Carfilzomib therapy shows promise for pre-kidney transplant patients

In continuation of my update on carfilzomib,

Early findings by researchers at the University of Cincinnati (UC) College of Medicine suggest that the use of a second generation cancer drug, carfilzomib, may provide an improved approach for the reduction of antibodies in potential kidney transplant candidates. The research team includes members from UC Transplant Clinical Research, UC's Division of Hematology Oncology and the Cincinnati Children's Hospital Medical Center's Biomedical Informatics division.

 carfilzomib

This pre-transplant drug therapy approach is aimed at reducing antibodies in kidney transplant candidates with greater success than with traditional methods and with reduced side effects.

Antibodies are Y-shaped proteins that in most instances are good because they help fight infection, but people can also make antibodies that work against other humans, which is often a major barrier to transplantation.

"Carfilzomib has been well tolerated by the first group of six study patients who experienced antibody reductions between 31 to 100 percent," says the study's lead author Simon Tremblay, PharmD, research associate in the UC College of Medicine's transplant research programs.

The study's preliminary findings will be presented at the annual American Transplant Congress on June 13, in Boston, Mass., where Tremblay will be awarded the American Transplant Society's Young Investigator award.

Since 2008, the UC research team has been developing therapies that target plasma cells—the cells that make antibodies. The first generation of drug therapy studied was the cancer drug bortezomib, a proteasome inhibitor that, like carfilzomib, is already approved by the Food and Drug Administration for treatment of multiple myeloma. In that 50 person study, which was published in 2015, a significant decrease in antibodies was observed. Furthermore, transplanted patients had low rejection rates and the chances of developing a new antibody against their kidney was also low. In addition, in some patients, antibodies remained suppressed for several months—something that has not previously been described with other approaches.

In the same scientific session, James Driscoll, MD, PhD, assistant professor in the UC College of Medicine's Division of Hematology Oncology, will present the results of translational research studies in the carfilzomib-treated patients. Driscoll will present new genomic data on plasma cells isolated from patients prior to and after receiving carfilzomib therapy.

"Our gene expression profiling studies in normal human plasma cells are giving us a detailed, comprehensive view of how plasma cells survive and avoid the death inducing effects of carfilzomib," says Driscoll. These studies, he says, were performed in collaboration with Bruce Aronow, PhD, at Cincinnati Children's.

Carfilzomib is one of four new regimens—described as "second-generation plasma cell targeted therapies that are being evaluated by the UC transplant Clinical Research Team, " says the principal investigator on both studies, E. Steve Woodle, MD, UC Health transplant surgeon and director of the division of transplantation at the UC College of Medicine.

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma

In continuation of my update on carfilzomib, JQ1 and ABT 199

New research from Roswell Park Cancer Institute (RPCI) shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Priyank Patel, MD, a fellow in the Department of Medicine at Roswell Park, is the first author and Francisco Hernandez-Ilizaliturri, MD, Clinical Chief of the Institute's Lymphoma/Myeloma Service, is the senior author of "Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)" (abstract 3038), which will be presented on Tuesday, April 19, at 8 a.m. CDT.

Diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, is an aggressive form of lymphoma. This research team reviewed a database of 650 patients with diffuse large B-cell lymphoma, identifying 36 patients whose tumors had two or more aberrant genes. Patients with mutations of the c-MYC, BCL2 and/or BCL6 genes — a subtype known as "double-hit lymphoma" — have especially have poor outcomes when treated with standard chemotherapy. The scientists evaluated the effectiveness of three novel anticancer drug candidates that targeted those proteins. In preclinical studies, the therapeutic agents ABT-199, JQ-1 and carfilzomib induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed when researchers combined ABT199 with carfilzomib and, to a lesser extent, with JQ1 in cancer cell lines.

"Increasing knowledge of genetics and molecular pathways has helped us identify a subgroup of patients who harbor aggressive aberrant gene mutations. Understanding the mechanisms of action and clarifying how these potential therapies work to inhibit cancer cell growth may result in improved outcomes for patients diagnosed with this aggressive type of lymphoma," says Dr. Hernandez-Ilizaliturri.

 Carfilzomib   JQ1  ABT-199

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma: New research from Roswell Park Cancer Institute shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

In continuation of my update on carfilzomib

Carfilzomib significantly improves outcomes in previously treated patients with relapsed or refractory multiple myeloma, shows a head-to-head comparison with bortezomib.

In the ENDEAVOR phase III trial, published in The Lancet Oncology, median progression-free survival (PFS) was 18.7 months for the 464 patients randomly assigned to receive open-label carfilzomib plus dexamethasone. This was significantly longer than the 9.4 months for the 465 participants treated with bortezomib and dexamethasone, and equated to a 47% risk reduction in favour of carfilzomib.

Moreover, a significantly higher proportion of carfilzomib- than bortezomib-treated patients achieved an objective response, at 77% versus 63%, and the duration of response was also longer in the former group, at a respective 21.3 and 10.4 months.

The most common side effects of grade 3 or worse that occurred more frequently in the carfilzomib than the bortezomib treatment arm were anaemia and hypertension, with rates of 14% versus 10% and 9% versus 3%, respectively.

However, peripheral neuropathy of grade 3 was observed in 2% of carfilzomib-treated patients and there were no grade 4 events, compared with 8% of patients in the bortezomib arm who experienced events of grade 3 or 4.

Serious adverse events occurred in 48% of patients in the carfilzomib group and in 36% of those given bortezomib, but Meletios Dimopoulos (National and Kapodistrian University of Athens, Greece) and team note that the number of discontinuations and deaths attributable to adverse events were comparable between the groups.

They conclude that carfilzomib plus dexamethasone could be considered for multiple myeloma patients for whom bortezomib is indicated.

Role for carfilzomib in relapsed, refractory multiple myeloma treatment

Three-drug regimen provides rapid, durable responses for multiple myeloma

In continuation of my update on three drug combination

A three-drug treatment for the blood cancer multiple myeloma provided rapid, deep and potentially durable responses, researchers report today online in Blood, the Journal of the American Society of Hematology, and yesterday, Sunday, June 3, 2012, at the American Society of Clinical Oncology's Annual Meeting in Chicago, IL, USA.

The researchers, led by Andrzej J. Jakubowiak, MD, PhD, professor of medicine and director of the multiple myeloma program at the University of Chicago Medical Center, found that combining carfilzomib, a next generation proteasome inhibitor, with two standard drugs -- lenalidomide and low-dose dexamethasone compared favorably to other frontline regimens.
The longer patients stayed on the therapy, the better their response. After at least eight 28-day cycles of treatment, 61 percent of the 36 patients who remained on the therapy had a stringent complete response, defined as no detectable tumor cells or myeloma protein in the blood or bone marrow; 78 percent had at least a near complete response. More than 90 percent of patients had no progression of their disease at two years.

"These rapid and durable response rates are higher than those achieved by the best established regimens for newly diagnosed multiple myeloma," said Jakubowiak. "We have observed excellent efficacy, the best reported to date, and very good tolerability, including limited peripheral neuropathy that has been problematic with other drug combinations."

 Ref : http://www.uchospitals.edu/news/2012/20120604-myeloma.html

 Three-drug regimen provides rapid, durable responses for multiple myeloma

Drug combination highly effective for newly diagnosed myeloma patients......

A three-drug combination treatment for the blood cancer multiple myeloma compares favorably to the best established therapy for newly diagnosed patients, according to a multi-center study led by Andrzej Jakubowiak, MD, PhD, professor of medicine and director of the multiple myeloma program at the University of Chicago Medical Center.

( Carfilzomib)

 (Lenalidomide)

( Thalidomide)

The combination includes an investigational medicine called carfilzomib combined with two standard medications: lenalidomide, an analogue of thalidomide, and low-dose dexamethasone, an anti-inflammatory with anti-cancer properties.

"This combination appears to deliver everything we expected and more," said Jakubowiak, who came to the University of Chicago this fall from the University of Michigan. "We have seen excellent efficacy — the best reported to date — without the neurotoxicity that has been problematic with other drug combinations."

Ref : http://www.uchospitals.edu/news/2011/20111206-myeloma.html

Carfilzomib could become new option for patients with relapsed myeloma, IMF says

 In continuation of my update on Carfilzomib
 

The International Myeloma Foundation (IMF), the oldest and largest foundation dedicated to improving the life and care of myeloma patients, today said promising data suggest that the new drug "carfilzomib" could become an important new option for patients whose myeloma stops responding to other therapies. Carfilzomib, from Onyx Pharmaceuticals, is a next-generation proteasome inhibitor that disrupts the life cycle of a cancer cell, and carfilzomib has shown favorable tolerability. Based on this Phase II clinical trial, Onyx could seek accelerated drug approval from the FDA by the end of 2010.

More....

Ref : http://myeloma.org/ArticlePage.action?tabId=0&menuId=0&articleId=3082&aTab=-1

Carfilzomib for multiple myeloma ?

The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. Therefore the researchers evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor - Carfilzomib.

The second-generation proteasome inhibitor carfilzomib is showing noteworthy response rates and low levels of adverse side effects among multiple myeloma patients in a phase II clinical trial.

The updated data from the 17-site study focuses on patients with relapsed or resistant multiple myeloma who have received one to three prior therapies, but not the drug bortezomib, the original proteasome inhibitor. The results are of grat importance because of the fact that multiple myeloma is an incurable, challenging disease with devastating consequences. While new agents are extending life expectancies, they often have adverse side effects, including severe neuropathy. Carfilzomib is showing good response rates, with an improved side effects, except for minor, included fatigue, nausea and anemia.

Ref : http://bloodjournal.hematologylibrary.org/cgi/content/full/110/9/3281/F1