Cyclin-Dependent Kinase Inhibitor for CLL

Combining the cyclin-dependent kinase (CDK) inhibitor dinaciclib (SCH 727965) with ofatumumab (Arzerra) resulted in activity in relapsed or refractory chronic lymphocytic leukemia, confirming the activity of dinaciclib in chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients with high-risk disease.

The estimated median progression-free survival (PFS) was 10.4 months and the median overall survival (OS) has not been reached.

The results of the phase 1b/2 clinical trial, sponsored by the National Cancer Institute, were presented at the American Society of Hematology annual meeting, held December 6-9, 2014 in San Francisco by Jeffrey Alan Jones, MD, of the Ohio State University Medical Center, Columbus, Ohio.

According to the study authors, responses improved with continued drug exposure, and discontinuation prior to best response could have impacted the observed response rates. The results warrant further research of dinaciclib in combination with other antibodies or kinase inhibitors, stated the study authors.

Of the 36 patients on trial, 42% (15) of patients had a partial response and 56% (20) of patients had stable disease. By cycle 6, of the 17 patients evaluated, 71% (12) of patients achieved a partial response.

After a median follow up of 5.5 months, the PFS was 10.38 months.

Chronic lymphocytic leukemia is the most frequently diagnosed form of adult leukemia and remains incurable. Those patients whose tumors harbor a particularly abnormal karyotype and deletion--that is part of chromosome 17 (del17p)--have a particularly high-risk form of lymphocytic leukemia with inferior survival. 

Dinanciclib is a small molecule, broad CDK inhibitor of CDK1, CDK2, CDK5, and CDK9. The drug has been shown to inhibit cell cycle progression and proliferation of tumor cells in vitro. The drug is also currently being tested for other cancer types: pancreatic cancer, melanoma, and triple-negative breast cancer.

CDK inhibitors have had notable single-agent activity in CLL/SLL, including patients with genetically high-risk disease, such as those with a del17p or TP53 mutated-tumors, Jones told OncoTherapy Network via email.

Ofatumumab is a fully human monoclonal antibody against CD20, which is present exclusively on B-cell lymphocytes. The agent is approved by the Food and Drug Administration for treatment of previously-treated CLL, as well as in combination with chlorambucil as a first-line treatment for CLL.

“The addition of a CD20 antibody has been shown to convey a survival advantage over chemo alone in prior studies, so there is always interest to explore that potential in combination with novel agents like CDK inhibitors,” said Jones.  “We were [also] interested to determine whether addition of a second agent with differing toxicity profile could help limit the risk for hyperacute tumor lysis syndrome, which was is an important concern in further developing dinaciclib or other CDK inhibitors in CLL/SLL.”

Dinaciclib was given as a 2-hour infusion on days 1, 8, and 15 of a 28-day cycle for a total of 6 cycles, and continued as a single-agent at the discretion of the treating physician. Ofatumumab was administered according to the approved CLL dose (300 mg on day 1, 1000 mg on day 8, and subsequently 1000 mg once every 28-day cycle. 

All patients received preventive measures for tumor lysis syndrome in the form of aggressive hydration with electrolyte solution, hospitalization for the first dinaciclib administration, as well as four premedications. Patients were also given anti-infective prophylaxis. 

Patients had a median age of 62.5 years and had had a median of two prior therapies. The 17p deletion was present in 69% (25) patients and a complex abnormal karyotype in 42% (15) patients. Patients received a median of 4 cycles of therapy and four of the patients (11%) are still on treatment.

There were no dose-limiting toxicities in the phase 1b part of the trial. The most common Grade 3 or higher adverse events were hyperglycemia (5), hypocalcemia (4), hypophosphatemia (13), leukopenia (12), anemia (11), and thrombocytopenia (9). Eight Grade 3 or higher infections occurred: pleural (1), lung (5), and sepsis (2).

One patient that was refractory to ibrutinib (Imbruvica) and IPI-145 (PI3K delta/gamma inhibitor), and had a high tumor burden, developed tumor lysis syndrome as well as Grade 5 sepsis. The risk of tumor lysis syndrome with CDK inhibitor therapy has been previously linked to a higher tumor burden.

“Aside from the risk for hyperacute tumor lysis syndrome, which concurrent treatment with ofatumumab appeared to mitigate, dinaciclib is a well-tolerated drug. Relatively few patients enrolled on the trial discontinued for treatment-related adverse events, and several patients treated in the phase 1 study," said Jones.