On December 22, 2015 Merrimack Pharmaceuticals, Inc. (Nasdaq: MACK) reported it filed an amendment to its ongoing Phase 2 clinical study of MM-121 (seribantumab) in patients with heregulin-positive non-small cell lung cancer (NSCLC) with the U.S. Food and Drug Administration (FDA) (Press release, Merrimack, DEC 22, 2015, View Source [SID:1234508631]). The amendment includes a change in primary endpoint to overall survival to enable a potential registration opportunity for MM-121.

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"We believe MM-121 has the potential to address the pervasive clinical problem of resistance in cancer. This amendment is intended to accelerate development of this new treatment option for heregulin-positive non-small cell lung cancer patients who are resistant to standard-of-care therapies," said Robert Mulroy, Merrimack’s President and CEO. "The financing we announced today will allow us to independently advance and retain sole ownership of MM-121. In light of this amendment, we are focusing the development of MM-121 on this indication."

MM-121 is a fully human monoclonal antibody targeting ErbB3. The ongoing clinical study in NSCLC is an open-label, biomarker-selected randomized study of MM-121 in combination with docetaxel or pemetrexed compared to docetaxel or pemetrexed alone, in patients with heregulin-positive, locally advanced or metastatic NSCLC. Three prior Phase 2 clinical studies demonstrated that a subset of biomarker positive patients treated with MM-121 had a statically significant reduction in the risk of progression, with hazard ratios in a range of 0.26 – 0.37.

"We are pleased with investigator enthusiasm for the trial, which highlights the high unmet medical need in metastatic non-small cell lung cancer. Consistent with our previous Phase 2 study, more than half of the patients screened to date have been biomarker positive," said Akos Czibere, M.D., Ph.D., MM-121 Global Development Lead at Merrimack. "Amending this study design is a significant step forward in the development path for MM-121 in non-small cell lung cancer, where there is an urgent need for novel, biomarker-directed therapies to help patients battle drug resistance. We look forward to advancing this therapy and providing a potential new treatment option for this patient population."

Under the filed amendment, Merrimack expects to enroll approximately 280 heregulin-positive patients who will be randomized (2:1) to receive MM-121 plus the investigator’s choice of docetaxel or pemetrexed, or the investigator’s choice of docetaxel or pemetrexed alone. Eligible patients for the study must have failed prior treatment with no more than three lines of therapy for locally advanced or metastatic disease and, where applicable, prior PDL1 therapy. The amended primary endpoint of the study will be overall survival. Secondary endpoints include progression free survival, objective response rate, safety and quality of life measures. Merrimack continues to open study sites in the United States, Canada, Asia and Europe. With this updated study design, Merrimack expects survival data in 2018.

About MM-121 (Seribantumab)

MM-121 is Merrimack’s wholly owned, fully human monoclonal antibody that targets ErbB3, a cell surface receptor that is activated by the ligand heregulin. Heregulin-driven ErbB3 signaling has been implicated as a mechanism of tumor growth and resistance to targeted, cytotoxic and anti-endocrine therapies. When used in the combination setting, MM-121 is designed to block ErbB3 signaling in order to enhance the anti-tumor effect of a combination therapy partner.

Merrimack is pursuing this Phase 2 study based on encouraging results from a broad MM-121 Phase 2 program which identified heregulin mRNA expression as a potential prognostic factor of poor response to standard-of-care therapy across multiple cancers. The results also indicated that patients with heregulin-positive tumors experienced a longer time to progression when they received a combination of MM-121 with their standard-of-care therapy as compared to patients who received the standard therapy alone. Across the three different standard-of care combination regimens, a consistent safety profile demonstrated a modest but tolerable increase in adverse events. An extensive translational component of the MM-121 clinical program was designed to establish clinically meaningful biomarkers that were initially identified using Merrimack’s systems biology approach and preclinical studies

On December 22, 2015 Stemline Therapeutics, Inc. (Nasdaq:STML) reported the opening of its SL-801 Investigational New Drug (IND) application and initiation of a broad clinical development program in multiple cancer types (Press release, Stemline Therapeutics, DEC 22, 2015, View Source [SID:1234508628]). SL-801 is an oral, reversible, small molecule inhibitor of Exportin 1 (XPO1), a promising and clinically validated oncology target overexpressed by many solid and hematologic cancers. SL-801 has demonstrated robust anti-cancer activity in animal models of multiple solid and hematologic malignancies.

Ivan Bergstein, M.D., Stemline’s Chief Executive Officer, stated, "We are pleased to have successfully advanced the SL-801 program quickly through IND opening. Our SL-801 development strategy builds upon current knowledge in the XPO1 space and is designed to evaluate the agent’s clinical potential across multiple cancer types early in the program." Dr. Bergstein concluded, "The clinical debut of SL-801 serves to advance our pipeline and greatly strengthen the company’s clinical and commercial potential."

On December 22, 2015 Merck and Pfizer reported the opening of trial sites for an international Phase III study of avelumab*, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody, in patients with platinum-resistant/refractory ovarian cancer (Press release, Pfizer, DEC 22, 2015, View Source [SID:1234508626]).

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The JAVELIN Ovarian 200 trial is the first Phase III study of a PD-L1 inhibitor investigated as a treatment for platinum-resistant/refractory ovarian cancer. The alliance also announced that the US Food and Drug Administration has provided approval to move forward with a Phase III study of avelumab as a maintenance treatment, in the first-line setting, in patients with locally advanced or metastatic urothelial cancer. The first trial sites are expected to open shortly.

"There are limited treatment options for women with ovarian cancer, and the prognosis for women with platinum-resistant ovarian cancer is especially poor," said Chris Boshoff, Vice President and Head of Early Development, Translational and Immuno-Oncology at Pfizer Oncology. "We have observed encouraging signs of early clinical activity of avelumab in patients with platinum-resistant or platinum-refractory ovarian cancer, and we hope to build on these results next year through a planned Phase III study of avelumab in combination with platinum therapy in patients with previously-untreated ovarian cancer."

This Phase III, randomized (1:1:1), open-label, parallel, multicenter, global study (JAVELIN Ovarian 200) is designed to evaluate the superiority of avelumab as a monotherapy or in combination with pegylated liposomal doxorubicin (PLD), compared with PLD alone, in treating patients with platinum-resistant/refractory ovarian cancer. The primary endpoint is overall survival (OS). Study investigators anticipate enrolling approximately 550 patients across more than 190 sites in Asia, Europe and North America.

Merck and Pfizer have also initiated a Phase III study (JAVELIN Bladder 100) investigating avelumab as a maintenance treatment, in the first-line setting, in patients with locally advanced or metastatic urothelial cancer. This is currently the only Phase III trial designed to evaluate an immunotherapy agent as a maintenance treatment, in the first-line setting, in patients with urothelial cancer.

"Locally advanced or metastatic urothelial cancer is another aggressive cancer, with the disease often progressing quickly following first-line treatment," said Dr. Alise Reicin, Head of Global Clinical Development at Merck’s biopharma business. "It’s an exciting time for the Merck-Pfizer Alliance as we continue to accelerate our clinical development program, and now into urothelial cancer. This disease has an exceptionally high unmet need and we believe there is potential for our anti-PD-L1 antibody to be part of future treatment strategies."

This open-label, multicenter, randomized, global, Phase III study is designed to evaluate the safety and efficacy of avelumab plus best supportive care (BSC), compared with BSC alone, in patients with unresectable locally advanced or metastatic urothelial cancer whose disease did not progress on (or following) completion of first-line treatment with a platinum-containing chemotherapy. The primary endpoint of the study is OS which will be assessed in two urothelial cancer patient populations: patients with PD-L1 positivity and all randomized patients.

JAVELIN Bladder 100 is expected to enroll 668 patients across more than 200 sites in 38 countries. PD-L1 expression status will be determined by retrospective analysis of mandatory tumor samples collected from patients enrolled in the trial. It is estimated that at least half of those patients randomized to treatment will be
PD-L1-positive.

The clinical development program for avelumab now includes more than 1,500 patients who have been treated across more than 15 tumor types, including breast cancer, gastric/gastro-esophageal junction cancers, head and neck cancer, melanoma, Merkel cell carcinoma, non-small cell lung cancer, ovarian cancer, renal cell carcinoma and urothelial (e.g. bladder) cancer. The alliance has initiated six pivotal trials, reaching its goal for 2015, with additional trials expected to initiate in 2016.

*Avelumab is the proposed International Non-proprietary Name for the anti-PD-L1 monoclonal antibody (MSB0010718C). Avelumab is under clinical investigation and has not been proven to be safe and effective. There is no guarantee any product will be approved in the sought-after indication by any health authority worldwide.

References
1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: View Source Accessed December 2015.
2. World Cancer Research Fund International. Ovarian Cancer Statistics. Available from: View Source Accessed November 2015.
3. NICE. Ovarian Cancer: Recognition and Initial Management.
View Source Accessed November 2015.
4. National Cancer Institute. Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (PDQ). Available from: View Source Accessed November 2015.
5. Lederman JA, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO (Free ESMO Whitepaper) clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 Suppl 6: vi24-32.
6. Ojavo LS, et al. Emerging immunotherapies in ovarian cancer. Discov Med 2015; 20: 97-109.
7. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer Version 2. 2015. Available at:´
View Source Accessed December 2015.
8. Malats N, Real FX. Epidemiology of Bladder Cancer. Hematol Oncol Clin North Am 2015; 29(2):177-89.

About Ovarian Cancer
Globally, ovarian cancer is the seventh most common cancer in women.1 Annually, nearly 239,000 cases are diagnosed worldwide.2 Ovarian cancer may be difficult to diagnose, as symptoms may appear only in the later stages, when the disease has spread beyond the ovaries.2 Outcomes for women with ovarian cancer are generally poor due to most patients presenting with advanced disease.3 The 5-year prevalence of women globally living with ovarian cancer is 22.6 per 100,000.2 Current treatment options for epithelial ovarian cancer may include surgery, radiotherapy, chemotherapy and targeted therapies.4 Women who are unable to undergo treatment with platinum-based chemotherapy, due to resistance or refractory disease, currently have very limited treatment options. Platinum-resistant ovarian cancer is defined as ovarian cancer that recurs within six months of completing primary chemotherapy with a platinum-based medication.5 Platinum-refractory ovarian cancer is defined as ovarian cancer that progresses during treatment with a platinum-based chemotherapy regimen.5 There is still a clear unmet need in ovarian cancer in relation to general disease awareness,2 improving initial investigations in primary and secondary care and novel therapies with demonstrable efficacy.6

About Urothelial Cancer
Urothelial cancer includes several tumors originating from the urothelial cells lining the bladder, renal pelvis and urethra.7 Bladder cancer accounts for 90% of urothelial cancers,7 and is the ninth most common cancer globally. Approximately 400,000 new cases of bladder cancer are diagnosed and 150,000 deaths are attributed to this disease each year.8 The incidence and mortality of bladder cancer have remained unchanged over the past 25 years.8

About Avelumab
Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

On December 22, 2015 Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported the enrollment of the first patient in its Phase 1 trial of LOXO-101 in pediatric patients with advanced solid or primary central nervous system (CNS) tumors (Press release, Loxo Oncology, DEC 22, 2015, View Source [SID:1234508625]). LOXO-101 is the only selective inhibitor of the tropomyosin receptor kinase (TRK) protein family in clinical development.

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"Given the promising early efficacy and tolerability results we have seen in adults with TRK fusion cancers, we are excited to explore the potential of LOXO-101 in children and adolescents with cancer," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "The TRK pathway has been implicated in many pediatric cancers, and this trial is an important step toward understanding LOXO-101 in these settings."

The Phase 1 clinical trial is a multicenter, open-label trial in pediatric patients with advanced solid or primary CNS tumors. Loxo Oncology plans to open as many as 15 clinical sites in the U.S. In the dose-escalation phase, LOXO 101 will be administered orally twice daily, with the initial starting dose level intended to match the pharmacokinetic exposures of the 100 mg twice daily dose that is currently being employed in the LOXO-101 Phase 2 basket trial in adult patients. The actual dose for each patient will depend on patient body size and age. The trial will also utilize a liquid formulation of LOXO-101 designed specifically for pediatric patients unable to swallow capsules. The primary endpoint of the trial is to explore the safety of LOXO-101. Secondary endpoints include the characterization of pharmacokinetic properties, the identification of the maximum tolerated dose and/or the Phase 2 dose, a description of antitumor activity, and a description of pain and health related quality of life impact.

In order to meet the criteria for enrollment, patients must be between one year of age and 21 years of age with a locally advanced or metastatic solid tumor or primary CNS tumor that has progressed, or was nonresponsive to available therapies, and for which no standard or available curative therapy exists. Patients at least one month old are eligible for enrollment if they have a diagnosis of infantile/congenital fibrosarcoma, with a documented NTRK fusion that has progressed, or was nonresponsive to available therapies, and for whom no standard or available curative therapy exists.

Additional patient cohorts may be enrolled in an expansion phase of the Phase 1 trial to better characterize safety and efficacy in patients with specific abnormalities in the NTRK genes or proteins.

The TRK pathway plays an important role in many pediatric cancers. TRK gene fusions have been described in pediatric tumor types such as infantile/congenital fibrosarcoma, congenital mesoblastic nephroma, secretory breast carcinoma, pontine glioma, and may occur at increased frequency in younger patients with other tumor types, according to proprietary Loxo Oncology analyses. TRK signaling may also play a role in neuroblastoma.

LOXO-101 has shown objective clinical responses in adult patients with tumors harboring TRK gene fusions in a Phase 1 trial. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in adult patients with solid tumors that harbor TRK gene fusions.

About LOXO-101

LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions, and a Phase 1 dose escalation trial in pediatric cancer patients. For additional information about both the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.