Tyrosine Kinase Inhibitor in Mantle Cell Lymphoma

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The Bruton’s Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II Trial

Luhua Wang, MD 1, Peter Martin, MD 2, Kristie A. Blum, MD 3, Brad S. Kahl, MD 4, Lauren S. Maeda, MD 5, Ranjana H. Advani, MD 6, Michael E. Williams, MD 7, Simon Rule, MD 8, Sara Rodriguez 9, Ching-Fai Pang, PhD 9, Eric Hedrick, MD 10 and Andre Goy, MD 11

1. Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
2. Department of Medicine, Division of Hematology-Oncology, Weill-Cornell Medical College, New York, NY
3. The Ohio State University, Columbus, OH
4. Department of Medicine-Hematology/Oncology, University of Wisconsin, Madison, WI
5. Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA
6. Medicine/Oncology, Stanford University Medical Center, Stanford, CA
7. University of Virginia, Charlottesville, VA
8. Department of Haematology, Derriford Hospital, Plymouth, United Kingdom
9. Pharmacyclics, Sunnyvale, CA
10. Pharmacyclics, Inc, Sunnyvale, CA
11. John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ

Introduction:

Bruton’s tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. PCI-32765 is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. In a phase I trial of PCI-32765 in relapsed B-cell malignancies, objective responses were observed in seven of nine patients with MCL. Reported here are preliminary results of an ongoing phase II study of single-agent PCI-32765 in previously treated MCL.

Methods and Patients:

Patients with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were eligible for study PCYC-1104. PCI-32765 was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was evaluated every 2 cycles and classified by 2007 NHL IWG criteria.

Results:

A total of 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) have been enrolled on study PCYC-1104 between February 16, 2011 and July 20, 2011. The median age is 67 years (62-72). The median number of prior treatment regimens is 2 (1-5). Five patients (13%) had received prior autologous or allogeneic stem cell transplantation. Seven patients (15%) had bulky disease. Thirty-nine patients who have initiated treatment and have reported adverse event (AE) information are the subject of this preliminary report. Twenty-four patients (12 bortezomib-naive, 12 bortezomib-exposed) have undergone at least 1 follow-up tumor assessment and are evaluable for efficacy. Treatment has been well tolerated. No patients have discontinued treatment due to AEs. Grade 1 or 2 diarrhea, fatigue, and nausea have been the most frequently reported AEs. Grade >3 AEs considered potentially related to PCI-32765 have occurred in 4/39 patients (11%). Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765. One death, in a patient who was enrolled but did not receive PCI-32765 due to rapid disease progression, has occurred on study. The objective response rate (ORR) by IWG criteria is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort. To date, 35/39 patients remain on PCI-32765; reasons for discontinuation include progressive disease (n=3) and investigator decision (n=1).

Conclusions:

Preliminary data from a phase II trial suggests that the potent Btk inhibitor PCI-32765 is well tolerated and induces a high rate of objective responses in patients with relapsed or refractory MCL. More mature safety and efficacy data will be updated in the presentation. Phase III trials of PCI-32765 in MCL are planned.

Disclosures:

Wang: Pharmacyclics: Research Funding. Off Label Use: PCI-32765 in mantle cell lymphoma in a phase 2 clinical trial . Martin: Pharmacyclics: Research Funding. Blum: Pharmacyclics: Research Funding. Kahl: Pharmacyclics: Research Funding. Maeda: Pharmacyclics: Research Funding. Advani: Pharmacyclics: Research Funding. Williams: Pharmacyclics: Research Funding. Rule: Pharmacyclics: Research Funding. Rodriguez: Pharmacyclics: Employment, Equity Ownership. Pang: Pharmacyclics: Consultancy. Hedrick: Pharmacyclics: Employment, Equity Ownership. Goy: Pharmacyclics: Research Funding.

Blood (ASH Annual Meeting Abstracts) 2011 American Society of Hematology

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In the recent American Association of Cancer Research (AACR) meeting held in Chicago, among the presentations were new classes of lymphoma therapies in development that target B cell signaling pathways. AACR is the premier cancer research convention for basic and translational research. It was the original cancer research organization that pre-dated its sister organization - the American Society of Clinical Oncology (ASCO).

The focus of the AACR meeting is basic research and the presentations are often geared toward PhD level scientific discovery. It provides insights into therapy options that may not arrive in the clinical arena for many years.

A prototypic agent of these new classes of lymphoma therapies, being Ibrutinib (PCI-32765), the Bruton's tyrosine kinase inhibitor. Bruton's tyrosine kinase (Btk) is a central mediator of B-cell receptor signaling which is essential for normal B-cell development. It is an orally administered irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells.

B-cells are the part of the immune system that produce antibodies and protect the body against invading micro-organisms or allergens. In ABC-DLBCL, the intracellular signaling pathway involved in B-cell activation and proliferation is constantly activated.

This signaling pathway, called NF-kappaB, is critical in immune function, following an encounter with antigen, lymphocytes need to be activated and proliferate so that there are sufficient numbers to deal with the invading organism. But in humans with ABC-DLBCL, this pathway is constitutively active and drives lymphocytes to proliferate continuously.

These malignant B-cells are resistant to apoptosis (cell death). Their unchecked growth is the basis of the lymph node tumors that are the hallmark of the disease.

Several themes seemed to emerge at the meeting:

That cancer patients are highly unique. In one presentation using phosphoprotein signatures to connect genetic features to phenotypic expression, the investigator conducted 21 phosphoprotein signatures and found 21 different patterns. This, he noted, reflected the "uniqueness" of each individual.

Additional themes included the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions.

Although virtually every presentation began with the obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Among the presentations was a discussion of NextGen genomic analysis, allowing an entire human genome to be sequenced within 24 hours. Mapping genetic elements has enabled investigators at the University of Pennsylvania to explore acute leukemia patients at diagnosis and at the time of recurrence. Based upon mutation analysis, different subsets of patients are observed. Mono and Oligo-clonal populations yield new subpopulations following cytoreductive therapy, wherein a small percentage of tumor cells survive and repopulate as the dominant clone.

The NextGen genomic analysis serves as the basis for new solid tumor studies in which breast biopsies are obtained, before and after therapy with aromatase inhibitors, to examine the clonality of the surviving populations.

William R. Sellers, MD, vice president of Novartis Institutes for BioMedical Research Oncology, described a high throughput robotic technology capable of conducting tens of thousands of combinatorial mixtures to determine drug interactions. What I found most interesting was the observation by this investigator that, “Cell culture remains the most effective means of testing drug combinations.” We agree wholeheartedly.

New classes of lymphoma therapies are in development that target B cell signaling pathways. A prototypic agent being Ibrutinib, the Bruton’s tyrosine kinase inhibitor. Additional developments are examining SYC as a target for small molecule inhibitors.

Our growing understanding of immune regulation is enabling investigators like James Allison to trigger tumor specific immunity. Agents like ipilumimab (AntiCTLA4), combined with other classes of small molecules and/or antibodies directed toward CD28, PD1, and ICOS regulation have the potential to change the landscape in diseases that extend from melanoma to prostate and breast.

The meeting had innumerable sessions and symposia that were geared toward or touched upon the field of metabolomics. As cells jockey for survival they both up- and down-regulate pathways essential to not only energy production but to the biosynthesis of critical metabolic intermediates. The regulation of PKM2 (pyruvate kinase isoenzyme) is now recognized as a pivotal point in the cell’s determination of catabolism (energy production), over anabolism (biosynthesis), with Serine concentrations playing an important regulatory role.

The PI3K pathway is an area of rapidly growing interest as new compounds target this key regulatory protein complex. Both selective and non-selective (pan PI3K) inhibitors are in clinical testing. Paul Workman’s group was honored for their seminal work in this and related areas of drug development. Robert Nagourney, MD, PhD, of Rational Therapeutics, reported his findings on the dual PI3K/mTOR inhibitor BEZ-235 (Nagourney, RA et al Proc AACR, 2586, 2012).

The double-edged sword of immune response was deftly covered by Dr. Coussens who described the profound tumor stimulatory effects of T-cell, B-cell and Macrophage infiltration into the tumor microenvironment. Small molecules now in development that down-regulate macrophage signaling may soon show promise alone or in combination with other classes of drugs.

The RAS/RAF pathway becomes ever more complex as we begin to unravel the feedback loops that respond to small molecule inhibitors like Erlotinib or Vemurafanib. Investigators like Dr. Neal Rosen from Memorial Sloan-Kettering Cancer Center have long argued that simple inhibition at one node in a cascade of signaling pathways will absolutely change the dynamic and redirect up and down stream signals that ultimately overcome inhibition. Strategies to control these “resistance” mechanisms are being developed. Once again we find that simple genomic analyses underestimate the complexity of human systems.

Among the regulatory topics at this year’s meeting was a special symposium on the development and testing of multiple novel (non-FDA approved) compounds in the clinical trial setting. There will need to be a new level of cooperation and communication forged between academia, regulatory entities and the pharmaceutical industry if we are to move this process forward. I am encouraged by the early evidence that all three are recognizing and responding to that reality.

The themes of this year’s meeting included:

1. A renewed focus on the biochemistry of metabolism

2. Clear progress in field of tumor immunology

3. The growing recognition that human tumors exist as microenvironments and not isolated single cells.

Probably the most gratifying point was the last point.

Functional cytometric profiling focuses on human tumor aggregates (microspheroids) isolated directly from patients as the most accurate models for chemotherapy selection and drug discovery appears to be gaining support.

Much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell’s metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time. Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

Protein Kinase Inhibitors in Cancer Treatment: Mixing and Matching?

[url]http://www.medscape.com/viewarticle/471462

Brighton researchers' discovery may prolong cancer patients

[url]http://cancerfocus.org/forum/showthread.php?t=3920

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(Bloomberg) - Pharmacyclics Inc., a drugmaker developing an experimental therapy for blood cancers, won “breakthrough” status from U.S. regulators for the medicine that may lead to quicker marketing approval.

Pharmacyclics and its partner, New Brunswick, New Jersey- based Johnson & Johnson, will submit the therapy, ibrutinib, to the Food and Drug Administration for approval before the end of the year, the companies said today in separate statements.

“This is a historic moment in oncology,” Bob Duggan, chief executive officer of Sunnyvale, California-based Pharmacyclics said in the statement. “We are truly honored to have received this breakthrough designation and are pleased for patients and clinicians with the FDA’s decision to expedite the development of ibrutinib.”

The breakthrough designation was created in legislation passed last year reauthorizing the FDA’s user fee programs for drug and device reviews. Companies that receive the status will have closer communication with top FDA staff to move drugs for serious diseases to market more quickly, Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said yesterday in an interview.

New drugs generally need three phases of clinical testing on safety and effectiveness to win FDA approval. Woodcock said the breakthrough status may lead to approval after just an expanded early stage clinical trial.

Ibrutinib blocks an enzyme called Bruton’s tyrosine kinase that aids certain cancers in spreading. The drug has breakthrough status for patients with Waldenstrom’s macroglobulinemia, and mantle cell lymphoma patients that have failed other therapies. Pharmacyclics said it’s currently testing the drug in five late-stage trials.

Mantle cell lymphoma is a type of B-cell non-Hodgkin lymphoma that typically strikes older adults, with about 5,000 new cases each year, Pharmacyclics said. Waldenstrom’s macroglobulinemia is a rarer type of lymphoma that affects 1,500 people a year and there are no approved treatments.