HPV: THE NEED

Advaxis’ Lm Technology™ immunotherapy targets HPV-associated cancers including cervical cancer, head & neck cancer, as well as anal cancer.

Cervical Cancer

THE MOST COMMON HPV-ASSOCIATED CANCER IN WOMEN

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

1 American Cancer Society. What is Cervical Cancer. Retrieved June 1, 2017 from https://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-key-statistics
2 Anna L. Beavis, Patti E. Gravitt and Anne F. Rositch (2017, January 23) American Cancer Society. Cancer Society. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States [Electronic Version]. Cancer, 123(6), 1044-1050. Retrieved June 1, 2017 from https://onlinelibrary.wiley.com/doi/10.1002/cncr.30507/full
3 National Institutes of Health.  Fact Sheets: Cervical Cancer.  October 2010.

 

AXALIMOGENE FILOLISBAC

There has only been one new treatment for cervical cancer in the past 30 years, with an average benefit of only 3 additional months of survival.  When treatment inevitably fails and the cancer progresses, there are no FDA approved options for these patients.  These are the forgotten women, and over 4000 of them die each year in the US.  This underserved population is the target for our leading drug candidate, axalimogene filolisbac  for metastatic cervical cancer and anal cancer.

While vaccines have proven effective at HPV prevention, they cannot treat or have any affect once the infection is contracted. Likewise, HPV-associated cancers cannot be treated with present-day HPV vaccines.

Because HPV vaccines have no therapeutic effect on HPV-associated cancers, there is an immediate need for new treatments that do. Until everyone is vaccinated, treatments will be needed, meaning therapeutic options need to be developed for at least the next 50 years.

Axalimogene filolisbac is the only known cancer immunotherapy agent shown in preclinical studies to alert the body’s immune system to the presence of cancer, diminish that cancer’s natural defense mechanisms and then rally the body’s killer T cells to attack the cancer. 

Axalimogene filolisbac clinical trials in HPV-related cancers

HPV is the most common viral infection of the reproductive tract and is the cause of a range of conditions in both females and males. In women, persistent infection with specific oncogenic types of HPV (most frequently alpha7 and alpha9 families) may lead to precancerous lesions which, if untreated, may progress to cervical cancer. There were approximately 570,000 new cases of cervical cancer caused by HPV worldwide in 2018 according to the World Health Organization (“WHO”). In the United States, there will be approximately 13,170 new cases of cervical cancer and approximately 4,250 deaths from cervical cancer in 2019 according to the American Cancer Society. Current preventative HPV vaccines such as Gardasil® and Cervarix® cannot treat or protect the large population of adults already infected with the virus, leaving several generations of women vulnerable. Furthermore, challenges with acceptance, accessibility, and compliance have resulted in suboptimal vaccination rates, with approximately 53% of young women and 44% of young men being fully vaccinated in the United States, according to statistics published by the Centers for Disease Control in 2017. Vaccination rates are even lower in other countries around the world.

"Just as we need options to prevent HPV-related cancers, there is a significant need for more therapeutic options to treat those with cancer. No woman should die from cervical cancer."

Deborah Arrindell

Vice President, Health Policy

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. 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.
In June 2019, Advaxis announced the closing of this study. Results from these clinical trials were not the basis for this decision to close the study, nor was the safety. The trial recently underwent its third Independent Data Monitoring Committee (IDMC) review with no safety issues noted. The company plans to unblind the AIM2CERV clinical data generated to date and anticipates submitting these data for publication. In addition, Advaxis will continue to pursue monetization opportunities for AXAL.

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"The 12-month survival rate of axalimogene filolisbac reached unprecedented levels in this study, which is both impressive and important given the lack of innovation in metastatic cervical cancer."

Warner K. Huh, MD

Director, Division of Gynecologic Oncology

PHASE 2 TRIAL RESULTS – AXALIMOGENE FILOLISBAC

In 2014, the company completed a randomized Phase 2 clinical trial (Lm -LLO-E7-15) in 109 women, conducted in India, with recurrent/refractory cervical cancer. The final results were presented at the 2014 American Society of Clinical Oncology (“ASCO”) Annual Meeting and showed that 32% (35/109) of patients were alive at 12 months, 22% (24/109) of patients were Long-term Survivors (“LTS”) alive greater than 18 months, and 18% (16/91) evaluable with adequate follow-up of patients were alive for more than 24 months. Of the 109 patients treated in the trial, LTS included not only patients with tumor shrinkage but also patients who had experienced stable disease or increased tumor burden. 17% (19/109) of the patients in the trial had recurrence of disease after at least two prior treatments for their cervical cancer; these patients comprised 8% (2/24) of LTS. Among the LTS, 25% (3/12) of patients had a baseline Eastern Cooperative Oncology Group (“ECOG”) performance status of 2, a patient population that is often excluded from clinical trials. Furthermore, a 10% objective response rate (including 5 complete responses and 6 partial responses) and a disease control rate of 38% (42/109) were observed. The addition of cisplatin chemotherapy to axalimogene filolisbac in this trial did not significantly improve overall survival or objective tumor response (p =0.9981).

In this trial, 109 patients received 254 doses of axalimogene filolisbac. Axalimogene filolisbac was found to be well tolerated with 38% (41/109) of patients experiencing mild to moderate Grade 1 or 2 transient adverse events associated with infusion; 1 patient experienced a Grade 3 Serious Adverse Events (“SAE”). All observed treatment-related adverse events either self-resolved or responded readily to symptomatic treatment.

Based on these results, the Gynecological Oncology Group (“GOG”) Foundation, Inc. (now a member of NRG Oncology), under the sponsorship of the Cancer Therapy Evaluation Program (“CTEP”) of the National Cancer Institute (“NCI”), conducted GOG-0265, an open-label, single-arm Phase 2 trial of axalimogene filolisbac in persistent or recurrent cervical cancer (patients must have received at least 1 prior chemotherapy regimen for the treatment of their recurrent/metastatic disease, not including that administered as a component of primary treatment) at numerous clinical sites in the U.S. The trial was a Simon 2-stage design, with the primary efficacy endpoint being 12-month survival, with the objective of the secondary efficacy endpoints to evaluate progression-free survival, overall survival and objective tumor response. The primary safety endpoints were to evaluate the number of patients with dose-limiting toxicities and the frequency and severity of adverse effects.

To evaluate the trial’s primary endpoint of 12-month overall survival rate, the GOG’s protocol featured a prospectively-defined logistic model-based calculation of the expected 12-month survival rate using key predictive factors significantly related to survival and derived from 17 serially conducted GOG/NRG 2-stage studies of inactive agents in persistent/recurrent metastatic cervical cancer (“PRmCC”) involving approximately 500 patients. This accumulated data by GOG used a consistent protocol design and a similar data collection methodology resulting in a robust and homogeneous patient dataset for the per protocol analysis of the primary endpoint. Per the trial protocol, this logistic model-based calculation was then used as a comparator for evaluating the 12-month survival rate of axalimogene filolisbac observed in GOG-0265.

The first stage of enrollment in GOG-0265 was successfully completed with 26 patients treated and met the predetermined safety and efficacy criteria required to proceed into the second stage of patient enrollment. Clinical data from the first stage of GOG-0265 was presented at the American Gynecological & Obstetrical Society (“AGOS”) annual meeting in September 2015. Overall survival at 12 months was 38.5% (10/26) (the predefined criteria for 12-month survival in order to progress to Stage 2 was ≥20%), and, among patients who had received the full treatment regimen of 3 doses of axalimogene filolisbac, the 12-month survival rate was 55.6% (10/18). The adverse events observed in the first stage of the trial have been consistent with those reported in other clinical studies with axalimogene filolisbac.

Stage 2 of the trial began enrollment in February 2015 which included a protocol amendment to allow patients to continue to receive repeat cycles of therapy until disease progression. Stage 2 enrollment was temporarily suspended with a clinical hold in October 2015 that resolved in mid-December 2015. Prior to re-initiating enrollment of a new cohort of Stage 2 patients, Advaxis and the GOG Foundation/NRG Oncology examined the 12-month survival rate and safety data obtained from the 24 patients who had previously enrolled in Stage 2. The Stage 2 population demonstrated that treatment with axalimogene filolisbac resulted in a 37.5% (9/24) 12-month survival rate. This data was consistent with the findings in Stage 1 that showed a 38.5% 12-month survival rate, despite a greater proportion of Stage 2 patients having previously taken and failed bevacizumab treatment prior to enrollment. Taken together, the available data from both stages of GOG-0265 comprise a Phase 2 clinical trial in 50 subjects with a 12 month survival rate of 38% (19/50). The protocol defined logistic model-based calculation of the expected 12-month milestone survival rate was calculated to be 24.5% using the key predictors from the patients enrolled in the trial. The 12-month survival rate of 38% for patients receiving axalimogene filolisbac in the trial represented a 52% improvement over the expected 12-month milestone survival rate of 24.5%.

Overall, 28 out of 50 (56%) patients experienced a Grade 1 or Grade 2 treatment-related adverse event (TRAE) associated with axalimogene filolisbac infusion. The most common (>30%) Grade 1 or Grade 2 TRAEs were fatigue, chills, anemia, nausea and fever. Eighteen (36%) patients experienced a Grade 3 TRAE and two patients experienced a Grade 4 AE, including a Klebsiella lung infection in one patient, and hypotension/cytokine related symptoms in another patient, which were considered possibly related to treatment.

In October 2016, upon review of these findings, the Company announced early closure of GOG-0265. Results from the GOG-0265 trial were presented as an oral late-breaker presentation at the Society of Gynecologic Oncology (“SGO”) annual meeting on March 14, 2017. Based on these data, the Company made a strategic decision to submit for conditional MAA in the European Union for axalimogene filolisbac to treat metastatic cervical cancer in patients who progress beyond first-line treatment in March 2018. However, Advaxis withdrew the application in July 2018 based on European Medicines Agency (EMA) feedback following its initial review indicating the application will likely need additional clinical data to support a conditional approval.

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"The fact that we are seeing increased T-cell response, evidence of epitope spreading, and signs of increased immune activation consistent with expansion and infiltration of activated T cells in the tumor at this preliminary point in the study suggests that AXAL has the potential to generate beneficial immunologic responses in patients with HPV+ head and neck cancer."

Andrew Sikora, MD, PhD

Associate Professor of Otolaryngology

PHASE 2 AXAL COMBO WITH DURVALUMAB STUDY

Advaxis also conducted a clinical trial with axalimogene filolisbac through a collaboration agreement with MedImmune, the global biologics research and development arm of AstraZeneca. This Phase 1/2, open-label, multicenter, dose determination and expansion cohort trial was designed to determine the recommended Phase 2 dose (“RP2D”) and evaluate the safety and efficacy of axalimogene filolisbac, in combination with MedImmune’s investigational anti-PD-L1 immune checkpoint inhibitor, IMFINZITM (“durvalumab”), as a treatment for patients with metastatic squamous or non-squamous carcinoma of the cervix and metastatic HPV-associated squamous cell carcinoma of the head and neck (“SCCHN”). The dose determination phase of the trial is complete. Two dose cohorts were enrolled. Cohort 1 enrolled 5 patients with metastatic cervical cancer who received 1 x 109 cfu of axalimogene filolisbac + 3 mg/mg durvalumab. Cohort 2 enrolled 3 patients with metastatic cervical cancer and 2 patients with SCCHN who received 1 x 109 cfu of axalimogene filolisbac + 10 mg/mg of durvalumab. No dose-limiting toxicities were observed in either cohort. The RP2D was determined to be 1 x 10 9 cfu for axalimogene filolisbac + 10 mg/mg for durvalumab. Preliminary data showed that two patients with metastatic cervical cancer achieved a durable complete response (with confirmation) and a partial response (without confirmation), respectively.

TRAEs were reported in 91% of patients; the majority were either Grade 1 (64%) or Grade 2 (55%) events. The most commonly reported TRAEs were chills, fever, nausea and hypotension. Three patients reported Grade 3 TRAEs (1 x 109 + 3 mg/kg – rigor/chills; 1 x 109 + 10 mg/kg – rigor/chills; and 1 x 109 + 10 mg/kg – diarrhea and shortness of breath). One patient experienced a Grade 4 TRAE of hypotension. As of February 27, 2018, the safety profile of the combination of axalimogene filolisbac and durvalumab was consistent with previous reported findings for both axalimogene filolisbac and durvalumab administered as monotherapy. However, on March 9, 2018, a clinical hold was issued for this study following submission by the Company of a safety report to the FDA regarding a patient death that occurred on February 27, 2018, post-dosing, involving acute respiratory failure after receiving nine months of combination therapy in the trial. New guidelines for the early detection and treatment of such rare events were agreed to with the FDA and were implemented in this and all other studies evaluating our Lm-based drug candidates. The clinical hold was lifted by FDA on July 12, 2018. Enrollment and dosing in all other Advaxis and durvalumab clinical programs were not affected by the clinical hold.

In November 2018, the Company announced that enrollment in the Part A expansion phase (N = 20 patients with SCCHN) and planned Part B expansion phase (N=90 patients with metastatic cervical cancer) had ended in order to maximize the efficient use of its resources. As of the latest data cut-off date of October 18, 2017, 7 patients receiving 1 x 10 9 axalimogene filolisbac + 10 mg/kg durvalumab had been enrolled. In the Part B expansion, a total of 32 patients with metastatic cervical cancer were randomized to receive either 10 mg/kg durvalumab alone (N=16 patients) or 1 x 10 9 axalimogene filolisbac + 10 mg/kg durvalumab (N = 16 patients) expansion phases.

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