Results from a Phase II trial shows that ibrutinib (also known as PCI-32765; 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one; Janssen Biotech, Inc. and Pharmacyclics), a first-in-class oral therapy that is a selective, irreversible, inhibitor of Bruton?s tyrosine kinase (BTK), offers rapid and sustained disease control as a monotherapy in untreated, relapsed and refractory chronic lymphocytic leukemia (CLL) patients, irrespective of characteristics that predict poor outcomes to chemoimmunotherapy.

Chronic lymphocytic leukemia or CKK, a B cell cancer that originates in the bone marrow, is the most common type of leukemia. Each year, approximately 16,000 patients are diagnosed with the disease in the US. The disease is a chronic disease of the elderly with an average survival of about 5 years. Patients commonly receive multiple lines of treatment over the course of their disease. Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL), which is limited to the lymph nodes, are considered the same underlying disease.

Bruton’s tyrosine kinase
Ibrutinib was designed to specifically target and selectively inhibit an enzyme called Bruton’s tyrosine kinase (BTK). BTK is a key mediator of at least three critical B-cell pro-survival mechanisms occurring in parallel ? regulation of apoptosis, adhesion, and cell migration and homing. Through these multiple signals, BTK regulation helps to direct malignant B-cells to lymphoid tissues, thus allowing access to a micro environment necessary for survival.

Advanced is clinical development
This study was discussed at today’s American Association for Cancer Research (AACR) annual meeting in Washington, DC together in addition to 8 other presentations covering advances in clinical and pre-clinical research with ibrutinib.

The phase II study, which was sponsored by the National Heart, Lung and Blood Institute, included an analysis of two CLL patient cohorts: the elderly, above 65 years of age, (n=24, of which 8 were treatment naive) and the high risk genetic group with a deletion of chromosome 17p (del 17p) (n=29, of which 15 were treatment naive). Many elderly patients with CLL are unable to tolerate aggressive therapies. Patients with deletion of chromosome 17p typically are poor responders to chemoimmunotherapy and have limited treatment options with no standard of care defined. Of all CLL patients enrolled in this trial, 72% had been characterized as Rai stage 3-4, indicating an advance stage, high risk patient population.

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The results of the study were presented by lead investigator Adrian Wiestner, M.D., PhD, Hematology Branch, NHLBI, National Institutes of Health. “Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” Wiestner noted. “Responses in this study appear to be durable, and results indicate the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach may greatly improve the lives of patients with this disease.”

The study also evaluated in vivo effects of ibrutinib using blood and tissue samples collected before and during treatment. Ibrutinib demonstrated rapid and sustained disease control in blood, lymph nodes, spleen and bone marrow. After 6 months, 95% of patients experienced a reduction in lymph node size and all showed reduction in spleen enlargement, with a median reduction of 55%. In 26 patients, for whom a bone marrow biopsy was done, tumor infiltration decreased by 82%.

Adverse events
The Progression Free Survival probability for these patients at 12 months was estimated to be 94%. Most adverse events were mild and manageable and included diarrhea, fatigue and rash, severe events occurred in less than 13% of patients.”We are very pleased with the continued research that is being demonstrated at AACR across 9 different presentations. These advances show the potential breadth of the ibrutinib program and provide further opportunities for us to pursue. We are grateful for the continued support of our collaborators, investigators, patients and shareholders,” said Bob Duggan, Pharmacyclics CEOand chairman of the board.

Ibrutinib has been designated as a FDA Breakthrough Therapy in CLL patients with deletion 17p, based on data from completed Phase I/II clinical studies, where ibrutinib as a monotherapy was used to treat patients with this disease. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease, and may provide a substantial improvement over existing therapies for this indication.

The effectiveness of ibrutinib alone or in combination with other treatments is being studied in several B-cell malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Waldenstrom’s macroglobulinemia and multiple myeloma.

For more information:

Clinical trials:
NCT01674322 – A Study to Determine the Absorption, Metabolism, and Routes of Excretion of (14C) Radiolabeled Ibrutinib in Healthy Male Participants
NCT01779791 – A Study of PCI-32765 (Ibrutinib) in Patients With Refractory Follicular Lymphoma
NCT01589302 – PCI-32765 (Ibrutinib) in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or B-cell Prolymphocytic Leukemia
NCT01804686 – A Long-term Extension Study of PCI-32765 (Ibrutinib)
NCT01626651 – A Study to Assess the Effect of Ketoconazole on the Pharmacokinetics of Ibrutinib in Healthy Participants
NCT01820936 – A Study to Determine the Effect of Food on the Pharmacokinetics of PCI-32765
NCT01569750 – A Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With CD20-Positive B-Cell Non Hodgkin Lymphoma
NCT01752426 – Pilot Study to Determine Effects of the Btk Inhibitor PCI-32765 on Leukemia Cell Kinetics and Trafficking, Using Heavy Water Labeling in Subjects With CLL and SLL
NCT01599949 – A Study to Evaluate the Efficacy and Safety of Ibrutinib, in Patients With Mantle Cell Lymphoma Who Progress After Bortezomib Therapy
NCT01611090 – A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
NCT01578707 – A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE?)
NCT01646021 – Study of Ibrutinib (a Bruton’s Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior TherapyNCT01776840 – A Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma
NCT01763021 – A Study to Assess the Effect of Rifampin on the Pharmacokinetics of PCI-32765 in Healthy Participants

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