A recent update of a multicenter Phase Ib/II clinical trial concludes that the novel Bruton?s Tyrosine Kinase (BTK) inhibitor PCI-32765 may be an important new targeted treatment approach for patients with chronic lymphocytic leukemia (CLL).
Chronic lymphocytic leukemia is the most common form of leukemia, with about 15,000 new cases annually in the U.S. About 4,400 Americans die of the disease each year.
On/Off switches
Tyrosine kinase enzymes are important targets for cancer research because they function as on/off switches in many cell functions and can signal cells to either maintain normal functioning or to grow uncontrollably, leading to cancer. Bruton’s Tyrosine Kinase (BTK) in particular is largely responsible for the signaling that drives normal B-cell development as well as mast cell activation through the high-affinity IgE receptor, making it a primary target for research on B-cell malignancies such as non-Hodgkin lymphoma (NHL).
Bruton’s Tyrosine Kinase (BTK) is essential to B-cell receptor (BCR) signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Researchers have demonstrate that the BTK protein and mRNA are significantly over expressed in Chronic Lymphocytic Leukemia (CLL)compared with normal B-cells.Although BTK is not always constitutively active in CLL cells, B-cell receptor (BCR) or CD40 signaling is accompanied by effective activation of this pathway.
Inhibiting BTK
The irreversible BTK inhibitor PCI-32765is an orally-administered BTK inhibitor that induces apoptosis, or programmed cell suicide, and inhibits function of malignant B-cells. Using PCI-32765, researcher have demonstrated modest apoptosis in CLL cells that is greater than that observed in normal B-cells. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-?B. Earlier promising studies of PCI-32765 have, furthermore, shown that the compound may be highly active and tolerable in patients with CLL.
Treatment of patients with CLL
The current analysis summarizes results of an ongoing study using PCI-32765 as a treatment for patients with relapsed CLL. Two cohorts of CLL patients were treated with PCI-32765 at doses of either 420 mg (n=27) or 840 mg (n=34) daily for 28-day cycles until they showed signs of disease progression. Nearly three-fourths (72%) of participating patients had at least one high-risk feature, indicating that they may not respond well to treatment.
Progression free survival
After a review of the current analysis, researchers concluded that PCI-32765 was associated with high rates of six-month progression-free survival in patients with relapsed CLL. At 10 months follow-up, 70% of patients in the 420 mg treatment group achieved an objective response to therapy (previously reported as 48%), and 44% of the patients in the 840 mg cohort achieved an objective response at six months follow-up. An additional 19% of the 420 mg cohort and 35% of the 840 mg cohort had a nodal partial response, meaning their disease responded to therapy as represented by a 50% or greater reduction in lymph node size, but some lymph nodules persisted. Importantly, 82% of patients remain on treatment, and only 8% have experienced progressive disease.
Two patients discontinued the trial because of adverse events, and six patients required a dose reduction. The most frequently reported adverse events included diarrhea, fatigue, nausea, and ecchymosis (apparent skin bruising). Serious adverse events (SAEs, which are considered relatively common among this immune-compromised patient population) occurred in 38% of patients, with 10% considered potentially related to treatment. Grade ?3 severe AEs considered potentially related to treatment occurred in 21% of patients. In addition, the majority of patients experienced high lymphocyte count, an event well-documented with this type of treatment, during the first two months of treatment that resolved over time.
?Usually patients with highly resistant and refractory CLL would have progressed and possibly died by this time, but 82% remain on PCI-32765 and continue to improve,? co-leader Dr. John C. Byrd, director of the division of hematology at Ohio State University Comprehensive Cancer Center ? Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC ? James) said.
Commenting on the trial results, lead author Susan O?Brien, MD, Professor in the Department of Leukemia at The University of TexasMD Anderson Cancer Centerin Houston said:?Our results suggest that PC-32765 has the potential to be highly effective and tolerable, and, more importantly, appears to be working well in patients with poor prognoses.As we become better equipped to target specific cellular functions, it is our hope that therapies like PCI-32765 will become effective interventions to manage disease in patients with CLL.?
?These interim findings are truly exciting because they provide additional evidence that PCI-32765 is a highly active oral therapeutic that produces a high rate of durable remissions ? the remissions last months on end ? with acceptable toxicity in relapsed and refractory CLL,? Byrd says. ?These responses last for many months in part because patients are willing to remain on the drug since the side effects are very tolerable,? Byrd noted.
Susan O’Brien, MD will present this study in an oral presentation on Tuesday, December 13, at 8:30 a.m. PST
For more information:
Program:Oral and Poster Abstracts
Poster:983
Type:Oral
Session:642. CLL – Therapy, excluding Transplantation: Relapse treatment, novel agents and treatment related complications
When: Tuesday, December 13, 2011: 7:30 AM
Where: Ballroom 20A (San Diego Convention Center)
Also read:
– Uckun FM, Tibbles HE, Vassilev AO. Bruton’s tyrosine kinase as a new therapeutic target. Anticancer Agents Med Chem. 2007 Nov;7(6):624-32.
– Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011 Jun 9;117(23):6287-96. Epub 2011 Mar 21.
Clinical trials:
– Safety and Tolerability Study of PCI-32765 in Chronic Lymphocytic Leukemia
– Safety and Efficacy of PCI-32765 in Subjects With Relapsed/Refractory Mantle Cell Lymphoma (MCL) (PCYC-1104-CA)
– Study of the Safety and Tolerability of PCI-32765 in Patients With Recurrent B Cell Lymphoma (PCYC-04753)
– Efficacy and Safety Study of PCI-32765 Combine With Ofatumumab in CLL (PCYC-1109-CA)
– Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia.
– Safety and Tolerability Study of PCI-32765 Combined With Fludarabine/Cyclophosphamide/Rituximab (FCR) and Bendamustine/Rituximab (BR) in Chronic Lymphocytic Leukemia (CLL)
– Studyof the Bruton’s Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma.
– Safety and Efficacy Study of Bruton’s Tyrosine Kinase Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma
– Btk Inhibitor in Recurrent B Cell Lymphoma.
PCI-32765 is being developed by Pharmacyclics, a clinical-stagebiopharmaceutical company focused on developing and commercializing innovative small molecule drugs for the treatment of cancer and immune mediated diseases.
The United States Patent & Trademark Office (USPTO) notified the company that its will issue a patent entitled “Inhibitors of Bruton’s Tyrosine Kinase” specifically claiming “an inhibited tyrosine kinase comprising an irreversible BTK inhibitor having a covalent bond to a cysteine residue of a Bruton’s tyrosine kinase (BTK)”. This U.S. patent 8,088,781 is set to issue on January 3, 2012.
