HPV-Associated Cancers

Cervical cancer, which is the most common HPV-associated cancer in women, is characterized by cancerous malignancies in the cervix. In 2017, it is expected that there will be approximately 12,820 new diagnoses of invasive cervical cancer in the United States,¹ and according to company market research, an estimated 16,000 new cases are expected in Europe. An estimated 4,210 women in the United States are expected to die from cervical cancer each year.¹

New data published in the journal Cancer in 2017 underscores the need for new therapeutic options as the research shows that the U.S. cervical cancer mortality rate is higher than initially thought. When accounting for hysterectomies, the mortality rate for cervical cancer is 10.1 per 100,000 black women and 4.7 per 100,000 white women, increased from previously recorded rates of 5.7 and 3.2, respectively.²

Worldwide, cervical cancer is the third most common cancer among women and the second most frequent cause of cancer-related death, accounting for nearly 300,000 deaths annually. In developing nations, it is often the most common cause of cancer-related death among women and a leading cause of death overall.³

Anal cancer is a fairly rare form of cancer in the United States, but the number of new cases has been rising over the past decade.⁴ On average, this cancer effects people in their early 60s. In 2017, an estimated 8,200 people in the United States, including 5,250 women and 2,950 men, will develop anal cancer.⁵ In Europe, there will be an estimated 1 new anal cancer case for every 100,000 males, and 3 in 100,000 females.⁶ An estimated 650 women and 450 men will die from the disease this year in the U.S.⁵

CERVICAL CANCER: PHASE 3 AIM2CERV STUDY

AXAL has shown promising anti-tumor activity and acceptable tolerability across several clinical trials. Advaxis has reached an agreement on a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA) in June 2016 for the Phase 3 AIM2CERV study, evaluating the safety and efficacy of AXAL administered in the adjuvant setting after completion of cisplatin-based chemotherapy and radiotherapy in patients with locally advanced cervical cancer at higher risk for recurrence, progression, or death. The study plans to enroll approximately 450 patients, and is on track with enrollment. The Phase 3 trial will be conducted in collaboration with the GOG Foundation, Inc, now part of NRG Oncology. AXAL also received Fast Track Designation from the FDA as an adjuvant therapy for HRLACC patients and was classified as an advanced-therapy medicinal product by the European Medicines Agency’s Committee for Advanced Therapies for the treatment of cervical cancer.

CERVICAL CANCER: PHASE 2 GOG-0265 STUDY

A phase 2 study was recently completed in collaboration with the GOG. GOG-0265, a single arm trial evaluating axalimogene filolisbac for the treatment of persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) had primary endpoints to assess the safety and efficacy of axalimogene filolisbac in women with PRmCC. The primary efficacy endpoint was overall survival at 12 months from initial treatment with axalimogene filolisbac. The primary safety endpoints were to evaluate the number of patients with dose-limiting toxicities and the frequency and severity of adverse effects.

The final efficacy results of GOG-0265 demonstrated that 38% of patients (n = 19/50) with heavily pretreated PRmCC were alive 12 months following treatment with axalimogene filolisbac. The GOG-0265 study protocol used a logistic model-based calculation to establish the expected 12-month survival rate. The model identified the key prognostic factors of age, race and performance status significantly related to survival from a database of approximately 500 patients with PRmCC who participated in 17 previous phase 2 studies conducted by the Gynecologic Oncology Group (GOG), now part of NRG Oncology. Using this model, the expected 12-month survival rate of patients enrolled in the study was calculated to be 24.5%. As a result, the 38% 12-month survival rate of patients treated with axalimogene filolisbac represents a 52% improvement over the expected survival rate and is the highest 12-month survival rate achieved to date in this setting. The probability of this survival improvement being detected by chance versus a true treatment effect was calculated to be 0.02. A compelling and ongoing complete response of 18.5 months was observed and the longest ongoing survival is 40.6 months.

The safety profile was consistent with previous clinical experience. The most common Grade 1 or Grade 2 treatment-related adverse events (TRAEs) were hypotension and symptoms related to cytokine release (e.g., nausea, chills, fever). Eighteen out of 50 patients experienced a Grade 3 TRAE and two out of 50 patients experienced a Grade 4 TRAE, which were hypotension and symptoms related to cytokine release.

ANAL CANCER: PHASE 2

Advaxis has collaborated with Brown University Oncology Group on a Phase 1/2 clinical study assessing the safety and efficacy of AXAL administered with concurrent standard chemotherapy and radiation treatment in HPV-associated locally advanced anal cancer. Preliminary data show clinical complete response and no recurrence in all 10 patients who completed the AXAL-containing treatment regimen.

In June 2016, Advaxis began dose administration for a Phase 2 clinical study of AXAL in metastatic anal cancer. The study is called FAWCETT (Fighting Anal Cancer with CTL-Enhancing Tumor Therapy), in honor of Farrah Fawcett, and is the company’s second Phase 2 study of AXAL in anal cancer. The two-part, multi-center, open-label study is designed to evaluate the efficacy and safety of AXAL as a monotherapy in patients with HPV-associated metastatic anal cancer who have received at least one prior treatment regimen for advanced disease.

Advaxis has also entered into a clinical trial collaboration agreement with the Radiation Therapy Oncology Group (RTOG) Foundation to evaluate the safety and efficacy of ADXS-HPV in a pivotal Phase 2/3 anal cancer trial, which will be run by NRG Oncology.

PHASE 2 AXAL COMBO WITH DURVALUMAB STUDY

AXAL is under evaluation in two clinical trials for HPV-associated head and neck cancer. The first is a “window of opportunity” Phase 2 study, conducted by the Icahn School of Medicine at Mount Sinai, investigating the effects of AXAL in patients newly diagnosed with HPV-positive head and neck cancer during the window of time between initial diagnosis and receiving any treatment, including surgery, chemotherapy or radiation. As of April 2016, the trial enrolled eight AXAL-treated patients and six no-treatment observational patients with stage II-IV HPVOPC. Clinical data showed increased T-cell response in several patients, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells into the tumor.

The second is a Phase 1/2 study evaluating the safety and efficacy of AXAL alone or in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab (MEDI4736), for the treatment of patients with advanced, recurrent or refractory cervical cancer and HPV-associated head and neck cancer. The first and second dose-escalation cohort in the trial has been completed, and the Companies have commenced enrollment for the Part A expansion and Part B of the study.