On December 7, 2016 Panther Biotechnology, Inc. reported that it has received positive feedback from the submission presented to the U.S. Food and Drug Administration ("FDA") pursuant to a Pre-IND (Investigational New Drug) meeting with the Division of Oncology Products 1 (DOP1) of the Center for Drug Evaluation and Research (CDER) of the FDA (Press release, Panther Biotechnology, DEC 7, 2016, View Source [SID1234517402]). The purpose of the requested meeting was to obtain FDA’s input regarding Panther’s plans for the development of TRF-DOX, Panther’s novel transferrin-doxorubicin conjugate initially planned for the treatment of platinum-resistant ovarian cancer. In preparation for the meeting, Panther submitted a Pre-IND Package to FDA that described the information Panther intends on submitting in the TRF-DOX IND submission planned in 2017. The IND is the regulatory vehicle that will allow for the initiation of clinical trials with TRF-DOX initially for the treatment of ovarian cancer.

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Panther submitted the request to seek guidance on a Phase 2a Open Label Sequential Cohort, Ascending Dose, Blinded, DOXIL controlled Study to Evaluate the Safety, Pharmacokinetics and Preliminary Efficacy of Multiple Doses of TRF-DOX Administered Intravenously every 4 weeks for up to 12 months to patients with Advanced Platinum-refractory or -resistant Ovarian Cancer. The primary objective will be to evaluate the safety and tolerability of TRF-DOX administered intravenously to subjects with advanced platinum-refractory or resistant ovarian cancer for up to 12 months. Secondary objectives are tumor response rate (complete and partial responses) assessed every 3 months for 12 months following treatment according to Response Evaluation Criteria in Solid Tumors version 1.1. (RESIST) criteria, progression-free survival at 6 and 12 months following first injection of TRF-DOX and overall survival at 6 and 12 months following first injection of TRF-DOX.

FDA reviewed Panther’s manufacturing, preclinical pharmacology and toxicology, and clinical plans for TRF-DOX and provided specific feedback. In general, FDA agreed with Panther’s plans and offered further recommendations and comments. The manufacturing and nonclinical pharmacology and toxicology plans with TRF-DOX were deemed adequate pending review of actual data by FDA in the IND.

In addition, FDA had input into the design of the Phase 2b clinical trial with TRF-DOX which will be considered in the protocol submitted with the IND.

"This is a significant leap for Panther as we prepare to enter clinical trials in the US and we look forward to getting started," stated Evan Levine, Chief Executive Officer of Panther. "We are extremely pleased and thankful for not only the valuable feedback we received from FDA but also from the productive recommendations to manage TRF-DOX through the next stage of clinical development. Based on earlier encouraging clinical results, we believe we may have a greater opportunity for increasing clinical benefit for patients receiving treatment."
TRF-DOX binds to transferrin receptors on tumor cells, inhibits cancer cell proliferation and causes cell death. TRF-DOX has been shown to exhibit increased cytotoxicity relative to unconjugated doxorubicin toward a variety of cancer cell lines and reduced cytotoxicity to normal cells. In addition to improvements in cytotoxicity and selectivity, TRF-DOX exhibits cytotoxic effects in many multidrug-resistant cells in vitro. Tumor targeting of doxorubicin to transferrin receptors on the cell membranes of tumor cells is intended to improve the therapeutic index of doxorubicin and to reduce the development of doxorubicin resistance.

On December 7, 2016 Abbott (NYSE: ABT) reported it has filed a complaint to terminate its proposed acquisition of Alere based on the substantial loss in Alere’s value following the merger agreement (Press release, Abbott, DEC 7, 2016, View Source [SID1234517000]).

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In the 10 months following the Jan. 30, 2016, signing of the agreement, Alere has suffered a series of damaging business developments, including the government eliminating the billing privileges of a substantial Alere division, the permanent recall of an important product platform, multiple new government subpoenas, including two new criminal subpoenas, and a five-month delay in filing its 10K coupled with admissions of internal control failures requiring restatement of its 2013-2015 financials.

"Alere is no longer the company Abbott agreed to buy 10 months ago," said Scott Stoffel, divisional vice president of external communications, Abbott. "These numerous negative developments are unprecedented and are not isolated incidents brought on by chance. We have attempted to secure details and information to assess these issues for months, and Alere has blocked every attempt. This damage to Alere’s business can only be the result of a systemic failure of internal controls, which combined with the lack of transparency, led us to filing this complaint."

Under terms of the merger agreement, Abbott may terminate the transaction if adverse events materially change Alere’s long-term prospects. Abbott filed its complaint seeking termination in the Delaware Court of Chancery, citing these events among others as material adverse events.

On December 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that updated interim results from an ongoing Phase II clinical trial of Puma’s investigational drug PB272 (neratinib), given as monotherapy and in combination with the anticancer drug fulvestrant, were presented at the 2016 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 7, 2016, View Source [SID1234516992]). The presentation entitled "Neratinib plus fulvestrant for ERBB2 mutant, HER2 non-amplified, estrogen receptor-positive, metastatic breast cancer: Preliminary analysis from the Phase II SUMMIT trial" was presented as a poster discussion by Dr. David Hyman, Director, Developmental Therapeutics at Memorial Sloan Kettering Cancer Center.

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Interim results from this trial were previously presented at the 2015 SABCS and included patients who were treated with neratinib monotherapy for metastatic breast cancer and whose tumors have a HER2 mutation. The presentation also discussed that a bidirectional cross-talk between hormone receptor and HER2 signaling pathways could lead to endocrine resistance due to activated HER2 signaling and ER-mediated tumor proliferation as a potential resistance mechanism to sustained HER2 inhibition. Preclinical xenograft data has demonstrated that the combination of an anti-estrogen with neratinib results in enhanced anti-tumor activity in preclinical models of estrogen receptor positive/HER2-positive breast tumors. Based on this, the SUMMIT study was amended to allow for the combination of neratinib plus fulvestrant in eligible postmenopausal hormone receptor-positive breast cancer patients. The presentation at SABCS included an update on both the neratinib monotherapy cohort and the neratinib plus fulvestrant cohort.

In the study, patients with HER2 mutant metastatic breast cancer were enrolled and received 240 mg of neratinib daily either as monotherapy or in combination with fulvestrant. All patients received loperamide (16 mg per day initially) prophylactically for the first cycle of treatment in order to reduce the neratinib-related diarrhea. For the 25 patients in the group who received neratinib monotherapy, 23 patients (92%) had HER2-negative disease, 19 patients (76%) were hormone receptor positive (estrogen receptor or progesterone receptor positive), and patients had received a median of 4 prior lines of therapy in the metastatic setting (range 0-8 prior regimens) before entering the trial. For the 17 patients in the trial who received neratinib plus fulvestrant, 15 patients (88%) had HER2-negative disease, 17 patients (100%) were hormone receptor positive (estrogen receptor or progesterone receptor positive), and patients had received a median of 4 prior lines of therapy in the metastatic setting (range 1-7 prior regimens) before entering the trial.

The interim efficacy results from the trial showed that for the 24 efficacy evaluable patients in the neratinib monotherapy cohort, 8 patients (33.3%) experienced an objective response, which included 3 patients with a complete response and 5 patients with partial responses. At week 8, 8 patients (33.3%) achieved an objective response, with 2 patients achieving a complete response and 6 patients achieving a partial response The secondary endpoints of the trial included confirmed objective response (complete response or partial response), clinical benefit rate and progression free survival (PFS). The results of the trial showed that 6 patients (25%) had a confirmed objective response, 10 patients (41.7%) demonstrated clinical benefit and the median progression free survival was 3.5 months.

For the 12 efficacy evaluable patients in the neratinib plus fulvestrant cohort, 7 patients (58.3%) experienced an objective response, which included 2 patients with a complete response and 5 patients with partial responses. At week 8, 5 patients (41.7%) achieved an objective response, with 2 patients achieving a complete response and 3 patients achieving a partial response. The secondary endpoints of the trial included confirmed objective response (complete response or partial response), clinical benefit rate and progression free survival (PFS). The results of the trial showed that 3 patients (25%) had a confirmed objective response, 7 patients (58.3%) demonstrated clinical benefit and the median progression free survival was 3.7 months. The progression free survival data may not be mature in the neratinib plus fulvestrant cohort as 4 of the 12 efficacy evaluable patients are continuing to receive study treatment without disease progression and an additional 5 patients have not yet had an assessment for efficacy.

The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 25 patients enrolled in the neratinib monotherapy arm, 6 patients (24%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for the patients in the neratinib monotherapy cohort was 1 day. No patient in the neratinib monotherapy cohort has permanently discontinued neratinib due to diarrhea and 5 patients (20%) have temporarily discontinued neratinib due to diarrhea and then restarted after the diarrhea subsided. For the 17 patients enrolled in the neratinib plus fulvestrant cohort, 2 of 17 patients (12%) experienced grade 3 diarrhea. The median duration of grade 3 diarrhea was 1 day and typically occurred during the first cycle of treatment. No patient (0%) in the neratinib plus fulvestrant cohort permanently discontinued neratinib due to diarrhea and 2 patients (12%) temporarily discontinued neratinib due to diarrhea and then restarted after the diarrhea subsided.

Dr. David Hyman, Director, Developmental Therapeutics at Memorial Sloan Kettering Cancer Center and principal investigator of the trial, stated, "Neratinib showed promising signs of clinical activity both as a single agent and in the patients treated with the combination of neratinib plus fulvestrant in this preliminary analysis of pre-treated HER2 mutant breast cancer patients. The safety profile of the drug was manageable and the diarrhea was not treatment-limiting with appropriate prophylaxis and management. We look forward to completing the ongoing neratinib plus fulvestrant cohort and moving this combination forward into future clinical development."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are very pleased with the preliminary activity seen with neratinib, both alone and in combination with fulvestrant in this cohort of patients with HER2 mutated breast cancer. We look forward to the completion of the trial and further development of the combination of neratinib and fulvestrant."

On December 7, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that a biomarker analysis of the NSABP FB-7 Phase II clinical trial of Puma’s investigational drug PB272 (neratinib) was presented at the 2016 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 7, 2016, View Source [SID1234516991]). The presentation entitled "An exploratory correlative biomarker analysis of NSABP FB-7, a phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide (AC) with postoperative T in women with locally advanced HER2-positive breast cancer" was presented as a poster presentation. This trial was sponsored by the NSABP Foundation, Inc.

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The FB-7 trial is a randomized Phase II clinical trial for women with HER2-positive locally advanced stage IIB-IIIC invasive breast cancer. Patients were randomly assigned to receive trastuzumab (T) or neratinib (N) or the combination (T+N) with weekly paclitaxel (P) followed by standard doxorubicin and cyclophosphamide chemotherapy (AC) administered prior to surgery. 126 U.S., Canadian, and European patients were randomly assigned to Arm 1 (T+P followed by AC), Arm 2 (N+P followed by AC) or Arm 3 (T+N+P followed by AC). The primary endpoint of the trial was pathological complete response rate (pCR) in the breast and lymph nodes. The clinical safety and efficacy data from this trial was presented at the 2015 SABCS.

A key secondary endpoint of the FB-7 trial was to evaluate molecular and genetic markers for correlation with response. Pre-treatment core biopsy samples (n=59) and post treatment surgical samples (n=17) were obtained from a subset of patients treated in the FB-7 trial. pCR data were available for 51 patients from the biomarker cohort. After excluding low tumor content non-evaluable samples, correlative biomarker analysis was performed in 42 patients.

Expression levels and the activation status of EGFR/HER2 signaling proteins were investigated. The results of the phosphorylated HER2 (phosphoHER2) showed that median levels of phosphoHER2 were higher in the patients who achieved a pCR with neratinib (n=7) than in the patients who did not achieve a pCR who received either trastuzumab (n=8, p=0.07) or the combination of trastuzumab plus neratinib (n=4, p=0.035). There was not a significant difference in the median levels of phosphoHER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.10).

The truncated form of HER2 known as p95HER2 was measured by the proprietary assay of Pierian Bioscience. p95HER2 represents a truncated form of the HER2 receptor that lacks the extracellular trastuzumab binding domain. It is believed to represent a mechanism of trastuzumab resistance. Median p95HER2 levels were higher in samples from patients who achieved a pCR with neratinib than in the patients who did not achieve a pCR who received either trastuzumab (p=0.027) or the combination of trastuzumab plus neratinib (p=0.009). There was not a significant difference in the median levels of p95HER2 in the patients who achieved a pCR with neratinib (n=7), trastuzumab (n=8, p=0.16) or the combination of trastuzumab plus neratinib (n=4, p=0.35).

The MammaPrint assay was performed on 59 samples to determine if there was any imbalance between arms. This assay is a genomic test that analyzes the activity of 70 genes and then calculates a recurrence score that is either low risk or high risk. The results of the MammaPrint showed that the patients in all three arms of the FB-7 trial were balanced with the median MammaPrint risk score being similar across arms. There were only three patients with a MammaPrint low score.

Dr. Samuel Jacobs, Emeritus Clinical Professor in the Department of Medicine, University of Pittsburgh School of Medicine, and the Director of Medical Affairs for the NSABP Foundation, Inc., said, "We are pleased to see the results of this exploratory biomarker analysis which suggests that activation of the HER pathway based on p95HER2 and phosphoHER2 may correlate with pCR to neratinib. Further biomarker analysis in additional datasets will be needed to determine which patients may derive the greatest benefit from neratinib."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to complete this biomarker analysis of neratinib. Further results of the biomarker analysis should help us to determine the best path forward for neratinib in the neoadjuvant treatment of HER2-positive early stage breast cancer."

On December 7, 2016 PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported the first article in a series of Q&A articles that will be conducted with some of the key team members of PharmaCyte’s planned clinical trial in locally advanced, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, DEC 7, 2016, View Source [SID1234516987]). PharmaCyte’s first Q&A article is with Dr. Matthias Löhr of the famed Karolinska Institute in Stockholm, Sweden. Dr. Löhr was the Principal Investigator of the two earlier clinical trials using the Cell-in-a-Box technology in patients with advanced, inoperable pancreatic cancer.

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As PharmaCyte prepares to meet with the FDA in a Pre-IND meeting, what are your general thoughts of the Cell-in-a-Box plus low dose ifosfamide therapy for pancreatic cancer once again getting a chance to prove itself in patients?

Dr. Matthias Löhr: "I feel very confident and also happy to see the revival of this treatment concept. I consider Cell-in-a-Box as a platform technology. The previously raised concerns relating to the consistent reproducibility of the micro-capsules have been met by Austrianova in the meantime. Pancreatic cancer is a medical emergency (View Source) and is rising amongst the cancer related deaths, this year surpassing breast cancer to become number three, and by 2030 to become number two."

As the Principle Investigator of both of the earlier clinical trials, what are some of the highlights you recognized that you feel will once again be seen in PharmaCyte’s upcoming trial?

Dr. Matthias Löhr: "When we treated the first patients, they did not believe that they were receiving chemotherapy because there were NO side effects at all in the initial trial. That should be the case in PharmaCyte’s upcoming trial. Besides this very subjective impression, albeit repeated by all patients, we measured the quality of life, which was excellent – considering the dire disease. We will be measuring the quality of life in the upcoming trial as well. Further, we saw an effect not only on the primary tumor in the pancreas (where the capsules were injected) but also in some patients on the liver metastasis. This can only be explained by an immunological bystander effect that will likely be investigated in more depth in the upcoming clinical trial. Finally, in the first trial, certain patients’ tumors went from inoperable to operable. That is certainly a possibility in PharmaCyte’s trial, especially since we will be giving more than two courses of ifosfamide like we did in the first trial."

Why do you feel this new trial design can succeed?

Dr. Matthias Löhr: "The locally advanced pancreatic cancers are not sufficiently covered by guidelines – there is no standard of care, hence a highly unmet medical need. This refers particularly to those patients who received first line therapy, e.g. a very strong one (FOLFIRINOX) or combination of gemcitabine with Abraxane. AFTER this therapy, there is nothing left, especially an alternative with a low likelihood of side effects. The selection of these patients (group) is certainly to an advantage of the Cell-in-a-Box technology, which is mostly localized, may have a systemic (immunological) effect and has virtually no side effects. We consider this an ideal setting to the advantage of our patients in this upcoming clinical trial."

What are your thoughts on the benefits of using more rounds of the chemotherapy prodrug ifosfamide as PharmaCyte’s trial design calls for in this upcoming clinical trial?

Dr. Matthias Löhr: "This will definitively improve the outcome of the patients in this upcoming clinical trial. We couldn’t do this in the original trial(s) as we had no information on the stability of the capsules and activity of the cells converting the chemotherapy drug ifosfamide. This has changed now with the data developed from the first two trials. We will continue to administer ifosfamide until the patients receive no further benefit from our therapy. We can do that because we know the capsules are robust for at least two years and that the cells within them continue to convert ifosfamide during the life of the patient."

What are your thoughts on going head to head with gemcitabine?

Dr. Matthias Löhr: "No sweat. Gemcitabine is still the standard, due to the excellent tolerability of the drug and will be the drug used second line, especially after heavy protocols such as FOLFIRINOX or gemcitabine/ Abraxane. In this pretreated patient group, one has to use something with a very low profile on side effects. This is certainly the case with our Cell-in-A-Box."

What are your impressions of the team that surrounds the technology as PharmaCyte heads into its planned clinical trial?

Dr. Matthias Löhr: "PharmaCyte has the visionary capacity to see the potential of this platform technology, with pancreatic cancer being the first indication. They reached out to the original team, both those developing the technology and conducting the early phase clinical trials. Taking this knowledge on board is certainly the most important factor to ensure success. Further, with both Dr. Manuel Hidalgo and Dr. Daniel Von Hoff, two eminent oncologists with a lifetime track record in oncology and especially pancreatic cancer, the starting conditions could not be better."