On December 8, 2015 Bio-Path Holdings, Inc., (NASDAQ: BPTH) ("Bio-Path"), a biotechnology company leveraging its proprietary DNAbilize liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer drugs, reported that data from the Phase I and safety segment of the Phase II clinical trials of its lead product candidate BP-100-1.01 (or BP1001, Liposomal Grb2 antisense) in the treatment of blood cancers were presented yesterday by Dr. Jorge Cortes, Deputy Chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center and Chair of Bio-Path’s Scientific Advisory Board, during a poster session at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Filing, 8-K, Bio-Path Holdings, DEC 8, 2015, View Source [SID:1234508508]).

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The poster, titled "Safety, Pharmacokinetics, and Efficacy of BP-100.1.01 (Liposomal Grb2 Antisense Oligonucleotide) in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoid Leukemia (ALL), and Myelodysplastic Syndrome (MDS)," included data from the first seven cohorts of the study. The eighth and final cohort is ongoing.

Data from Cohorts 1 through 6 of the dose-finding monotherapy study demonstrated that BP1001 at doses up to 90 mg/m2 is well tolerated and suggests possible anti-leukemia activity. Of the evaluable patients, all showed a transient drop in circulating blast percentage.

Cohort 7 was the first cohort in the safety segment of the Phase II clinical trial (also referred to as Phase Ib) and evaluated the toxicity of BP1001 at the 60 mg/m2 dose level, combined with low-dose cytarabine (LDAC) chemotherapy in patients with advanced acute myeloid leukemia (AML). Bio-Path previously reported that one evaluable patient in Cohort 7 had achieved complete remission (CR) during treatment, and a second patient who demonstrated improvement in bone marrow blasts at the end of the first treatment cycle was continuing BP1001 treatment as part of an additional treatment cycle. The second patient has achieved CR after two treatment cycles and is continuing therapy in a fourth treatment cycle.

"We are thrilled that two of the three evaluable patients suffering from advanced AML in our first cohort of the safety segment of the Phase II trial have now achieved complete remission during treatment with Liposomal Grb2 combined with low-dose cytarabine," said Peter Nielsen, President and Chief Executive Officer of Bio-Path. "The data we have seen to date are especially encouraging because the patients evaluated in our study were refractory and treatment resistant, having been on an average of four prior therapies. We continue to make progress with the eighth cohort of the trial, which is evaluating three patients being treated with 90 mg/m2 of Liposomal Grb2 antisense in combination with frontline LDAC, and look forward to successfully completing the safety portion of the Phase II clinical study."

About BP1001

BP1001 is a neutral-charge, liposome-incorporated antisense drug substance designed to inhibit Grb-2 protein expression. The protein Grb-2 is essential to cancer cell signaling because it is utilized by oncogenic tyrosine kinases to induce cancer progression. Suppressing the function or expression of Grb-2 should interrupt its vital signaling function and have a therapeutic application in cancer.

On December 8, 2015 SRI International reported a new collaborative program between scientists at SRI Biosciences, a division of SRI International, and physician-researchers from Stanford Cancer Institute (SCI) will pursue development of novel compounds to treat multiple forms of cancer and other conditions (Press release, SRI International, DEC 8, 2015, View Source [SID:1234508506]).

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This SRI Biosciences- Stanford Drug Discovery and Development Program has been created in response to a significant drop in the early pipeline of innovative new drugs, and builds on a history of partnerships among investigators from both institutions. The combined basic research, drug discovery and drug development expertise of researchers from SCI and SRI Biosciences has successfully advanced numerous projects, and the new program adds structure, support and coordination to such efforts.

Previous collaborations have yielded new therapeutic candidates, including Tirapazamine, an experimental anticancer drug discovered by SRI and SCI investigators and brought to Phase III clinical trials. Several other SRI-SCI developed compounds are currently undergoing preclinical testing.

Recently, Stanford professor of Neurology and Neurological Sciences, Stanford University School of Medicine Tony Wyss-Coray, Ph.D., and SRI Biosciences director of Medicinal and Synthetic Chemistry Mary Tanga, Ph.D., jointly discovered and developed a small molecule agonist of the TGF-beta signaling pathway for Alzheimer’s disease. The new agent has successfully moved through preclinical development and is continuing into clinical trials.

"The SCI-SRI Biosciences collaboration provides a fully integrated engine for taking ideas to the investigational new drug (IND) stage and beyond," said Nathan Collins, Ph.D., executive director of the Pharmaceutical and Chemical Technologies Section in SRI Biosciences. "Our focus is on developing ‘first-in-class’ drugs and delivering improved outcomes for patients."

The program brings together teams of multidisciplinary scientists in both discovery and refinement of novel compounds and targets, and it provides access to the critical scientific infrastructure necessary for disease mechanism understanding and target discovery, and drug discovery and development through clinical safety and proof of concept.

"Advances in genomic and molecular analysis of individual patients and their cancers are creating new therapeutic opportunities," said Stanford Cancer Institute Director Beverly S. Mitchell, M.D. "We are excited to work with the skilled SRI Biosciences researchers to enhance our drug development efforts."

The program will be co-led by Sanjay V. Malhotra, Ph.D., FRSC, associate professor of radiation oncology at Stanford, and Nathan Collins. Together they will coordinate and support a diverse and evolving group of investigators and technical experts to advance promising projects.

On December 8, 2015 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) has accepted and granted Priority Review for a supplemental New Drug Application (sNDA) for XALKORI (crizotinib) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive (Press release, Pfizer, DEC 8, 2015, View Source [SID:1234508503]).

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In April 2015, XALKORI received Breakthrough Therapy designation by the FDA for this potential indication. If approved, XALKORI would be the first FDA-approved biomarker-driven therapy for the treatment of ROS1-positive metastatic NSCLC. XALKORI is currently indicated for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The projected FDA action date is April 2016.

Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists.1

"ROS1 represents the second molecular subgroup of NSCLC in which XALKORI has demonstrated a level of anti-tumor activity that can potentially make a meaningful difference for patients," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "The development of XALKORI in this subgroup of patients is an example of the capability of precision medicine to identify treatments for patients whose tumors contain rare genetic mutations, such as ROS1-positive metastatic NSCLC."

ROS1 rearrangement occurs when the ROS1 gene attaches to another gene and changes the way each gene normally functions, which can contribute to cancer-cell growth. Epidemiology data suggest that ROS1 rearrangements occur in approximately one percent of NSCLC cases. Of the estimated 1.5 million new cases of NSCLC worldwide each year, roughly 15,000 may be driven by oncogenic ROS1 fusions. 2,3

The submission to the FDA is based on data from a multicenter, single-arm Phase 1 study (Study 1001) that evaluated XALKORI in 53 patients with ROS1-positive metastatic NSCLC.3 Data from 50 of these patients were published in the November 20, 2014 issue of The New England Journal of Medicine and showed that XALKORI exhibited marked anti-tumor activity in patients with ROS1-positive metastatic NSCLC. Additionally, the safety profile of XALKORI in ROS1-positive metastatic NSCLC was consistent with that observed in patients with ALK-positive metastatic NSCLC. 4

About XALKORI (crizotinib)

XALKORI is a kinase inhibitor indicated in the U.S. for the treatment of patients with metastatic non-small cell lung cancer whose tumors are anaplastic lymphoma kinase-positive as detected by an FDA-approved test. XALKORI has received approval in more than 85 countries including Australia, Canada, China, Japan, South Korea and the European Union.

XALKORI Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1669). Transaminase elevations generally occurred within the first 2 months. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1669), 2.9% of XALKORI-treated patients had any grade ILD, 1.1% had Grade 3/4, and 0.5% had fatal ILD. These cases generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1560), 2.1% of patients had QTcF (corrected QT by the Fridericia method) ≥500 ms and 5.0% had an increase from baseline QTcF ≥60 ms by automated machine-read evaluation of ECG. Avoid use in patients with congenital long QT syndrome. Consider periodic monitoring with ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or ≥60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc ≤480 ms, then resume at a reduced dose.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.3% of patients treated with XALKORI (N=1669). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of ≥60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (N=1669). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 62% of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryofetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%) decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breast feed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

On December 8, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported the initiation of an open-label, Phase 1/2 safety and tolerability study examining the investigational combination of varlilumab and Roche’s atezolizumab (MPDL3280A) in patients with unresectable stage III or IV renal cell carcinoma (RCC) (Press release, Celldex Therapeutics, DEC 8, 2015, View Source [SID:1234508499]).

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Celldex previously announced the collaboration with Roche to evaluate the novel immunotherapy combination in March 2015. Under the terms of the agreement, Roche will provide atezolizumab, and Celldex will be responsible for conducting and funding the study. Varlilumab is currently being studied in five Phase 1/2 combination studies.

Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. Atezolizumab is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing PD-L1 from binding to PD-1 and B7.1 on anti-tumor T cells. By inhibiting PD-L1, atezolizumab may enable the activation of anti-tumor T cells. These two antibodies are part of a new class of investigational medicines known as cancer immunotherapies. They are designed to harness the body’s own immune system to fight cancer through separate yet complementary mechanisms of action that may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells.

Data from multiple preclinical tumor models suggest the combination of these two mechanisms are synergistic and enhance anti-tumor immune response compared to either agent alone. Also, in a Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory RCC were observed, including a durable partial response (duration of response = 13.6+ months) that continued to decrease in tumor volume over time and prolonged stable disease (four patients with a range of 5.3 to 36.2+ months).

"Together, preclinical and clinical data suggest that combining varlilumab and atezolizumab may enhance anti-tumor immune responses compared to monotherapy," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "Varlilumab is an attractive candidate for combination immunotherapy across a variety of cancers due to its target’s restricted expression and strong activity in a variety of tumor models, as well as positive data and a favorable safety profile from our Phase 1 study."

Study Design

Phase 1 study portion

The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of varlilumab at 0.3, 1.0 and 3.0 mg/kg combined with atezolizumab at 1200 mg in order to identify a recommended dose for the Phase 2 portion of the study. The Phase 1 portion will enroll patients with unresectable stage III or IV melanoma, RCC, triple negative breast cancer, bladder cancer, head and neck cancer or non-small cell lung cancer (NSCLC).

Phase 2 study portion

The Phase 2 portion of the study will enroll patients with RCC. The primary objective of this portion of the study is to assess the preliminary anti-tumor efficacy of the varlilumab/atezolizumab combination measured by objective response rate (ORR). Secondary objectives include safety and tolerability, pharmacokinetics, immunogenicity and further assessment of anti-tumor activity across a broad range of endpoints.

In total, the Phase 1/2 study is anticipated to include up to 10 sites in the United States and enroll approximately 60 patients. In each 12-week cycle for both phases of the trial, varlilumab and atezolizumab will be administered once every three weeks (four doses). Patients will be treated with varlilumab until intolerance, disease progression or completion of up to 4 cycles. There is no limit on the duration of treatment with atezolizumab.

About Varlilumab

Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs.

On December 8, 2015 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported that the company has submitted a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for Vosaroxin for the treatment of acute myeloid leukemia in patients aged 60 years and older (Press release, Sunesis, DEC 8, 2015, View Source [SID:1234508495]).

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The application is subject to validation by the EMA, a process which typically takes one month, before the formal regulatory review of the application begins.

"Submission of an MAA for vosaroxin in relapsed refractory AML was our top priority in 2015. This milestone brings us closer to delivering a new option to a patient population which has seen little improvement in treatment standards in the last 40 years," said Daniel Swisher, Chief Executive Officer of Sunesis. "We believe the European market opportunity is significant, and look forward to providing updates on our progress with the application throughout 2016."

About QINPREZO (vosaroxin)
QINPREZO (vosaroxin) is an anti-cancer quinolone derivative (AQD), a class of compounds that has not been used previously for the treatment of cancer. Preclinical data demonstrate that vosaroxin both intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-selective DNA damage, G2 arrest and apoptosis. Both the U.S. Food and Drug Administration (FDA) and European Commission have granted orphan drug designation to vosaroxin for the treatment of AML. Additionally, vosaroxin has been granted fast track designation by the FDA for the potential treatment of relapsed or refractory AML in combination with cytarabine. Vosaroxin is an investigational drug that has not been approved for use in any jurisdiction.

The trademark name QINPREZO is conditionally accepted by the FDA and the EMA as the proprietary name for the vosaroxin drug product candidate.