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Dinaciclib Shows Activity In Relapsed Multiple Myeloma (ASH 2012)

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Published: Dec 18, 2012 1:10 pm

Results from a Phase 1/2 study show that dinaciclib has anti-myeloma activity in relapsed multiple myeloma patients.

“The current study shows encouraging potential for the single-agent [use of dinaciclib] in patients with relapsed multiple myeloma,” said Dr. Shaji Kumar from the Mayo Clinic, who presented the results at the American Society of Hematology (ASH) meeting last week. He added that the treatment was also “well-tolerated with toxicity that was manageable.”

However, Dr. Kumar explained that further studies are needed to determine an optimal dosing schedule and to evaluate dinaciclib in combination with other drugs.

Dinaciclib (SCH727965) is currently being developed by Merck (NYSE: MRK). It is a small molecule that inhibits enzymes called cyclin-dependent kinases, which regulate the cell cycle and are often overactive in cancer cells. Dinaciclib interrupts the cell cycle by inhibiting these kinases, ultimately causing the cell to die.

Preclinical studies have shown that Velcade (bortezomib) is more effective when cyclin-dependent kinases are inhibited.  Therefore, this study was conducted to determine the efficacy and safety of dinaciclib before being tested in combination with Velcade.

Dr. Kumar and his colleagues enrolled 27 patients with relapsed myeloma between July 2009 and November 2012.  The median age of the patients was 66 years.

The study participants had been diagnosed with myeloma a median of 3.5 years prior to the start of the study, and they had all received up to, but no more than, four prior lines of therapy.

All patients had previously been treated with Revlimid (lenalidomide), thalidomide (Thalomid), or pomalidomide, and 89 percent of the patients had previously been treated with Velcade.

Additionally, 41 percent of the patients were considered high-risk due to chromosomal abnormalities.

The first 19 study participants were included in Phase 1 of the study. These patients were divided into three different groups, each of which received a single 30 mg/m2, 40 mg/m2, or 50 mg/m2 infusion of dinaciclib once every three weeks, along with 20 mg of dexamethasone (Decadron) to reduce infusion-related side effects.

One patient treated with 40 mg/m2 of dinaciclib experienced severe constipation, possibly related to the treatment.

Based on the results from Phase 1 of the study, Dr. Kumar and his colleagues concluded that 50 mg/m2 of dinaciclib was the maximum tolerated dose.  The team went on to use this dose in Phase 2 of the study.

During the two phases of the study, patients received a median of 2 cycles of dinaciclib.

Among all study participants, 15 percent responded, with 7 percent achieving a very good partial response and 7 percent achieving a partial response.

The overall response rate was highest (33 percent) in the six patients treated with the 40 mg/m2 dose.  It was 11 percent in the 18 patients treated with the 50 mg/m2 dose, and none of the three patients treated with 30 mg/m2 of dinaciclib responded.

Although the issue was not discussed during Dr. Kumar's presentation, the observed dose-response relationship for dinaciclib raises the possibility that the drug may be similar to elotuzumab, in the sense that, with elotuzumab, a dose lower than the maximum tolerated dose has proven to be the most effective dose.

During his discussion of the dinacilib response rates, Dr. Kumar emphasized that the drug was clearly effective in lowering monoclonal protein levels.

“Roughly half of the patients had a paraprotein [M-protein] decrease,” he explained.

After a median follow-up time of 14.5 months, 22 percent of the patients had not progressed yet and 44 percent of the patients were still alive.

Dr. Kumar and his colleagues concluded that dinaciclib was well tolerated.  He stated during his talk that the most common side effects were primarily gastrointestinal issues, but that most of them were mild or moderate.

The most common severe side effects were low white blood cell counts (26 percent neutropenia and 26 percent leucopenia), diarrhea (7 percent), fatigue (7 percent), and blurred vision (7 percent).

Dr. Kumar also noted that an upcoming Phase 1 clinical trial will evaluate dinaciclib in combination with Velcade and dexamethasone in relapsed myeloma patients.  The study will also evaluate weekly and every three-week dosing schedules for dinaciclib.

For more information, please refer to abstract 76 on the ASH 2012 meeting website as well as Dr. Kumar’s presentation slides, which he has made available for download and viewing as a courtesy to The Beacon’s readers.

Photo by IndyDina with Mr. Wonderful on Flickr - some rights reserved.
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One Comment »

  • nancy shamanna said:

    Thanks for the article and clear slide presentation on the study of Dinaciclib, done at the Mayo Clinic. The kinase enzyme inhibitor seems to work best at a concentration lower than the highest tolerated dose, which is nice. it is very interesting to read of this type of new research, which might translate into more treatments being available later.