On November 23, 2015 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported the initiation of its rolling new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for pacritinib, an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R (Press release, CTI BioPharma, NOV 22, 2015, View Source;p=RssLanding&cat=news&id=2114525 [SID:1234508312]). As part of the application, CTI BioPharma and its partner, Baxalta Incorporated (Baxalta), are seeking accelerated approval and priority review for pacritinib for the treatment of patients with intermediate and high-risk myelofibrosis with low platelet counts of less than 50,000 per microliter (<50,000/uL). If approved for the requested indication, pacritinib would be the first JAK2 inhibitor approved for the treatment of patients with myelofibrosis with platelet counts of less than 50,000/uL – a specific patient population for which there are currently no approved drugs. The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis. CTI BioPharma and Baxalta plan to complete the submission before the end of 2015.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Myelofibrosis (a type of myeloproliferative neoplasm) is a rare, but serious and life-threatening chronic bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. Myelofibrosis is associated with significantly reduced quality of life and shortened survival, can affect patients of all ages (with a median affected age being 65 years) and an estimated prevalence in the United States of approximately 18,000 patients.

"We believe the initiation of the rolling NDA submission represents a major step forward toward potentially offering pacritinib as a next generation JAK2/FLT3 inhibitor to patients with this rare and chronic type of blood cancer," said James A. Bianco, M.D., President and CEO of CTI BioPharma. "We are excited to have achieved this milestone and look forward to working with the FDA during the review process, with the goal of bringing this important treatment to market – which we hope will fill an unmet need for many patients whose lives are profoundly impacted by myelofibrosis."

The submission includes data from the PERSIST-1 Phase 3 trial – as well as data from Phase 1 and 2 studies of pacritinib. Submission of an NDA after a single Phase 3 trial under accelerated approval, instead of waiting to complete two Phase 3 trials, could potentially reduce time to market by up to 14 months. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high-risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment emergent thrombocytopenia on another JAK2 therapy; or patients who are intolerant to or whose symptoms are not well controlled (or sub-optimally managed) on another JAK2 therapy.

About Myelofibrosis and Myeloproliferative Neoplasms
Myelofibrosis is a one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of hematological blood cancers. The three main types of MPNs are myelofibrosis, polycethemia vera, and essential thrombocythemia.1 Myelofibrosis is a serious and life-threatening chronic bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue, and pain.

The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S. of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis2 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia.3 The median survival for high-risk patients is less than one and a half years; median survival for myelofibrosis patients overall is approximately six years.4

About Pacritinib
Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis, including but not limited to patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy, or patients who are intolerant of, or whose symptoms are sub-optimally managed on other JAK2 inhibitor therapy. The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Pacritinib does not have regulatory approval and is not commercially available.

CTI BioPharma and Baxalta (NYSE:BXLT) are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.

On November 23, 2015 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported findings from an investigator-sponsored preclinical study showing the potential synergistic effect of combining pacritinib, an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R, with an epidermal growth factor receptor (EGFR) inhibitor in decreasing brain tumor initiating cells (BTIC) viability (Press release, CTI BioPharma, NOV 22, 2015, View Source;p=RssLanding&cat=news&id=2114521 [SID:1234508311]). BTICs have cancer stem cell characteristics and are believed to be responsible for disease initiation and recurrence. Additionally, high rates of mutations in BTICs may lead to the rapid emergence of resistance in GBM, the most common and aggressive primary brain cancer. Given that upregulation of the JAK/STAT pathway may be a common mechanism of resistance to EGFR antagonists, the current study demonstrates the potential for combination therapies with pacritinib to be a promising therapeutic avenue in GBM. The early phase findings also showed prolonged survival in an intracerebral BTIC xenograft preclinical model of human GBM when delivered in combination with temozolomide.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

These findings were presented by Ms Katharine Jensen from the laboratory of Drs Artee Luchman and Samuel Weiss, at the Hotchkiss Brain Institute, University of Calgary in an oral presentation (abstract #ATPS-52) during the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) held November 19-22, 2015 in San Antonio, Texas.

"Although activating mutations in EGFR are common in GBM, physiological challenges with drug penetration, drug pharmacokinetics and rapid emergence of resistance have resulted in EGFR inhibitors showing limited effectiveness as monotherapies," said Dr. Weiss, Professor at the University of Calgary’s Cumming School of Medicine and Director of the Hotchkiss Brain Institute. "Our findings support the hypothesis that combination therapy, for example targeting both the JAK/STAT pathways inhibited by pacritinib and EGFR, may improve clinical outcomes for patients with GBM."

"The tolerability profile of pacritinib observed in the clinic to date, along with the ability to achieve meaningful intracerebral levels in preclinical models, makes it a candidate to be explored for use in combination therapy for GBM," said Jack W. Singer, M.D., Chief Scientific Officer and Global Head of Translational Medicine at CTI BioPharma. "We believe these findings further support the potential for clinical trials of pacritinib in difficult to treat, non-hematological cancers."

The combination of pacritinib with one of three different EGFR inhibitors (afatinib, lapatinib, erlotinib) each resulted in decreased BTIC viability. Additionally, the effect of combining pacritinib with afatinib was shown to be synergistic in BTIC growth inhibition. Ongoing investigations are focusing on whether combinatorial therapy can improve survival in a preclinical model.

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis, including but not limited to patients with disease-related thrombocytopenia, patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy, or patients who are intolerant of, or whose symptoms are sub-optimally managed on other JAK2 inhibitor therapy. The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Pacritinib does not have regulatory approval and is not commercially available.

CTI BioPharma and Baxalta Incorporated (NYSE:BXLT) are parties to a worldwide license agreement to develop and commercialize pacritinib. CTI BioPharma and Baxalta will jointly commercialize pacritinib in the U.S. while Baxalta has exclusive commercialization rights for all indications outside the U.S.

About Glioblastoma Multiforme

According to the National Cancer Institute, GBM is the most common and deadliest type of primary brain tumor in adults. GBM has an incidence of two to three per 100,000 adults per year, and accounts for 52 percent of all primary brain tumors.1 The current standard of care for patients with GBM is a surgical resection, if possible, followed by radiation given with concurrent temozolomide. The prognosis for the majority of patients with GBM is poor with median survival of approximately 14.6 months with less than 30 percent of patients surviving two years using current therapies.2

On November 21, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from three studies investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in combination with three other immunotherapies – epacadostat, IMLYGICTM (talimogene laherparepvec), and ipilimumab – in patients with advanced melanoma (Press release, Merck & Co, NOV 21, 2015, View Source [SID:1234508309]). The findings, which were featured in separate oral presentations today at the Society for Melanoma Research 2015 International Congress (SMR) in San Francisco, showed robust anti-tumor activity with KEYTRUDA in all three combinations studied.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We have demonstrated the benefit of KEYTRUDA as a single agent in advanced/metastatic melanoma and we are now also looking to identify potential combinations for patients with this devastating disease," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "The combination data presented at SMR, including KEYTRUDA combined with epacadostat or IMLYGIC, may further our goal of improving outcomes without substantial increased toxicity."

Additionally, updated data presented at SMR from a Phase 3 study of KEYTRUDA as a single agent showed superior overall response rates (ORR) and progression free survival (PFS) compared to ipilimumab in ipilimumab-naïve patients, with twice as many patients achieving PFS on KEYTRUDA compared to ipilimumab. As previously reported, the study met its endpoint of overall survival. Patient-reported outcomes from the same study were also presented. The KEYTRUDA clinical development program to date includes patients with more than 30 tumor types in more than 160 clinical trials, including more than 80 trials that combine KEYTRUDA with other cancer treatments.

Early Findings from the KEYNOTE-037 Study (KEYTRUDA with Epacadostat)

KEYNOTE-037 is an ongoing Phase 1/2 study of KEYTRUDA (pembrolizumab) in combination with epacadostat (INCB024360) – an investigational selective IDO1 inhibitor – in patients with advanced cancers. The trial is a collaboration between Merck and Incyte Corporation. Data from the melanoma cohort of this study were presented on Nov. 21 at 2:50 p.m. PST by Dr. Omid Hamid, director, Melanoma Center, The Angeles Clinic and Research Institute. These data were previously presented earlier this month at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting as part of a presentation that included several tumor types. The SMR data includes additional safety data.

Early data from this trial showed that in 19 patients with advanced melanoma, the combination of KEYTRUDA (two doses studied – 2 mg/kg or 200 mg every three weeks) with epacadostat (four doses studied – 25, 50, 100 or 300 mg twice daily) demonstrated an ORR of 53 percent (n=10/19), including three complete responses (CRs) and seven partial responses (PRs). The disease control rate (DCR) was 74 percent (n=14/19).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA as a single agent. Fifteen percent (n=9/60) of patients assessed for safety across tumor types experienced Grade 3 investigator-assessed, treatment-related adverse events, including rash (8%), arthralgia (2%), AST increased (2%), mucosal inflammation (2%) and nervous system disorder (2%). Three patients discontinued treatment – one for Grade 3 arthralgia, one for Grade 3 AST increased, and one for Grade 2 nervous system disorder. No Grade 4 treatment-related adverse events or deaths were observed.

As previously announced, based on these findings, a Phase 3 trial of this combination is planned.

Early Findings from the MASTERKEY-265 Study (KEYTRUDA with IMLYGIC)

MASTERKEY-265 is an ongoing Phase 1b study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with IMLYGIC – a herpes simplex virus-1 (HSV-1)-based oncolytic immunotherapy – in patients with previously untreated, unresected advanced melanoma. The trial is a collaboration between Merck and Amgen. Data from this study were presented on Nov. 21 at 3:20 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Data presented were of 16 evaluable patients and the first analysis of this study; results showed that the combination of KEYTRUDA (200 mg every two weeks) with IMLYGIC (up to 4 mL of 106 PFU/mL, then 108 PFU/mL every two weeks) resulted in an unconfirmed ORR of 56.3 percent (n=9/16) (95% CI, 19.8, 70.1), including two CRs and seven PRs. The DCR was 68.8 percent (n=11/16) (95% CI, 11, 58.7).

Treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA (pembrolizumab). All 21 patients enrolled had at least one adverse event, and most were Grades 1 and 2. The most common adverse events (occurring in at least 30% of patients) of any grade were fatigue (52%), pyrexia (48%), chills (43%), rash (38%), headache (33%), and nausea (33%). Grade 3 adverse events included headache (5%) and diarrhea (5%). Treatment-related Grade 3 adverse events occurring in 5 patients included anemia, hyperglycemia, hypoglycemia, hypophosphatemia, headache, macular rash and generalized rash. No dose-limiting toxicities were reported.

Based on these findings, a Phase 3 part of this trial is planned.

Early Findings from the KEYNOTE-029 Study (KEYTRUDA with Ipilimumab)

KEYNOTE-029 is an ongoing Phase 1/2 study evaluating the safety, efficacy, and tolerability of KEYTRUDA in combination with low-dose ipilimumab in patients with advanced melanoma to investigate whether lower doses of ipilimumab improve the tolerability of the combination regimen. Early findings from this study were presented on Nov. 21 at 2 p.m. PST by Dr. Georgina Long, associate professor, Melanoma Institute Australia, University of Sydney.

Early findings in 72 evaluable patients with advanced melanoma showed that KEYTRUDA (2 mg/kg every three weeks) in combination with low-dose ipilimumab (1 mg/kg every three weeks for four doses) demonstrated an ORR of 56 percent (95% CI, 43-67), including three CRs and 37 PRs. The DCR was 79 percent (95% CI, 68-88).

Treatment-related adverse events were observed in 93 percent (n=67/72) of patients. Grade 3-4 treatment-related adverse events were observed in 36 percent of patients (n=26/72), including lipase increased (8%), amylase increased (6%), ALT increased (6%), AST increased (4%), rash (3%), and diarrhea (1%). Grade 3-4 immune-mediated adverse events included thyroiditis, hypophysitis, type 1 diabetes mellitus, pneumonitis, colitis, hepatitis, pancreatitis, severe skin reactions and renal events. There were no treatment-related deaths.

Additional Findings from the KEYNOTE-006 Study

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study of patients with unresectable stage 3 or 4 advanced melanoma who were naïve to ipilimumab and had no more than one prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every two weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). Today’s findings provide data on additional endpoints of ORR and PFS based on six months of additional follow-up (median follow-up of 13.8 months), as well as the first-time presentation of patient-reported outcomes. Results were featured in two poster sessions by Dr. Jacob Schachter, Ella Lemelbaum Institute for Melanoma, Sheba Medical Center, and Dr. Teresa Petrella, Sunnybrook Health Sciences Centre, University of Toronto.

Findings showed PFS rates for KEYTRUDA at 12 months were twice as high as ipilimumab – 37.7 percent in the KEYTRUDA every two week cohort and 36.3 percent in the every three week group, compared to 17.2 percent with ipilimumab (hazard ratio: 0.60 [95% CI, 0.49-0.74] and hazard ratio: 0.59 [95% CI, 0.48-0.73], respectively). Additionally, the ORR was 36.2 and 36.1 percent in patients receiving KEYTRUDA every two weeks or every three weeks, respectively [(95% CI, 30.6-42.1) and (95% CI, 30.4-42.1), respectively], compared to 12.9 percent for ipilimumab (95% CI, 9.2-17.5).

There continued to be no treatment-related deaths in the KEYTRUDA arm and there were no treatment-related deaths in the ipilimumab arm beyond one that was previously reported. Grade 3-5 treatment-related adverse events were lower for KEYTRUDA than for ipilimumab – 15.1 and 12.6 percent of patients receiving KEYTRUDA every two weeks and every three weeks had Grade 3-4 adverse events, respectively, compared to 19.9 percent of those receiving ipilimumab. Immune-mediated treatment-related adverse events were consistent with previously reported safety data for KEYTRUDA and included hypothyroidism, hyperthyroidism, colitis, hepatitis, hypophysitis, pneumonitis, type 1 diabetes mellitus, uveitis, myositis and nephritis.

Also reported at SMR from this study was a prespecified analysis of new patient-reported health-related quality of life (HRQoL) outcomes, based on measures such as physical, emotional, cognitive, and social functioning (based on European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire). The study showed that HRQoL was maintained to a greater degree with KEYTRUDA than with ipilimumab – the change from baseline at week 12 (difference in least squares) for KEYTRUDA was -2.3 (95% CI, -5.21 to 0.62) for the two-week group and -2.6 (95% CI, -5.44 to 0.23) for the three-week group, respectively, compared to -9.9 (95% CI, -13.01 to -6.72) for the ipilimumab arm.

In addition, KEYTRUDA was associated with a better symptom profile. Patients in the KEYTRUDA arms had smaller increases from baseline in fatigue, pain, dyspnea, appetite loss, and diarrhea, indicating that although these symptoms worsened with KEYTRUDA, they did so to a lesser degree than with ipilimumab. KEYTRUDA also resulted in improvements over baseline in nausea and vomiting and insomnia, whereas these symptoms worsened with ipilimumab.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA is also indicated at the same dosing for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. These indications are approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Pneumonitis occurred in 19 (3.5%) of 550 patients with NSCLC, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis in patients, receiving KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients with melanoma, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA.

Colitis occurred in 4 (0.7 %) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

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

Hypophysitis occurred in 2 (0.5%) of 411 patients with melanoma, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Hypophysitis occurred in 1 (0.2 %) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients with melanoma, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients with melanoma, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

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

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

Across clinical studies with KEYTRUDA, the following clinically significant, immune-mediated adverse reactions have occurred: bullous pemphigoid and Guillain-Barré syndrome. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients with melanoma treated with KEYTRUDA (pembrolizumab): exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

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

Among the 411 patients with metastatic melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

Among the 550 patients with metastatic NSCLC, KEYTRUDA was discontinued due to adverse reactions in 14% of patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in 2% or more of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), decreased appetite (25%), dyspnea (23%), and cough (29%).

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

On November 21, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported the presentation of positive overall survival (OS) results from coBRIM, the phase 3 pivotal trial evaluating COTELLIC (cobimetinib) in patients with previously untreated resectable, locally advanced or metastatic melanoma carrying a BRAF V600E or V600K mutation, in combination with vemurafenib (Press release, Exelixis, NOV 21, 2015, View Source;p=RssLanding&cat=news&id=2114503 [SID:1234508308]). Dr. Victoria Atkinson, Medical Oncologist at Princess Alexandra Hospital, Queensland, Australia, presented the data during a late-breaking abstract oral presentation this afternoon at the Society for Melanoma Research (SMR) 2015 International Congress, which is being held November 18-21 in San Francisco. COTELLIC is a selective inhibitor of MEK that was discovered by Exelixis and is now the subject of a worldwide collaboration agreement between Exelixis and Genentech, a member of the Roche Group.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In October 2015, Exelixis announced the coBRIM trial met its OS secondary endpoint, demonstrating a statistically significant increase in OS for the combination of COTELLIC and vemurafenib compared to vemurafenib monotherapy. Today’s presentation was the first to include detailed data on the endpoint. The median OS was 22.3 months for the combination of COTELLIC and vemurafenib versus 17.4 months for vemurafenib alone, corresponding to a 30% reduction in the rate of death for the combination as compared to vemurafenib alone (hazard ratio [HR]=0.70, 95% confidence interval [CI] 0.55-0.90, p= 0.005). Ongoing study monitoring did not identify any new safety signals.

"The overall survival benefit for COTELLIC and vemurafenib observed in the coBRIM trial further underscores the positive impact that the combination of these two therapies can have on the treatment of advanced BRAF V600 mutation-positive melanoma," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis.

On November 10, 2015, the U.S. Food and Drug Administration (FDA) approved COTELLIC as a treatment for patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib. COTELLIC was first approved in Switzerland in late August 2015. The COTELLIC approvals are based on data from coBRIM, the phase 3 pivotal trial conducted by Genentech in 495 patients with previously untreated unresectable, locally advanced or metastatic melanoma carrying a BRAF V600 mutation (detected by the cobas 4800 BRAF Mutation Test). Genentech sponsored the U.S. New Drug Application and Roche sponsored the Swiss regulatory application. Roche also filed a Marketing Authorization Application (MAA) with the European Medicines Agency in late 2014, and the Committee for Medicinal Products for Human Use issued a positive recommendation on the MAA in September 2015. Roche anticipates a decision from the European Commission by year-end.

About the COTELLIC Development Collaboration

Exelixis discovered COTELLIC internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop COTELLIC.

Under the terms of collaboration, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote COTELLIC in the United States and, under the terms of the agreement, the company is fielding 25 percent of the U.S. sales force, closely coordinating its efforts with Genentech. Outside of the United States, Exelixis is eligible to receive royalties on any sales.

About COTELLIC in Combination with Vemurafenib

COTELLIC and vemurafenib are prescription medicines used in combination to treat melanoma that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene. Found in approximately half of melanomas, mutated BRAF causes abnormal signaling inside cancer cells leading to tumor growth. Vemurafenib is designed to inhibit some mutated forms of BRAF and COTELLIC is designed to inhibit some forms of MEK. Both BRAF and MEK are proteins in a cell signaling pathway that help control cell growth and survival. When used in combination, COTELLIC and vemurafenib are thought to reduce cancer cell growth longer than with vemurafenib alone. A patient’s healthcare provider will perform a test to make sure COTELLIC and vemurafenib are right for the patient. It is not known if COTELLIC and vemurafenib are safe and effective in children under 18 years of age.

About the coBRIM Trial

CoBRIM is an international, randomized, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of 60 mg once daily of cobimetinib plus 960 mg twice daily of vemurafenib compared to 960 mg twice daily of vemurafenib plus placebo. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomized to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS is the primary endpoint. Secondary endpoints include PFS by independent review committee, objective response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.

About Melanoma and its BRAF V600 Mutation-Positive Form

Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years. It is projected that approximately half of all melanomas, and eight percent of solid tumors, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival.

COTELLIC Important Safety Information

Before taking COTELLIC, patients should tell their doctor if they:

have any previous or current skin problems other than melanoma
have any medical conditions and/or are on any medications that increase your risk of bleeding
have any heart problems
have any eye problems
have any liver problems
have any muscle problems
have any other medical conditions
are pregnant or plan to become pregnant. COTELLIC can harm an unborn baby.

Patients who take COTELLIC should use effective methods of birth control during treatment, for at least two weeks after stopping COTELLIC, and for at least two months after stopping vemurafenib.

Patients should talk to their healthcare provider about birth control methods that may be right for them.
Patients should tell their healthcare provider right away if they become pregnant or think they are pregnant during treatment with COTELLIC.

are breastfeeding or plan to breastfeed. It is not known if COTELLIC passes into breast milk, so patients should not breastfeed during treatment with COTELLIC and for two weeks after the final dose. Patients should talk to their healthcare provider about the best way to feed their baby during this time.

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements because some types of medicines will make COTELLIC more harmful or less effective. Patients should know the medicines they take and keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.

Patients should avoid sunlight while taking COTELLIC. COTELLIC can make patients’ skin sensitive to sunlight and cause them to burn more easily and get severe sunburns. To help protect against sunburn:

When patients go outside they should wear clothes that protect their skin, including their head, face, hands, arms and legs.
Patients should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
COTELLIC may cause serious side effects, including:

Risk of skin cancers. COTELLIC may cause skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma or basal cell carcinoma).

Patients must check their skin and tell their doctor right away about any skin changes, including:

new wart
skin sore or reddish bump that bleeds or does not heal
change in size or color of a mole
A patient’s healthcare provider should check their skin before they start taking COTELLIC and every two months while taking COTELLIC. A patient’s healthcare provider may continue to check their skin for six months after they stop taking COTELLIC.

Increased risk of bleeding. COTELLIC may cause bleeding, including blood in the urine, rectal bleeding, unusual or excessive vaginal bleeding, bleeding of the gums and bleeding within the brain (cerebral hemorrhage).

A patient should tell their healthcare provider right away if they experience any of these symptoms:
red or black stools that look like tar
blood in the urine
headache, dizziness or feeling weak
abdominal pain
unusual vaginal bleeding

Heart problems that can lead to inadequate pumping of the blood by the heart. A patient’s healthcare provider should perform tests before the patient starts taking COTELLIC and during a patient’s treatment with COTELLIC to check the ability of the heart to pump blood. Signs and symptoms of a decrease in the amount of blood pumped include:

persistent coughing or wheezing
shortness of breath
swelling of their ankles and feet
tiredness
increased heart rate
Rash. Patients should tell their healthcare provider right away if they experience any of these symptoms:
a rash that covers a large area of their body, blisters or peeling skin

Eye problems. Patients should tell their healthcare provider right away if they experience any of these symptoms during treatment with COTELLIC:

blurred vision
distorted vision
partly missing vision
halos
any other vision changes
Some of these eye problems may be a result of something called "serous retinopathy" (a build-up of fluid under the retina of the eye). A patient’s healthcare provider should check their eyes if they notice any of the symptoms above.

Abnormal liver test or liver injury. A patient’s healthcare provider should perform blood tests before the start taking COTELLIC, and during treatment. A patient should tell their healthcare provider right away if you experience any of these symptoms:

yellowing of their skin or the white of their eyes
dark or brown (tea color) urine
nausea or vomiting
feeling tired or weak
loss of appetite

Increased levels of an enzyme in the blood. Creatine phosphokinase (CPK) is an enzyme that is primarily found in the muscle, heart and brain. Treatment with COTELLIC may increase the level of this enzyme in your blood and be a sign of muscle damage. A patient’s healthcare provider should perform a blood test before and during treatment. Increased blood levels of CPK can also be an indication of a serious condition caused by injury to the muscles (rhabdomyolysis). A patient should tell their healthcare provider right away if they experience any of these symptoms:

muscle aches
muscle spasms and weakness
dark, reddish urine

Photosensitivity. A patient’s skin may become more sensitive to sunlight while taking COTELLIC. A patient should tell their healthcare provider if they notice any of the following symptoms:
red, painful, itchy skin that is hot to touch
sun rash
skin irritation
bumps or tiny papules
thicken, dry, wrinkled skin

The most common side effects of COTELLIC include:

diarrhea
sunburn or sun sensitivity
nausea
vomiting
fever

A patient’s healthcare provider will take blood tests while they are taking COTELLIC. The most common changes to blood tests include:

increased blood levels of liver enzymes (gamma glutamyltransferase [GGT], alanine aminotransferase [ALT] or aspartate aminotransferase [AST])
increased blood level of enzyme from muscle (creatine phosphokinase)
decreased blood level of phosphate, sodium or potassium
increased blood level of liver or bone enzyme (alkaline phosphatase)
decreased blood level of a type of white blood cell (lymphocyte)
Patients should tell their healthcare provider if they have any side effect that bothers them or that does not go away.

These are not all the possible side effects of COTELLIC. For more information about side effects, patients should ask their healthcare provider or pharmacist. Patients should call their doctor for medical advice about side effects.

On November 20, 2015 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) (Aptose or the Company), a clinical-stage company developing new therapeutics and molecular diagnostics that target the underlying mechanisms of cancer, reported that the Food and Drug Administration (FDA), following a voluntary suspension of dosing by the Company and discussions with the Company, placed the Phase Ib clinical trial of APTO-253 in patients with hematologic cancers on clinical hold (Press release, Aptose Biosciences, NOV 20, 2015, View Source;p=RssLanding&cat=news&id=2114349 [SID:1234508462]). This hold is intended to ensure patient safety on the trial and to ensure manufacturing and dosing procedures are consistent with the appropriate documented quality standards.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The voluntary suspension of dosing by the Company was initiated as a result of a planned preliminary review, which was accelerated to evaluate manufacturing processes and procedures upon the report of an operational difficulty with an IV infusion pump at a clinical site. The pump experienced back pressure during IV patient dosing at the point of the filter. Further review discovered preliminary concerns regarding the documentation records of the manufacturing procedures of the drug product associated with APTO-253.

The Company stated that a complete safety review of all patient files had been completed prior to initial discovery of the manufacturing documentation irregularities, and there have been no drug-related serious adverse events (SAEs) reported. The observed pharmacokinetic levels in the patients treated were within the expected range.

"We are disappointed by these events and have engaged an independent third party review. Importantly, this finding does not undermine the positive safety profile that APTO-253 has demonstrated in clinical development, and we remain confident in its potential as a promising therapeutic option for patients with acute myeloid leukemia and other hematologic malignancies," said William G. Rice, Ph.D., Chairman, President and CEO. "While we expect some delay in the clinical trial, we are committed to ensuring that upon re-initiation of clinical dosing the drug product is of the highest standards. We plan to provide updated timeline guidance as soon as practical."

Key Points:

An internal review identified potential documentation irregularities and the Company voluntarily and immediately suspended dosing of patients out of an abundance of caution to ensure safety.

Aptose currently possesses a sufficient supply of API to create fresh batches of drug product for the resumption of clinical dosing upon FDA approval and guidance.

New contract manufacture organizations have been identified to manufacture fresh batches of cGMP clinical supply upon completion of investigation and in coordination with FDA guidance.

Overall effect to the Phase Ib trial timeline is expected to be partially mitigated by initiation of the new trial sites and updated timeline will be reported as soon as determined.