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Saturday, May 30, at 8:00 A.M. CDT. The data will be presented during ASCO (Free ASCO Whitepaper)’s 51st Annual Meeting by Dr. Laurie Sehn, British Columbia Cancer Agency/University of British Columbia (Abstract #LBA8502, Monday, June 1, 10:09-10:21 A.M. CDT), and subsequently at the 20th annual congress of the European Hematology Association (EHA) (Free EHA Whitepaper) and the 13th International Conference on Malignant Lymphoma (ICML) in June 2015.

Data from this pivotal study will be submitted to the U.S. Food and Drug Administration, European Medicines Agency and other health authorities around the world for approval consideration.

About the GADOLIN Study

GADOLIN (NCT01059630; GA04753g) is a Phase III open-label, multicenter, randomized two-arm study evaluating Gazyva plus bendamustine followed by Gazyva alone for up to two years compared to bendamustine alone. GADOLIN included 413 patients with indolent NHL whose disease progressed during or within six months of prior Rituxan-based therapy. The primary endpoint of the study is progression-free survival (PFS) as assessed by an independent review committee (IRC), with secondary endpoints including PFS as assessed by investigator review, response rate (RR), best response and overall survival (OS).

Results to be presented at ASCO (Free ASCO Whitepaper) showed:

The median PFS was not reached in the Gazyva-based treatment group versus 14.9 months with bendamustine alone (HR=0.55, p=0.0001) as assessed by IRC.

The median PFS with Gazyva-based treatment was more than double that with bendamustine alone (29.2 months vs. 14.0 months, HR=0.52, p<0.0001), as assessed by investigator review.

No unexpected safety signals were identified in the Gazyva-based treatment arm. Grade 3-4 adverse events that occurred in at least two percent of patients in the Gazyva-treated group or bendamustine alone group included low white blood cell count (33 percent vs. 26.3 percent), low blood platelet count (10.8 percent vs. 16.2 percent), infusion-related reactions (10.8 percent vs. 5.6 percent), low red blood cell count (7.7 percent vs. 10.1 percent), low white blood cell count with fever (4.6 percent vs. 3.5 percent), nausea (1 percent vs. 3 percent), fatigue (1.5 percent vs. 2.5 percent), diarrhea (1 percent vs. 2.5 percent), vomiting (2.1 percent vs. 1 percent), respectively.

About Non-Hodgkin’s Lymphoma
There are two main types of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). NHL represents approximately 85 percent of all lymphomas diagnosed. There are more than 60 different types of NHL that fall under two subsets, aggressive and indolent (slow-growing). According to the American Cancer Society, it is expected that nearly 72,000 people will be diagnosed with NHL in the United States in 2015, and nearly 20,000 will die from the disease.

Most cases of NHL start in B-lymphocytes, cells that are part of the body’s immune system and help to defend the body against infections. B-cell lymphoma develops when these cells become cancerous and begin to multiply and collect in the lymphatic system, such as lymph nodes, lymphatic tissues or the spleen.

About Gazyva

Gazyva is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body’s immune system. Gazyva is thought to have an increased ability to induce direct cell death and induces greater activity in how it recruits the body’s immune system to attack B-cells (antibody dependent cellular cytotoxicity; ADCC) when compared to Rituxan. Gazyva was discovered by Roche Glycart AG, a wholly owned, independent research unit of Roche. In the United States, Gazyva is part of a collaboration between Genentech and Biogen Idec.

Gazyva is being studied in a large clinical program, including the Phase III GOYA and GALLIUM studies. GOYA is comparing Gazyva head-to-head with Rituxan plus chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) and GALLIUM is comparing Gazyva head-to-head with Rituxan plus chemotherapy in first line indolent NHL. Additional combination studies investigating Gazyva with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.

Gazyva Indication

Gazyva is a prescription medicine used with the chemotherapy drug, chlorambucil, to treat chronic lymphocytic leukemia (CLL) in adults who have not had previous CLL treatment.

Important Safety Information

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that can become serious or life-threatening, including:

Hepatitis B Virus (HBV): Hepatitis B can cause liver failure and death. If a patient has had history of hepatitis B infection, Gazyva could cause it to return. Patients should not receive Gazyva if they have active hepatitis B liver disease. The patient’s doctor or healthcare team will need to screen for hepatitis B before, and monitor the patient for hepatitis during and after, treatment with Gazyva. Sometimes this will require treatment for hepatitis B. Symptoms of hepatitis include: worsening of fatigue and yellow discoloration of skin or eyes.

Progressive Multifocal Leukoencephalopathy (PML): PML is a rare and serious brain infection caused by a virus. PML can be fatal. A patient’s weakened immune system could put the patient at risk. The patient’s doctor will watch for symptoms. Symptoms of PML include: confusion, difficulty talking or walking, dizziness or loss of balance, and vision problems.

Additional possible serious side effects of Gazyva:

Patients must tell their doctor right away about any side effects they experience. Gazyva can cause side effects that may become severe or life threatening, including:

Infusion Reactions: These side effects may occur during or within 24 hours of any Gazyva infusion. Some infusion reactions can be serious, including, but not limited to, severe allergic reactions (anaphylaxis), acute life-threatening breathing problems, or other life-threatening infusion reactions. If a patient has a reaction, the infusion is either slowed or stopped until the patient’s symptoms are resolved. Most patients are able to complete infusions and receive medication again. However, if the infusion reaction is serious, the infusion of Gazyva will be permanently stopped. The patient’s healthcare team will take a few steps to help lessen any side effects the patient may have to the infusion process. The patient may be given medicines to take before each Gazyva treatment.

Signs of infusion reactions may include: dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, and chest pain.
Tumor Lysis Syndrome (TLS): Gazyva works to break down cancer cells quickly. As cancer cells break apart, their contents are released into the blood. These contents may cause damage to organs and the heart, and may lead to kidney failure requiring the need for dialysis treatment. The patient’s doctor may prescribe medication to help prevent TLS. The patient’s doctor will also conduct regular blood tests to check for TLS. Symptoms of TLS may include nausea, vomiting, diarrhea, and tiredness.

Infections: While a patient is taking Gazyva, the patient may develop infections. Some of these infections may be severe. Fatal infections have been reported, so the patient should be sure to talk to the doctor if the patient thinks the patient has one. Patients with active infection should not be treated with Gazyva. Infections may continue even after the patient stops taking Gazyva. The patient’s doctor may prescribe medications to help prevent infections. Symptoms of infection include fever and cough.

Low White Blood Cell Count: When a patient has an abnormally low count of infection-fighting white blood cells, it is called neutropenia. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s white blood cell counts. Neutropenia can develop during or after treatment with Gazyva. It may also last for more than one month. If a patient’s white blood cell count is low, the patient’s doctor may prescribe medication to help prevent infections.

Low Platelet Count: Platelets help stop bleeding or blood loss. Gazyva may reduce the number of platelets the patient has in the blood. This may affect the clotting process. While the patient is taking Gazyva, the patient’s doctor will do blood work to check the patient’s platelet count.
Most common side effects of Gazyva

The most common side effects of Gazyva are infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.

Before receiving Gazyva, patients should talk to their doctor about:

Immunizations: Before receiving Gazyva therapy, the patient should tell the patient’s healthcare provider if the patient has recently received or is scheduled to receive a vaccine. Patients who are treated with Gazyva should not receive live vaccines.

Pregnancy: A patient should tell the doctor if the patient is pregnant, plans to become pregnant, or is breastfeeding. It is not known if Gazyva may harm the patient’s unborn baby or pass into the patient’s breast milk. The patient should use birth control while using Gazyva and for 12 months after treatment. Mothers who have been exposed to Gazyva during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. The patient should speak to the doctor about discontinuing Gazyva if the patient is breastfeeding.

Patients must tell their doctor about any side effect that bothers them or that does not go away.

These are not all of the possible side effects of Gazyva. For more information, patients should ask their doctor or pharmacist.

Gazyva is available by prescription only.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the full Prescribing Information, including Boxed WARNINGS, for additional Important Safety Information.

Rituxan Indications

Rituxan (rituximab) is indicated for the treatment of patients with:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent

Previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy

Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy
Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC)
Rituxan is not recommended for use in patients with severe, active infections.

Important Safety Information:

Rituxan can cause serious side effects that can lead to death, including:

Infusion Reactions: may occur during or within 24 hours of the infusion. The patient’s doctor should give the patient medicines before their treatment. Symptoms can include hives, rash, itching, facial or oral swelling, sudden cough, shortness of breath, difficulty breathing, weakness, dizziness, feeling faint, racing heart or chest pain.
Severe Skin and Mouth Reactions: symptoms can include painful sores, ulcers, or blisters on the skin, lips or mouth; peeling skin; rash; or pustules.

Hepatitis B Virus (HBV) Reactivation: may cause serious liver problems including liver failure and death. If patients have had hepatitis B or are carriers of HBV, receiving Rituxan could cause the virus to become an active infection again. Patient should not receive Rituxan if they have active HBV liver disease. The patient’s doctor will do blood tests to check for HBV infection prior to treatment and will monitor the patient during and for several months following their treatment.

Progressive Multifocal Leukoencephalopathy (PML): a rare, serious brain infection that can lead to severe disability and death and for which there is no known prevention, treatment or cure. Symptoms can include difficulty thinking, loss of balance, changes in speech or walking, weakness on one side of the body or blurred or lost vision.

What are the additional possible serious side effects of Rituxan?

Patients must tell their doctor right away about any side effects they experience. Rituxan can cause serious side effects that can lead to death, including:

Tumor Lysis Syndrome (TLS): may cause kidney failure and the need for dialysis treatment, abnormal heart rhythm and can lead to death. The patient’s doctor may give the patient medicines before their treatment to help prevent TLS.

Serious Infections: can happen during and after treatment and can lead to death. These infections may be bacterial, fungal or viral. Symptoms can include fever; cold or flu symptoms; earache or headache; pain during urination; white patches in the mouth or throat; cuts or scrapes that are red, warm, swollen or painful.

Heart Problems: symptoms can include chest pain and irregular heartbeats that may require treatment. The patient’s doctor may need to stop their treatment.

Kidney Problems: the patient’s doctor should do blood tests to check how well the patient’s kidneys are working.
Stomach and Serious Bowel Problems: can include blockage or tears in the bowel that can lead to death. Stomach area pain during treatment can be a symptom.

Low Blood Cell Counts: the patient’s blood cell counts may be monitored during treatment.

The most common side effects of Rituxan are infusion reactions, chills, infections, body aches, tiredness and low white blood cells.

Patients must tell their doctor if they are pregnant, plan to become pregnant or are breastfeeding. It is not known if Rituxan may harm the patient’s unborn baby or pass into the patient’s breast milk. Women should use birth control while using Rituxan and for 12 months after treatment.

Patients must tell their doctor about any side effect that bothers them or that does not go away.

These are not all of the possible side effects of Rituxan. For more information, patients should ask their doctor or pharmacist.

Report side effects to the FDA at (800) FDA-1088 or View Source Report side effects to Genentech at (888) 835-2555.

Please see the Rituxan full Prescribing Information, including Most Serious Side Effects, for additional important safety information at View Source

On May 30, 2015 CTI BioPharma and Baxter International reported data from PERSIST-1 – a randomized Phase 3 registration-directed trial examining pacritinib for the treatment of myelofibrosis – in a late-breaking oral session at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), May 29-June 2, 2015 in Chicago, Ill (Press release, Baxter International, JUN 5, 2015, View Source [SID:1234505233]). Pacritinib is an investigational oral multikinase inhibitor with specificity for JAK2 and FLT3. Data presented at ASCO (Free ASCO Whitepaper) (Abstract #LBA7006) show that compared to best available therapy (exclusive of a JAK inhibitor), pacritinib therapy resulted in a significantly higher proportion of patients with spleen volume reduction and control of disease-related symptoms. Data were also selected for inclusion in the official ASCO (Free ASCO Whitepaper) Press Program.

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"Myelofibrosis is a difficult-to-treat, rare chronic blood cancer in need of new options that can help overcome the many unique and burdensome symptoms that patients with this disease face on a regular basis, such as blood transfusions and debilitating pain and fatigue," stated Claire Harrison, M.D., Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, London, United Kingdom and one of the principal investigators for PERSIST-1. "Based on data showing improvement in bone marrow function, pacritinib may have the potential to modify disease in the sickest patients as monotherapy and warrants further evaluation in combination with other potential disease-modifying agents."

Myelofibrosis is associated with significantly reduced quality of life and shortened survival. Spleen enlargement (splenomegaly) is a common and debilitating symptom of myelofibrosis. As the disease progresses, the body slows production of important blood cells and within one year of diagnosis the incidence of disease-related thrombocytopenia (very low blood platelet counts), severe anemia, and red blood cell transfusion requirements increase significantly.

PERSIST-1 Findings Presented at ASCO (Free ASCO Whitepaper)
PERSIST-1 is a randomized (2:1), controlled Phase 3 registration-directed trial comparing the efficacy and safety of pacritinib to best available therapy (BAT) – which included a range of currently utilized off-label treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis), regardless of the patients’ platelet counts. At study entry, 46 percent of patients were thrombocytopenic; 32 percent of patients had platelet counts less than 100,000 per microliter (<100,000/uL); and 16 percent of patients had platelet counts less than 50,000 per microliter (<50,000/uL); normal platelet counts range from 150,000 to 450,000 per microliter. The median duration of treatment was 16.2 months in patients treated with pacritinib, compared to 5.9 months in patients treated with BAT. The majority (79 percent) of patients on the BAT arm eventually crossed over to receive pacritinib therapy.

As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population (ITT). These results included patients with severe or life-threatening thrombocytopenia. Data presented at ASCO (Free ASCO Whitepaper) show that when measuring the volume of spleen reduction, the greatest difference in treatment arms was observed in evaluable patients with the lowest platelet counts (<50,000/uL platelets) (33.3 percent with pacritinib vs 0 percent with BAT) (p=0.037).

Beyond the statistically significant reductions in spleen volume, patients treated with pacritinib also experienced a sustained improvement in myelofibrosis-associated symptoms or Total Symptom Score (TSS) as measured by the Myeloproliferative Neoplasm Symptom Assessment Form electronic diary (MPN-SAF TSS and MPN-SAF TSS 2.0). The patient-reported outcomes instrument captures in an electronic diary how a patient feels or functions in relation to their health condition or treatment, including: fatigue, concentration, early satiety/fullness, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. When measuring the secondary endpoint (the proportion of patients with a 50 percent or greater reduction in TSS from baseline to Week 24), patients treated with pacritinib experienced greater improvement in their symptoms when compared to BAT, regardless of their baseline platelet counts (ITT patient population: 24.5 percent of pacritinib-treated patients vs 6.5 percent of BAT-treated patients) (p<0.0001); Evaluable patient population: 40.9 percent of pacritinib-treated patients vs 9.9 percent of BAT-treated patients) (p<0.0001).

Twenty-five percent (25%) of patients treated with pacritinib who were severely anemic and transfusion dependent – requiring at least six units of blood in the 90 days prior to study entry – became transfusion independent, compared to zero patients treated with BAT (p<0.05). Among patients with the lowest baseline platelets (<50,000/uL) who received treatment with pacritinib, a significant increase in platelet counts was observed over time compared to BAT (p=0.003) – with a 35 percent increase in platelet counts from baseline to Week 24.

The most common adverse events, occurring in 10 percent or more of patients treated with pacritinib within 24 weeks, of any grade, were: mild to moderate diarrhea (53.2 percent vs 12.3 percent with BAT), nausea (26.8 percent vs 6.6 percent with BAT), anemia (22.3 percent vs 19.8 percent with BAT), thrombocytopenia (16.8 percent vs 13.2 percent with BAT), and vomiting (15.9 percent vs 5.7 percent with BAT). Of the patients treated with pacritinib, 3 discontinued therapy and 13 patients required dose interruption (average one week) for diarrhea. Patients received a daily full dose of pacritinib over the duration of treatment. Gastrointestinal symptoms typically lasted for approximately one week and few patients discontinued treatment due to side effects. There were no Grade 4 gastrointestinal events reported.

"Results from PERSIST-1 add to the growing body of data showing the potential for pacritinib to address an unmet medical need that currently exists for patients with myelofibrosis, particularly patients with severely low platelet counts that result either from their disease or as a side effect from current treatment," said James A. Bianco, M.D., CTI BioPharma’s President and CEO. "Based on the results observed in this trial, we are continuing to advance the broad clinical development program for pacritinib across a range of hematologic malignancies."

"PERSIST-1 is the most inclusive randomized study of patients with myelofibrosis ever conducted, as we believe it is truly representative of healthcare providers’ real-world clinical experience, including patients with advanced disease, severe cytopenias, and a broad range of platelet count levels with the greatest need for effective treatment options," said David Meek, Head of Oncology at Baxter BioScience. "We look forward to advancing the clinical trial program of pacritinib for the treatment of myelofibrosis and to sharing these data with regulatory authorities."

Data will be presented today by Ruben Mesa, M.D., Deputy Director, Mayo Clinic Cancer Center, Chair of the Division of Hematology & Medical Oncology, Mayo Clinic Cancer Center in both the official ASCO (Free ASCO Whitepaper) Press Program (titled ‘Targeted Therapy’) at 8:00 a.m. CT, as well as in a late-breaking oral session at 2:37 p.m. CT.

About the PERSIST Phase 3 Development Program of Pacritinib
Pacritinib is currently being evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis. The PERSIST clinical trials are intended to support a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis, including but not limited to patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy, or patients who are intolerant of, or whose symptoms are sub-optimally managed on other JAK2 inhibitor therapy. The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

PERSIST-1 is a randomized (2:1), open-label, multinational Phase 3 clinical trial comparing the efficacy and safety of pacritinib with that of best available therapy (BAT), other than JAK inhibitors, in 327 enrolled patients with primary and secondary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF), without exclusion for low platelet counts. PERSIST-2 is a randomized (2:1), open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to BAT, including the approved JAK1/JAK2 inhibitor dosed according to product label for patients with myelofibrosis whose platelet counts are less than or equal to 100,000 per microliter. The trial is designed to enroll up to 300 patients in North America, Europe, Australia, New Zealand, and Russia. Additional details are available at www.clinicaltrials.gov or www.PERSISTprogram.com.

CTI BioPharma and Baxter BioScience, which is expected to become Baxalta in mid-2015, entered into a worldwide license agreement in November 2013 to develop and commercialize pacritinib. CTI BioPharma and Baxter will jointly commercialize pacritinib in the U.S. while Baxter has exclusive commercialization rights for all indications outside the U.S.

About Pacritinib
Pacritinib is an oral multikinase inhibitor with specificity for JAK2 and FLT3. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia, and lymphoma. The kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and chronic lymphocytic leukemia (CLL) due to its potent inhibition of c-fms, IRAK1, JAK2, and FLT3.1

About Myelofibrosis and Myeloproliferative Neoplasms
Myelofibrosis is a one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers. The three main types of MPNs are myelofibrosis, polycethemia vera, and essential thrombocythemia.2 Myelofibrosis is a serious and life-threatening chronic bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain.

The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S. of which myelofibrosis accounts for approximately 18,000 patients.3 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia.4 The median survival for high-risk patients is less than one and a half years; median survival for myelofibrosis patients overall is approximately six years.5

On May 30, 2015 Bellicum Pharmaceuticals reported the presentation of a poster at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) highlighting the potent anti-tumor effects of CAR T cells constructed with its novel, proprietary, dual co-stimulatory domain, "MC" (MyD88/CD40) (Press release, Bellicum Pharmaceuticals, MAY 30, 2015, View Source;p=RssLanding&cat=news&id=2055229 [SID:1234505205]). MC is incorporated alongside Bellicum’s proprietary CaspaCIDe safety switch in the Company’s CIDeCAR product candidates, including BPX-401.

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The studies evaluated in vivo tumor-killing abilities of two different CIDeCARs: CD19-targeted CIDeCAR cells (BPX-401) were evaluated in a Raji lymphoma model, and Her2-targeted CIDeCAR cells were evaluated in an SK-BR-3 breast cancer model.

Study Highlights:

MC co-stimulation resulted in increased T cell proliferation and enhanced efficacy in lymphoma and solid tumor models in vivo compared to control CAR T cells that included the more commonly utilized co-stimulatory molecule, CD28.

The Company’s CD19-targeted CAR (BPX-401) elicited dose-dependent elevation of cytokines, analogous to cytokine release syndrome, but cytokine levels were rapidly normalized upon administration of rimiducid, without loss of tumor control.
The percentage of BPX-401 cells eliminated upon rimiducid administration was dose-dependent across a 2-3 log range.
"We believe the development of more potent CAR T cells will be critical to success in bulky lymphomas and solid tumors," commented Tom Farrell, Bellicum’s President and Chief Executive Officer. "These data suggest that our novel, dual co-stimulatory domain, MC, enhances anti-tumor efficacy compared to traditional CAR constructs.
Furthermore, the risk of toxicity can be mitigated through our proprietary CaspaCIDe safety switch, potentially in such a way that therapeutic benefit can be maintained even when the switch is activated."

The poster, titled "MyD88/CD40-based costimulation to enhance survival and proliferation of chimeric antigen receptor (CAR)-modified T cells," can be accessed on the Events and Presentations page of the Company’s website.

On May 29, 2015 Merck reported new investigational data evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy from the KEYNOTE-012 Phase 1b study in 132 pre-treated patients with recurrent or metastatic head and neck cancer, regardless of PD-L1 expression status (Press release, Merck & Co, MAY 29, 2015, View Source [SID:1234504899]). In the evaluable patients, the overall response rate (ORR) (confirmed and unconfirmed) was 24.8 percent for KEYTRUDA (200 mg fixed dose every three weeks) (n=29/117) (95% CI, 17.3-33.6). When looking at HPV status, the ORR was similar among HPV-positive and HPV-negative disease (20.6 percent [n=7/34] and 27.2 percent [n=22/81], respectively) (95% CI, 8.7-37.9 and 17.9-38.2). These data, featured in the ASCO (Free ASCO Whitepaper) Press Program today, will be presented in an oral session by Dr. Tanguy Seiwert, The University of Chicago, on Monday, June 1 at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #LBA6008).

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Merck has initiated a comprehensive clinical development program for KEYTRUDA evaluating a fixed dosing regimen (200 mg every three weeks) in head and neck cancer across multiple lines of therapy as monotherapy and in combination with chemotherapy and other agents. Results from KEYNOTE-012 were first presented at the 2014 ASCO (Free ASCO Whitepaper) Annual Meeting and showed 19.6 percent ORR for KEYTRUDA (10 mg/kg every two weeks) in heavily pre-treated patients with advanced head and neck cancer with tumor cells positive for PD-L1 expression.

"Advanced head and neck cancer is a severe and life-altering condition. Unfortunately we have few effective treatment options, particularly for patients whose disease is not responding to current therapies," said Dr. Seiwert. "As a practicing oncologist, I am very encouraged by the durable responses demonstrated with pembrolizumab in this study, and look forward to data being shared in the future from the additional confirmatory studies now being conducted in advanced head and neck cancer."

"The totality of the data presented at ASCO (Free ASCO Whitepaper) furthers our understanding of the clinical potential of KEYTRUDA in head and neck cancer, regardless of PD-L1 expression or HPV status," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Based on the results observed to date, we are advancing multiple registrational studies in head and neck cancer including randomized evaluations of overall survival and progression-free survival with KEYTRUDA, as monotherapy and in combination with chemotherapy, compared to standard of care."

Additional Results from KEYNOTE-012 in Advanced Head and Neck Cancer

Additional findings from KEYNOTE-012, the first and largest Phase 1b study of an anti-PD-1 therapy in advanced head and neck cancer, showed tumor shrinkage was achieved in 56 percent of total evaluable patients who had measurable disease with one post baseline scan (n=59/106). The median duration of response was not reached (7.3+ – 25.1+ weeks among patients with a confirmed response), with a median follow up duration of 5.7 months (0.2 – 8.7 months). At the time of the analysis, 86 percent of patients who responded continued to respond to treatment (n=25/29). The data are based on an analysis conducted with a cut-off of March 23, 2015.

Adverse events in the study were consistent with previously reported safety data for KEYTRUDA (n=132). The most common treatment-related adverse events (occurring in greater than or equal to 5% of patients) included: fatigue (15.2%), hypothyroidism (9.1%), decreased appetite (7.6%), rash (7.6%), dry skin (6.8%), and pyrexia (6.8%). Some patients experienced adverse events of special interest, including hypothyroidism (10.6%), pneumonitis (3.0%), thyroiditis (2.3%), colitis (0.8%), interstitial lung disease (0.8%), acquired epidermolysis bullosa (0.8%), drug induced liver injury (0.8%), epidermolysis (0.8%), and diabetic ketoacidosis (0.8%). Four patients experienced adverse events of special interest that resulted in treatment discontinuation. There were no treatment-related deaths.

About the KEYNOTE-012 Study

KEYNOTE-012 is an ongoing multi-center, non-randomized Phase 1b trial evaluating the safety, tolerability and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg every two weeks or 200 mg IV every three weeks) in patients with advanced triple negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial cancer, or advanced gastric cancer. The primary endpoints of the study include overall safety, tolerability, and anti-tumor activity (as measured by RECIST v1.1); secondary endpoints include progression-free survival (PFS), overall survival (OS), and duration of response.

About Head and Neck Cancer

Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. The leading modifiable risk factors for head and neck cancer include tobacco and heavy alcohol use. Other non-modifiable risk factors include infection with certain types of HPV, also called human papillomaviruses. Each year there are approximately 400,000 cases of cancer of the oral cavity and pharynx, in addition to approximately 160,000 cancers of the larynx, resulting in approximately 300,000 deaths.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the ‘gatekeeper’ mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

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