On October 26, 2015 Spectrum Pharmaceuticals, Inc. (NasdaqGS: SPPI), a biotechnology company with fully integrated commercial and drug development operations and a primary focus in Hematology and Oncology, reported the Company has initiated the planned Phase 3 clinical study for apaziquone, its novel, potent pro-drug, and the first patient was dosed on Friday, October 23, 2015 (Press release, Spectrum Pharmaceuticals, OCT 26, 2015, View Source [SID:1234507790]). Apaziquone is an alkylating agent being investigated as intravesical treatment to address the unmet medical need for patients with non-muscle invasive bladder cancer (NMIBC), administered as one or two instillations immediately following transurethral resection of bladder tumors (TURBT).

“Apaziquone has the potential to usher in an importantly needed paradigm shift in the treatment of NMIBC, as the first new drug in its indication in over 40 years,” said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Pharmaceuticals. “This Phase 3 study has been specifically designed to address important lessons learned from the previous apaziquone Phase 3 studies, as well as recommendations from the FDA that improve chances of a successful study outcome. Pooled data from the previously completed Phase 3 studies that enrolled over 1,600 patients, showed a statistically significant reduction in the 2-year Recurrence rate and strong safety data. These existing Phase 3 data form the basis of the NDA that we plan to submit to FDA before the end of the year. Because of the high frequency of recurrences, the overall cost for the treatment of bladder cancer in the U.S. is a staggering $3.4 billion annually, most of which is related to direct treatment of the disease. We are hopeful that we can get this drug to the market as soon as possible to meet the significant unmet medical need.”

“I am impressed with the data and the activity of apaziquone in NMIBC that I have seen so far in clinical trials,” said Lawrence Karsh, MD, FACS, Director of Research at The Urology Center of Colorado. “In bladder cancer patients, there is, unfortunately, a high rate of recurrence that necessitates frequent surgeries. Due to the high rate of recurrence, there is significant patient morbidity and the disease is expensive to treat. There is a strong scientific rationale for the use of a chemotherapeutic agent post-TURBT, and NCCN guidelines recommend the post-TURBT instillation of a chemotherapeutic agent. However, no drug has been specifically approved for post-TURBT instillation in the US for this group of patients. The addition of a new effective therapy for this recurring disease would help to address the high unmet medical need, offer patients an important new treatment option, and potentially reduce the healthcare costs associated with the treatment of NMIBC.”

In accordance with the SPA agreement, this Phase 3 trial will be a randomized, double-blind, placebo-controlled, multicenter trial that will enroll patients with Ta, G1-G2 NMIBC. Patients will be randomized to receive either one instillation of apaziquone, two instillations of apaziquone, or placebo with a primary endpoint of Time to Recurrence. Since apaziquone is known to be inactivated in presence of blood, the new protocol requires the dosing of apaziquone in a 30-90 minute window post-TURBT. Patients randomized to receive two instillations of apaziquone, will receive the second dose approximately two weeks after surgery, further minimizing the potential for drug inactivation due to bleeding. In addition, the protocol recommends that patients with significant post-operative bleeding not receive apaziquone.

Apaziquone is an anticancer pro-drug that is activated by bio-reductive enzymes that are over-expressed in bladder cancer cells, rendering it into a highly cytotoxic alkylating agent. Spectrum has conducted two multi-center, international, randomized Phase 3 trials of a single intravesical instillation of apaziquone (4 mg) into the bladder in the immediate post-operative period after surgical resection of low-grade NMIBC. Pooled data from the two studies (n=1,615) showed a statistically significant treatment effect for the primary study endpoint, i.e., a reduction in the 2-Year Recurrence Rate, in favor of apaziquone (p-value = 0.0218), and in a key secondary endpoint, Time to Recurrence (p-value = 0.0096).

About Bladder Cancer

According to the National Cancer Institute, bladder cancer is the fifth most common malignancy in the US with 74,000 new cases of bladder cancer expected in 2015, and currently over 500,000 patients living with the disease. Due to the high recurrence rate, intensive surveillance strategies, and expensive annual treatment costs, bladder cancer has the highest per patient costs with an overall cost estimated at around $3.4 billion. Non-muscle invasive bladder cancer is a form of bladder cancer that is localized in the surface layers of the bladder, and has not invaded or spread to the deeper muscle layer. Approximately 70% of all patients newly diagnosed with bladder cancer have NMIBC. Urologists treat the disease predominantly by TURBT. In the U.S., there are approximately 300,000 TURBT procedures every year to treat bladder cancer. Because of the high recurrence rate, both professional urology associations and NCCN Guidelines recommend the instillation of a cytotoxic agent following TURBT for NMIBC, although in the U.S., there are no FDA-approved agents for this indication.

About Special Protocol Assessments

A Special Protocol Assessment is a written agreement between a Sponsor and the U.S. Food and Drug Administration on the design, execution and analysis for a clinical trial that may form the basis of a new drug application, or NDA. Final marketing approval depends upon the efficacy results, safety profile and an evaluation of the risk/benefit of treatment demonstrated in the Phase 3 clinical program.

On October 26, 2015 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported topline results from the KEYNOTE-010 study of KEYTRUDA (pembrolizumab) in advanced non-small-cell lung cancer (NSCLC) demonstrating that the trial met its primary objective (Press release, Merck & Co, OCT 26, 2015, View Source [SID:1234507789]).

KEYNOTE-010 is a randomized, pivotal Phase 2/3 trial comparing two doses of KEYTRUDA (the FDA-approved 2mg/kg dose and a higher, investigational 10mg/kg dose, each given every 3 weeks), to docetaxel, a commonly used chemotherapy. Patients were enrolled who had failed prior systemic therapy for advanced NSCLC and whose tumors had PD-L1 (programmed death ligand-1) expression tumor proportion scores (TPS) of 1 percent or more. Outcomes were assessed in patients whose tumors were strongly PD-L1 positive (defined as TPS of 50 percent or more), and in all PD-L1 positive patients. A topline analysis revealed that treatment with KEYTRUDA was associated with longer overall survival (OS) compared with docetaxel treatment. This was true for both the approved and the investigational dose of KEYTRUDA, which showed similar efficacy. It was also true in both the first set of patients analyzed – those with a TPS of 50 percent or greater – and for all enrolled patients, all of whom had a TPS of 1 percent or greater. Treatment with KEYTRUDA, at both doses, also provided superior progression-free survival (PFS) versus that achieved following treatment with docetaxel in patients whose tumors had TPS values equal to or greater than 50 percent. For PFS, KEYTRUDA treatment was numerically but not statistically superior to docetaxel in the all PD-L1 positive group, again at both doses. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies in patients with advanced NSCLC.

“The results from this trial provide part of a growing body of evidence supporting the potential of KEYTRUDA in the treatment of non-small-cell lung cancer,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “Advancing the standard of care in cancer requires a collaborative effort, and we are grateful to the patients, institutions and caregivers who participated in this study. We look forward to sharing our complete data with the scientific community and with regulatory agencies in the near future.”

About the KEYNOTE-010 Study

KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study (ClinicalTrials.gov, NCT01905657) evaluating two doses of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m^2 every three weeks) in 1034 patients with NSCLC who experienced disease progression after platinum-containing systemic therapy and whose tumors expressed PD-L1. The primary endpoints were OS and PFS. Tumor response was assessed at week 12, then every 6 weeks thereafter per RECIST 1.1 criteria by independent, central, blinded, radiographic review and investigator-assessed, immune-related response criteria.

About KEYTRUDA (pembrolizumab) in the U.S.

In lung cancer, 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. In melanoma, KEYTRUDA is indicated 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. The label for KEYTRUDA currently says that an improvement in survival or disease-related symptoms has not yet been established, and the continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Safety Information for KEYTRUDA (pembrolizumab)

Pneumonitis occurred in 19 (3.5%) of 550 patients, 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 occurred in 4 (0.7%) of 550 patients, 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 (pembrolizumab). 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 1 (0.2%) of 550 patients, 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 for Grade 2 and withhold or discontinue for Grade 3 or Grade 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients, 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. 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.

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.

The following clinically significant, immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: rash, vasculitis, hemolytic anemia, serum sickness, myasthenia gravis, bullous pemphigoid, and Guillain-Barré syndrome.

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 (pembrolizumab).

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.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast, and prostate cancers combined. The two main types of lung cancer are non-small-cell and small-cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year relative survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be four percent.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.