July 27, 2017

Bone Remodeling Clinical Trial Assessment

Carolina Schinke, M.D., assistant professor, conducts research that leads to development of new clinical trials.

Bone disease is a major issue for the majority of multiple myeloma patients.  Lytic lesions, fractures and collapse of vertebra in the spine — primary causes of pain and debilitation — can significantly compromise quality of life.

Clinical treatment for myeloma includes a focus on minimizing the effects of bone disease, preventing progression of bone destruction, and taking measures to increase healthy bone development.

With the goal of identifying the most effective treatments for optimal outcomes both now and in the future, clinical treatment is sometimes provided through clinical trials. The Myeloma Center has always emphasized the importance of well-designed clinical trials so that patients can benefit from innovative and cutting-edge care.

“Phase II Prospective Evaluation of Bone Remodeling During Ixazomib Treatment,” a clinical trial at the Myeloma Center under the direction of Maurizio Zangari, M.D., director of myeloma bone disease research, is intended to evaluate the effect of Ixazomib on inducing osteoblast activation in patients with relapsed/refractory myeloma. Ixazomib is a proteasome inhibitor ­— a drug that blocks the action of proteasomes, which are large protein complexes that help destroy other cellular proteins when they are no longer needed. Osteoblasts are cells that create new bone.

“The study is specifically investigating the effectiveness of Ixazomib as a single agent without other drugs,” Zangari said.

Ixazomib was approved by the U.S. Food and Drug Administration (FDA) in November 2015, under the brand name Ninlaro, as the first oral proteasome inhibitor to be used in combination with Revlimid (lenalidomide) and dexamethasone, a type of corticosteroid.

The safety and efficacy of Ninlaro had earlier been demonstrated in an international, randomized, double–blind clinical trial of 722 patients whose myeloma had relapsed or did not respond to previous treatment. (In a double-blind study neither the patients nor the investigators know which patients are in the test and control groups.)  Ninlaro was granted priority review status by the FDA, a designation that is given to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition.

Zangari is hopeful that analysis of the trial data will yield positive results. “It would be a boon for patients to only have to take one drug that is administered orally instead of intravenously. The goal is to minimize side effects of multiple drugs, simplify how the drug is taken, and obtain an excellent outcome,” he said.

The estimated completion date for the trial is September 2017.

About Clinical Trials

Clinical trials — research studies that involve people — provide a mechanism for testing new treatments in a safe, structured manner and gleaning data that enables statistically valid analysis. They are key to making progress against cancer and complications associated with cancer and making sure that patients have access to the most effective care.

Clinical trials are the final step in a long process that begins with research in a laboratory. Before any new treatment or drug is used with people in clinical trials, researchers work for many years to understand its effects on cancer cells in the lab to try to figure out the side effects it may cause.

Clinical trials involve a series of phases, with each phase designed to answer a specific research question. If a new treatment is successful in one phase, it proceeds to the next phase for further testing. During the early phases (phases 1 and 2), researchers determine whether a new treatment is safe, what its side effects are, the optimal dosage, and whether the treatment has a clear-cut benefit, such as slowing tumor growth.

In the later phase (phase 3), researchers study whether the treatment works better than current standard therapy and they compare the safety of the new treatment to the safety of current treatments. Phase 3 trials enroll large numbers of patients to ensure efficacy and continue monitoring patients for adverse effects. Phase 4 trials look at long-term safety and effectiveness after a new treatment has been approved by the FDA and is on the market.

Phase I trials enroll a small number of patients, usually 15
to 30.

Phase II trials, with a focus on determining effectiveness of the new drug or treatment, typically enroll about 100 patients.

Phase III trials can enroll from 100 to several thousand patients, especially in the case of trials conducted at multiple sites.

Clinical trials go through a highly prescribed approval process before they are cleared to enroll patients. There are numerous regulatory steps along the way, all designed to ensure the scientific integrity and patient safety of the proposed treatment(s). The overall goal is to have the potential benefits outweigh the possible risks for clinical trial participants. Multiple oversight committees, including an institutional review board (IRB), which is charged with protecting the rights and welfare of human subjects, make sure that federal, institutional, and ethical guidelines are followed by principal investigators and research staff.

The UAMS IRB has been accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) since 2005. An independent, non-profit accrediting body, AAHRPP ensures that human research protection programs meet rigorous standards. Accredited organizations must provide evidence — through policies, procedures and practices — of their commitment to scientifically and ethically sound research.     >>

Nathan Petty, director of clinical trials and regulatory affairs at the Myeloma Center, describes the process of bringing a clinical trial from idea inception to patient enrollment as a highly disciplined path.

“The process demands great attention to detail and understanding of local and federal regulations.  In order to successfully execute a clinical trial, one must understand how to implement and adhere to the regulatory requirements throughout the clinical research process,” Petty said. “It can take months to get a clinical trial to the point that patients can be consented and enrolled on study.”                                          

Once patients are enrolled, clinical research assistants coordinate with research nurses and doctors to carefully monitor patient compliance to the protocol and record treatment progress, response to treatment and adverse reactions, if any.

“Everything must be documented. Every ‘t’ must be crossed and every ‘i’ dotted,” Petty said. Petty oversees a staff of more than 45 including research nurses, regulatory specialists, clinical research assistants, finance administrators and specimen procurement staff.

Successful treatments for cancer, including myeloma, are in large part the result of clinical trials. With a solid infrastructure for clinical trials operations, the Myeloma Center has made tremendous progress over the decades in developing effective therapies aimed at curing myeloma and improving quality of life.

“If we can simplify treatments and enable patients to live fuller lives, we are indeed making progress,” Zangari said.