On March 29, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported their combination study with MedImmune, the global biologics research and development arm of AstraZeneca, has completed the first dose-escalation cohort in a study evaluating axalimogene filolisbac (AXAL) in combination with durvalumab and has commenced the second dose-escalation cohort (Press release, Advaxis, MAR 29, 2016, View Source [SID:1234510102]).

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The study is evaluating the safety and efficacy of AXAL, Advaxis’ lead immunotherapy candidate, in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab, for the treatment of patients with advanced, recurrent or refractory human papillomavirus (HPV)-associated cervical cancer and HPV-associated head and neck cancer.

"I am proud that we have reached this stage because combination therapies hold great potential for cancer patients," said Daniel J. O’Connor, President and Chief Executive Officer at Advaxis. "This trial is exploring how we can harness the power of immuno-oncology to block anti-tumor T-cell immunity and simultaneously target HPV-associated cancers. It is these kinds of combination therapies that may dramatically change the course of how we treat cancer."

The first dose-escalation cohort evaluated AXAL at 1×109 cfu with 3mg/kg durvalumab and the second dose-escalation cohort will now examine AXAL at 1×109 cfu in combination with 10mg/kg durvalumab. Upon completion of dose escalation, the Phase II study will randomize 90 patients to receive AXAL in combination with durvalumab vs. durvalumab alone. The primary efficacy endpoints include objective response rate and progression-free survival.

The companies plan to submit an abstract to a major medical meeting on the dose-escalation portion of the study in the second half of the year. Further information about the Phase I/II study can be found on ClinicalTrials.gov, using Identifier NCT02291055.

About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide. In the United States, nearly 13,000 new cases are diagnosed annually and approximately 4,100 deaths are reported because of cervical cancer. According to the WHO/ICO Information Centre on HPV and Cervical Cancer, about 3.9 percent of women in the U.S. are estimated to harbor high-risk cervical HPV infection at a given time, and 71.7 percent of invasive cervical cancers are attributed to high-risk HPV strains.

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ 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 2 study in recurrent/refractory cervical cancer, AXAL 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. AXAL has Orphan Drug Designation in the U.S. for the treatment of invasive cervical cancer, head and neck, and anal cancer.

About Durvalumab

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 can be expressed by tumors to evade detection by the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks the PD-L1 interaction with PD-1, countering the tumor’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, bladder, gastric, pancreatic, HCC and blood cancers.

On March 29, 2016 Bayer reported that the Ministry of Health, Labour and Welfare (MHLW) in Japan has granted marketing authorization for Xofigo (radium-223 dichloride, radium-223) for the treatment of patients with castration-resistant prostate cancer and bone metastases (Press release, Bayer, MAR 29, 2016, View Source [SID:1234510092]). The product is already approved in more than 40 countries worldwide, including the U.S. and the countries of the European Union (EU).

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"A majority of men living with advanced prostate cancer develop bone metastases, resulting in symptoms that can interfere with daily life, such as tiredness, weakness or difficulty doing normal activities, and decreased overall survival," explained Dr. Hiroji Uemura, associate professor and department director of Urology and Renal Transplantation, Yokohama City University Medical Center. "Xofigo has an anti-tumor effect that enables us to directly target bone metastases and potentially prolong survival, a critical treatment goal for patients with advancing disease. In addition, it is expected to delay the time to the first symptomatic skeletal event."

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide, and its incidence is rising in Japan. Prostate cancer is the fifth leading cause of death from cancer in men worldwide and the sixth leading cause of death from cancer in Japanese men.

"We are pleased that Xofigo is now available in Japan, providing a new and innovative therapy with a proven clinical benefit to patients with advanced disease," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "Prostate cancer has a significant impact on men in Japan, and this is an important step in our ongoing commitment to deliver therapies to patient’s need."

The approval is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial, as well as data from additional trials to evaluate the safety and efficacy of radium-223 in Japanese patients. At the interim analysis of the ALSYMPCA trial, radium-223 significantly improved overall survival (OS) [HR=0.681 (95% CI 0.542-0.857), p=0.00096]. The second analysis conducted after the study was unblinded showed a further improvement in OS for patients treated with radium-223 vs. placebo, with a median OS of 14.9 months vs. 11.3 months [HR=0.695 (95% CI 0.581-0.832)]. Median time to first symptomatic skeletal event, a secondary endpoint in ALSYMPCA, was 15.6 months for radium-223 versus 9.8 months for placebo [HR= 0.658 (95% CI 0.522-0.830)].

The most common adverse events (occurring at a rate of 25% or greater, all grades) in patients receiving radium-223 in the ALSYMPCA trial were bone pain (patients treated with radium-223: 51.7%, patients in the placebo group: 63.5%), nausea (35.5%, 33.9%), anemia (31.2%, 30.6%), fatigue (26.5%, 25.9%), diarrhea (25.7%, 15.0%). The most common hematologic laboratory abnormalities were anemia (31.2%, 30.6%), neutropenia (5.0%, 1.0%), pancytopenia (2.0%, 0%), thrombocytopenia (4.2%, 0.3%) and lymphocytopenia (0.8%, 0.3%).

ALSYMPCA Trial Design
The ALSYMPCA trial was a Phase III, randomized, double-blind, placebo-controlled international study of Xofigo with best standard of care vs. placebo with best standard of care in symptomatic castration-resistant prostate cancer (CRPC) patients with bone metastases. Interim and updated analyses of the trial showed Xofigo significantly improved overall survival.

About Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
The stage of prostate cancer is one of the most important factors in determining treatment options and the outlook for recovery. If prostate cancer spreads, or metastasizes, beyond the prostate gland, it often first grows into nearby tissues or lymph nodes before spreading to the bones.

CRPC is an advanced form of prostate cancer. Approximately nine in 10 patients with advanced prostate cancer (90 percent) develop bone metastases, impacting survival and quality of life. In fact, bone metastases lead to an increased risk of morbidity and death in patients with CRPC. Therefore, diagnosing and treating bone metastases at the earliest onset is critical for patients.

About Xofigo (radium-223 dichloride)
Xofigo is an alpha particle-emitting therapeutic anti-tumor pharmaceutical. The active ingredient in Xofigo is the alpha particle-emitting isotope radium-223, which mimics calcium and selectively targets bone, specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The high linear energy transfer of alpha emitters leads to a high frequency of double-strand DNA breaks in adjacent tumor cells, resulting in a potent cytotoxic effect. The alpha particle range from radium-223 is less than 100 micrometers, which minimizes damage to the surrounding normal tissue.

In countries of the EU, Xofigo is indicated for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Radium-223 is also being studied in additional trials for men with prostate cancer as well as in Phase II studies for women with breast cancer.

On March 29, 2016 AstraZeneca reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved Tagrisso (osimertinib, AZD9291) 80mg once-daily tablets for the treatment of patients with epidermal growth factor receptor (EGFR) T790M mutation-positive inoperable or recurrent non-small cell lung cancer (NSCLC) that is resistant to EGFR tyrosine kinase inhibitor (TKI) therapy (Press release, AstraZeneca, MAR 29, 2016, View Source [SID:1234510091]).

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Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "We continue to move at an unprecedented pace with osimertinib, with the full approval in Japan following closely the recent US and EU approvals. As first-in-class lung cancer treatment directed at the T790M mutation, we are delighted that this targeted medicine is now available to patients in Japan to address the existing unmet medical need."

Dr. Tetsuya Mitsudomi, Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine said: "A significant proportion of Japanese patients with lung cancer have the EGFR mutation and about 60% of them are likely to develop the T790M resistance mutation following initial TKI treatment. Osimertinib enables us to respond to this disease progression in a precise and logical way as clearly demonstrated in clinical trials, with potential to make a meaningful difference to the lives of Japanese patients."

Approximately 30-40% of Asian patients with NSCLC have the EGFR mutation at diagnosis. Nearly two out of three patients with NSCLC whose disease progresses after treatment with an EGFR-TKI develop the T790M mutation, for which treatment options are currently limited. Osimertinib targets both the EGFR mutation involved in cancer development and T790M, a mutation that makes tumours resistant to existing treatment with EGFR-TKIs. Patients with EGFRm NSCLC, who experience disease progression, should be tested for their mutation status through a validated diagnostic test. AstraZeneca has collaborated with Roche to develop the cobas EGFR Mutation Test v2 as the companion diagnostic for osimertinib.

The Japanese approval is based on data from the two multinational AURA Phase II trials (AURA extension and AURA2), with 22% of patients enrolled from Japan. The studies demonstrated efficacy in patients who had progressed on or after treatment with an EGFR-TKI and whose tumours tested positive for the EGFR T790M mutation. The overall objective response rate (ORR, a measurement of tumour shrinkage) was 61.3% (95% CI: 54.2% to 68.1%) in AURA extension (n=199), and 70.9% (95% CI: 64.0% to 77.1%) in AURA2 (n=199) (1 May 2015 cut-off).

In the two AURA Phase II studies (n=411), the most commonly reported adverse events assessed by the investigator were rash/acne (37.7%), diarrhoea (36.5%), dry skin/eczema, etc. (28.5%), nail disorder including paronychia, etc (23.4%). In Japanese patients (n=80), the incidence of interstitial lung disease (ILD; including pneumonitis etc.), as assessed by the investigator, for all grades was 6.3% (1 May 2015 cut-off). Warnings and precautions include ILD, QT interval prolongation, hepatic impairment and haematological changes.

AstraZeneca has agreed a Risk Management Plan with the Japanese Health Authority.

The full Japanese approval was granted seven months after the New Drug Application submission in August 2015. The Japanese approval for osimertinib was granted under the Priority Review mechanism of the MHLW, in recognition of the submitted data and the life-threatening nature of the disease. The Japanese approval follows US FDA Accelerated Approval in November 2015 and European Commission conditional marketing authorisation in February 2016. Interactions with regulatory authorities in the rest of the world are ongoing.

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined. Patients who have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC patients in Europe and 30-40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with the approved EGFR-TKIs, gefitinib, erlotinib or afatinib, this resistance is caused by the secondary mutation, T790M.

About osimertinib

Osimertinib 80mg once-daily tablet is the first medicine indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC. Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.

Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III trial in patients with EGFR T790M-positive, locally advanced or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, and in combination with other compounds.