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