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Advaxis and MedImmune Commence Enrollment in Phase I/II Study of Axalimogene Filolisbac (ADXS-HPV) in Combination With Durvalumab (MEDI4736) for the Treatment of HPV-Associated Cancers

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.

Novartis drug Odomzo® gains EU approval for locally advanced basal cell carcinoma, providing new non-invasive therapy for patients

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]).

"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.

10-K – Annual report [Section 13 and 15(d), not S-K Item 405]

(Filing, 10-K, Immunomedics, AUG 19, 2015, View Source [SID:1234507298])

OPKO Lab Signs Contracts with Leading Preferred Provider Networks for Laboratory Testing Services Including the 4Kscore® Test

On August 19, 2015 OPKO Health, Inc. (NYSE:OPK) reported that it has entered into agreements with Stratose, Three Rivers Provider Network and Fortified Provider Network for testing services from OPKO Lab, including the 4KscoreTest, the only blood test that accurately identifies an individual patient’s risk for high-grade, aggressive cancer (Press release, Opko Health, AUG 19, 2015, View Source [SID:1234507300]). The cumulative contracts, with some of the largest healthcare PPO network providers in the U.S., will give over 25 million people access to the testing services of OPKO Lab.

"These agreements demonstrate the value of the portfolio of testing services offered by OPKO Lab, including the 4Kscore Test," said David Okrongly, Ph.D., President of OPKO Diagnostics. "We are gratified at the growing acceptance by health plan customers of the value offered to patients and physicians by the 4Kscore Test and our other testing services. We look forward to providing these services to their network participants."

OPKO Lab, a full service urological testing laboratory, is the provider of the 4Kscore Test. The 4Kscore Test is the only blood test that accurately identifies an individual patient’s risk for high-grade, aggressive cancer and is now included in the NCCN 2015 Guidelines for Prostate Cancer Early Detection.

"The expansion of insurance coverage for our proprietary tests such as the 4Kscore Test is a major focus for OPKO," said Phillip Frost, M.D., OPKO’s Chairman and Chief Executive Officer. "We expect insurance coverage to further accelerate after the closing of the pending Bio-Reference Laboratories acquisition."

About the 4Kscore Test

The 4Kscore Test is the only blood test that accurately identifies an individual patient’s risk for aggressive prostate cancer, the lethal form of prostate cancer. The 4Kscore Test uses a proprietary algorithm that incorporates the blood levels of four different prostate-derived kallikrein proteins, Total PSA, Free PSA, Intact PSA and Human Kallikrein-2 (hK2), plus the patient’s age, Digital Rectal Exam (DRE) status (nodule / no nodule) and prior negative biopsy status (yes / no) to calculate the percentage risk (probability) of finding a Gleason Score 7 or higher grade of prostate cancer. The four kallikrein panel of biomarkers utilized in the 4Kscore Test is based on over a decade of research conducted by scientists at Memorial Sloan-Kettering Cancer Center and leading European institutions and is established as a recommended standard of care in the 2015 NCCN Prostate Cancer Early Detection Guidelines. The 4Kscore Test provides individualized risk for the presence of aggressive prostate cancer and adds new information to the shared decision making discussion between the urologist and the patient.

8-K – Current report

On August 19, 2015 Immunomedics, Inc. (Nasdaq:IMMU) reported financial results for the fourth quarter and fiscal year ended June 30, 2015 (Filing, 8-K, Immunomedics, AUG 19, 2015, View Source [SID:1234507297]). The Company also highlighted recent key developments and planned activities for its clinical pipeline.

Fourth Quarter Fiscal 2015 Results

Total revenues for the fourth quarter of fiscal year 2015, which ended on June 30, 2015, were $2.4 million as compared to total revenues of $1.2 million for the same quarter last fiscal year. The increase of $1.2 million in total revenues this quarter was primarily due to a $1.0 million license fee revenue earned upon reaching a clinical milestone in the Company’s Collaboration Agreement, as amended, with Bayer (formerly Algeta ASA). There was no license fee revenue recorded in the same quarter last fiscal year.

Total costs and expenses for the current quarter were $13.6 million, as compared to $13.1 million for the same period in 2014, representing an increase of $0.5 million, or 4%. This increase was driven primarily by $1.1 million higher research and development expenses from increased clinical trial cost for the Phase 3 PANCRIT-1 registration study of yttrium-90-labeled clivatuzumab tetraxetan for the therapy of patients with advanced pancreatic cancer, and increased product development and manufacturing expenses related to the expansion of clinical studies for the two antibody-drug conjugate (ADC) programs. The increase in research and development expenses was partially offset by $0.4 million decreased general and administrative costs mainly from reduced legal and professional fees.

Interest expense this quarter related to the 4.75% Convertible Senior Notes was $1.4 million, including the amortization of $0.2 million debt issuance costs. There was no interest expense for the same quarter last fiscal year.

Net loss attributable to our stockholders this quarter was $12.4 million, or $0.13 per basic share, compared with a net loss attributable to our stockholders of $11.8 million, or $0.13 per basic share for the same quarter in fiscal 2014. The increase in net loss this quarter was primarily due to the increase in research and development expenses and interest expense, partially offset by the decrease in legal and professional fees, as described above.

Fiscal Year 2015 Results

Total revenues for fiscal year 2015 were $5.7 million as compared to $9.0 million for fiscal year 2014, representing a decrease of $3.3 million or 37%. The decrease in total revenues this fiscal year primarily resulted from $4.6 million of license fee revenue earned from the Bayer Collaboration Agreement during fiscal 2014, which was partially offset by the Agreement’s $1.0 million clinical milestone payment in fiscal year 2015.

Total costs and expenses for the fiscal year ended June 30, 2015 were $51.9 million, as compared to $44.6 million for fiscal 2014, representing an increase of $7.3 million, or 16%. This increase was driven primarily by $8.0 million higher research and development expenses from the continuing efforts of the Phase 3 PANCRIT-1 clinical trial in pancreatic cancer and increased clinical trial expenses and manufacturing costs for the ADCs’ clinical studies, as well as a $0.9 million increase in legal and professional fees, principally from the arbitration proceedings with Takeda-Nycomed. The increase in cost and expenses this fiscal year was partially offset by the prior year’s $1.2 million of cost from the recognition of manufacturing costs related to the Bayer Agreement, which did not recur in the current year.

Interest expense this fiscal year for the Convertible Senior Notes due 2020 was $2.1 million, including the amortization of $0.3 million debt issuance costs. There was no interest expense last fiscal year.

Net loss attributable to our stockholders for the fiscal year ended June 30, 2015 was $48.0 million, or $0.51 per basic share, as compared to net loss attributable to our stockholders of $35.4 million, or $0.42 per basic share, in fiscal year 2014. The increase in net loss of $12.6 million this fiscal year was primarily due to increased research and development costs attributable to clinical trials, increased legal and professional fees, interest expense, and lower license fee revenue from Bayer.

As of June 30, 2015, cash, cash equivalents, and marketable securities totaled $99.6 million.

"We are pleased to have a strong balance sheet to support the development of our clinical pipeline," commented Peter P. Pfreundschuh, Vice President Finance and Chief Financial Officer. "To that end, cash requirements in fiscal year 2016 are expected to be in the range of $52 to $54 million, which include the production of sacituzumab govitecan for a Phase 3 registration trial in metastatic triple-negative breast cancer anticipated in calendar year 2016, the ongoing PANCRIT-1 trial, and interest on the convertible notes," Mr. Pfreundschuh added.

The Company’s key clinical developments and future planned activities:

Epratuzumab

In July 2015, UCB announced that the two Phase 3 EMBODY clinical trials for epratuzumab in systemic lupus erythematosus did not meet the primary clinical efficacy endpoints in either dose in both studies. Treatment response in patients who received epratuzumab in addition to standard therapy was not statistically significant when compared to those who received placebo in addition to standard therapy. UCB is in the process of analyzing the full set of data from both studies. A high level review of the safety data did not identify any new safety concerns.
Sacituzumab Govitecan (IMMU-132)

Interim Phase 2 results with sacituzumab govitecan in patients with advanced, metastatic lung cancers will be reported in an oral presentation on Monday, September 7, 2015 at the 16th World Conference on Lung Cancer to be held in Denver, CO.

At the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO meeting"), updated results from a Phase 2 study of sacituzumab govitecan in patients with metastatic triple-negative breast cancer were presented. Among the 49 patients evaluated for response, 31%, or 15 patients, showed a reduction in tumor size of 30% or more. They included 2 patients with complete response. For the 48 responding patients who received the optimal doses of 8 or 10 mg/kg, the interim median progression-free survival, ("PFS"), was 6.0 months. The median prior cancer therapies for this group of patients was 4 (range, 1-11). (For more information on the updated results, please refer to the Company’s press release at View Source).

Sacituzumab govitecan also produced promising anti-tumor activity with durable responses in patients with metastatic lung cancer. For the 25 patients who responded to the ADC with either a 30% or more tumor shrinkage or stable disease, all 11 patients with small-cell lung cancer and 12 of 14 patients with non-small-cell lung cancer, or 86%, had a time to progression that was longer than their last therapy. These patients had previously failed a median of 2.5 (range, 1-7) and 3 (range, 1-8) cancer treatments, respectively. (View Source).

Also reported at the same ASCO (Free ASCO Whitepaper) meeting were results in patients with heavily-pretreated, metastatic gastrointestinal cancers. Even in this late-stage setting, a majority of patients, 57%, responded to sacituzumab govitecan with partial responses and durable stable disease, including 2 esophageal cancer patients and 1 colorectal cancer patient with a partial response. (View Source).
Labetuzumab Govitecan (IMMU-130)

Interim results from a Phase 2 study of labetuzumab govitecan in patients previously treated with at least one prior irinotecan-containing regimen for their metastatic colorectal cancer were reported in an oral presentation at the 2015 ASCO (Free ASCO Whitepaper) meeting. For the 33 patients who received the ADC once a week at the 8 or 10 mg/kg dose levels, the interim median PFS was 4.4 months, with 22% of these patients still benefiting from their cancer not progressing. In 32 patients with at least one response assessment following treatments, the disease control rate of 78%, with 1 partial response and 24 patients reporting stable disease as their best response. (View Source).
Clivatuzumab Tetraxetan

Final results from a Phase 1b study of yttrium-90-labeled clivatuzumab tetraxetan with or without low-dose gemcitabine in patients with metastatic pancreatic cancer after two or more prior therapies have been published online in the European Journal of Cancer. (View Source(15)00645-0/fulltext).
Veltuzumab

The Office of Orphan Products Development of the U.S. Food and Drug Administration has granted orphan status for the use of veltuzumab for the treatment of immune thrombocytopenia.