On April 15, 2015 Pfizer reported that the Phase 3 PALOMA-3 trial for IBRANCE (palbociclib) met its primary endpoint of demonstrating an improvement in progression-free survival (PFS) for the combination of IBRANCE plus fulvestrant compared with fulvestrant plus placebo in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer following disease progression during or after endocrine therapy (Press release, Pfizer, APR 15, 2015, View Source [SID:1234503011]). The study was stopped early due to efficacy based on an assessment by an independent Data Monitoring Committee (DMC). These are the first randomized Phase 3 trial results for IBRANCE, a new anti-cancer medicine with the novel mechanism of cyclin-dependent kinase 4/6 (CDK 4/6) inhibition.

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"The results of this trial are especially important because they help us understand the potential of IBRANCE to improve outcomes in patients with this difficult to treat cancer. We’re gratified to be able to stop the trial early and are engaging in discussions with health authorities regarding a regulatory path forward," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology.

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The adverse events observed with IBRANCE in combination with fulvestrant in PALOMA-3 were generally consistent with their respective known adverse event profiles. Detailed efficacy and safety results from PALOMA-3 will be submitted for presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2015 Annual Meeting.

IBRANCE was approved by the U.S. Food and Drug Administration (FDA) in February 2015 as a first-line treatment for women with advanced or metastatic estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancer. IBRANCE (palbociclib), in combination with letrozole, is indicated for the treatment of postmenopausal women with ER+/HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.i This indication is approved under accelerated approval based on PFS.i Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The confirmatory Phase 3 trial, PALOMA-2, is fully enrolled. IBRANCE is not approved for the use being investigated in PALOMA-3 or for any indication in any market outside the U.S.

The full prescribing information for IBRANCE can be found at www.IBRANCE.comExternal Links icon.

Important IBRANCE (palbociclib) Safety Information from the U.S. Prescribing Information

Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur.

Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the first two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate.

Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE.

Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%).

Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%).

General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously.

Patients should be encouraged to take their dose at approximately the same time each day.

Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.

Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modification of IBRANCE is recommended based on individual safety and tolerability.

Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided.

Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

About PALOMA-3

PALOMA-3 (also known as Study A5481023) is a randomized (2:1), multi-center, double blind Phase 3 study designed to assess the PFS of IBRANCE (125 mg once daily for three out of four weeks in repeated cycles) in combination with fulvestrant versus fulvestrant (500 mg intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each subsequent 28 day cycle) plus placebo in women with HR+, HER2- metastatic breast cancer whose disease has progressed during or after endocrine therapy. PFS is defined as time from randomization to time of disease progression or death from any cause. PALOMA-3 is a multi-center trial with more than 150 global sites participating and 521 patients enrolled.

On April 15, 2015 Novartis reported Phase III data published in The Lancet showed that treatment with Arzerra (ofatumumab) plus chlorambucil, a chemotherapy, resulted in a statistically significant improvement in progression free survival (PFS) versus chlorambucil alone in treatment-naïve patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy was considered inappropriate, mainly due to advanced age or the presence of comorbidities (Press release, Novartis, APR 15, 2015, View Source [SID:1234503003]).

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CLL, the most commonly diagnosed adult leukemia in Western countries, accounts for approximately 1 in 4 cases of all leukemia[1],[2]. The average age at the time of diagnosis is approximately 71 years[2], and the majority of patients with CLL have at least one comorbidity such as hypertension, diabetes, heart disease or COPD[4],[5].

"Finding effective treatments with clinically acceptable safety profiles for elderly patients with CLL and for those with co-existent chronic and potentially life-threatening conditions continues to be a challenge," said Prof. Peter Hillmen, St. James’s University Hospital, Leeds, United Kingdom and lead study author. "The results published in The Lancet reinforce our understanding that the combination of ofatumumab plus chlorambucil provides this patient population a treatment option that improves clinical health outcomes in CLL."

The primary endpoint of the study was PFS according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines[6]. In this clinical study, median PFS was improved by 71% in the group receiving ofatumumab plus chlorambucil compared to the chlorambucil alone group (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors. More patients in the group receiving ofatumumab plus chlorambucil (50%) experienced adverse events (AEs) of grade 3 or greater compared to chlorambucil alone (43%), with neutropenia being the most common adverse event (26% vs. 14%). Grade 3/4 infusion-related reactions (IRRs) were reported in 10% of patients receiving ofatumumab plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported.

"The results presented in The Lancet demonstrate that the addition of Arzerra to chlorambucil resulted in a significant improvement in progression free survival, with an acceptable safety profile," said Alessandro Riva, M.D., Global Head, Novartis Oncology Development and Medical Affairs. "We are excited that Arzerra is now part of the Novartis Oncology portfolio of products, and look forward to building upon the body of evidence that supports the clinical benefit of Arzerra for appropriate patients with CLL."

These Phase III data formed the basis for regulatory approvals in the United States (US) and European Union (EU) in 2014, as well as the recent inclusion of Arzerra plus chlorambucil in the National Comprehensive Cancer Network (NCCN) treatment guidelines.

About the Study
This prospective, randomized, open-label, Phase III study (COMPLEMENT 1, NCT00748189) included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate. Patients in the study were randomized 1:1 to treatment with up to twelve cycles of ofatumumab in combination with chlorambucil or up to twelve cycles of chlorambucil alone.

The primary endpoint of the study was PFS according to the iwCLL updated 2008 NCIWG guidelines[6], using a blinded independent endpoints review committee. Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), complete response (CR) rate, time to response, duration of response, time to next therapy (TTNT), safety assessments, pharmacokinetics, pharmacogenetics, and quality of life.

Findings from the study showed a 71% improvement in median PFS in the group receiving ofatumumab plus chlorambucil compared to the group receiving chlorambucil alone (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Patients in the group receiving ofatumumab plus chlorambucil [n=221] showed similar improvements in PFS across age groups compared to the chlorambucil alone [n=226]. Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors.

Additionally, patients in the combination arm also experienced significantly longer TTNT when compared to chlorambucil alone (39.8 months vs 24.7 months, respectively; HR 0.49 [95% CI: 0.36, 0.67]; p<0.0001). Patients in the combination arm had a higher ORR (82% of patients vs 69% of patients, respectively; odds ratio 2.16 [95% CI: 1.36-3.42]; p=0.001), with a better CR rate (14% of patients vs 1% of patients, respectively). Compared to those on chlorambucil alone, patients in the combination arm had a duration of response of 22.1 months versus 13.2 months (HR 0.56 [95% CI: 0.43, 0.74]; p<0.001).

More patients in the group receiving Arzerra plus chlorambucil (combination) experienced AEs of grade 3 or greater (50%) compared to chlorambucil alone (43%). The most common AEs (>=2%) reported were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions. Overall, AEs leading to treatment withdrawal were similar in both groups (13% vs 13%). AE frequency with Arzerra plus chlorambucil was similar for older patient groups (>=65 years old) compared with chlorambucil alone. Neutropenia occurred more frequently in the combination group, but did not result in a higher rate of infection, and thrombocytopenia and anemia were more frequently observed in the chlorambucil alone group. The most common infections were respiratory tract infections (27% for combination vs 31% for chlorambucil alone) and there were similar frequencies of sepsis (3% vs 2%) and opportunistic infections (4% vs 5%) reported in the combination and chlorambucil alone groups, respectively.

Grade 3/4 IRRs were reported in 10% of patients receiving Arzerra plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported. Deaths during treatment or within 60 days after the last dose were similar in both groups (3% vs 3%).

About Arzerra
Arzerra (ofatumumab) is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Arzerra is also approved for first-line use in Russia, Iceland, Norway, Luxembourg and Brazil.

In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

Arzerra is marketed under a co-development and collaboration agreement between Genmab and Novartis, as successor in interest to GSK.

Important Safety Information for Arzerra (ofatumumab)
Treatment with Arzerra may cause side effects, some of which are serious and life-threatening.

Treatment with Arzerra may cause a side effect called an infusion reaction, which may be serious and possibly life-threatening. Before treatment with Arzerra, doctors will prescribe 3 types of medicine to their patients to help reduce the risk of an infusion reaction including, a steroid (to reduce swelling and other symptoms of inflammation), a pain reliever, and an antihistamine (to reduce allergic reactions). Even though patients receive these medicines, they may still have an infusion reaction. If an infusion reaction occurs, the doctor will stop their patient’s treatment with Arzerra so the infusion reaction can be treated. Patients should tell their doctor or seek medical treatment right away if they have any of these symptoms while receiving Arzerra or within 24 hours after receiving Arzerra: fever, chills, rash, hives, chest pain, back pain, stomach pain, swelling, dizziness, blurred vision, drowsiness, headache, cough, wheezing, or trouble breathing.

Treatment with Arzerra may cause hepatitis B virus (HBV) infection to reoccur, which may cause serious liver problems and death. Patients should tell their doctor if they have had HBV infection or are a carrier of HBV. Before starting Arzerra, doctors will do a blood test to check for HBV infection. In some patients, additional blood tests may be done during and several months after treatment. Patients should call their doctor right away if they feel more tired than usual or notice a yellowing of the skin or eyes. These may be symptoms of hepatitis.

Progressive multifocal leukoencephalopathy (PML) is a rare brain infection that can occur with treatment with Arzerra. PML causes severe disability and can lead to death. Patients should call their doctor right away if they notice new medical problems or problems that are getting worse, such as confusion, dizziness or loss of balance, difficulty talking or walking, or strength, vision or other problems that have lasted over several days.

Tumor lysis syndrome (TLS) can occur with treatment with Arzerra. TLS is caused by the fast breakdown of cancer cells, which then release their contents into the blood. This may lead to serious problems, including kidney failure or an abnormal heartbeat. Doctors may do a blood test to check their patients for TLS and may give medicines before starting treatment with Arzerra to help prevent TLS.

Treatment with Arzerra can increase patients’ chances for getting infections. Some infections, such as pneumonia, bronchitis, and sepsis (a blood infection), can be serious, and in some cases, life-threatening. Patients should call their doctor right away if they have a cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra. These symptoms may be signs of a serious infection.

Arzerra can cause low blood cell counts (white blood cells, platelets, and red blood cells). These low blood cell counts can be severe and, in some cases, lead to death. Low white blood cells counts (neutropenia), can happen during treatment. Neutropenia can occur 42 days or longer after the end of treatment with Arzerra and may also last between 24 and 42 days after the last treatment dose. Doctors should regularly check their patient’s blood to see if they have low blood cell counts. Patients should call their doctor right away if they have any bleeding, bruising, red or purple spots on their skin, paleness, worsening weakness, tiredness, cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra.

After a patient receives Arzerra, they should not receive live vaccines until the doctor who prescribed Arzerra has told them that they may do so.

The most common side effects with Arzerra include infusion reactions, feeling tired, low white blood cell count, shortness of breath, pneumonia, rash, fever, nausea, cough, bronchitis, diarrhea, upper respiratory tract infection and low red blood cell count.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).