On January 12, 2015 Provectus Biopharmaceuticals, Inc. (NYSE MKT: PVCT, www.pvct.com), a clinical-stage oncology and dermatology biopharmaceutical company ("Provectus"), reported that patients have been dosed in both its Phase 3 clinical trial of PV-10, Provectus’ novel investigational drug for cancer, for Stage III locally advanced cutaneous melanoma and its Phase 1b/2 clinical trial of PV-10 in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with Stage IV melanoma (Press release, Provectus Pharmaceuticals, JAN 12, 2016, http://www.pvct.com/pressrelease.html?article=20160112.1 [SID:1234508779]). In addition, the Company confirmed that it continues to enroll patients in all of its active oncology studies.

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Eric Wachter, Chief Technology Officer of Provectus, said, "With patients starting treatment in both of these studies, the clock is ticking to interim results and ultimately the completion of these studies. Our recruitment activities are moving ahead and we are hopeful that these studies will play critical roles in demonstrating effectiveness and safety of PV-10 in melanoma."

PHASE 3 STUDY

The Phase 3 study is an international multicenter, open-label, randomized controlled trial (RCT) of single-agent intralesional (IL) PV-10 versus systemic chemotherapy to assess treatment of locally advanced cutaneous melanoma in patients who are BRAF V600 wild-type and have failed or are not otherwise candidates for ipilimumab or another immune checkpoint inhibitor. Subjects in the PV-10 arm receive IL PV-10 to all of their melanoma lesions. Subjects in the comparator arm receive the investigator’s choice of dacarbazine or temozolomide as determined by investigator preference and/or local availability of the agent. Effectiveness will be assessed by comparison of progression-free survival (PFS) between all intent-to-treat (ITT) subjects in the two study arms. The primary outcome measure of PFS is assessed every 12 weeks up to 18 months using RECIST 1.1 criteria. Secondary outcome measures include complete response rate (CRR) and its duration (assessed every 12 weeks up to 18 months); and overall survival (OS) assessed every 12 weeks up to 18 months. Safety and tolerability will be assessed by monitoring the frequency, duration, severity and attribution of adverse events and evaluating changes in laboratory values and vital signs. For more details on the study, please visit View Source

Currently, three sites are recruiting patients, with four additional sites nearing opening of enrollment. Additional sites are in process of being added in the coming weeks.

St. Luke’s Hospital and Health Network, Easton, PA;
Atlantic Health System, Morristown, NJ
University of Louisville, Louisville, KY;
Huntsman Cancer Institute, Salt Lake City, UT; (not yet recruiting),
M.D. Anderson Cancer Center, Houston, TX; (not yet recruiting),
Sharp Memorial Hospital, San Diego, CA; (not yet recruiting),
Princess Alexandra Hospital, Brisbane, Australia; (not yet recruiting).
Dr. Wachter noted, "We are currently finalizing amendments to the protocol that will refine the eligible patient population, consistent with a trial to be expanded this year beyond our historic base in the U.S. and Australia, and to afford additional flexibility in choice of comparator to address the changing treatment options available to patients globally."

PHASE 1b/2 STUDY

The Phase 1b/2 study is an international multicenter, open-label, sequential phase study of intralesional PV-10 in combination with systemic immune checkpoint inhibition. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible for study participation. In the current Phase 1b portion of the study, all participants will receive the combination of IL PV-10 and pembrolizumab (i.e., PV-10 + standard of care). In the subsequent Phase 2 portion of the study, participants will be randomized 1:1 to receive either the combination of IL PV-10 and pembrolizumab or pembrolizumab alone (i.e., PV-10 + standard of care vs. standard of care).

Up to 24 subjects will be enrolled in the Phase 1b portion of the study. Each subject in this cohort will receive the combination of IL PV-10 and pembrolizumab. The expected completion date is in 2016 for the Phase 1b portion of the study.

A total of an estimated 120 subjects will be randomized in a 1:1 ratio to the two treatment arms (i.e., PV-10 + pembrolizumab or pembrolizumab alone) in the Phase 2 portion of the study. This number of subjects may be modified based on emerging evidence of preliminary efficacy and effect size from the Phase 1b portion of the study.

Subjects assigned to receive PV-10 in Phase 1b and 2 will receive initial IL PV-10 to their injectable cutaneous and subcutaneous lesions commencing on study Day 1 for up to 13 weeks (i.e., the investigational treatment phase of the study). PV-10 may be re-administered at 21-day (3-week) intervals during this period to any remaining, uninjected cutaneous and subcutaneous lesions until all injectable cutaneous and subcutaneous lesions have been injected. Lesions that fail to exhibit complete ablation may be re-injected on this schedule.

Pembrolizumab will be administered at 21-day (3-week) intervals per prescribing information (label) commencing on study Day 1 for up to 24 months or until disease progression, toxicity requiring discontinuation of study treatment or study termination.

Response assessment in both phases of the study will be based on PFS using RECIST 1.1 criteria.

Dr. Wachter added, "Current research suggests that using anti-cancer drugs in combination can have additive or synergistic effects that can improve the outcomes patients experience. KEYTRUDA and PV-10 together may prove more effective than either agent alone in treating certain cases of melanoma. We believe that our current Phase 3 study that tests PV-10 on its own for Stage III patients is designed to prove its effectiveness, but we also believe that we should examine combination therapies to maximize potential benefit to patients, especially those with advanced disease."

The details of the study are available at View Source

For a complete history of Provectus’ research into PV-10 as an investigational treatment for melanoma, visit https://www.pvct.com/pv10melanoma.html.

On January 12, 2016 BioLineRx Ltd. (NASDAQ/TASE: BLRX) reported a collaboration with MSD, known as Merck in the US and Canada, to support a Phase 2 study investigating BioLineRx’s BL-8040 in combination with KEYTRUDA (pembrolizumab), MSD’s anti-PD-1 therapy, in patients with metastatic pancreatic cancer (Press release, BioLineRx, JAN 12, 2016, View Source [SID:1234508778]). The study is an open-label, multicenter, single-arm trial designed to evaluate the safety and efficacy of this combination in patients with metastatic pancreatic adenocarcinoma.

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BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells and to be effective at inducing direct tumor cell death. Additional findings in the field of immuno-oncology suggest that CXCR4 antagonists may be effective in inducing the migration of anti-tumor T cells into the tumor micro-environment. 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. The Phase 2 study will evaluate the clinical response, safety and tolerability of the combination of these therapies as well as multiple pharmacodynamic parameters, including the ability to improve infiltration of T cells into the tumor and their reactivity.

"We are extremely happy to collaborate with MSD, a pioneer and world leader in cancer immunotherapy. This marks the entrance of BL-8040 into this exciting field, which is already transforming the lives of many cancer patients," stated Dr. Kinneret Savitsky, Chief Executive Officer of BioLineRx. "Because certain tumors exhibit only a modest response to existing immunotherapies, we are increasingly seeing clinical studies involving combinations of immuno-oncology agents with other classes of drugs. We are initiating this study with the hope that it will show that the combination of BL-8040 with KEYTRUDA has the potential to expand the benefit of immunotherapy to cancer types currently resistant to immuno-oncology treatments, such as pancreatic cancer, which represents a significant unmet medical need. If this potential can be realized, it will be an extremely important advance in the fight against cancer, as well as a seminal milestone for BioLineRx."

"Today, there is a great opportunity and need to bring forward new scientific breakthroughs for the treatment of pancreatic cancer," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, MSD Research Laboratories. "Evaluating the potential of combination therapies through strategic collaborations in difficult-to-treat tumor types continues to be an important part of our immuno-oncology clinical development program for KEYTRUDA."

The agreement is between BioLineRx and MSD, through a subsidiary. Per the terms of the agreement, the trial will be sponsored and performed by BioLineRx. The study is planned to commence by mid-2016. Upon completion of the study, or at any earlier point, both parties will have the option to expand the collaboration to include a pivotal registration study. Additional details of the collaboration were not disclosed.

BioLineRx will hold a conference call to discuss the collaboration today, January 12, 2016, at 10:00 am EST. To access the conference call, please dial 1-888-281-1167 from the U.S. or +972-3-918-0610 internationally. The call will also be available via live webcast through BioLineRx’s website . A replay of the conference call will be available approximately two hours after completion of the live conference call. To access the replay, please dial 1-888-326-9310 from the U.S. or +972-3-925-5904 internationally. The replay will be available through January 15, 2016.

About Pancreatic Cancer

There are a number of types of pancreatic cancer. Based on available worldwide numbers, in 2012, pancreatic cancers of all types were the seventh most common cause of cancer deaths. According to the American Cancer Society, in 2015 nearly 50,000 were diagnosed with pancreatic cancer and an estimated 40,000 will die from the disease. The most common type of pancreatic cancer is pancreatic adenocarcinoma, which accounts for about 85 percent of cases. These adenocarcinomas start within the part of the pancreas that makes digestive enzymes. There are usually no symptoms in the early stages of the disease and symptoms that are specific enough to suggest the onset of pancreatic cancer typically do not develop until the disease has reached an advanced stage. The five-year survival rate of pancreatic adenocarcinoma is around 7 percent.

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and certain hematological indications. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells from the bone marrow, thereby sensitizing these cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing apoptosis. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, and T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

On January 12, 2016 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) and granted Priority Review for venetoclax for the treatment of people with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, including those with 17p deletion (Press release, Genentech, JAN 12, 2016, View Source [SID:1234508776]).

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Venetoclax is a small molecule inhibitor of the BCL-2 protein being developed in partnership with AbbVie, and was granted Breakthrough Therapy Designation by the FDA in April 2015 for the treatment of people with previously treated (relapsed or refractory) CLL with 17p deletion.

"Venetoclax is a potential new way to treat this difficult type of chronic lymphocytic leukemia," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "We look forward to working with AbbVie and health authorities to bring this first-of-its-kind medicine to people who need more options."

A Priority Review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat serious or life-threatening diseases and to help ensure people have access to them through FDA approval as soon as possible. The NDA for venetoclax is based in part on data from the pivotal Phase II M13-982 study. A Marketing Authorization Application (MAA) has also been validated by the European Medicines Agency (EMA).

About Study M13-982
The NDA for venetoclax is based in part on data from the pivotal Phase II M13-982 study. M13-982 (NCT01889186) is a Phase II, open-label, single arm, multicenter study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated chronic lymphocytic leukemia (CLL) with 17p deletion. The study included 107 patients with relapsed or refractory disease, and all but one had 17p deletion. Additionally, about 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort. The primary endpoint of the study is overall response rate (ORR) as determined by an independent review committee (IRC), and secondary endpoints include complete response (CR), partial response (PR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

Results from the study were recently presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting showing:

The study met its primary endpoint, with an ORR of 79.4 percent among the 107 patients with relapsed or refractory disease receiving venetoclax, as assessed by IRC. In addition, 7.5 percent of patients achieved a complete response with or without complete recovery of blood counts in the bone marrow (CR/CRi).
Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 patients also had bone marrow assessments and six were MRD-negative.
At one year, 84.7 percent of all responses and 94.4 percent of MRD-negative responses were maintained. The one-year PFS and OS rates were 72 percent and 86.7 percent, respectively.
The most common serious adverse events were fever (7 percent), low red blood cell count as a result of immune response (7 percent), pneumonia (6 percent) and low white blood cell count with fever (5 percent). The most common Grade 3-4 adverse events were low white blood cell count (40 percent), low red blood cell count (18 percent) and low platelet count (15 percent). Grade 3 or higher infection occurred in 20 percent of patients. Laboratory tumor lysis syndrome was reported in five patients; none had clinical consequences.
About Venetoclax (RG7601, GDC-0199/ABT-199)
Venetoclax is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). It is believed that blocking BCL-2 may restore the signaling system that tells cells, including cancer cells, to self-destruct. The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). In collaboration with AbbVie, venetoclax is being evaluated in a robust development program as a single agent or in combination with other medicines. There are ongoing Phase II and III studies for venetoclax in CLL, and Phase I and II studies are also ongoing in several other blood cancers, including indolent NHL, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma (MM).

About Chronic Lymphocytic Leukemia (CLL)
CLL is one of the most common forms of blood cancer, and each year there are an estimated 5,000 deaths from CLL in the United States. Although signs of CLL may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of cancerous cells.
In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis (programmed cell death) called p53. The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases.