On June 30, 2016 Leap Therapeutics, an immuno-oncology company, reported updated results from a clinical trial of its lead candidate DKN-01, a monoclonal antibody against the Dickkopf-1 (DKK1) protein (Press release, Leap Therapeutics, JUN 30, 2016, View Source [SID:1234513644]). Data from the trial demonstrated clinical activity in patients with relapsed or refractory cancer of the esophagus or gastro-esophageal junction (GEJ), indications with few or no approved therapies.

In Study Parts A and B, the dose escalation and dose confirmation phases, eight of 22 patients achieved a partial response (“PR”) per RECIST v1.1. Preliminary data indicated an overall progression-free survival (“PFS”) of 3.9 months, and 6.2 months and 3.2 months for patients with adenocarcinoma (AC) and squamous cell carcinoma (ESCC), respectively. DKN-01 was generally well tolerated. The data were presented today by Deva Mahalingam, M.D., of the University of Texas Health Science Center and an investigator on the trial, at the European Society for Medical Oncology’s World Congress on Gastrointestinal Cancer in Barcelona.

“Relapsed or refractory esophageal carcinomas are typically highly invasive and have a poor prognosis. The clinical activity we have seen to-date has been promising and is greater than expected compared to historical controls,” commented Dr. Mahalingam.

“The results from the study of DKN-01 in combination with paclitaxel are promising. We look forward to the data from the next phases of this trial and further interrogating the activity of DKN-01 in additional trials going forward,” commented David Ryan, M.D. of Massachusetts General Hospital and an investigator on the trial.

Results from Part A and Part B of the P102 Study of DKN-01 in Esophageal Carcinoma:

Twenty-seven patients with cancer of the esophagus or GEJ were enrolled in Parts A and B; 22 were evaluable per the protocol at the date of this analysis
The combination of DKN-01 and paclitaxel was safe and well tolerated at all doses with no treatment related severe adverse events (SAEs) related to either DKN-01 or paclitaxel
The most frequently reported DKN-01-related AEs were fatigue, diarrhea, and decreased appetite
Eight patients (36.4%) had PRs and nine (40.9%) patients had best responses of Stable Disease, with a total disease control rate of 77%
Durable responses with patients remaining on therapy for 12+ months
Two long-term patients (one AC, one ESCC) with PRs continue on DKN-01 monotherapy with continued deepening of response as a single agent
Preliminary overall PFS for patients with adenocarcinoma of the esophagus or GEJ of 6.2 months and patients with squamous cell carcinoma of 3.2 months
About Esophageal Cancer

Esophageal cancer is an aggressive disease with 17,000 patients diagnosed annually in the US and 400,000 diagnosed worldwide. Over 50% of patients are diagnosed with advanced disease, with an expected overall survival limited to 8-12 months. There are no approved therapies for relapsed or refractory disease of the esophagus, with the majority of patients receiving single-agent paclitaxel as a 2ND-line therapy. While studies of efficacy are limited, response rates have historically ranged between 5-15% and progression-free survival of 1-3 months.

About DKN-01

DKN-01 is a humanized IgG4 monoclonal antibody with neutralizing activity against the Dickkopf-1 (DKK1) protein. DKK1 expression in cancer tissue has been associated with poor prognosis in multiple cancers, and recent literature suggests DKK1 has a critical role in mediating an immuno-suppressive tumor microenvironment. DKN-01 is currently being studied in clinical trials in esophageal cancer and cholangiocarcinoma. DKN-01 additionally demonstrated single agent activity in NSCLC in a Phase 1 dose escalation study that was presented at ASCO (Free ASCO Whitepaper) 2014.?

On June 30, 2016 Leap Therapeutics, an immuno-oncology company, reported updated results from a clinical trial of its lead candidate DKN-01, a monoclonal antibody against the Dickkopf-1 (DKK1) protein (Press release, Leap Therapeutics, JUN 30, 2016, View Source [SID:1234513644]). Data from the trial demonstrated clinical activity in patients with relapsed or refractory cancer of the esophagus or gastro-esophageal junction (GEJ), indications with few or no approved therapies.

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In Study Parts A and B, the dose escalation and dose confirmation phases, eight of 22 patients achieved a partial response ("PR") per RECIST v1.1. Preliminary data indicated an overall progression-free survival ("PFS") of 3.9 months, and 6.2 months and 3.2 months for patients with adenocarcinoma (AC) and squamous cell carcinoma (ESCC), respectively. DKN-01 was generally well tolerated. The data were presented today by Deva Mahalingam, M.D., of the University of Texas Health Science Center and an investigator on the trial, at the European Society for Medical Oncology’s World Congress on Gastrointestinal Cancer in Barcelona.

"Relapsed or refractory esophageal carcinomas are typically highly invasive and have a poor prognosis. The clinical activity we have seen to-date has been promising and is greater than expected compared to historical controls," commented Dr. Mahalingam.

"The results from the study of DKN-01 in combination with paclitaxel are promising. We look forward to the data from the next phases of this trial and further interrogating the activity of DKN-01 in additional trials going forward," commented David Ryan, M.D. of Massachusetts General Hospital and an investigator on the trial.

Results from Part A and Part B of the P102 Study of DKN-01 in Esophageal Carcinoma:

Twenty-seven patients with cancer of the esophagus or GEJ were enrolled in Parts A and B; 22 were evaluable per the protocol at the date of this analysis
The combination of DKN-01 and paclitaxel was safe and well tolerated at all doses with no treatment related severe adverse events (SAEs) related to either DKN-01 or paclitaxel
The most frequently reported DKN-01-related AEs were fatigue, diarrhea, and decreased appetite
Eight patients (36.4%) had PRs and nine (40.9%) patients had best responses of Stable Disease, with a total disease control rate of 77%
Durable responses with patients remaining on therapy for 12+ months
Two long-term patients (one AC, one ESCC) with PRs continue on DKN-01 monotherapy with continued deepening of response as a single agent
Preliminary overall PFS for patients with adenocarcinoma of the esophagus or GEJ of 6.2 months and patients with squamous cell carcinoma of 3.2 months

About Esophageal Cancer
Esophageal cancer is an aggressive disease with 17,000 patients diagnosed annually in the US and 400,000 diagnosed worldwide. Over 50% of patients are diagnosed with advanced disease, with an expected overall survival limited to 8-12 months. There are no approved therapies for relapsed or refractory disease of the esophagus, with the majority of patients receiving single-agent paclitaxel as a 2ND-line therapy. While studies of efficacy are limited, response rates have historically ranged between 5-15% and progression-free survival of 1-3 months.

About DKN-01

DKN-01 is a humanized IgG4 monoclonal antibody with neutralizing activity against the Dickkopf-1 (DKK1) protein. DKK1 expression in cancer tissue has been associated with poor prognosis in multiple cancers, and recent literature suggests DKK1 has a critical role in mediating an immuno-suppressive tumor microenvironment. DKN-01 is currently being studied in clinical trials in esophageal cancer and cholangiocarcinoma. DKN-01 additionally demonstrated single agent activity in NSCLC in a Phase 1 dose escalation study that was presented at ASCO (Free ASCO Whitepaper) 2014.?

On June 30, 2016 Array BioPharma (Nasdaq: ARRY) reported the submission of a New Drug Application (NDA) for binimetinib in patients with advanced NRAS-mutant melanoma to the U.S. Food and Drug Administration (FDA) (Press release, Array BioPharma, JUN 30, 2016, View Source [SID:1234513643]). The submission is based on results of the pivotal Phase 3 NEMO (NRAS MELANOMA AND MEK INHBITOR) study, which found binimetinib significantly extended median progression-free survival (PFS), the study’s primary endpoint, as compared with dacarbazine.

Array BioPharma.
“The new drug application for binimetinib represents Array’s first – an important milestone for this promising compound and our Company,” said Ron Squarer, Chief Executive Officer, Array BioPharma. “NRAS-mutant melanoma represents an often overlooked subset of advanced disease without meaningful treatment options beyond immunotherapy and NEMO is the first-ever trial to meet a PFS endpoint in this population. We look forward to working with the FDA as they evaluate our application and the potential for binimetinib as a treatment option for these patients.”

In the NEMO study, binimetinib significantly extended median PFS at 2.8 months, as compared with 1.5 months observed with dacarbazine [hazard ratio (HR)=0.62 (95% CI 0.47-0.80), p<0.001] in patients with advanced NRAS-mutant melanoma. In the pre-specified subset of patients who received prior treatment with immunotherapy, including ipilimumab, nivolumab or pembrolizumab, patients who received binimetinib experienced 5.5 months of median PFS (95% CI, 2.8–7.6), compared with 1.6 months for those receiving treatment with dacarbazine (95% CI, 1.5–2.8). Mr. Squarer added, "While the results in the pre-specified sub-group of patients who had received prior treatment with immunotherapy are of interest, interpretation beyond overall consistency with the primary result should be made with care. Array anticipates that the primary consideration for marketing approval will be the results for the primary endpoint of the trial." In addition to improving PFS, binimetinib also demonstrated significant improvement in overall response rate (ORR) and disease control rate (DCR). While there was no statistically significant difference demonstrated in overall survival, the median overall survival (mOS) favored the binimetinib arm. Confirmed ORR was 15 percent (95% CI, 11-20 percent) in patients receiving binimetinib vs. 7 percent (95% CI, 3-13 percent) in patients receiving dacarbazine. DCR for patients receiving binimetinib was 58 percent (95% CI, 52-64 percent) vs. 25 percent (95% CI, 18-33 percent) for patients receiving dacarbazine. mOS was estimated at 11.0 months in patients receiving binimetinib vs. 10.1 months for patients treated with dacarbazine [(HR) = 1.0 (95% CI 0.75-1.33), p=0.499]. Under the NEMO protocol, and in accordance with accepted statistical practice, the subgroup analyses of OS are formally conducted only if the key secondary endpoint of OS reached statistical significance. Binimetinib was generally well-tolerated and the adverse events (AEs) reported were consistent with previous results in NRAS-mutant melanoma patients. Grade 3/4 AEs reported in greater than or equal to 5 percent of patients receiving binimetinib included increased creatine phosphokinase (CPK) and hypertension. The NEMO results were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Congress earlier in June. About NEMO The NEMO trial, (NCT01763164), is an international, randomized Phase 3 study evaluating the safety and efficacy of 45 mg BID binimetinib, compared to 1,000 mg/m2 dacarbazine dosed every three weeks. Prior immunotherapy treatment was allowed. The primary endpoint of the study is PFS, and secondary endpoints include overall survival (OS), ORR and DCR. Patients underwent radiographic assessment of disease status every six weeks, and assessment of progression was determined by blinded central review. Over 100 sites across North America, Europe, South America, Asia and Australia participated in the study. About NRAS-Mutant Melanoma Melanoma is the fifth most common cancer among men and the seventh most common cancer among women in the United States, with more than 76,000 new cases and nearly 10,000 deaths from the disease projected in 2016. Activating NRAS mutations are present in up to 20 percent of patients with metastatic melanoma, and is a poor prognostic indicator for these patients. Treatment options for this population remain limited beyond immunotherapy, and patients face poor clinical outcomes and high mortality. About Binimetinib MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, non-small cell lung, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor, which targets key enzymes in this pathway. Binimetinib is currently being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer. Array projects COLUMBUS top-line results availability during the third quarter of 2016 - See more at: View Source#sthash.Le65pqS9.dpuf