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(iii) complete our ongoing Phase II FB-7 trial of PB272 as a neoadjuvant treatment for patients with HER2-positive breast cancer (anticipated in the first half of 2015)
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Source: press release, 5/11/15. http://www.pumabiotechnology.com/pr20150511.html

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Alan H. Auerbach, CEO, President and Chairman of the Board, commented on results for the NSABP FB-7 phase-II randomized clinical trial evaluating neoadjuvant therapy regimens with weekly Paclitaxel plus Neratinib or Trastuzumab or Neratinib and Trastuzumab followed by Doxorubicin and Cyclophosphamide with postoperative Trastuzumab in women with locally advanced HER2-Positive breast cancer. He stated, "We should have the results from that some time in the first half of 14'."
Source: Goldman Sachs 35th Annual Healthcare Conference, 6/12/14.

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NSABP FB-7 - A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens With Weekly Paclitaxel Plus Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide With Postoperative Trastuzumab in Women With Locally Advanced HER2-Positive Breast Cancer
Enrollment: 141
Study Start Date: October 2010
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01008150?term=neratinib&id=FB-7&ra...

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Neratinib (PB-272) MBCOncologyBreast Cancer (metastatic)HER-2 receptor inhibitorHER-2 receptor

Mechanism of action: Neratinib (PB-272) is an orally available, 6,7-disubstituted-4-anilinoquinoline-3-carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase with potential antineoplastic activity. Neratinib binds to the HER-2 receptor irreversibly, thereby reducing autophosphorylation in cells, apparently by targeting a cysteine residue in the ATP-binding pocket of the receptor. Treatment of cells with this agent results in inhibition of downstream signal transduction events and cell cycle regulatory pathways; arrest at the G1-S (Gap 1/DNA synthesis)-phase transition of the cell division cycle; and ultimately decreased cellular proliferation. Neratinib also inhibits the epidermal growth factor receptor (EGFR) kinase and the proliferation of EGFR-dependent cells.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2015-07-01 - 2015-09-30

Results:

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Puma Biotechnology Announces Results of Phase II Trial of PB272 in Neoadjuvant Treatment of HER2-Positive Locally Advanced Breast Cancer

"NSABP FB-7: A Phase II Randomized Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel plus Trastuzumab or Neratinib or Trastuzumab and Neratinib Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer"
LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, announced that results from a randomized Phase II clinical trial of Puma's investigational drug PB272 (neratinib) in the neoadjuvant treatment of locally advanced HER2-positive breast cancer were presented at the 2015 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas. The presentation entitled "NSABP FB-7: A Phase II Randomized Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel plus Trastuzumab or Neratinib or Trastuzumab and Neratinib Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer" will be presented today at the poster discussion session. This trial was sponsored by the NSABP Foundation, Inc.

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 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 is pathological complete response rate (pCR) in the breast and lymph nodes.

Tumor tissue was collected on patients at the time of diagnosis. This tissue will be analyzed for several biomarkers including AKT, cMET, EGFR, ESR-alpha, HER2, HER3, HER4, p95 HER2 and PI3K and intrinsic subtypes. A key secondary endpoint of this trial is the molecular and genetic correlates of response for each of these biomarkers. The analysis of these biomarkers is ongoing and will be presented at a medical meeting in 2016.

For the intent-to-treat patient population (hormone receptor positive (HR+) and hormone receptor negative (HR-)), the pCR rate for Arm 1 was 38.1%, for Arm 2 was 33.3% and for Arm 3 was 50.0%. For the HR+ patients, the pCR rate for Arm 1 was 29.6%, for Arm 2 was 27.6% and for Arm 3 was 30.4%. For the HR- patients, the pCR rate for Arm 1 was 57.1%, for Arm 2 was 46.2% and for Arm 3 was 73.7%.

Data Table: http://investor.pumabiotechnology.com/press-release/puma-biotechnology-a...

The most frequently observed severe adverse event in the two neratinib treated arms of the trial (Arm 2 and Arm 3) was diarrhea. In the first 19 patients treated in Arm 2 of the trial, high dose loperamide (16 mg per day initially) as primary prophylaxis was not given to prevent the neratinib-related diarrhea. In this subset of patients the grade 3 diarrhea rate was 42% (8/19). In the next 10 patients treated in Arm 2 and the first 20 patients treated in Arm 3, high dose primary prophylaxis (16 mg per day initially) with loperamide was given during the initial two weeks of the first cycle of treatment. Using two weeks of intensive loperamide prophylactically, the grade 3 diarrhea rate in Arm 2 was 30% (3/10) and the grade 3 diarrhea rate in Arm 3 was 35% (7/20). In the next 13 patients in Arm 2 and 22 patients in Arm 3, high dose prophylaxis (16 mg per day initially) was given for the entire first cycle of treatment (4 weeks). The grade 3 diarrhea rate was 15% (2/13) in Arm 2 and 23% (5/22) in Arm 3.

Data Table: http://investor.pumabiotechnology.com/press-release/puma-biotechnology-a...

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 promising clinical activity of neratinib in combination with trastuzumab as measured by pCR rates in the hormone receptor negative patients. We look forward to completing the biomarker analysis to determine which patients may derive the greatest benefit from this dual anti-HER2 therapy.”

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to complete this neoadjuvant trial of neratinib, both as a single agent and as a dual HER2 therapy in combination with trastuzumab. The 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."
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Source: press release, 12/10/15. http://investor.pumabiotechnology.com/press-release/puma-biotechnology-a...

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