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 20, 2015 Aduro Biotech, Inc. (Nasdaq:ADRO), a clinical-stage immunotherapy company, reported the presentation of an overview of novel antibody and combination strategies designed to stimulate durable anti-tumor response at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Symposium on Immuno-Oncology 2015, taking place November 20-21, 2015, in Lausanne, Switzerland (Press release, Aduro BioTech, NOV 20, 2015, View Source;p=RssLanding&cat=news&id=2114366 [SID:1234508296]). The presentation was featured in a keynote lecture delivered at the ESMO (Free ESMO Whitepaper) symposium by Andrea van Elsas, Ph.D., chief scientific officer of Aduro Biotech Europe, titled, "Immunomodulatory Antibodies Beyond PD-1."

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 presentation focused on advancements in the field of immuno-oncology involving combination antibody approaches targeting T cells (e.g. CD27 agonists), the tumor-immune interfaces (e.g. CD47 – SIRP(alpha) axis), dendritic cells and macrophages and bispecific antibodies. Dr. van Elsas also discussed promising early work with new agonists such as cyclic dinucleotides (CDNs).

"Recent advances in immunotherapy are bringing about a new era of cancer medicine and revolutionizing the development of novel treatments across a broad range of cancer types," said Dr. van Elsas. "Checkpoint inhibitors have clearly demonstrated clinical benefit as single agent therapy in some patient populations, but emerging data suggests combination therapy may be required to extend this benefit to a majority of patients. At Aduro, our focus is on advancing multiple therapeutic approaches that have the potential to yield powerful immunotherapy combinations."

During the presentation, Dr. van Elsas summarized the three diverse immunotherapy platforms that Aduro focuses on that aim to disrupt the tumor microenvironment and harness patients’ immune systems to fight multiple cancer targets:

– LADD (live, attenuated, double-deleted Listeria mononcytogenes) involving bacteria-based mobilization of the immune system

– CDNs targeting small molecule activation of the Stimulator of Interferon Genes (STING) receptor leading to T cell priming specific for tumor neoantigens

– B-select technology targeting first or best-in-class agonist and antagonist monoclonal antibodies (mAbs)

Additionally, key topics that were highlighted in the presentation included:

– Preclinical data demonstrating potent anti-tumor activity of ADU-S100, a proprietary molecule based on Aduro’s CDN platform technology

– ADU-S100’s ability to induce innate immunity through STING, a critical receptor to activate immune cells including dendritic cells in the tumor microenvironment

– The formulation of ADU-S100 with GVAX into the cancer vaccine – "STINGVAX" – that was shown to be active in anti-PD1 resistant tumors. GVAX is a family of cancer immunotherapies acquired by Aduro in 2013

– Research demonstrating mode-of-action of CD27 agonistic antibodies

– Research demonstrating how antibodies that block CD47 – SIRP(alpha) interaction to enhance tumor killing and rejection as well as elicit functional cytotoxic T lymphocytes (CTL)

Aduro believes this research underscores the critical importance of not only overcoming immune suppression, but also activating and stimulating the immune system using Aduro’s CDN approach targeting the STING receptor and Aduro’s LADD-based immunotherapies.

On November 20, 2015 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations with a primary focus in Hematology and Oncology, reported the Company has submitted an IND application to the U.S. Food and Drug Administration (FDA) and plans to initiate a Phase 2 breast cancer study in the U.S. as soon as possible (Press release, Spectrum Pharmaceuticals, NOV 20, 2015, View Source [SID:1234508297]).

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!

"This Phase 2 study is an important step for us to solidify our registration strategy in the U.S.," said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. "The potential target market for Poziotinib is large, and metastatic breast cancer patients continue to progress despite availability of several drugs. Poziotinib has shown promising early clinical activity in Phase 1 trials in patients who had failed multiple lines of treatment including the HER2-directed therapies, trastuzumab and lapatinib. The U.S. Phase 2 trial was designed based on learnings from Phase 1 and Hanmi’s ongoing Phase 2 trials in Korea. We are planning a fast to market strategy as a single agent in parallel with the development of a broader indication using poziotinib in combination with other approved therapies for use in earlier stage disease."

The Phase 2 study is planned to be an open-label study that will enroll approximately 70 patients with HER-2 positive metastatic breast cancer, who have failed at least one or more HER-2 directed therapy. The dose and schedule of oral poziotinib will be based on clinical experience from the studies in Korea, and in addition include the use of prophylactic therapies to help minimize known side-effects of HER2-directed therapies.

Poziotinib is a novel, oral pan-HER inhibitor that irreversibly blocks signaling through the Epidermal Growth Factor Receptor (EGFR, HER) Family of tyrosine-kinase receptors, including HER1 (erbB1; EGFR), HER2 (erbB2), and HER4 (erbB4), and importantly, also HER receptor mutations; this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, gastric cancer, etc. Currently, poziotinib is being investigated by Hanmi in several mid-stage trials in different solid tumor indications including EGFR-mutant NSCLC, gastric cancer, head & neck cancer and HER2 positive breast cancer.

On November 20, 2015 ImmunoCellular Therapeutics, Ltd. ("ImmunoCellular") (NYSE MKT:IMUC) reported the presentation today of recently updated overall survival (OS) results and immune response data from the phase 2 trial of ICT-107 in patients with newly diagnosed glioblastoma (Press release, ImmunoCellular Therapeutics, NOV 20, 2015, View Source [SID:1234508298]). ICT-107 is a dendritic cell-based immunotherapy targeting multiple tumor-associated antigens on glioblastoma stem cells. The data are being presented at the 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, being held in San Antonio, TX. The data from the phase 2 trial continue to indicate a survival advantage in the ICT-107 treated group compared to the control group. The data also show a significant association between immune response and survival, especially in HLA-A2 positive (HLA-A2+) patients, which is the target patient population for the phase 3 registration trial.

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!

IOS results were analyzed at three years after the last patient enrolled. For the 124-patient intent-to-treat population (ITT), median OS was 1.6 months or 10% better for ICT-107 patients than control. The difference in the Kaplan-Meier (KM) survival curves for this patient population was not statistically significant.

Updated OS results for the pre-specified subgroup of HLA-A2+ patients continue to support selecting this patient population alone for a well powered phase 3 trial. For the MGMT methylated, HLA-A2+ PP population, median OS was 13.8 months or 58% better for ICT-107 treated patients than control. For the MGMT unmethylated, HLA-A2+ per-protocol (PP) population, median OS was 4.0 months or 34% better for ICT-107 treated patients than control. The differences in the KM survival curves for these two pre-specified phase 2 sub-populations were not powered for, and did not achieve, statistical significance.

ELISPOT evaluation of antigen-specific immune response demonstrated a more frequent immune response in HLA-A2+ patients compared with HLA-A1 patients, and this difference was statistically significant. This increased immune response in HLA-A2+ patients further supports the selection of HLA-A2+ patients exclusively for inclusion in the phase 3 trial.

In HLA-A2+ patients, immune response was shown to be associated with survival. 60% of ICT-107 treated patients demonstrated a statistically significant immune response compared to only 36% of control patients. In a KM comparison of OS for immune responders versus non-responders, the responder curve showed a statistically significant survival benefit with a log-rank p-value of 0.0084. For ICT-107 treated patients, the KM comparison of OS for responders versus non-responders showed a statistically significant survival benefit with a log-rank p-value of 0.0147. The Company believes that the relationship between immune response and OS supports the phase 3 design improvement of adding more ICT-107 doses for patients in the first year of the protocol.

Immune response did not differ statistically for MGMT methylated compared to unmethylated patients. This result supports including both MGMT types of patients in phase 3 testing.

Of particular interest was the unexpected finding that there was an increased immune response in some control patients post-treatment. One potential explanation is that the phase 2 control (activated dendritic cells without peptide loading) was immunologically active. The phase 3 design employs a different control comprising the patients’ own monocytes, which are less immunologically active than dendritic cells. This control could help clarify a potential survival difference between ICT-107 and control treated patients.

The data are being presented at SNO by John S. Yu, MD, Founder of ImmunoCellular Therapeutics. Dr. Yu commented: "The final data from the phase 2 trial continue to demonstrate the therapeutic value of ICT-107 as a potential treatment for patients with newly diagnosed glioblastoma, and strongly support advancing to phase 3 testing. The clear association between immune response and survival is an important finding that we believe validates the immunotherapeutic mechanism of ICT-107 and strengthens our optimism for the phase 3 trial."

Andrew Gengos, ImmunoCellular Chief Executive Officer, said: "Based on these newly updated phase 2 survival results and the supporting immune response data, we are confident of the design improvements we have built into the phase 3 trial, and look forward to treating our first patient in the coming weeks. The phase 3 trial initiation represents a major milestone in the company’s path toward building a leading cancer immunotherapy company."

Phase 3 Registration Trial Sites Open; First Patient Anticipated to be Treated Soon

The phase 3 registrational trial of ICT-107 is designed as a randomized, double-blind, placebo-controlled study of over 400 HLA-A2+ subjects, which will be conducted at about 120 sites in the US, Canada and the EU. The primary endpoint in the trial is overall survival, which the FDA and EU regulators have stated is the appropriate endpoint for registrational clinical studies in glioblastoma. Secondary endpoints include progression-free survival and safety, as well as overall survival in the two pre-specified MGMT subgroups.

Multiple clinical trial sites have been opened for patient enrollment in the US, with additional sites anticipated to open in Canada and Europe in the coming weeks and months.

ImmunoCellular has reached agreement with the US FDA on a Special Protocol Assessment (SPA) relative to the primary and secondary endpoints as well as the statistical plan for the phase 3 trial. ImmunoCellular has also been awarded a $19.9 million grant from the governing Board of the California Institute for Regenerative Medicine (CIRM), California’s stem cell agency, to implement the phase 3 registration trial.

Background on the ICT-107 Phase 2 Trial

The ICT-107 phase 2 trial was a randomized, double-blind, placebo-controlled phase 2 study of the safety and efficacy of ICT-107 in patients with newly diagnosed glioblastoma multiforme following resection and chemoradiation. ICT-107 is an intradermally administered autologous immunotherapy consisting of the patient’s own dendritic cells pulsed with six synthetic tumor-associated antigens: AIM-2, MAGE-1, TRP-2, gp100, HER-2, IL-13Rα2. The placebo control consisted of the patient’s unpulsed dendritic cells.

A total of 124 patients were randomized at 25 clinical trial sites in the US. One third of the patients or 43 patients were treated with placebo, and the treatment arm included two thirds or 81 patients. All patients in the trial received standard-of-care temozolomide. The regimen was four induction doses of ICT-107 after chemoradiation, and then maintenance doses until the patient progresses. The primary endpoint of the trial was OS, defined as the time from randomization until date of death or the last date the patient is known to be alive. Secondary endpoints included PFS, defined as the time from randomization until the date of documented progressive disease or death, whichever occurs first, or the last date the patient is known to be alive and progression-free if progression or death is not observed. Other secondary endpoints included the rates of OS and PFS at six months after surgery, then assessed every three months until the end of the study. Safety and immune response were additional secondary endpoints.

For patients, families and physicians seeking additional information about the ICT-107 phase 3 trial, please consult www.clinicaltrials.gov.

On November 20, 2015 Kancera reported an operational update on the PFKFB3 and HDAC6 projects as well as the EU-funded epigenetically targeted parasitic project A-PARADDISE (Press release, Kancera, NOV 20, 2015, View Source;releaseID=1076542 [SID:1234508302]).

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 PFKFB3 project
Recent studies conducted within the framework of the collaboration with Prof. Thomas Helleday show that treatment with Kancera’s PFKFB3 inhibitor KAN0438757 alone inhibits an aggressive breast cancer tumor formed by the cell line MB231 (triple negative breast cancer). The human cancer cells were transplanted into zebra fish and four days treatment with KAN0438757 reduced the size of the tumor by more than 50% in comparison with the control treatment. The results support that Kancera’s PFKFB3 inhibitor is effective when reaching the tumor in sufficient concentration. Previously reported results show that Kancera’s PFKFB3 inhibitor KAN0438757 is able to counteract cancer cell repair of the DNA. Hence there are grounds to examine whether a more potent effect of PFKFB3 inhibitors can be achieved against triple negative breast cancer by combining the treatment with e.g. DNA damaging radiation. However, such a combination effect remains to be demonstrated in vivo.

The HDAC6 project
Since May 2015, when Kancera’s first patent application in the HDAC6 project entered the international stage, new series of potent and selective inhibitors of the enzyme has been developed. An additional patent application that covers these new HDAC6 inhibitors will be registered before the end of January, 2016. In order facilitate the filing of the new patent application, Kancera has decided to postpone the publication of the first patent application for one year.

In June 2015, Vinnova announced that Kancera’s HDAC6 project had been awarded a grant of SEK 2,000,000 for the further development of HDAC6 inhibitors against cancer. The first installment of SEK 436,000 was paid in July. Vinnova has now decided to bring forward the second installment of SEK 750,000 to December 2015.

EU projektet mot parasitsjukdomar – A-PARADDISE
In February 2014 Kancera received an initial payment from the EU amounting to € 523,655 for the execution of the A-PARADDISE project. This project is a collaboration between 15 research groups on three continents to develop drugs against severe parasitic diseases: malaria, schistosomiasis, leishmaniasis and Chagas disease. The project issued an interim report which now has been approved by the EU. This means that a further installment of the grant will be paid to Kancera at year-end according to plan. This installment amounts to € 285,000.

For further information, please contact,

Thomas Olin, CEO: +46 (0) 735 20 40 01
Address:
Kancera AB (publ)
Karolinska Institutet Science Park, Banvaktsvägen 22
SE 171 48 Solna

Please visit the company website; View Source

About the PFKFB3 project
By blocking mechanisms which enable the cancer cells to adapt to periods of oxygen deprivation, possibilities open for new treatment strategies. Kancera’s project is based on a specific inhibition of the enzyme PFKFB3 resulting in a decreased metabolism in cancer cells, and decreased cell growth. In addition, research shows that PFKFB3 is involved in the regulation of both angiogenesis and division of cells, two critical processes that contribute to tumor growth. PFKFB3 is more common in oxygen-deficient tumor tissue compared to healthy tissue, which makes a targeted effect therapy with fewer side effects than traditional chemotherapy possible. Inhibition of PFKFB3 is expected to starve and weaken the tumor cells by reducing their glycolysis and cell division. This is a way to overcome the current problems of tumor resistance to radiation and chemotherapy.

About the HDAC6 project
Histone deacetylases (HDACs) are primarily involved in removing acetyl groups from the so-called histones and thereby affect how our genes are stored and activated in the cell nucleus. Some HDACs also affect the cell function outside the cell nucleus. HDAC6 belongs to this group of HDACs with a major biological role in the regulation of the cancer cell´s ability to migrate and to form metastases. The use of HDAC inhibitors in the treatment of cancer patients has so far yielded promising results, but has been limited due to severe side effects. For this reason, the pharmaceutical industry is now looking for more selective inhibitors of individual HDAC enzymes. Kancera´s discovery of selective HDAC6 inhibitors may provide a solution on how health care could take advantage of the anti-cancer effects of HDAC inhibitors without causing the patient severe side effects.

About the EU-project against parasitic diseases – A-PARADDISE
A-PARADDISE (Anti-Parasitic Drug Discovery in Epigenetics) is an EU-funded project (contract n° 602080), which aims to identify new drug targets for anti-parasitic drug discovery as well as to develop already available lead compounds to candidate drugs against schistosomiasis. The project will also develop lead compounds and possibly drug candidates against targets in the following parasites (diseases): Leishmania (Leishmaniasis), Trypanosoma cruzi (Chagas disease) and Plasmodium falciparum (malaria). The A-PARADDISE project builds on the completed and highly successful SEtTReND project which was focused against schistosomiasis.