On July 7, 2015 Provectus Pharmaceuticals reported that varied locoregional treatments for hepatocellular carcinoma and metastatic colorectal cancer liver metastases are producing promising clinical results, according to a study presented here at the 2015 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer (ESMO-GI) (Press release, Provectus Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506186]).

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"We have seen interesting data on locoregional therapies for hepatocellular carcinoma and colon cancer," stated Chris Verslype, MD, University Hospital, Leuven, Belgium, on July 4. "These therapies are gaining interest due to the fact that the liver is the predominant site of disease for most of these tumours."

Dr. Verslype commented on trials across several phases presented at the meeting.

Guy van Hazel, MD, University of Western Australia, Perth, Australia, updated and extended results, on July 4, of SIRFLOX, a phase 3 trial of first-line FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)-based chemotherapy with or without selective internal radiation therapy (SIRT) in metastatic colorectal cancer patients with liver-dominant metastases. Improvement in progression-free survival, the primary endpoint, was not achieved in patients receiving SIRT. Disease progression in the liver, however, was reduced by 31% in patients receiving SIRT (SIR-Spheres; delivered as yttrium-90 microspheres via a hepatic artery injection).

Dr. van Hazel’s new SIRFLOX data pertained to 318 patients (159 FOLFOX plus bevacizumab; 159 FOLFOX plus bevacizumab plus SIRT) who had metastases only in the liver. Among them, progression-free survival with SIRT was extended by 8.7 months (FOLFOX plus bevacizumab, 12.4 months; FOLFOX plus bevacizumab plus SIRT, 21.1 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.48-0.86; P = .003). Among patients who had liver and extrahepatic metastases, however, the improvement in progression-free survival with SIRT was not significant (16.7 vs 12.6 months; P = .147). Dr. van Hazel noted that cumulative incidence of liver progression was superior for SIRT in patients with or without bevacizumab (P = .018 and .028, respectively).

"We saw that first-line radioembolisation in combination with bevacizumab and chemotherapy is able to retard progression in the liver, and it does seem to be safe," commented Dr. Verslype. "We feel, at our institution in Leuven, that we should restrict this to patients with very limited extrahepatic disease, where we can probably make a difference in the long run for our patients."

The phase 2 EORTC (European Organisation for Research and Treatment of Cancer) 40004/CLOCC trial, the first study prospectively investigating the efficacy of radiofrequency ablation added to standard systemic treatments in patients with nonresectable colorectal liver metastases, included 152 patients randomised to 6 months of systemic treatment with or without radiofrequency ablation. In ~75% of the patients, the systemic treatment was FOLFOX (with bevacizumab in ~17%). Prior reports showed the primary objective of overall survival of >38% at 30 months to have been met with 61.7% overall survival in the group receiving systemic treatment plus radiofrequency ablation and with 57.6% overall survival among those receiving systemic treatment only (NS), said Theo Ruers, MD, The Netherlands Cancer Institute, Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands, on July 3. Median progression-free survival, however, at a median follow-up of 4.4 years, was significantly longer for the radiofrequency group (16.8 vs 9.9 months; HR, 0.63; P = .025).

Progression-free survival at a median follow-up of 9.7 years was 2.0% for those receiving systemic therapy and 22.3% for systemic therapy plus radiofrequency ablation (HR, 0.57: 95% CI, 12.7-33.7; P = .005). Eight-year overall survival was 8.8% for systemic therapy alone and 35.9% for radiofrequency ablation (HR, 0.58, 95%; 95% CI, 0.38-0.88; P = .01). Progressive disease was the main cause of death (56.7% systemic plus radiofrequency ablation, 81.4% systemic only).

The findings, despite the small sample size, "encourage the use of ablative techniques as a treatment modality in patients with nonresectable colorectal liver metastases," said Dr. Ruer.

A third study, a phase 1 study of locoregional chemoablation with PV-10 (10% rose bengal solution), included patients with liver tumours (nonresectable hepatocellular carcinoma or liver metastases) of ≥1 cm.

The study demonstrated safety and activity, said Paul Goldfarb, MD, Sharp Clinical Oncology Research, San Diego, California, on July 2. PV-10 has shown high complete response rates and durable local control in phase 2 testing in metastatic melanoma and is currently in phase 3 testing.

This first presentation of 6 patients with evaluable liver data revealed only injection-site and photosensitivity reactions, with stable disease in all tumours and some partial responses. An expansion cohort includes 24 patients.

PV-10 is injected directly into lesions and has been shown to have effects on noninjected and distant lesions.

"We may expect some immunological effects with this kind of treatment, so locoregional treatment doesn’t necessarily mean that the effect of the therapy remains limited to the tumour itself in the liver. There may be effects on distant tumour sites," Dr. Verslype concluded.

On July 7, 2015 NanoString Technologies reported the publication of a study online in Clinical Cancer Research that reinforces the ability of the company’s Prosigna Breast Cancer Assay to inform physician treatment decisions by predicting which patients are most likely to benefit from chemotherapy (Press release, NanoString Technologies, JUL 7, 2015, View Source [SID:1234506184]). The study, entitled "Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay," was conducted in collaboration with Spanish researchers from Vall d’Hebron Institute of Oncology (VHIO), University of Barcelona, and University Hospital ‘Virgen de la Victoria’ of Malaga. The publication can be found online at View Source

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"These results highlight the value of considering tumor biology in the diagnostic evaluation of early stage breast cancer," said Dr. Aleix Prat, Head Medical Oncology Department at Hospital Clínic, University of Barcelona and Principal Investigator. "The results also support the findings of prior studies, which have shown that ROR score and intrinsic subtype are strong predictors of response to chemotherapy."

The study authors evaluated the correlation between numerical risk score provided by Prosigna, referred to as the ROR or Prosigna score, and response to a modern neoadjuvant chemotherapy (NAC) regimen consisting of anthracyclines and taxanes. The study demonstrated that ROR score and intrinsic subtype as determined by Prosigna are strong predictors of response to NAC, confirming expectations that high-risk tumors are significantly more responsive to systemic chemotherapy than low-risk tumors. The authors reported that ROR score significantly predicted pathologic complete response to NAC in hormone receptor-positive patients with node-negative or node-positive (1-3 positive nodes) disease (p = 0.027). Further analysis revealed that for every 20 point increase in the ROR score, a patient was 59.1% more likely to respond to NAC. Finally, the authors concluded that intrinsic subtypes, as determined by Prosigna, are predictive of chemotherapy sensitivity, as referenced in the recently updated St. Gallen International Breast Cancer Guidelines.

"This new evidence confirms Prosigna’s ability to predict response to chemotherapy," said Brad Gray, President and Chief Executive Officer of NanoString. "These results are complementary to the large body of data showing that Prosigna identifies women who are at such low risk that they may be spared overtreatment with chemotherapy."

Although the reported study results were based on the analysis of core needle biopsies, Prosigna is currently indicated for use with excisional biopsies only. Additionally, in the United States, the Prosigna patient report does not include information related to intrinsic subtype.

About the Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Dx Analysis System

The Prosigna Assay provides a risk category and numerical score for assessment of the risk of distant recurrence of disease at 10 years in postmenopausal women with node-negative (Stage I or II) or node-positive (Stage II), hormone receptor-positive (HR+) breast cancer. Based on the PAM50 gene signature initially discovered by Charles Perou, Ph.D. and colleagues, the Prosigna Assay is an in vitro diagnostic tool that utilizes gene expression data weighted together with clinical variables to generate a risk category and numerical score to assess a patient’s risk of distant recurrence of disease. The Prosigna Assay measures gene expression levels of RNA extracted from formalin-fixed paraffin embedded (FFPE) breast tumor tissue previously diagnosed as invasive breast carcinoma.

The Prosigna Assay requires minimal hands-on time and runs on NanoString’s proprietary nCounter Dx Analysis System, which offers a reproducible and cost-effective way to profile many genes simultaneously with high sensitivity and precision.

The nCounter Dx Analysis System is a highly automated and easy-to-use platform that utilizes a novel digital barcoding chemistry to deliver high precision multiplexed assays. The system is available in the multi-mode FLEX configuration, which is designed to meet the needs of high-complexity clinical laboratories seeking a single platform with the flexibility to run the Prosigna Breast Cancer Assay and, when operated in the "Life Sciences" mode, process translational research experiments and multiplexed assays developed by the laboratory.

In the United States, the Prosigna Assay is available for diagnostic use when ordered by a physician. The Prosigna Assay has been CE-marked and is available for use by healthcare professionals in the European Union and other countries that recognize the CE Mark, as well as Canada, Israel, Australia, New Zealand, Turkey, South Africa and Hong Kong.

In the U.S., the Prosigna Assay is indicated in female breast cancer patients who have undergone surgery in conjunction with locoregional treatment consistent with standard of care, either as:

(1) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-negative, Stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors or (2) a prognostic indicator for distant recurrence-free survival at 10 years in postmenopausal women with Hormone Receptor-Positive (HR+), lymph node-positive (1-3 nodes), Stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors. The device is not intended for patients with four or more positive nodes.

For more information, please visit www.prosigna.com.

On July 7, 2015 Clovis Oncology reported that it has commenced an underwritten public offering of shares of its common stock to raise aggregate proceeds of approximately $275 million (Press release, Clovis Oncology, JUL 7, 2015, View Source;p=RssLanding&cat=news&id=2065404 [SID:1234506183]). All shares of the common stock to be sold in the offering will be offered by Clovis Oncology.

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Clovis Oncology intends to use the net proceeds of the offering for general corporate purposes, including commercial planning and sales and marketing expenses associated with the potential launches of rociletinib and rucaparib, if approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in the United States and the European Union, respectively, funding of its development programs, general and administrative expenses, acquisition or licensing of additional product candidates or businesses and working capital.

J. P. Morgan Securities LLC is acting as lead book-running manager and representative of the underwriters for the offering. Credit Suisse Securities (USA) LLC is also acting as a joint book-runner, and Stifel and Mizuho Securities are acting as co-managers for the offering.

In addition, Clovis Oncology intends to grant the underwriters a 30-day option to purchase up to an additional 15 percent of the number of shares sold on the same terms and conditions. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

This offering is being made only by means of a prospectus supplement and related prospectus. Copies of the prospectus supplement and related prospectus relating to this offering may be obtained from J. P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717 or by calling toll-free (866) 803-9204.

The shares are being offered pursuant to an effective shelf registration statement. This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor will there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On July 6, 2015 Provectus Biopharmaceutical reported that it is partnering with a global pharmaceutical company to help bring to market its investigative drug for cancer, PV-10, in mainland China, Hong Kong and Taiwan (Press release, Provectus Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506182]).

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The letter of intent with Boehringer Ingelheim comes weeks after the Knoxville clinical-stage oncology and dermatology biopharmaceutical company announced a partnership with Pfizer, which jointly filed a patent application allowing for the use of PV-10 in combination with other types of drugs.

"We finally have the beginnings of serious validation by global pharma entities," said Peter Culpepper, the company’s chief financial and operating officer. "We’re starting to feel good and momentum is moving."

Provectus is in the midst of a Phase 3 clinical trial for PV-10, designed for injection into solid tumors to selectively target and destroy cancer cells in liver and melanoma.

The company, which is traded on the New York Stock Exchange, recently raised $13.1 million in a public offering of common stock and warrants, nearly doubling the company’s cash. An over-allotment option allowing for the purchase of additional shares may generate additional revenue.

Provectus intends to use the net proceeds of the offering for clinical development, working capital and general corporate purposes.

"We’re on the right track," Culpepper said. "We have the right people we’re talking to, but we legitimately need data."

The company is finally in a position to generate that data, he added.

It has in place a supply chain to manufacture the drug, intellectual property in various locations, a mechanism for data through Moffitt Cancer Center and the University of Illinois at Chicago, and now collaborations with big pharma companies that "agree with us and want to help."

On July 7, 2015 Provectus Pharmaceuticals reported two patients – one with hepatocellular carcinoma (HCC) and one with colorectal cancer (CRC) metastatic to the liver – had non-existent liver cancer at more than 40 months follow-up after a single injection of PV-10 to the liver (Press release, Provectus Pharmaceuticals, JUL 7, 2015, View Source [SID:1234506181]).

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The study, presented at the ESMO (Free ESMO Whitepaper) 17th World Congress on Gastrointestinal Cancer, 1-4 July, Barcelona, Spain, represents the first report of a chemoablative effect for PV-10 outside melanoma.

For HCC, the sixth most common cancer in the world and the third leading cause of cancer-related deaths globally (WHO, 2008), there is a clear unmet need for more effective therapies.

Treatment of HCC with chemotherapy, surgical resection, transplantation and other approaches (such as cryoablation, radiofrequency ablation, and chemoablation) have increased overall survival, but remain suboptimal.

The recent GIDEON study showed sorafenib, currently the only approved first line treatment in HCC, delivers a median overall survival of 10 months in patients under 70 years, and 20 months in patients older than 70 years.

PV-10, a 10% solution of rose bengal originally used as a textile dye and later as an agent to stain necrotic tissue in the cornea, has demonstrated high rates of complete response and durable response in metastatic melanoma.

In phase 2 data, presented last October at ESMO (Free ESMO Whitepaper), 50% of a subgroup of 28 patients with stage III melanoma who had all their cutaneous lesions injected with PV-10 achieved a compete response (where tumours totally disappeared) and 71% achieved an overall response (complete and partial response).

In animal models the investigators have successfully ablated liver, renal, breast and pancreatic tumours with PV-10.

"We had particularly high hopes of PV-10 working in liver cancer because these tumours are encapsulated with the result injected drugs should stay put longer," says Eric Wachter, the author of the abstract who co-developed PV-10.

For the current study two cohorts of patients, one with non-resectable HCC (n=6 patients overall, 7 tumours injected) and the second with other forms of cancer metastatic to the liver (n=7, 3 colorectal tumours, 2 non-small cell lung, 2 melanoma and 1 ovarian) underwent a single percutaneous injection of PV-10 guided by CT to one target lesion in the liver at least 1 cm in diameter.

The administered dose was 0.25 to 0.50 mL per cm³ lesion volume.

Patients could receive injection to a second tumour after initial follow-up of at least 28 days.

For the first analysis of five patients (six tumours) who had longer-term assessment, two patients showed no evidence of disease at more than 40 months follow-up according to RECIST and EASL criteria.

• The first patient was a 68 year old male with HCC (hepatitis B cirrhosis) alive at 54 months follow-up with no evidence of disease.
• The second patient was a 61 year old male with metastatic CRC alive at 42 months follow-up with no evidence of disease.

Furthermore, at up to 54 months follow-up 10 out of the initial 13 patients were alive, with one death due to cardiac comorbidity, one to serious adverse events and one to HCC progression.

Adverse events were generally limited to injection site reactions and photosensitivity and resolved without sequelae, with elevated liver enzymes observed during the first week after treatment.

"Having liver cancer patients alive at up to 54 months of follow-up with no evidence of disease is remarkable. This is even more extraordinary when you consider these patients received just one or two intralesional injections.

The study suggests that PV-10 has moved beyond just melanoma and may be agnostic to tumour type," says Wachter.

As with melanoma, the mechanism of PV-10 in HCC and metastatic liver disease is believed to be due to local chemoablative effects where the agent enters lysosomes causing tumour necrosis that can stimulate immunological effects.

In melanoma, patients injected with PV-10 have shown increased T cells in peripheral blood following injection including CD8 , CD4 , CD3 and NKT.

On the basis of these results Provectus Biopharmaceuticals, Inc. announced the signing of a Letter of Intent (LoI) with Boehringer Ingelheim China on July 2 to collaborate in bringing PV-10 to market in mainland China.

Together the two companies are planning phase 1b/2 studies of PV-10 in combination with standard of care (SOC) in liver cancer.

Provectus is also planning to expand the current cohort to 24 subjects with HCC and liver metastases, and also to HCC patients on sorafenib.
"We are confident that Boehringer Ingelheim’s expertise in navigating the regulatory requirements in China will prove beneficial to us," says Peter Culpepper, CFO and COO of Provectus.

With an estimated 400,000 new cases of HCC in China each year and 372,000 deaths, he adds, there is an urgent need for new treatments.

"The reason for the huge number of HCC cases in China is driven by population, hepatitis infection and aflatoxin, a fungal contaminant in maize that acts as a liver carcinogen."

Currently a phase 3 study of PV-10 versus dacarbazine or temozolomide is ongoing in patients with cutaneous and subcutaneous stage IIIB or IIIC melanoma.