On January 9, 2017 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported a clinical collaboration with Merck (known as MSD outside the United States and Canada) (Press release, Aduro Biotech, JAN 9, 2017, View Source [SID1234517322]). The companies will investigate the combination of CRS-207, Aduro’s LADD (live, attenuated double-deleted) based immunotherapy, with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) for the treatment of gastric cancer.

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"CRS-207 has demonstrated the ability to induce an anti-tumor immune response in clinical trials in other tumor types that over express the tumor antigen, mesothelin," said Dirk G. Brockstedt, Ph.D., executive vice president of Research and Development at Aduro. "Gastric cancer is an immune-sensitive mesothelin-expressing tumor where PD-1 checkpoint inhibitors have shown some activity. The combination of inducing an immune response through CRS-207, while simultaneously suppressing the cancer’s ability to evade the immune system through a PD-1 checkpoint inhibitor, has resulted in synergistic anti-tumor activity in pre-clinical studies. We aspire to reproduce this activity in the clinic in patients with gastric cancer."

The multicenter Phase 1 study, planned to begin in the first half of the year, will enroll patients with metastatic gastric cancer who have failed at least two prior therapies to receive the combination of CRS-207 and pembrolizumab.

About LADD and CRS-207
LADD is Aduro’s proprietary platform of live, attenuated double-deleted Listeria monocytogenes strains that have been engineered to generate a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity.

CRS-207 is one of a family of product candidates based on Aduro’s LADD immunotherapy platform that has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

On January 9, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that the US Food and Drug Administration (FDA) has accepted the Company’s investigational new drug (IND) application for autologous genetically modified T-cells expressing an affinity optimized T-cell receptor (TCR) specific for MAGE-A4 in patients with multiple malignant solid tumors (Press release, Adaptimmune, JAN 9, 2017, View Source [SID1234517320]). This will be Adaptimmune’s third wholly-owned therapeutic candidate to enter clinical trials. The IND is now active.

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Under this IND, Adaptimmune will initiate a Phase I, open-label, modified 3+3 dose escalation study of autologous T-cells genetically engineered with an affinity optimized MAGE-A4 TCR in HLA*02 positive patients with inoperable locally advanced or metastatic melanoma, and urothelial, head and neck, ovarian, non-small cell lung, esophageal, and gastric cancers expressing MAGE-A4. Patients will receive preconditioning with modified fludarabine and cyclophosphamide as used in the Company’s ongoing synovial sarcoma study. This multi-tumor study will enroll up to 32 patients.

On January 9, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported that it has successfully transferred sponsorship of the two ongoing Phase 1 clinical trials evaluating its Checkpoint kinase 1 (Chk1) inhibitor, SRA737, from the Cancer Research UK Centre for Drug Development to the company (Press release, ProNAi Therapeutics, JAN 9, 2017, View Source [SID1234517317]). In accordance with the license agreement for SRA737, a $2.0 million fee is due to CRT Pioneer Fund LP for the achievement of this milestone.

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"SRA737 targets Chk1, a key cell cycle checkpoint and central regulator of the DDR network, an exciting emerging target in oncology that has broad clinical and commercial potential," said Dr. Nick Glover, President and CEO of Sierra Oncology. "We are pleased to announce that the formal transfer of sponsorship to Sierra Oncology of these two actively recruiting clinical trials was completed as planned and ahead of schedule. Our goal is to provide an update from these studies within twelve months that will further inform our development strategy."

Professor Paul Workman, Chief Executive and President of The Institute of Cancer Research, London, added, "Working with Sierra Oncology, we have made very promising progress with these studies. I’m confident that SRA737 – which was discovered here at the ICR – is in excellent hands for the future. Sierra is developing a sophisticated strategy for advancing SRA737 and we look forward to continuing to collaborate in taking this agent forward together for the benefit of cancer patients."

In September 2016, Sierra Oncology licensed the exclusive worldwide rights to SRA737, a highly selective, orally available, small molecule inhibitor of Chk1. SRA737 was discovered and initially developed by scientists in the Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research (ICR) in collaboration with Sareum Holdings plc (LSE AIM: SAR), with funding provided by Cancer Research UK, the ICR and Sareum. SRA737 is being investigated in two recently initiated Phase 1 clinical trials in patients with advanced solid tumors: a monotherapy trial and a trial of SRA737 in combination with chemotherapy. (ClinicalTrials.gov identifiers: NCT02797964 and NCT02797977).

"Working with the ICR and The Royal Marsden NHS Foundation Trust, we are charting an expanded and optimized development plan for SRA737. In particular, we are keen to evaluate SRA737’s potential to induce synthetic lethality as monotherapy in certain genetically-defined patient cohorts, while also exploring its potentiating effects in combination with chemotherapy," added Dr. Barbara Klencke, Chief Development Officer of Sierra Oncology. "Concurrently we are also conducting preclinical research evaluating SRA737 in combination with other DDR agents including PARP inhibitors and our proprietary Cdc7 inhibitor, SRA141, as well as with immuno-oncology therapeutics. Results of this research, expected in late 2017, will guide a potential next wave of clinical development for our asset, possibly further broadening its therapeutic utility."

On January 9, 2017 Incyte Corporation (Nasdaq:INCY) and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the decision to advance the clinical development program investigating the combination of epacadostat, Incyte’s investigational oral selective IDO1 inhibitor, with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, Incyte, JAN 9, 2017, View Source [SID1234517316]).

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With the expansion of the clinical development program, the companies plan to initiate pivotal studies of epacadostat in combination with KEYTRUDA in four additional tumors: non-small cell lung cancer, renal cell carcinoma, bladder cancer and squamous cell carcinoma of the head and neck. Presentations of data from the ongoing studies of epacadostat in combination with KEYTRUDA, which support this decision, are expected at upcoming medical meetings.

"We are very pleased to announce the decision with Merck to initiate additional Phase 3 studies that will further evaluate the clinical utility of epacadostat in combination with KEYTRUDA," said Steven Stein, M.D., Incyte’s Chief Medical Officer. "Data from across the ECHO development program for epacadostat continues to be accrued, including from the ECHO-202 Phase 2 cohorts in combination with KEYTRUDA which support the decision to move forward into pivotal studies beyond melanoma. We look forward to initiation of these new Phase 3 trials as we seek to help improve clinical outcomes for patients with these cancers."

"The expansion of our clinical trial program with Incyte is an important component of our comprehensive approach to investigating the potential for KEYTRUDA in combination with promising compounds, such as epacadostat, to help make a difference in the lives of people with these cancers," said Dr. Roy Baynes, senior vice president, head of clinical development, and Chief Medical Officer, Merck Research Laboratories.

About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study investigating pembrolizumab in combination with epacadostat or placebo for the first-line treatment of patients with advanced or metastatic melanoma, is also underway. ECHO-301 was initiated in June 2016 and initial data from this study are expected to be available in 2018.

About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor pembrolizumab improved response rates compared with studies of the immune checkpoint inhibitors alone.

About KEYTRUDA (pembrolizumab)
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 administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.
KEYTRUDA Indications and Dosing
Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA (pembrolizumab) is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) 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.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. 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.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. 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.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA (pembrolizumab) for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. 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 betablockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. 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.
KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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 to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA (pembrolizumab) can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 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.

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

KEYTRUDA (pembrolizumab) was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

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.