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  #11  
Old 01-13-2014, 03:44 PM
gdpawel gdpawel is offline
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Default CLL Trial Stopped as Ibrutinib Shows Significant Benefits

A phase 3 clinical trial in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) has been stopped early after significant benefit was seen with ibrutinib (Imbruvica, Pharmacyclics/Janssen).

The novel drug, a first-in-the class inhibitor of Bruton's tyrosine kinase, is currently awaiting approval for use in CLL (with a decision expected from the US Food and Drug Administration before the end of February); it was approved in November 2013 for use in mantle cell lymphoma.

Ibrutinib has stirred up considerable excitement in hematology circles, with experts describing it as a "turning point" in the treatment of CLL and "a step change" in the treatment of mantle cell lymphoma.

The trial that has just been stopped because of benefit, known as RESONATE, was a phase 3 study conducted at more than 70 clinical sites across 10 countries. It involved 391 patients with relapsed or refractory CLL or SLL who had received at least 1 previous therapy. A head-to-head comparison trial, it pitched the oral drug ibrutinib against the intravenous drug ofatumumab (Arzerra, GlaxoSmithKline), which was approved for CLL in 2009.

According to a press release from Pharmacyclics, an interim analysis of this trial showed that patients on ibrutinib had a statistically significant improvement in progression-free survival (the primary end point of the study), as well as in overall survival (a secondary end point), when compared with ofatumumab.

No further details were given, and the results are due to be presented at an upcoming meeting.

As a result of this finding, the Independent Data Monitoring Committee recommended that the trial be stopped and that any patients on ofatumumab be offered treatment with ibrutinib.

Earlier Trial Now Published

An earlier trial with ibrutinib showing "encouraging" efficacy in elderly patients with previously untreated CLL has just been published in the January issue of the Lancet Oncology.

The results come from a phase 1b/2 study, conducted in the United States, of 29 patients with CLL and 2 patients with SLL who had previously not been treated. (This was a part of a larger study — the greater part of this study was conducted in patients who had been previously treated, and these results were reported last year.)

All patients were at least 65 years of age, and most patients (74%) were at least 70 years old. They all received oral ibrutinib once daily at a dose of 420 mg (some initially received the higher dose of 840 mg, but this was discontinued after comparable activity of the 2 doses was shown).

After a median follow-up of 22.1 months, a complete response was reported in 4 patients (13%), a partial response in 17 (55%), and a nodular partial response in 1 (3%). The overall objective response rate was 71% (22 of 31 patients).

The authors, led by Susan O'Brien, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, say the trial shows that ibrutinib is well tolerated and effective in older patients with CLL, and support the continued assessment of this drug in this population of patients.

Notably Good Toxicity, But Questions Remain

In an accompanying comment, Jennifer Brown, MD, from the Dana-Farber Cancer Institute in Boston, comments that the toxicity profile of single-agent ibrutinib was "notably good, with low myelosuppression and few infections," and this makes it "potentially very appealing as a therapeutic option, especially for elderly patients."

An interesting feature of ibrutinib activity is that most patients have prolonged stable remissions (i.e., persistent disease, rather than complete remissions), Dr. Brown comments. However, this persistence of disease does raise the concern that resistant clones can emerge over time, she notes, adding that this has been reported in patients who have relapsed on ibrutinib (J Clin Oncol. 2013;31[15 suppl]:abstr 7014).

An additional concern is that this may result in Richter's transformation, in which CLL is transformed into an aggressive lymphoma, which can be fatal, she adds. This has also been reported in patients who have relapsed on ibrutinib (in 1 patient in this current study, and in 7 of 11 patients in the other part of this trial).

These concerns emphasize some of the remaining questions on how to best use ibrutinib, and in particular if it may be best to use the drug in combination with an agent that produces deeper remissions, Dr. Brown adds.

The only agent so far to have shown an early definitive overall survival benefit in CLL is rituximab (Rituxan, Genentech/Roche), and hence a combination of ibrutinib with rituximab is very appealing — and trials of this combination are in progress, she notes.

Despite the unanswered questions, there is hope that ibrutinib, which is the first of several extremely active novel agents coming out of development, will lead to "striking benefit for patients in the coming years," Dr. Brown comments.

Lancet Oncol. 2014;15:3-5, 48-58.

[url]http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970513-8/abstract

[url]http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970558-8/fulltext

Citation: CLL Trial Stopped as Ibrutinib Shows Significant Benefits. Medscape. Jan 09, 2014.
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  #12  
Old 03-06-2014, 12:41 PM
gdpawel gdpawel is offline
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Default Ibrutinib in relapsed/refractory (RR) CLL

Just approved in CLL, this Bruton tyrosine kinase inhibitor was the centerpiece of several Phase I-II ASH papers, all of which also continue to demonstrate high levels of activity, including in patients with del(17p) disease.

– Ibrutinib alone

A report from the NCI of the first 53 patients enrolled on a Phase II trial demonstrated that two thirds of these individuals responded. Most of the remaining patients responded in nodes and other sites but with increasing rather than decreasing white blood cell counts. This lymphocytosis is observed with a variety of the new small B-cell receptor inhibitors and may be part of a demargination syndrome with cells being discharged into circulation from the protected microenvironment of the marrow, spleen and the lymph nodes. With time the white counts eventually decrease — often normalizing — and this has led to a special response classification of “partial response with lymphocytosis” that occurred in 28% of 47 evaluable patients for an overall response rate of 94%. Dr Kahl views these cases as essentially CRs because the circulating cells eventually die, and it’s not clear if abrogating this phenomenon with another antineoplastic agent like R or chemotherapy adds to long-term treatment benefit.

[url]http://www.researchtopractice.com/sites/default/files/5mjc/5MJCASH2014/4/4/pdf/5MJCASH2014_4-Farooqui.pdf

– Ibrutinib with R

Thirty-eight of 40 (95%) patients on this Phase II trial experienced objective responses, and Dr Kahl views this higher rate compared to ibrutinib monotherapy as mainly the result of counteracting the initial lymphocytosis and notes it remains to be seen if this will affect long-term outcome and survival. An ongoing randomized Phase II trial in RR CLL evaluating ibrutinib alone or with R will hopefully provide part of the answer to this important question.

[url]http://www.researchtopractice.com/sites/default/files/5mjc/5MJCASH2014/4/5/pdf/5MJCASH2014_4-Burger.pdf

– Ibrutinib with BR

Although 93% of 30 patients responded in this Phase Ib trial, as per Dr Kahl it’s not clear that bendamustine is adding anything to ibrutinib or as previously stated that R provides long-term benefit. Dr Kahl, like most or all investigators, is currently using ibrutinib in relapsed CLL as per the indication, but it will be interesting to see how this evolves as more data accumulate on earlier use, particularly in cases with adverse cytogenetic factors and for the elderly.

[url]http://www.researchtopractice.com/sites/default/files/5mjc/5MJCASH2014/4/6/pdf/5MJCASH2014_4-Brown525.pdf

Test Shown to Reduce Early Cancer Deaths is Now Available to Patients

[url]http://cancerfocus.org/forum/showthread.php?t=4031
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  #13  
Old 08-09-2014, 11:01 PM
gdpawel gdpawel is offline
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Default FDA approved idelalisib (Zydelig) for three types of blood cancers

The U.S. Food and Drug Administration (FDA) has approved idelalisib (Zydelig) for the treatment of patients with three types of blood cancers.

Idelalisib is being granted traditional approval to treat patients with relapsed chronic lymphocytic leukemia (CLL). Used in combination with rituximab (Rituxan), idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing comorbidities. Idelalisib is the fifth new drug with Breakthrough Therapy designation to be approved by the FDA and the third drug with this designation approved to treat CLL.

The FDA is also granting idelalisib accelerated approval to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. Idelalisib is intended to be used in patients who have received at least two prior systemic therapies.

Progress in CLL

“In less than a year, we have seen considerable progress in the availability of treatments for chronic lymphocytic leukemia,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The FDA approved obinutuzumab (Gazyva) in November 2013, ibrutinib (Imbruvica) in February 2014, and a new use for ofatumumab (Arzerra) in April 2014 to treat CLL. Both obinutuzumab and ofatumumab also received Breakthrough Therapy designation for this indication. Like the other two drugs, idelalisib was also granted Orphan Drug designation because it is intended to treat a rare disease.

Idelalisb’s safety and effectiveness to treat relapsed CLL were established in a clinical trial of 220 participants who were randomly assigned to receive idelalisib and rituximab or placebo and rituximab. The trial was stopped for efficacy following the first prespecified interim analysis point, which showed participants treated with idelalisib and rituximab had a median progression-free survival of 10.7 months compared to about 5.5 months for participants treated with placebo and rituximab. Results from a second interim analysis continued to show a statistically significant improvement for idelalisib and rituximab over placebo and rituximab.

New Indications for Non-Hodgkin Lymphomas

Idelalisib’s safety and effectiveness to treat relapsed follicular lymphoma and relapsed small lymphocytic lymphoma were established in a clinical trial with 123 participants with indolent non-Hodgkin lymphomas. All participants were treated with idelalisib and were evaluated for objective response rate. Results showed 54% of participants with relapsed follicular lymphoma and 58% of participants with small lymphocytic lymphoma experienced complete or partial disappearance of their cancer.

The FDA is approving idelalisib to treat follicular lymphoma and small lymphocytic lymphoma under the agency’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts confirmatory clinical trials.

Side Effects

Idelalisib carries a Boxed Warning alerting patients and health-care professionals of fatal and serious toxicities including liver toxicity, diarrhea and colitis, pneumonitis, and intestinal perforation that can occur in idelalisib-treated patients. Idelalisib is also being approved with a Risk Evaluation and Mitigation Strategy (REMS) comprised of a communication plan to ensure health-care providers who are likely to prescribe idelalisib are fully informed about these risks.

Common side effects include diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.

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