On January 22, 2016 OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics, announced updated survival data from the company’s Phase 1b clinical trial of demcizumab (anti-DLL4, OMP-21M18) at the Gastrointestinal Cancers Symposium (Press release, OncoMed, JAN 22, 2016, View Source [SID:1234508842]).

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The Phase 1b dose-escalation and expansion study assessed the safety, biomarker, and anti-tumor activity of demcizumab and gemcitabine plus Abraxane (paclitaxel protein-bound particles for injectable suspension) (albumin bound) in 32 previously untreated patients with advanced pancreatic cancer. Demcizumab in combination with chemotherapy had an acceptable safety profile. The updated Kaplan-Meier estimated median progression-free survival was 7.1 months and median overall survival was 12.7 months for the patients who received the demcizumab-gemcitabine-Abraxane combination. Current standard-of-care treatment for advanced pancreatic cancer with gemcitabine and Abraxane, based on Phase 3 data, has median progression-free survival of 5.5 months and median overall survival of 8.5 months.1

"Pancreatic cancer remains a difficult-to-treat tumor and patients with this disease are in need of new and improved treatment options. We are very encouraged by the safety and early efficacy results observed in our Phase 1b clinical trial of demcizumab in pancreatic cancer," said Jakob Dupont, M.D., OncoMed’s Chief Medical Officer. "In this updated data set from our Phase 1b study of demcizumab plus standard of care in thirty-two patients with pancreatic cancer, we are pleased to see the median overall survival extend beyond 12.5 months. Overall, the safety, response, progression-free and overall survival data observed in our single-arm Phase 1b clinical study support our ongoing Phase 2 randomized YOSEMITE clinical trial for the treatment of first-line metastatic pancreatic cancer."

A randomized Phase 2 "YOSEMITE" trial in first-line pancreatic cancer patients with metastatic disease is currently being conducted at more than 50 centers in the U.S., Canada, Europe and Australia. Approximately 200 patients will be randomized into one of three study arms. Patients in Arm 1 will receive standard-of-care gemcitabine plus Abraxane plus placebo. Patients in Arm 2 patients will receive standard of care plus one course of demcizumab 3.5 mg/kg every two weeks for six doses (70 days). Patients in Arm 3 will receive standard of care with demcizumab for two courses. OncoMed expects to complete enrollment of the Phase 2 trial in 2016 and data from this trial is anticipated in early 2017.

Additional Phase 1b Results
In total 56 subjects were enrolled in this Phase 1b trial. The first 24 subjects received the double of demcizumab and gemcitabine and after a protocol amendment 32 subjects received demcizumab (in a truncated fashion) with the new standard of care of gemcitabine plus Abraxane.

Fourteen of the 28 (50%) evaluable patients who received the demcizumab-gemcitabine-Abraxane combination had a RECIST partial response (unconfirmed) and 11 achieved stable disease, resulting in a clinical benefit rate of 89 percent.

Demcizumab and gemcitabine plus Abraxane were generally well tolerated with fatigue, nausea and vomiting being the most common drug related toxicities. Truncated demcizumab therapy (i.e. 70 days of therapy) appears to prevent the onset of late cardiopulmonary toxicity, as none of the 32 patients treated in this manner developed heart failure or pulmonary hypertension. Pharmacodynamic analyses demonstrated clear down regulation of Notch pathway gene expression at the Phase 2 dose of demcizumab.

These data are being presented today in a poster titled "A Phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) +/- nab-paclitaxel in patients with pancreatic cancer" (Abstract 341), during Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract. OncoMed previously presented data on demcizumab’s safety, response rates and preliminary survival benefit from the Phase 1b study during the 2015 ASCO (Free ASCO Whitepaper) Annual Meeting. Results presented today provide eight months of additional follow-up on survival benefit.

About Pancreatic Cancer
Pancreatic cancer is the third leading cause of cancer-related deaths. According to the American Cancer Society, each year in the United States there are approximately 49,000 new cases of pancreatic cancer and 41,000 deaths. The majority of patients with pancreatic cancer are diagnosed after their cancer has spread locally and/or metastasized to distant organs. The average life expectancy after the diagnosis of metastatic pancreatic cancer is less than one year.

About Demcizumab (anti-DLL4, OMP-21M18)
Demcizumab is a humanized monoclonal antibody targeting Delta-like Ligand 4 (DLL4), a key member of the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing cancer stem cell frequency, disrupting angiogenesis in the tumor and augmenting anti-tumor immune responses by decreasing tumor myeloid-derived suppressor cells (MDSCs).

Demcizumab is currently being studied in two randomized Phase 2 clinical trials. The YOSEMITE trial is testing demcizumab with gemcitabine plus Abraxane versus gemcitabine plus Abraxane in first-line advanced pancreatic cancer patients. The DENALI trial is testing demcizumab with pemetrexed and carboplatin versus pemetrexed and carboplatin alone in first-line advanced non-small cell lung cancer patients. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing. A Phase 1 trial combining demcizumab with the anti-PD1 antibody pembrolizumab in solid tumor patients is planned to initiate in early 2016. Demcizumab is part of OncoMed’s collaboration with Celgene Corporation.

Patients interested in learning more about participating in a demcizumab clinical trial may learn more by calling 1-866-914-7347 or emailing [email protected].

On January 22, 2016 Takeda Pharmaceutical Company Limited (TSE:4502) reported that the European Commission (EC) has approved a Type II variation for ADCETRIS (brentuximab vedotin) to include data on the retreatment of adult patients with relapsed or refractory (R/R) Hodgkin lymphoma or R/R systemic anaplastic large cell lymphoma (sALCL) who previously responded to ADCETRIS and who later relapse (Press release, Takeda, JAN 22, 2016, View Source [SID:1234508837]). The decision from the EC follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) in October 2015.

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ADCETRIS was granted conditional marketing authorization by the EC in 2012 for the treatment of R/R CD30+ Hodgkin lymphoma following autologous stem cell transplant (ASCT), or at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and for R/R sALCL.

The SmPC variation includes an update to the clinical sections, including safety, to include data on retreatment of adult patients who have responded to previous treatment with ADCETRIS (CR or PR) under the existing indications, but later relapsed.

The Type II variation is based on data from the Phase 2 SGN35-006 Part A study that demonstrated effective anti-tumor responses can be achieved in the majority of R/R Hodgkin lymphoma and sALCL patients with ADCETRIS retreatment. The safety and efficacy results from this trial were consistent with the positive profile demonstrated in the pivotal Phase 2 studies (SGN35-003 and SGN35-004).

"ADCETRIS has transformed the treatment landscape for relapsed/refractory Hodgkin lymphoma and sALCL patients in Europe, and has emerged as a most valuable tool to induce a remission. However, lymphoma is a relentless disease, and relapse occurs in some of these very difficult to treat patients. Now, with the opportunity for retreatment, we can offer patients with very limited options another chance to potentially benefit from ADCETRIS," said Professor Anton Hagenbeek, M.D., Ph.D., Professor of Hematology, Department of Hematology, Academic Medical Center in the University of Amsterdam.

"The EC decision to include data on retreatment in the ADCETRIS label is important in advancing care for patients battling these diseases," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda. "We look forward to continuing our ongoing clinical program of ADCETRIS in Hodgkin lymphoma and sALCL, as well as in a variety of other forms of lymphoma, with the goal of bringing this important therapy to patients who might benefit from it."

For further details about the EC decision, please visit the EMA website: www.ema.europa.eu/ema.

SGN35-006 Part A Study
The SGN35-006 Part A study, entitled "Treatment with SGN-35 in patients with CD30-positive hematologic malignancies who have previously participated in an SGN-35 study," was a Phase 2, multicenter, open-label study. The study was designed to evaluate ADCETRIS retreatment in patients with Hodgkin lymphoma (20 patients) or sALCL (8 patients) that recurred after a previous response to ADCETRIS (Part A). Primary objectives were safety and anti-tumor response. Secondary objectives were duration of tumor control, including duration of response and progression-free survival (PFS), overall survival (OS) and incidence of anti-therapeutic antibodies (ATA).

For more information about the trial, please visit www.clinicaltrialsregister.eu.

About Hodgkin 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. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell expresses CD30.

About Anaplastic Large Cell Lymphoma
Anaplastic Large Cell Lymphoma (ALCL) is a type of aggressive T-cell lymphoma, comprising about 3 percent of all non-Hodgkin lymphomas (NHL) in adults and between 10 and 30 percent of all NHL in children. There are two distinct forms/types of ALCL, including primary cutaneous ALCL and systemic ALCL (sALCL). sALCL is a clinically aggressive, systemic lymphoma that primarily involves lymph nodes and expresses CD30.

About ADCETRIS
ADCETRIS (brentuximab vedotin) 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 proprietary technology by Seattle Genetics. 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 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 Hodgkin lymphoma 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 systemic anaplastic large cell lymphoma (sALCL). In January 2016, the European Commission approved a Type II variation to include data on the retreatment of adult patients with Hodgkin lymphoma or sALCL who previously responded to ADCETRIS and who later relapse. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

ADCETRIS is being evaluated broadly in more than 45 ongoing clinical trials, including the Phase 3 ALCANZA trial and two additional Phase 3 studies, one in frontline classical Hodgkin lymphoma and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

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.

On January 21, 2016 Amgen (NASDAQ: AMGN) reported that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) of Kyprolis (carfilzomib) for Injection in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy (Press release, Amgen, JAN 21, 2016, View Source [SID:1234508835]). The FDA also approved Kyprolis as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. This FDA decision converts to full approval the initial accelerated approval Kyprolis received in July 2012 as a single agent.

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"Kyprolis is the only approved therapy for relapsed multiple myeloma with proven efficacy as a single agent, doublet and triplet combination that is offered in a variety of doses to meet individual patient needs," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Importantly, this new approval supports the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer."

"Multiple myeloma remains an incurable disease where relapse inevitably occurs and over time patients become resistant to treatments," said Dr. Ruben Niesvizky, director of the Multiple Myeloma Center at Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center. "As a clinician, I’m pleased with the tremendous progress that we have seen in the past 12 months in multiple myeloma treatment. This FDA approval is important because it provides physicians with flexible options for Kyprolis use in helping to manage this challenging disease."

The approval is based on results from the Phase 3 head-to-head ENDEAVOR study. This was a superiority trial in which the primary endpoint was progression-free survival (PFS). The data showed patients with relapsed multiple myeloma treated with Kyprolis and dexamethasone achieved 50 percent greater PFS of 18.7 months compared to 9.4 months in those receiving Velcade (bortezomib) and dexamethasone (HR=0.53; 95 percent CI: 044, 0.65 p<0.0001), a current standard of care in relapsed multiple myeloma. Patients in the study were treated until disease progression. The most common adverse reactions (greater than or equal to 20 percent) in the Kyprolis arm were anemia, diarrhea, dyspnea, fatigue, insomnia, pyrexia and thrombocytopenia.

This new indication for Kyprolis is the second in six months. In July 2015, the FDA approved another expanded indication for Kyprolis in combination with lenalidomide and dexamethasone (KRd) for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and very aggressive disease that accounts for approximately one percent of all cancers.2-4 In the U.S., there are nearly 90,000 people living with, or in remission from, multiple myeloma.5 Approximately, 26,850 Americans are diagnosed with multiple myeloma each year and 11,240 patient deaths are reported on an annual basis.5

About ENDEAVOR
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with low-dose dexamethasone (Kd), versus bortezomib with low-dose dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. In a clinical trial, measuring the PFS is one way to demonstrate how well a treatment works.6

As stated above, Kd was superior to bortezomib and dexamethasone (Vd) and demonstrated significantly longer PFS. Improvement in PFS in the Kd arm compared to the Vd arm was seen across all pre-specified subgroups, including bortezomib-naïve patients, those with high- or standard-risk cytogenetics and with or without prior transplantation.

Kd also demonstrated improvement over Vd for secondary endpoints, achieving a higher overall response rate (77 percent vs. 63 percent; p<0.0001) and lower rate of grade 2 or higher neuropathy events (6 percent [95 percent CI: 4, 8] vs. 32 percent [95 percent CI: 28, 36]). In the Kyprolis and bortezomib groups, 54.3 percent and 28.6 percent of patients achieved a very good partial response or better (p<0.0001), and 12.5 percent and 6.2 percent of patients achieved a complete response or better (p<0.0001), respectively. Overall survival data are not yet mature and continue to be monitored.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. A number of known adverse drug reactions were reported at a higher rate in the Kyprolis group compared with the bortezomib group, including any-grade dyspnea, hypertension, pyrexia, and cough as were any-grade cardiac failure (grouped term; 8 percent vs. 3 percent) and acute renal failure (grouped term; 8 percent vs. 5 percent).

Rates of grade 3 or higher adverse events were 73 percent in the Kyprolis group and 67 percent in the bortezomib group. Grade 3 or higher adverse events of interest in the Kyprolis and bortezomib groups included hypertension (preferred term; 9 percent vs. 3 percent), dyspnea (preferred term; 5 percent vs. 2 percent), cardiac failure (grouped term; 5 percent vs. 2 percent), acute renal failure (grouped term; 4 percent vs. 3 percent), ischemic heart disease (grouped term; 2 percent vs. 2 percent) and pulmonary hypertension (grouped term; 0.6 percent vs. 0.2 percent).

Patients received treatment until progression with Kyprolis as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For Cycle 1 only, Kyprolis was administered at 20 mg/m2 on days 1 and 2, and if tolerated followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for subsequent cycles. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

About Kyprolis (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.7 Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.8 In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.8 The irreversibility of Kyprolis’ binding has also been shown to offer a more sustained inhibition of the targeted enzymes.9

Kyprolis is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan.

For more information, please visit www.kyprolis.com.

Patient Support Program
Amgen is proud to offer Onyx Pharmaceuticals 360 (Onyx 360) which is a patient support program designed to provide personalized services to patients living with cancer. Upon enrollment, patients are paired with a dedicated Onyx 360 Oncology Nurse Ambassador who is trained to help navigate their treatment journey and address daily and long term concerns. Onyx 360 also provides access to a network of resources and third-party services including transportation, emotional support and financial and product reimbursement assistance. Onyx 360 services are provided to patients at no cost. For more information, please visit www.kyprolis.com/support-during-treatment.

Editor’s Note: Dr. Niesvizky is an advisory board member for and paid consultant to Onyx Pharmaceuticals, Inc.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

INDICATION(S)

KYPROLIS (carfilzomib) is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
KYPROLIS (carfilzomib) is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients > 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuroradiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse events occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse events occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

On January 21, 2016 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 preliminary data from Part 1 of the ongoing Phase 1 clinical trial of FPA144 in patients with solid tumors, including gastric cancer, at a poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) 2016 Gastrointestinal Cancers Symposium in San Francisco (Filing, 8-K, Five Prime Therapeutics, JAN 21, 2016, View Source [SID:1234508834]).

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"These data suggest that FPA144 is well tolerated, and we were pleased to see early evidence of anti-tumor activity in two out of the six patients with 3+ FGFR2b-positive gastric cancer and in a patient with 2+ FGFR2b-positive bladder cancer enrolled in Part 1a of our Phase 1 trial," said Lewis T. "Rusty" Williams, M.D., Ph.D., president and chief executive officer of Five Prime. "Based on these encouraging data, we plan to continue evaluating FPA144 as a monotherapy in refractory gastric cancer, as a combination therapy in the front-line gastric cancer setting and as a potential treatment for other types of cancer."

The poster titled, "FPA144-001: A first in human study of FPA 144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody in patients with advanced solid tumors," will be presented during the "Cancers of the Esophagus and Stomach" session on Thursday, January 21, 2016 from 12:30-2:00 pm and 5:30-7:00 pm, Pacific Time. The poster will be made available at View Source

FPA144 Phase 1 Safety and Pharmacokinetic Summary

• Safety data from 27 patients and pharmacokinetic (PK) data from 23 patients from Part 1a (3+3 dose escalation in solid tumor patients) and Part 1b (parallel escalating doses in gastric cancer patients)

• FPA144 was well tolerated in patients with advanced solid tumors up to 15 mg/kg

• No dose-limiting toxicities (DLTs) were observed and a maximum-tolerated dose (MTD) was not reached in Part 1

• The most common treatment-emergent adverse events were Grades 1 or 2 and self-limiting

• The safety profile appears differentiated from small molecule kinase inhibitors targeting FGF receptors; for example, no treatment-related hyperphosphatemia was observed

• The most common treatment-related adverse events were:

fatigue (25.9%), nausea (11.1%), diarrhea (7.4%), dizziness (7.4%) and dry eye (7.4%)

• PK characteristics support once every other week or less frequent dosing

Preliminary Data on Anti-tumor Activity

• Anti-tumor activity in patients with gastric cancer whose tumors overexpress the FGFR2b protein (the initial target patient population for FPA144):

o First radiographic assessment by RECIST 1.1 of anti-tumor activity in six patients with FGFR2b-positive gastric cancer in Part 1b

o 2 Partial Responses (1 confirmed who received 6 mg/kg, 1 unconfirmed who received 10 mg/kg)

o 3 Stable Disease (2 confirmed who received 3 mg/kg and 10 mg/kg, respectively; 1 unconfirmed who received 10 mg/kg)

o 1 Progressive Disease (who received 10 mg/kg)

o Patients were classified 3+ by an IHC molecular diagnostic test

• Anti-tumor activity in a patient with urothelial bladder cancer:

o A confirmed Partial Response by CT (RECIST 1.1) and metabolic response by PET was observed in a urothelial bladder cancer patient who received 3 mg/kg from Part 1a

o The patient’s tumor was classified 2+ by an IHC molecular diagnostic test, suggesting that FPA144 may be active in tumors with moderate levels of FGFR2b protein overexpression

o Encourages investigation of the potential for FPA144 therapy in tumor types other than gastric cancer

• All patients who showed anti-tumor activity received doses below the 15 mg/kg dose being assessed in Part 2 of the trial

"We at START are excited by these data and the ability to partner with Five Prime to create and rapidly execute an innovative trial design that can be used broadly to develop targeted cancer therapies efficiently," said Tony Tolcher, M.D., Director of Clinical Research at South Texas Accelerated Research Therapeutics (START), an active site in the Phase 1 trial. "FPA144 appears well tolerated and without the significant toxicities that have limited other drugs targeting this pathway. Gastric cancer patients have a significant unmet need and a drug like FPA144 could represent an important advancement in their treatment options."

About the FPA144 Phase 1 Trial
Parts 1a and 1b of the Phase 1 study evaluated the safety and pharmacokinetics (PK) of escalating doses of FPA144 in 27 patients with solid tumors, including gastric cancer patients. Enrollment at the recommended dose of 15 mg/kg is underway in Part 2 of the Phase 1 trial, evaluating the safety, PK and efficacy of biweekly infusions of FPA144 in up to 70 gastric cancer patients, with the additional aim of exploring the correlation between efficacy and FGFR2 gene amplification and FGFR2b protein overexpression. Tumor testing for FGFR2b protein overexpression is being conducted centrally, using a proprietary immunohistochemistry assay. Tumors are also being assessed for FGFR2 gene amplification by FISH analysis. Trial endpoints include safety, PK, response rate and duration of response.

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

About Gastric Cancer
Globally, gastric cancer is the sixth most common malignancy with the third highest mortality. Globally, the prevalence of gastric cancer is approximately 1.5 million patients, of which an estimated 5%, or approximately 80,000, have FGFR2 gene-amplified tumors that overexpress FGFR2b. Given the relatively small population of gastric cancer patients that overexpress the FGFR2b protein and the poor survival of these patients, this indication is expected to be an orphan indication in the U.S.