Patients in the BR arm are allowed to crossover
While this press release from Pharmacyclics broadens the potential role of ibrutinib in treating CLL and improves on an already strong chemo-immunotherapy option, one other small but vital piece of news was not included in most of the media coverage.
After the unblinding, patients in the BR arm will be allowed to crossover to receive ibrutinib.
While this would appear to be the only ethical way to proceed, it was not the standard way to run a clinical trial until very recently.
We are extraordinarily thankful to the patients and providers who fought to push patients’ lives ahead of clean data.
Yes, we may lose some overall survival (OS) data if we allow a crossover, but consider the cost of that data.
Dr. Susan O’Brien’s powerful ASCO POST from 2013 should be mandatory reading for all patients and all clinical trial investigators.
I quote her referring to the earlier RESONATE trial: “Once the primary endpoint has been met, not allowing crossover has caused considerable dismay in the oncology community, not to mention among patients. It is my understanding that the FDA strongly opposed allowing crossover. I presume that is because the FDA also wants to see if there is a survival advantage.”
If that is not clear enough, read her conclusion:
“There are people on the control arm of RESONATE who will probably have disease progression and die. Presumably, that is what FDA believes is necessary to document improved survival.”
Since then, trial designs are increasingly allowing interim analysis and the option to crossover when there is a significant survival advantage.
That patient centric design will save future lives.
So good news on two fronts.
Here is the press release:
Independent Data Monitoring Committee Unanimously Recommends Unblinding of IMBRUVICA® (ibrutinib) Phase III Combination HELIOS Trial Based on Interim Analysis Showing Significant Improvement in Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
SUNNYVALE, Calif., March 16, 2015 /PRNewswire/ — Pharmacyclics, Inc. (NASDAQ: PCYC) announced today that an Independent Data Monitoring Committee reviewed and assessed HELIOS (CLL3001), an international, Phase III, randomized, double-blind, placebo-controlled trial evaluating IMBRUVICA® (ibrutinib) in combination with bendamustine and rituximab (BR) versus placebo in combination with BR in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL or SLL, respectively), and unanimously recommended that the study be unblinded based on clinically meaningful and statistically significant treatment benefit in the IMBRUVICA arm. The study has met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS). The safety profile of IMBRUVICA in combination with BR was consistent with prior clinical experience. IMBRUVICA is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
“We are delighted by the superior efficacy observed in CLL and SLL patients treated with IMBRUVICA in combination with BR compared to patients in the placebo-controlled BR arm and look forward to sharing these results with the scientific community and U.S. regulators,” said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. “These results build upon early results in the Phase I/II program and are very encouraging as we continue to explore the benefits IMBRUVICA provides to patients when it is combined with other treatments.”
HELIOS, a Janssen-sponsored trial, enrolled 578 CLL or SLL patients who had received at least one line of prior systemic therapy. Patients were randomized to receive either IMBRUVICA orally, once daily in combination with six cycles of BR or placebo orally, once daily with six cycles of BR, with the IMBRUVICA or placebo treatment continuing until disease progression or unacceptable toxicity.
These top-line results will be submitted for presentation at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting and the full results will be submitted for publication in a peer-reviewed journal. A full study report is being prepared and will be submitted to health authorities for future labeling considerations. More information about the study can be found on www.clinicaltrials.gov.
About IMBRUVICA IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK).1 BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.1,2 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.1
IMBRUVICA is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, a genetic mutation that occurs when part of chromosome 17 has been lost, and patients with Waldenstrom’s macroglobulinemia.1
IMBRUVICA is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for the MCL indication based on overall response rate (ORR). Continued approval for the MCL indication may be contingent upon verification of clinical benefit in confirmatory trials.1
IMBRUVICA is being studied alone and in combination with other treatments in several blood cancers. Over 5,100 patients have been treated in clinical trials of IMBRUVICA conducted in 35 countries by more than 800 investigators. Currently, 13 Phase III trials have been initiated with IMBRUVICA and 58 trials are registered on www.clinicaltrials.gov.
IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway, and is the only product to have received three Breakthrough Therapy Designations.
To learn more about the medical terminology used in this news release, please visit http://stedmansonline.com/.
- IMBRUVICA is indicated to treat people with:
- Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
- Chronic lymphocytic leukemia (CLL) with 17p deletion
- Waldenstrom’s macroglobulinemia
- Mantle cell lymphoma (MCL) who have received at least one prior therapy – accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Patients taking IMBRUVICA for CLL or WM should take 420 mg taken orally once daily (or three 140 mg capsules once daily).
Patients taking IMBRUVICA for MCL should take 560 mg taken orally once daily (or four 140 mg capsules once daily).
Capsules should be taken orally with a glass of water. Capsules should be taken whole. Do not open, break, split or chew the capsules.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.
The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.
Second Primary Malignancies – Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).
Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Seven percent of patients receiving IMBRUVICA® discontinued treatment due to adverse events.
CYP3A Inhibitors – Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.
CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose.
For additional important safety information, please see Full Prescribing Information at http://www.imbruvica.com/downloads/Prescribing_Information.pdf.
About Pharmacyclics: Pharmacyclics, Inc. (NASDAQ: PCYC) is a biopharmaceutical company focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune mediated diseases. The company’s mission is to build a viable biopharmaceutical company that designs, develops and commercializes novel therapies intended to improve quality of life, increase duration of life and resolve serious unmet medical needs. It will do so by identifying and controlling promising product candidates based on scientific development and administrative expertise, developing its products in a rapid, cost-efficient manner and, pursuing commercialization and/or development partners when and where appropriate.
Pharmacyclics markets IMBRUVICA and has three product candidates in clinical development and several preclinical molecules in lead optimization. The company is committed to high standards of ethics, scientific rigor and operational efficiency as it moves each of these programs to commercialization. Pharmacyclics is headquartered in Sunnyvale, CA. To learn more, please visit www.pharmacyclics.com.
NOTE: This announcement may contain forward-looking statements made in reliance upon the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements, among others, relating to our future capital requirements, including our expected liquidity position and timing of the receipt of certain milestone payments, and the sufficiency of our current assets to meet these requirements, our future results of operations, our expectations for and timing of ongoing or future clinical trials and regulatory approvals for any of our product candidates, and our plans, objectives, expectations and intentions. Because these statements apply to future events, they are subject to risks and uncertainties. When used in this announcement, the words “anticipate”, “believe”, “estimate”, “expect”, “expectation”, “goal”, “should”, “would”, “project”, “plan”, “predict”, “intend”, “target” and similar expressions are intended to identify such forward-looking statements. These forward-looking statements are based on information currently available to us and are subject to a number of risks, uncertainties and other factors that could cause our actual results, performance, expected liquidity or achievements to differ materially from those projected in, or implied by, these forward-looking statements. Factors that may cause such a difference include, without limitation, our need for substantial additional financing and the availability and terms of any such financing, the safety and/or efficacy results of clinical trials of our product candidates, our failure to obtain regulatory approvals or comply with ongoing governmental regulation, our ability to commercialize, manufacture and achieve market acceptance of any of our product candidates, for which we rely heavily on collaboration with third parties, and our ability to protect and enforce our intellectual property rights and to operate without infringing upon the proprietary rights of third parties. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, performance or achievements and no assurance can be given that the actual results will be consistent with these forward-looking statements. For more information about the risks and uncertainties that may affect our results, please see the Risk Factors section of our filings with the Securities and Exchange Commission, including our Form 10-K for the year ended December 31, 2013 and quarterly reports on Form 10-Q. We do not intend to update any of the forward-looking statements after the date of this announcement to conform these statements to actual results, to changes in management’s expectations or otherwise, except as may be required by law.
IMBRUVICA is a registered trademark of Pharmacyclics, Inc.
SOURCE Pharmacyclics, Inc.
 IMBRUVICA Prescribing Information, January 2015
 Genetics Home Reference. Isolated growth hormone deficiency. Available at: http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Accessed March 2015.
To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/independent-data-monitoring-committee-unanimously-recommends-unblinding-of-imbruvica-ibrutinib-phase-iii-combination-helios-trial-based-on-interim-analysis-showing-significant-improvement-in-progression-free-survival-in-patient-300051103.html
SOURCE Pharmacyclics, Inc.
Brian Koffman 3/18/15