On October 16, 2017 Exelixis, Inc. (NASDAQ:EXEL) reported that its global phase 3 CELESTIAL trial met its primary endpoint of overall survival (OS), with cabozantinib providing a statistically significant and clinically meaningful improvement in median OS compared to placebo in patients with advanced hepatocellular carcinoma (HCC) (Press release, Exelixis, OCT 16, 2017, View Source [SID1234520939]). The independent data monitoring committee for the study recommended that the trial should be stopped for efficacy following review of the second planned interim analysis. CELESTIAL is a randomized, global phase 3 trial of cabozantinib versus placebo in patients with advanced HCC who have been previously treated with sorafenib. The safety data in the study were consistent with the established profile of cabozantinib. Based on these results, Exelixis plans to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2018. Detailed results from CELESTIAL will be submitted for presentation at a future medical conference.

“We are excited that these positive results from the phase 3 CELESTIAL trial bring us one step closer to the potential of offering previously treated patients with this aggressive form of advanced liver cancer a much-needed new treatment option,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “This is an important milestone for the cabozantinib development program; we are committed to studying cabozantinib in a range of tumor types as part of our mission to deliver medicines that improve treatment outcomes and give patients hope for the future.”

Exelixis will discuss the trial results with regulatory authorities and determine next steps for the trial, including offering patients currently receiving placebo the opportunity to cross over to cabozantinib.

In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. Orphan drug designation is granted to treatments for diseases that affect fewer than 200,000 people in the U.S. and provides certain incentives for medications intended for the treatment, diagnosis or prevention of rare diseases. At present, these incentives include seven years of marketing exclusivity for the orphan indication, certain federal grants, tax credits, and waiver of certain FDA fees.

About the CELESTIAL Study
CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at 50 percent and 75 percent of the planned 621 events.

About HCC
Liver cancer is the third-leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most common form, making up about three-fourths of the nearly 41,000 cases that will be diagnosed in 2017 in the U.S.1,2 Without treatment, patients with advanced disease usually survive less than 6 months, and it is estimated that 29,000 people will die due to liver cancer in the U.S.2,3 Worldwide, nearly 800,000 new cases are diagnosed annually, and the disease accounts for more than 700,000 deaths each year.4

About CABOMETYX (cabozantinib)
CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance. CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. In February of 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland.

On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.

CABOMETYX is not indicated for the treatment of advanced HCC.

Please see Important Safety Information below and full U.S. prescribing information at View Source

U.S. Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose. Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation. Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided. Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose. Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential. Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On October 16, 2017 Exelixis, Inc. (NASDAQ:EXEL) reported that the U.S. Food and Drug Administration (FDA) has determined the company’s supplemental New Drug Application (sNDA) for CABOMETYX (cabozantinib) for patients with previously untreated advanced renal cell carcinoma (RCC) to be sufficiently complete to permit a substantive review (Press release, Exelixis, OCT 16, 2017, View Source [SID1234520938]). The FDA granted Priority Review of the filing and assigned a Prescription Drug User Fee Act (PDUFA) action date of February 15, 2018.

“The acceptance of the sNDA filing with a Priority Review is an important regulatory milestone for CABOMETYX and for our mission to improve treatment outcomes for patients with cancer,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “We look forward to working with the FDA as they review the application in our effort to offer CABOMETYX to patients with previously untreated metastatic RCC who are in need of new treatment options.”

The sNDA is based on data from CABOSUN, a randomized phase 2 trial conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP).

An sNDA is an application to the FDA that, if approved, will allow a drug sponsor to make changes to a previously approved product label, including modifications to the indication. CABOMETYX was previously approved by the FDA on April 25, 2016 for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. The approval was based on results from the phase 3 METEOR trial, which demonstrated that CABOMETYX provided a statistically significant and clinically meaningful improvement in overall survival, progression-free survival (PFS), and objective response rate as compared with everolimus in this patient population.

Please see Important Safety Information below and full U.S. prescribing information at View Source

About the CABOSUN Study

On May 23, 2016, Exelixis announced that CABOSUN met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS compared with sunitinib in patients with advanced intermediate- or poor-risk RCC as determined by investigator assessment. CABOSUN was conducted by The Alliance for Clinical Trials in Oncology as part of Exelixis’ collaboration with the NCI-CTEP. These results were first presented by Dr. Toni Choueiri at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress, and published in the Journal of Clinical Oncology (Choueiri, JCO, 2016).1 In June 2017, a blinded independent radiology review committee (IRC) confirmed that cabozantinib provided a clinically meaningful and statistically significant improvement in the primary efficacy endpoint of investigator-assessed PFS. Results from the IRC review were presented by Dr. Toni Choueiri at the ESMO (Free ESMO Whitepaper) 2017 Congress.

CABOSUN was a randomized, open-label, active-controlled phase 2 trial that enrolled 157 patients with advanced RCC determined to be intermediate- or poor-risk by the IMDC criteria. Patients were randomized 1:1 to receive cabozantinib (60 mg once daily) or sunitinib (50 mg once daily, 4 weeks on followed by 2 weeks off). The primary endpoint was PFS. Secondary endpoints included overall survival and objective response rate. Eligible patients were required to have locally advanced or metastatic clear-cell RCC, ECOG performance status 0-2 and had to be intermediate or poor risk per the IMDC criteria (Heng, JCO, 2009).2 Prior systemic treatment for RCC was not permitted.

About Advanced Renal Cell Carcinoma

The American Cancer Society’s 2017 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.3 Clear cell RCC is the most common type of kidney cancer in adults.4 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 12 percent, with no identified cure for the disease.5 Approximately 30,000 patients in the U.S. and 68,000 globally require treatment, and an estimated 14,000 patients in the U.S. each year are in need of a first-line treatment for advanced kidney cancer.6

The majority of clear cell RCC tumors have lower than normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.7,8 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.9-12 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.7,8

About CABOMETYX (cabozantinib)

CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis and drug resistance. CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.

On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced RCC who have received prior anti-angiogenic therapy. In February of 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. This agreement was amended in December of 2016 to include commercialization rights for Ipsen in Canada. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced RCC in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. Ipsen also submitted to European Medicines Agency (EMA) the regulatory dossier for cabozantinib as a treatment for first-line advanced RCC in the European Union on August 28, 2017; on September 8, 2017, Ipsen announced that the EMA validated the application.

On January 30, 2017, Exelixis and Takeda Pharmaceutical Company Limited announced an exclusive licensing agreement for the commercialization and further clinical development of cabozantinib for all future indications in Japan, including RCC.

CABOMETYX is not indicated for the treatment of previously untreated advanced RCC.

U.S. Important Safety Information

Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.

Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.

Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.

Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.

Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.

Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS. Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose. Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation. Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided. Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose. Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential. Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.

On October 16, 2017 Celsion Corporation (NASDAQ:CLSN) reported publication of the manuscript, “Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions,” in Clinical Cancer Research, a high impact, peer-reviewed medical journal (Press release, Celsion, OCT 16, 2017, View Source [SID1234520937]).

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The article reports on one of the largest controlled studies in hepatocellular carcinoma (HCC). It provides a comprehensive review of ThermoDox, Celsion’s proprietary heat-activated liposomal encapsulation of doxorubicin, for the treatment of primary liver cancer, also known as hepatocellular carcinoma or HCC. The article details learnings from the Company’s 701 patient HEAT Study and includes results from computer simulation studies and includes interesting findings from a post hoc subgroup analysis, all of which are consistent with each other and which — when examined together — suggest a clearer understanding of a key ThermoDox heat-based mechanism of action: the longer the target tissue is heated, the greater the doxorubicin tissue concentration. Additionally, the article explores a new hypothesis prompted by these findings: ThermoDox, when used in combination with Radiofrequency Ablation (RFA) standardized to a minimum dwell time of 45 minutes (sRFA ≥ 45 min), may increase the overall survival (OS) of patients with HCC. The lead author is Won Young Tak, M.D., Ph.D., Professor Internal Medicine, Gastroenterology & Hepatology, Kyungpook National University Hospital Daegu, Republic of Korea, and there are 22 HEAT Study co-authors along with Nicholas Borys, M.D., Celsion’s senior vice president and chief medical officer. The article is available online in the October 2017 issue of the journal, Clinical Cancer Research, at View Source

To test and confirm the HEAT Study post hoc subgroup analysis, Celsion is conducting the Phase III OPTIMA Study, a global, pivotal, double-blind, placebo-controlled clinical trial (Clinical Trials.gov NCT021126560). Developed in consultation with leading primary liver cancer researchers, and statistical and regulatory experts, and based on extensive analysis of prior clinical and preclinical studies of ThermoDox plus standardized RFA, the OPTIMA Study is evaluating ThermoDox in combination with RFA standardized to a minimum of 45 minutes across all investigators and sites for treating lesions 3 to 7 centimeters, versus standardized RFA alone.

Global interest in ThermoDox as a potential treatment option for HCC was recently showcased in the Company sponsored R&D Day held in New York City on October 12, 2017. Lead OPTIMA Study clinical investigators representing various geographical regions (Asia-Pacific and Europe) and multiple medical disciplines (hepatology, interventional radiology and surgery) presented their past and current experiences with ThermoDox for the treatment of primary liver cancer. The final OS analysis demonstrated that in a large, well bounded, subgroup of patients (n=285 patients, 41% of the previous 701 patient HEAT Study), treatment with a combination of ThermoDox and standardized RFA provided an average 58% improvement in OS compared to standardized RFA alone. The Hazard Ratio (HR) is 0.63 (95% CI 0.43 – 0.93) with a p-value of 0.0198. In this large subgroup, median OS for the ThermoDox plus standardized RFA group translates into a 25.4 month (more than 2.1 years) survival benefit over the standardized RFA only group – totaling approximately 80 months (6-1/2 years, which is considered a curative treatment for HCC) for the ThermoDox plus standardized RFA group versus 53 months for the standardized RFA only group.

“There is clear evidence that the duration of the RFA regimen is critical when treating patients with ThermoDox, and the totality of the data presented in the newly published article in the peer reviewed journal, Clinical Cancer Research, demonstrate that ThermoDox plus standardized RFA has a strong potential to serve as a curative therapy for patients with liver cancer,” said Professor Won Young Tak, M.D., Ph.D., lead investigator in South Korea for the Company’s HEAT and OPTIMA studies. “The OPTIMA Study is designed to validate this approach in an indication where there exists a strong unmet need for effective treatment options.”

In August 2017, the OPTIMA Study’s Independent Data Monitoring Committee (IDMC), comprised of medical and scientific experts who are responsible for reviewing and evaluating patient safety and efficacy data, completed a planned interim analysis of the first 50% of patients randomized in the trial as of April 2017 and unanimously recommended that the OPTIMA Study continue as planned based on the risk to benefit analysis by the Committee. The OPTIMA Study to date has accumulated data within acceptable safety parameters. The Company announced that enrollment in the OPTIMA Study is approaching 70% of the 550 patients necessary to ensure that its primary end point, overall survival, can be evaluated with statistical significance. The statistical plan for the OPTIMA Study calls for two interim efficacy analyses by the IDMC. The Company currently projects full patient enrollment by mid-2018 and the first pre-planned efficacy analysis after 118 overall survival events by the first quarter of 2019.

“There is an urgent need for new and better treatment options for HCC, the third leading cause of cancer in the world. We believe strongly that ThermoDox may be an important new approach for the treatment of HCC. We are now fully committed to the OPTIMA Study and to learning more about how this combination therapy of standardized RFA plus ThermoDox may significantly prolong the survival of, if not cure, patients suffering from this extremely deadly cancer,” stated Michael H. Tardugno, Celsion’s chairman, president and chief executive officer, in response to the article’s publication. “Supported with an independent endorsement by the National Institutes of Health, the OPTIMA Study and ThermoDox may prove to be the most important oncology research in a generation,” Mr. Tardugno added.

On November 29, 2016, the Company announced results from an independent retrospective analysis conducted by the National Institutes of Health on the intent-to-treat population of the 701 patient HEAT Study of ThermoDox plus optimized RFA for the treatment of primary liver cancer. The NIH analysis, which sought to evaluate the correlation between RFA burn time per tumor volume (min/ml) and clinical outcome, concluded that increased RFA “burn time” per tumor volume significantly improved overall survival (OS) in patients with solitary lesions treated with RFA + ThermoDox compared to patients treated with RFA alone. The NIH analysis included 437 patients with a single lesion from the Company’s HEAT Study, the same patient population being treated in the Company’s ongoing Phase III OPTIMA study. The NIH findings are consistent with Celsion’s own analysis of the HEAT Study data, which demonstrated that over a 3.5 year period, there was a statistically significant survival benefit consistent with the HEAT Study in patients treated with ThermoDox plus optimized RFA over the optimized RFA only group.

“We are highly focused on successfully executing the ongoing OPTIMA study,” stated Nicholas Borys, Celsion’s chief medical officer. “With independent confirmation by the NIH of the relationship between RFA heating time and the significant impact that it has on overall survival when combined with ThermoDox, OPTIMA Study investigators fully recognize the value of the findings from the HEAT Study, reinforcing their interest and support for our highly de-risked, ongoing global Phase III OPTIMA Study, and to accomplishing our chief goal, the delivery of ThermoDox as a novel, first-line treatment to HCC patients worldwide.”

About the OPTIMA Study
The Phase III OPTIMA Study is expected to enroll up to 550 patients in up to 70 clinical sites in the United States, Europe, China and Asia Pacific, and will evaluate ThermoDox in combination with optimized RFA, which will be standardized to a minimum of 45 minutes across all investigators and clinical sites for treating lesions three to seven centimeters, versus optimized RFA alone. The primary endpoint for the trial is Overall Survival, which is supported by post-hoc analysis of data from the Company’s 701 patient HEAT Study, where optimized RFA has demonstrated the potential to significantly improve survival when combined with ThermoDox. The statistical plan calls for two interim efficacy analyses by an independent Data Monitoring Committee.

ThermoDox has received U.S. FDA Fast Track Designation and has been granted orphan drug designation for primary liver cancer in both the U.S. and Europe. Further, the U.S. FDA has provided ThermoDox with a 505(b)(2) registration pathway. Subject to a successful trial, the OPTIMA Study has been designed to support registration in all key primary liver cancer markets. Celsion fully expects to submit registrational applications in the USA, Europe and China. The Company believes that applications will be accepted in South Korea, Taiwan and Vietnam, three other large and important markets for ThermoDox subject to approval in Europe, China or the USA.

About ThermoDox
Celsion’s most advanced program is a heat-mediated, tumor-targeting drug delivery technology that employs a novel heat-sensitive liposome engineered to address a range of difficult-to-treat cancers. The first application of this platform is ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD), whose novel mechanism of action delivers high concentrations of doxorubicin to a region targeted with the application of localized heat at 40°C, just above body temperature. In one of its most advanced applications, ThermoDox, when combined with radiofrequency thermal ablation (RFA), has the potential to address a range of cancers. For example, RFA in combination with ThermoDox has been shown to expand the “treatment zone” with a margin of highly concentrated chemotherapy when treating individual primary liver cancer lesions. The goal of this application is to significantly improve efficacy.

Celsion’s LTLD technology leverages two mechanisms of tumor biology to deliver higher concentrations of drug directly to the tumor site. The first: Rapidly growing tumors have leaky vasculature, which is permeable to liposomes and enables their accumulation within tumors. Leaky vasculature influences a number of factors within the tumor, including the access of therapeutic agents to tumor cells. Administered intravenously, LTLD is engineered to allow significant accumulation of liposomes at the tumor site at the time of radiofrequency ablation as these liposomes recirculate in the blood stream. The second: When the tumor tissue is heated to a temperature of 40°C or greater, the heat-sensitive liposome rapidly changes structure and the liposomal membrane selectively dissolves, creating openings that release the chemotherapeutic agent directly into the tumor and into the surrounding vasculature. Drug concentration increases as a function of the accumulation of liposomes at the tumor site, but only where the heat is present. This method targets only the tumor and the area related to tumor invasion, supporting precise drug targeting.

On October 16, 2017 AVEO Oncology (NASDAQ:AVEO) reported that results from the Phase 1 portion of the Phase 1/2 TiNivo study will be presented in an oral presentation at the 16th International Kidney Cancer Symposium, to be held November 3-4, 2017 in Miami (Press release, AVEO, OCT 16, 2017, View Source [SID1234520934]). The TiNivo trial is a Phase 1/2 multicenter trial of FOTIVDA (tivozanib) in combination with Bristol-Myers Squibb’s OPDIVO (nivolumab), an immune checkpoint, or PD-1, inhibitor, for the treatment of advanced renal cell carcinoma (RCC). As previously reported, the Phase 1 portion of the trial enrolled six patients, and found that the combination of tivozanib and nivolumab was well tolerated to the full dose and schedule of single agent tivozanib, with no dose limiting toxicities. Enrollment in the Phase 2 portion in ongoing. The trial is being led by the Institut Gustave Roussy in Paris under the direction of Bernard Escudier, MD, Chairman of the Genitourinary Oncology Committee.

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Details for the presentation are as follows:

Title: TiNivo: A Phase Ib Dose Escalation Trial of Tivozanib and Nivolumab in Renal Cell Carcinoma
Presenter: Laurence Albiges, M.D., Ph.D., Head, Genitourinary Unit, Institute Gustave Roussy
Session Title: Abstracts
Date and Time: Friday, November 3, 2017, 5:25-6:25 PM ET

About Tivozanib (FOTIVDA)

Tivozanib (FOTIVDA) is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) discovered by Kyowa Hakko Kirin and approved for the treatment of adult patients with advanced renal cell carcinoma in the European Union plus Norway and Iceland. It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers.

On October 16, 2017 Actinium Pharmaceuticals, Inc. (NYSE American:ATNM) (“Actinium” or “the Company”), a biopharmaceutical company developing innovative targeted therapies for cancers lacking effective treatment options, reported that it will present at the BIO Investor Forum being held on October 16-17th at the Westin St. Francis Hotel in San Francisco, California (Press release, Actinium Pharmaceuticals, OCT 16, 2017, View Source [SID1234520933]). Details for Actinium’s presentation are below:

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Date: Tuesday, October 17, 2017
Time: 3:00 PM PT
Room: Elizabethan C

Members of Actinium’s management team will be available for one-on-one meetings with conference attendees. To arrange a meeting with management, please contact Steve O’Loughlin, Actinium’s Principal Financial Officer, at [email protected] or utilize the conference partnering system View Source

About BIO Investor Forum

The BIO Investor Forum is an international biotech investor conference focused on investment trends and opportunities in life sciences, with unbiased emphasis on venture stage growth and emerging public companies as well as those poised to join the growth “watch list” in 2018.