On January 23, 2016 Amgen (NASDAQ: AMGN) reported the presentation of detailed results of a Phase 3 study with Vectibix (panitumumab) and best supportive care (BSC) compared to BSC alone (Press release, Amgen, JAN 23, 2016, View Source;p=RssLanding&cat=news&id=2131695 [SID:1234508846]). The study met its primary endpoint, demonstrating a statistically significant improvement in overall survival (OS) in patients with chemorefractory wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC; n=377 total). This is the first Phase 3 Vectibix study to include an analysis of efficacy of Vectibix by wild-type KRAS (exon 2) and in wild-type RAS tumor mutation status in its primary analysis, providing important information about OS in these populations. These results, in addition to secondary endpoint data, were presented at the 2016 Gastrointestinal Cancers Symposium (GICS) in San Francisco.

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The study (GICS abstract #642) showed that patients with wild-type KRAS (exon 2) mCRC treated with Vectibix and BSC achieved a median OS of 10 months compared to 7.4 months for patients treated with BSC alone (hazard ratio [HR]=0.73, 95 percent confidence interval [CI]=0.57-0.93, p=0.0096). Data from a key secondary endpoint showed that patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC treated with Vectibix and BSC achieved a median OS of 10 months compared to 6.9 months for patients treated with BSC alone (n=270; HR=0.70, 95 percent CI=0.53-0.93, p=0.0135). Patients with mutant RAS mCRC did not benefit from Vectibix treatment (n=54; OS HR=0.99, 95 percent CI=0.49-2.00). The safety profile was comparable to the known safety profile of Vectibix when administered as a single agent, with skin, nail, gastrointestinal and electrolyte disorders being the most frequently reported adverse events.

"Amgen has played a significant role in the advancement of personalized medicine, applying cutting-edge science and technology in our efforts to target therapies to the patients who are most likely to benefit. Amgen is committed to understanding cancer biology through studies like this," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "As well as providing additional insights into the way Vectibix works in mCRC, these data support expanding biomarker screening to include wild-type RAS."

Colorectal cancer is the third most common cancer worldwide, with approximately 1.2 million cases occurring globally each year.1,2 Approximately 20 percent of colon cancers are diagnosed at the metastatic stage, when the disease has already spread to distant organs, a diagnosis associated with only a 12 percent five-year survival rate.3 Using molecular approaches to identify unique genetic signatures in mCRC has the potential to help improve treatment outcomes. Of the few biomarkers in colorectal cancer, RAS genes (KRAS, NRAS) have a validated impact on treatment outcomes.4,5

Abstracts are currently available on the GICS website.

About ‘0007 Study (NCT01412957)
This Phase 3 global, multicenter, randomized, open-label study was designed to evaluate OS with Vectibix and BSC compared to BSC alone in patients with chemorefractory wild-type KRAS (exon 2) mCRC.

Key secondary endpoints included progression-free survival (PFS) in patients with wild-type KRAS mCRC, as well as OS and PFS in patients with wild-type RAS (absence of mutations in exons 2, 3 and 4 of KRAS and NRAS) mCRC, objective response rate (ORR) and safety in both wild-type KRAS (exon 2) and wild-type RAS groups.

Patients were randomized 1:1 to receive 6 mg/kg of Vectibix every 14 days and BSC, or BSC alone (as defined by the investigator). There were a total of 377 patients enrolled:

324 out of 377 subjects with RAS mutation status determined (86 percent ascertainment rate)
Out of 324
270 had wild-type RAS (83 percent)
54 were found to be mutant RAS (17 percent)
189 patients for KRAS (exon 2) group for Vectibix and BSC

Treatment with Vectibix combined with BSC in patients with wild-type KRAS resulted in median PFS of 3.6 months versus 1.7 months with BSC alone (HR=0.51, 95 percent CI=0.41-0.64, p=0.0001). In patients with wild-type RAS, the Vectibix combination resulted in median PFS of 5.2 months versus 1.7 months with BSC alone (HR=0.46, 95 percent CI=0.35-0.59, p=0.0001).

For patients with wild-type KRAS, ORRs were 27.0 percent with Vectibix versus 1.6 percent with BSC (HR=24.9, 95 percent CI=7.5-123.8, p<0.0001). For patients with wild-type RAS, ORRs were 31.0 percent with Vectibix versus 2.3 percent for BSC (ODDS Ratio=20.0, 95 percent CI=5.9-101.6, p<0.0001).

Patients with mutant RAS mCRC did not benefit from Vectibix treatment (OS HR=0.99, 95 percent CI=0.49-2.00). No new safety signals were seen in this study. The safety profile was comparable to the known safety profile of Vectibix when administered as a single agent, with skin, nail, gastrointestinal and electrolyte disorders being the most frequently reported adverse events.

About Vectibix (panitumumab)
Vectibix is the first fully human monoclonal anti-epidermal growth factor receptor (EGFR) antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer (mCRC). Vectibix was approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

In May 2014, the FDA approved Vectibix for use in combination with FOLFOX, as first-line treatment in patients with wild-type KRAS (exon 2) mCRC. With this approval, Vectibix became the first-and-only biologic therapy indicated for use with FOLFOX, one of the most commonly used chemotherapy regimens, in the first-line treatment of mCRC for patients with wild-type KRAS mCRC.

Important U.S. Product Information
Vectibix is indicated for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

As first-line therapy in combination with FOLFOX
As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy
Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

WARNING: DERMATOLOGIC TOXICITY
Dermatologic Toxicity: Dermatologic toxicities occurred in 90 percent of patients and were severe (NCI-CTC grade 3 or higher) in 15% of patients receiving Vectibix monotherapy.

In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin and skin fissures.

Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses and sepsis have been observed in patients treated with Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions and skin sloughing has also been observed in patients treated with Vectibix. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (e.g., Stevens-Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix concerning dermatologic toxicity are provided in the product labeling. Vectibix is not indicated for the treatment of patients with colorectal cancer that harbor somatic mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."

Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents.

Additionally, in Study 3, 272 patients with RAS-mutant mCRC tumors received Vectibix in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix and FOLFOX versus FOLFOX alone.

Progressively decreasing serum magnesium levels leading to severe (Grade 3-4) hypomagnesemia occurred in up to 7% (in Study 2) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix treatment, periodically during Vectibix treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.

In Study 1, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.

Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix in combination with chemotherapy.

Fatal and non-fatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. In the event of acute onset or worsening of pulmonary symptoms, interrupt Vectibix therapy. Discontinue Vectibix therapy if ILD is confirmed.

In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix versus the risk of pulmonary complications must be carefully considered.

Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix for acute or worsening keratitis.

In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions. NCI-CTC grade 3–4 adverse reactions occurring at a higher rate in Vectibix-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%; primarily occurring in patients with diarrhea), hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).

NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

Advise patients of the need for adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy. Vectibix may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, it should not be resumed earlier than 2 months following the last dose of Vectibix.

Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Women who are nursing during Vectibix treatment are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

In Study 1, the most common adverse reactions (> 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction.

In Study 3, the most commonly reported adverse reactions (> 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus and dry skin. Serious adverse reactions (> 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration.

To see the Vectibix Prescribing Information, including Boxed Warning visit www.vectibix.com.
In the EU, Vectibix is currently indicated for the treatment of adult patients with wild-type RAS mCRC:

in first-line in combination with FOLFOX and FOLFIRI.
in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan).
as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

On January 22, 2016 Celgene Corporation (NASDAQ: CELG) reported that results from multiple analyses presented during the 2016 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) evaluated the outcomes of second-line treatments following ABRAXANE (paclitaxel protein-bound particles for injectable suspension)(albumin-bound) and gemcitabine (AG) in first-line metastatic pancreatic cancer patients (Press release, Celgene, JAN 22, 2016, View Source [SID:1234508848]).

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In particular, a post-hoc analysis of MPACT, the pivotal phase III study of AG compared with gemcitabine alone in first-line metastatic pancreatic cancer evaluated the outcomes of patients who received a second-line treatment during an observational extension of the study.

A total of 347 (40%) patients received second-line therapy in the extension, and of those patients, the majority (77%, including 132 who had received AG in the first line and 135 who had received gemcitabine alone) received 5-FU-based therapies or capecitabine combinations.

A post hoc analysis of overall survival (OS) was conducted and demonstrated that patients (n=170) who received AG, followed by second-line therapy had a median OS of 12.8 months, compared with 9.9 months for patients (n= 177) who received gemcitabine alone, followed by second-line therapy. Of patients receiving second-line therapies, the majority (n=132) received 5FU or capecitabine-containing regimens and had a median OS of 13.5 months. Patients receiving FOLFIRINOX (FFX) following AG (n=18) had the longest median overall survival at 15.7 months. OS was calculated using the Kaplan-Meier method.

The analysis provided data demonstrating the feasibility of second-line treatment in patients with MPC after first-line AG.

"As the body of research and approved options increase in pancreatic cancer, there is now evidence that second-line treatment is feasible and beneficial for certain patients with metastatic disease," said Dr. David Goldstein, medical oncologist at Prince of Wales Hospital in Sydney, Australia and the lead investigator of the analysis. "We are seeing an exciting evolution in the treatment of this disease and for patients and physicians, it is now time to consider a total treatment plan when choosing an initial therapy."

A retrospective cohort study performed using data U.S. community data from Navigating Cancer, an electronic medical record platform, sought to compare the time to treatment discontinuation and database persistence, used as a proxy for OS, between AG and FFX in the first-line setting.

The analysis showed that time to treatment discontinuation and database persistence for patients with first-line metastatic pancreatic cancer (n=202) were numerically similar (8.6 in each arm) between AG (n=122) and FFX (n=80). With the exception of the age of patients, which favored FFX (median age 67 for AG years vs. 61.4 years for FFX), baseline characteristics were generally similar between the groups.

There was a higher incidence of adverse events (all grades) with FFX compared with AG (95% vs. 84%). Most common AE’s that led to discontinuation were anemia (8% for FFX and 2% for AG), neutropenia (6% for each), and dehydration (5% and 3%, respectively)

The analysis also evaluated various treatment plans including first-line AG, followed by second-line 5-FU-based therapies and first-line FFX, followed by second-line gemcitabine-based therapies. The duration of treatment for the AG arm was a median 8.7 months, compared with 8.4 months for the FFX arm (p=0.52). Further, the database persistence (proxy for OS) for patients receiving AG followed by 5-FU-based therapies (n=25) was a median 12.7 months, compared with 9.3 months for patients receiving FFX followed by gemcitabine-based therapies (n=41) (p=0.48).

There were four additional studies evaluating the sequence of AG followed by 5-FU-based therapies at the meeting:

Outcome of second-line treatment (2L Tx) following nab-paclitaxel (nab-P) + gemcitabine (G) or G alone for metastatic pancreatic cancer (MPC). (Goldstein #333)
Comparative effectiveness and resource utilization of nab-paclitaxel plus gemcitabine (nab-P+G) versus FOLFIRINOX (FFX) in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) in a U.S. community oncology setting (Braiteh #433)
Can the sequence of chemotherapy regimens influence outcome in patients with metastatic pancreatic adenocarcinoma (MPAC)? (Schmidt #428)
Irinotecan and infusional 5-fluorouracil (mFOLFIRI) in patients with refractory advanced pancreas cancer (APC): A single institution experience. (Bupathi #215)
Indications

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS
Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS
Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS
Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment
Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

On January 22, 2016 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus" or the "Company"), reported that an abstract discussing the immunologic effects of PV-10 on colon cancer cells has been accepted for presentation at the 11th Annual Academic Surgical Congress to be held February 2-4, 2016, at the Hyatt Regency in Jacksonville, Florida (Filing, 8-K, Provectus Pharmaceuticals, JAN 22, 2016, View Source [SID:1234508843]).

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The abstract, titled "PV-10 Induces Potent Immunogenic Apoptosis in Colon Cancer Cells," will be presented by Dr. A.V. Maker. It is co-authored by N. M. Kunda, J. Qin, G. Qiao working out of the University Of Illinois At Chicago, Division Of Surgical Oncology, Department Of Surgery, College Of Medicine, Chicago, IL, USA. The team of authors also includes B. Prabhakar of the University Of Illinois At Chicago, Department Of Microbiology & Immunology, College Of Medicine, Chicago, IL, USA. Dr. Maker belongs to both Departments.

The presentation is scheduled for 7:30-9:30 am on Tuesday, February 2, 2016, in City Terrace 5 at the Hyatt Regency in Jacksonville. The abstract can be found at: View Source

About the Academic Surgical Congress

The Academic Surgical Congress is organized by the Association for Academic Surgery (AAS) and the Society of University Surgeons (SUS). The purpose of the AAS is: to stimulate young surgeons and surgical scientists to pursue careers in academic surgery and support them in establishing themselves as investigators and educators; to provide a forum for senior surgical residents, fellows and junior faculty members to present papers on subjects of clinical, laboratory or educational research; and to facilitate the development of young surgeons and surgical scientists as investigators and educators. Its additional mission is to inspire and develop young academic surgeons. The SUS exists to advance the art and science of surgery by (1) the encouragement of its members to pursue original investigations both in the clinic and in the laboratory; (2) the development of methods of graduate teaching of surgery with particular reference to the resident system; (3) free and informal interchange of ideas pertaining to the above subjects.

On January 22, 2016 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of discovering, developing and commercializing novel immuno-oncology product candidates, including both cellular immunotherapy and checkpoint inhibitor platforms, reported the presentation of data that describe a combination therapy of indoximod, an IDO pathway inhibitor, plus gemcitabine/nab-paclitaxel, for patients with metastatic pancreatic cancer (Press release, NewLink Genetics, JAN 22, 2016, View Source [SID:1234508841]). This combination immunotherapeutic approach was well tolerated and shows encouraging durable responses with a delayed pattern and a 42 percent objective response rate, including one complete response (CR), according to data presented at the 2016 Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco.

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"The preliminary overall response rate is certainly promising, but I am particularly intrigued by the pattern of delayed and durable responses potentially suggesting an immune mediated mechanism of action," said Nathan Bahary, MD, PhD, Associate Professor in the Division of Oncology and Medical Director of the Pancreatic Cancer Program at the University of Pittsburgh Medical Center, and principal investigator of the study.

These data come from the Phase 1b portion of the trial that included 12 patients who were evaluable for a response. To date, this Phase 1/2 trial has enrolled 50 patients, with a target enrollment of 80 patients in the Phase 2 portion.

In the Phase 1b portion of the trial, the combination therapy with indoximod had an objective response rate of 42 percent (5/12), including one CR. The MPACT study, which established gemcitabine/nab-paclitaxel as standard of care for patients with metastatic pancreatic cancer, demonstrated an objective response rate of 23 percent.

"Pancreatic cancer continues to be one of the deadliest of all malignancies with very limited options for the patients. I am delighted to be part of this study with gemcitabine/nab-paclitaxel in combination with the immunomodulatory agent indoximod, targeting the IDO pathway, as this combination approach seems to offer a potential benefit with minimal added toxicity," said Andrea Wang-Gillam, MD, PhD, Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine in St. Louis.

These data are being presented today at ASCO (Free ASCO Whitepaper) GI, during Poster Session B (12:30-2:00PM and 5:30-7:00PM), "Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract," correspond to abstract number 452 entitled, "Results of the Phase 1b Portion of a Phase 1/2 trial of the Indoleamine 2,3-dioxygenase Pathway (IDO) Inhibitor Indoximod plus Gemcitabine/Nab-Paclitaxel for the Treatment of Metastatic Pancreas Cancer."

About Indoximod

Indoximod is an orally available small molecule that has shown the potential to interfere with multiple targets within the indoleamine 2,3-dioxygenase (IDO) pathway. It is designed to be used in combination with other therapeutic agents to maximize the body’s immune response against a range of tumor types. Indoximod is currently in multiple Phase 2 clinical trials for the treatment of patients with breast, prostate, pancreatic, melanoma and brain cancers and in Phase 1 clinical trials for the treatment of pediatric patients with primary malignant brain tumors.

On January 22, 2016 Celgene Corporation (NASDAQ:CELG) report that 10 studies highlighting combinations that include a foundation of ABRAXANE (paclitaxel protein-bound particles for injectable suspension)(albumin-bound) and gemcitabine are being presented during the 2016 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI), establishing the therapy as the foundation for research in first-line metastatic pancreatic cancer (Press release, Celgene, JAN 22, 2016, View Source [SID:1234508840]).

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"ABRAXANE is the only chemotherapy approved in combination with gemcitabine based on an improvement in overall survival for first line metastatic pancreatic cancer patients and is fast becoming the standard of care in this extremely difficult to treat disease," said Jacqualyn A. Fouse, Ph.D., President, Hematology/Oncology for Celgene. "We are excited that ABRAXANE plus gemcitabine is serving as the foundation for a new wave of potential treatments that may further improve the treatment paradigm in this disease and are fully committed to continuing to serve these patients."

Studies evaluating new combinations added to ABRAXANE plus gemcitabine being presented at the meeting include:

– Results from a phase 1b study of the anti-cancer stem cell agent demcizumab and gemcitabine +/- nab-paclitaxel in patients with PC (Abstract 341) – Hidalgo

– Results from a phase 1b study of cancer stem cell pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (Abstract 284) – Shahda

– Results of the phase 1b portion of a phase 1/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreatic cancer. (Abstract 452) – Bahary

– A trial in progress update on nab-paclitaxel (nab-P) + nivolumab (Nivo) ± gemcitabine (Gem) in patients (pts) with advanced pancreatic cancer (PC). (Abstract TPS475) – Firdaus

– A trial in progress update on a randomized, multicenter, double-blind, placebo-controlled study of the Bruton tyrosine kinase inhibitor, ibrutinib, v. placebo in combination with nab-paclitaxel and gemcitabine in first-line mPC (Abstract TPS483) – Tempero

– Interim results of a randomized phase 2 study of PEGPH20 added to nab-paclitaxel/gemcitabine in patients with stage 4 previously untreated pancreatic cancer. (Abstract 439) – Hingorani

– Trial in progress update on a multicenter phase 2 study of istiratumab (MM-141) plus nab-paclitaxel (A) and gemcitabine (G) in metastatic pancreatic cancer (MPC). (TPS481) – Ko

– Trial in progress update on a phase 1 trial with cohort expansion of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and mPC (TPS467) – Soares

– Results from a trial "Synergy of water soluble prodrug triptolide (minnelide) with gemcitabine and nab-paclitaxel in pancreatic cancer. (Abstract 259) – Dudeja

– Results from the RAINIER trial: A randomized, double-blinded, placebo-controlled phase 2 trial of gemcitabine plus nab-paclitaxel combined with apatorsen or placebo in patients with metastatic pancreatic cancer (Abstract 419)- Ko

Abraxane plus gemcitabine is not approved in the combinations identified above.

Indications

ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500 cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE
Sepsis

Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels
Pneumonitis

Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin > 1.5 x ULN and AST ≤10 x ULN)
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment
Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
Monitor patients closely