On August 20, 2015 Pfizer Inc. reported that the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application (MAA) for IBRANCE (palbociclib) in combination with endocrine therapy for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer (Press release, Pfizer, AUG 20, 2015, View Source [SID:1234507305]). With this validation, the Pfizer application is complete and the EMA will now begin the review procedure.

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"The MAA for IBRANCE is based on the results from the PALOMA-1 and PALOMA-3 trials, which demonstrated significant clinical benefit for women with HR+/HER2- advanced or metastatic breast cancer," said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. "The acceptance of our application for review by the EMA represents a significant step towards potentially bringing IBRANCE to women with metastatic breast cancer in Europe, and Pfizer looks forward to working with the EMA on the review procedure."

The submission is based on the final results of the PALOMA-1 and PALOMA-3 trials in metastatic breast cancer. Both trials demonstrated that IBRANCE in combination with an endocrine therapy improved progression-free survival (PFS) compared to endocrine therapy alone.

The Phase 3 PALOMA-3 study evaluated IBRANCE in combination with fulvestrant compared to a standard of care, fulvestrant, plus placebo in women with HR+/HER2- metastatic breast cancer whose disease had progressed during or after endocrine therapy. The results were presented as a late-breaker at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and published in The New England Journal of Medicine in June 2015. The Phase 2 PALOMA-1 study evaluated IBRANCE in combination with letrozole compared to letrozole alone in postmenopausal women with estrogen receptor-positive (ER+)/HER2- locally advanced or metastatic breast cancer who had not received previous systemic treatment for their advanced disease. Results were presented in an oral presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and published in The Lancet Oncology in 2014.

About IBRANCE (palbociclib)

IBRANCE is an oral, first-in-class inhibitor of cyclin-dependent kinases (CDKs) 4 and 6.1 CDKs 4 and 6 are key regulators of the cell cycle that trigger cellular progression.2,3

In the European Union, IBRANCE is an investigational agent and has not been approved.

IBRANCE was approved by the U.S. Food and Drug Administration (FDA) in February 2015 for use in combination with letrozole as a treatment for postmenopausal women with ER+/HER2- advanced breast cancer as initial endocrine-based therapy for their metastatic disease.1 The effectiveness of IBRANCE in these patients is based on a study that measured PFS.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. IBRANCE has also received regulatory approval in Albania, Chile and Macau.

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).

On August 20, 2015 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, and MedImmune, the global biologics research and development arm of AstraZeneca, reported that enrollment has commenced in a Phase I/II clinical trial of axalimogene filolisbac (ADXS-HPV), Advaxis’s investigational Lm Technology immunotherapy, in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab (MEDI4736), for the treatment of patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer (Press release, Advaxis, AUG 20, 2015, View Source [SID:1234507301]).

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The two-part, open-label Phase I/II study is designed to evaluate the safety and efficacy of axalimogene filolisbac as a monotherapy and in combination with durvalumab in approximately 66 patients. Phase I is a dose-confirmation combination study with axalimogene filolisbac and durvalumab, which is expected to establish the maximum tolerated dose. The Phase II portion of the study will randomize patients to receive axalimogene filolisbac monotherapy, durvalumab monotherapy, or the combination. The primary efficacy endpoints include objective response rate and progression-free survival. Further information about the Phase I/II study can be found on ClinicalTrials.gov, using Identifier NCT02291055.

"We are pleased to have initiated patient enrollment for this combination immunotherapy study and look forward to evaluating this immunotherapy combination in the clinic, with the hopes of confirming the preclinical anti-tumor effects," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis. "The initiation of our combination immunotherapy study with MedImmune adds to what has become a rapidly expanding clinical development pipeline for Advaxis involving our Lm Technology immunotherapy platform alone and in combination with potentially synergistic technologies."

Axalimogene filolisbac and durvalumab are members of a new class of cancer treatments known as immunotherapies, which are designed to enhance the body’s own defenses in fighting cancer. Data from preclinical studies suggest that Advaxis’s Lm Technology immunotherapies in combination with a checkpoint inhibitor, such as durvalumab, may lead to an enhanced anti-tumor immune response. Results from the Phase I/II study will determine the future clinical development program for the combination.

About Cervical Cancer

Cervical cancer is the fourth most common cancer and the most common cause of mortality in women worldwide with 528,000 new cases reported annually and an estimated 266,000 deaths in 2012; the majority of which is diagnosed in less-developed countries. Within the U.S., approximately 12,900 cases of invasive cervical cancer are diagnosed annually and up to 30 percent are diagnosed with locally advanced disease. Despite a well-established and adopted standard of care for the treatment of locally advanced cervical cancer, consisting of cisplatin and radiotherapy administered concurrently, a large percentage of these patients, particularly those with high risk features and/or poor prognostic factors, will experience cancer recurrence and ultimately die of their disease. These patients represent a subpopulation of locally advanced cervical cancer with the highest unmet medical need and where the need for new therapeutic options is greatest as there are no approved therapies for this specific patient population.

About HPV-Associated Head and Neck Cancer

The incidence of HPV-associated head and neck cancers has been increasing at an epidemic rate, while head and neck cancers from other causes have been decreasing. According to the WHO, approximately 15-20 percent of the 400,000 new cases of head and neck cancer are HPV-related. In the U.S., there are about 12,000 new cases of HPV-associated head and neck cancer per year, affecting men about three times more frequently than women. HPV-associated head and neck cancer is growing fastest in developed countries like the U.S.

About Axalimogene Filolisbac

Axalimogene filolisbac (ADXS-HPV) is Advaxis’s lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase II study in recurrent/refractory cervical cancer, axalimogene filolisbac showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the company’s Lm Technology.

About Durvalumab

Durvalumab (MEDI4736) is an investigational human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, countering the tumor’s immune-evading tactics.

Durvalumab was accelerated into Phase III clinical development in non-small cell lung cancer and head and neck cancer. The OCEANS clinical development program will evaluate durvalumab as monotherapy and in combination with a cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal antibody tremelimumab, in lung cancer, across the spectrum of the disease. In head and neck cancer, durvalumab is being investigated in three late stage studies (HAWK, CONDOR and EAGLE) as monotherapy and in combination with tremelimumab, looking at patients with different PD-L1 expression status who have failed on chemotherapy.

A comprehensive development program for durvalumab is underway across multiple tumor types, including gastric, pancreatic and bladder cancer, in addition to lung and head and neck cancers.

On August 20, 2015 Novartis reported that the European Commission has approved Odomzo (sonidegib, formerly LDE225) 200 mg capsules for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) who are not amenable to curative surgery or radiation therapy[1] (Press release, Novartis, AUG 20, 2015, View Source [SID:1234507299]).

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"I have seen first-hand the devastating impact advanced basal cell carcinoma can have on those living with the disease. As the lesions are usually highly visible and located predominantly on the face, they can impact patients both physically and emotionally," said Reinhard Dummer, MD, Professor and Vice Chairman, Department of Dermatology at the University of Zurich. "The approval of Odomzo brings new hope in the form of a non-invasive option to help treat this disfiguring and potentially life-threatening disease."

Basal cell carcinoma (BCC) consists of abnormal, uncontrolled growths or lesions that arise in the skin’s basal cells, which line the deepest layer of the epidermis (the outermost layer of the skin)[3] and accounts for more than 80% of non-melanoma skin cancers[4]. Advanced BCC is thought to represent roughly 1-10% of all cases of BCC[5]-[7]. Although BCC rarely becomes advanced, there have been few treatment options at this stage of the disease. Worldwide incidence of BCC is rising by 10% each year due to factors such as an aging population and increased ultraviolet exposure[8].

The EU approval of Odomzo was based on data from the Phase II randomized, double-blind, multi-center BOLT (Basal cell carcinoma Outcomes in LDE225 Trial) study in patients with laBCC not amenable to local therapy or metastatic basal cell carcinoma (mBCC). In patients with laBCC treated with Odomzo 200 mg, the objective response rate (ORR) was 56% per central review and 71% per investigator review. The median duration of response per central review has not been reached. The median progression-free survival was 22 months per central review and 19 months per investigator review. The most frequent grade 3 and 4 adverse reactions occurring in at least 2% of patients treated with Odomzo 200 mg were fatigue, decreased weight and muscle spasms[1].

"We are pleased to have a new treatment option for European patients living with advanced basal cell carcinoma," said Bruno Strigini, President, Novartis Oncology. "This milestone follows the recent approval of Odomzo in the US and is the latest example of our commitment to precision oncology and developing targeted treatments to address unmet needs."

The EU approval follows a positive opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) in June 2015 and applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein. Outside the EU, Odomzo is approved in the United States, Australia and Switzerland. Additional regulatory submissions are being reviewed by health authorities worldwide.

About the BOLT Clinical Trial
The primary endpoint of the BOLT study was ORR of patients treated with Odomzo 200 mg and 800 mg, defined as the proportion of patients with confirmed complete or partial tumor response, or shrinkage, as measured by a central review committee. There was no evidence of better ORR among patients with laBCC randomized to receive Odomzo 800 mg daily. The secondary endpoints included duration of response, time to tumor response and progression-free survival as determined by central review[1].

Patients with laBCC treated with Odomzo 200 mg (n=66) were followed for at least 18 months unless discontinued earlier. The ORR per central review of 56% (95% confidence interval: 43, 68) consisted of 5% (n=3) complete responses (CR), or 23% using a pre-specified CR assessment similar to other laBCC trials, and 52% (n=34) partial responses (PR). The 71% ORR (95% confidence interval: 59, 82) per investigator review consisted of 9% (n=6) CR and 62% (n=41) PR[1].

The evaluation of tumor response was based on a composite assessment of modified Response Evaluation Criteria in Solid Tumors (mRECIST) that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography (World Health Organization (WHO) adapted criteria) and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of CR[1].

The most serious risks of Odomzo are embryofetal toxicity and musculoskeletal adverse reactions including rhabdomyolysis. Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, may occur with Odomzo and other drugs that inhibit the hedgehog pathway. The incidence of musculoskeletal adverse reactions in patients with laBCC treated with Odomzo 200 mg was 54%, with 8% reported as grade 3 or 4. Adverse reactions occurring in more than 10% of patients treated with Odomzo 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting and pruritus. The most frequent grade 3 and 4 adverse reactions occurring in at least 2% of patients treated with Odomzo 200 mg were fatigue, decreased weight and muscle spasms[1].

About Odomzo
Odomzo (sonidegib, formerly LDE225) is an oral, selective smoothened (SMO) inhibitor approved by the European Commission for the treatment of adult patients with laBCC who are not amenable to curative surgery or radiation therapy[1]. SMO is a molecule that regulates the hedgehog (Hh) signaling pathway, which plays a critical role in stem cell maintenance and tissue repair, as well as in advanced basal cell carcinoma[9]-[11]. Odomzo is currently in clinical development in other diseases.

Outside of the European Union, Odomzo is approved in the United Sates for laBCC that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy; in Australia for the treatment of laBCC that is not amenable to curative surgery or radiation therapy, or for those with mBCC; and in Switzerland for the treatment of advanced BCC that is not amenable to curative surgery or radiotherapy. Additional regulatory submissions are being reviewed by health authorities worldwide.

IMPORTANT SAFETY INFORMATION
Important note: please see the locally approved full prescribing information.

Odomzo is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) who are not amenable to curative surgery or radiation therapy. Dosage and administration for adults is one 200 mg dose taken orally once daily on an empty stomach, at the same time each day.

Odomzo is contraindicated in women who are pregnant or breast-feeding.

Creatine phosphokinase (CK) levels should be checked prior to starting treatment and as clinically indicated thereafter, for example, if muscle related symptoms are reported. If clinically notable elevation of CK is detected, renal function should be assessed. Dose modification or interruption guidelines should be followed. Patients should be closely monitored for muscle related symptoms if Odomzo is used in combination with certain medications that may increase the potential risk of developing muscle toxicity. Doctors should closely monitor patients with neuromuscular disorders due to an increased risk of muscle toxicity.

Patients should be instructed not to donate blood while taking Odomzo and for at least 20 months after ending treatment.

Women of childbearing potential must use highly effective contraception while receiving Odomzo. Contraception must be continued for 20 months after ending treatment. Negative pregnancy status must be confirmed by a test performed by a healthcare provider prior to initiation of Odomzo treatment. Odomzo must not be used during pregnancy. Women must not breast feed while taking Odomzo and for at least 20 months after ending treatment.

Men should not father a child or donate semen while taking Odomzo and for at least 6 months after ending treatment. Sexually active males must use a condom, regardless of vasectomy status, during intercourse and for at least 6 months after ending treatment.

Male and female fertility may be compromised with Odomzo. Fertility preservation strategies should be discussed prior to starting treatment with Odomzo.

Odomzo can cause side effects. Very common (>=10%) adverse drug reactions include amenorrhea, decreased appetite, dysgeusia, headache, nausea, diarrhea, vomiting, abdominal pain, alopecia, pruritus, muscle spasms, myalgia, musculoskeletal pain, fatigue, pain, and weight loss. Common (between 1 to 10%) adverse drug reactions include constipation, dyspepsia, gastroesophageal reflux disorder, rash, abnormal hair growth, myopathy (muscular fatigue and muscular weakness), and dehydration.

Very common laboratory abnormalities include decreased hemoglobin, decreased lymphocyte count, increased amylase, increased blood glucose, increased lipase, increased serum creatine phosphokinase, increased serum creatinine, increased alanine amino transaminase (ALT), and increased aspartate amino transaminase (AST).

Concomitant use of strong CYP3A inhibitors and inducers must be avoided. If a strong CYP3A inducer must be used concomitantly with Odomzo, consideration should be given to increasing the dose of Odomzo by 200 mg increments to a maximum daily dose of 800 mg.

Doctors should carefully monitor patients for adverse drug reactions with concomitant use of substrates of CYP2B6 and CYP2C9 enzymes or BCRP transporter, especially those with a narrow therapeutic range.

Due to overlapping toxicities, patients taking Odomzo who are also taking medications known to increase the risk of muscle-related toxicity may be at increased risk of developing muscle-related adverse events. Patients should be closely monitored and dose adjustments should be considered if muscle symptoms develop.