On April 3, 2018 Eleven Biotherapeutics, Inc. (NASDAQ: EBIO), a late-stage clinical company developing next-generation antibody-drug conjugate (ADC) therapies for the treatment of cancer, reported that preliminary efficacy and safety data from its ongoing Phase 3 VISTA trial of Vicinium in patients with non-muscle invasive bladder cancer (NMIBC) who have been previously treated with bacillus Calmette-Guérin (BCG) have been selected for presentation during a plenary session currently scheduled for Monday, May 21, 2018 at 11:00 a.m. PT at the American Urological Association Annual Meeting taking place in San Francisco (Press release, Eleven Biotherapeutics, APR 3, 2018, View Source [SID1234525376]). Vicinium is a fusion protein, designed to be a next-generation ADC, that targets the epithelial cell adhesion molecule (EpCAM) antigens on the surface of bladder cancer cells to deliver a potent cytotoxin into those cells.

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Data, as reported in the abstract published online today, are from a subgroup of the first 75 evaluable carcinoma in situ patients. Within these patients, preliminary findings show that greater than 95 percent expressed EpCAM on the surface of tumor cells, the target of Vicinium. Efficacy data as measured by complete response rates at three-months will be reported during the plenary session. Vicinium has been well-tolerated. Treatment-related adverse events (AEs) were reported in 46 percent of patients, the majority of which were Grade 1 or 2. The most common of these were dysuria (12%), UTI or pollakiuria (10%) and hematuria (7%), which are often associated with catheter-delivered treatments into the bladder and bladder cancer itself. As of the December 2017 data cut off, three treatment-related serious AEs were reported, including renal failure (CTCAE Grade 5) with cholestatic hepatitis (Grade 4) in one patient and acute kidney injury (Grade 3) in a second patient who recovered.

In March 2018, recruitment was completed in the VISTA trial, a single-arm registration study designed in accordance with U.S. Food and Drug Administration’s final guidance for developing treatments for BCG-unresponsive NMIBC.
"When treatment with today’s standard of care, BCG, is no longer an option, the next treatment option is typically removal of the patient’s bladder, a challenging, life-altering procedure that many patients elect not to undergo," said Stephen Hurly, president and chief executive officer of Eleven Biotherapeutics. "Vicinium has demonstrated that it is a well-tolerated and active agent in patients with BCG unresponsive NMIBC in studies to-date. We are excited to be presenting the first preliminary data from our Phase 3 VISTA trial of Vicinium for patients with NMIBC at this year’s AUA meeting. During our plenary presentation, we will share initial efficacy findings and data supporting the favorable safety we have observed so far with Vicinium. We believe Vicinium holds tremendous potential as a treatment for bladder cancer, and we look forward to sharing these and additional data later in the year."
The company plans to host a conference call in conjunction with the data presentation, with details to follow.
About the VISTA Clinical Trial
The VISTA trial is an open-label, multicenter, single-arm Phase 3 clinical trial evaluating the efficacy and tolerability of Vicinium in patients with high-risk non-muscle invasive bladder cancer (NMIBC) that is carcinoma in situ (CIS, cancer found on the inner lining of the bladder that has not spread into muscle or other tissue) or papillary (cancer that has grown from the bladder lining out into the bladder but has not spread into muscle or other tissue), who have been previously treated with bacillus Calmette-Guérin (BCG). The primary endpoint of the trial is the complete response rate in patients with CIS with or without papillary disease and durability of that response. Patients in the study receive locally administered Vicinium twice a week for six weeks, followed by once-weekly treatment for another six weeks, then treatment every other week for up to two years. Topline data assessing responses and durability of responses at three-months on treatment are expected in mid-2018, with 12-month data anticipated in mid-2019.

About Vicinium
Vicinium, Eleven Biotherapeutics’ lead product candidate, is a next-generation antibody-drug conjugate developed using the company’s proprietary Targeted Protein Therapeutics platform. Vicinium is comprised of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas Exotoxin A (ETA). Vicinium is constructed with a stable, genetically engineered linker to ensure the payload remains attached until it is internalized by the cancer cell, which is believed to decrease the risk of toxicity to healthy tissues, thereby improving its safety. In prior clinical studies conducted by Eleven Biotherapeutics, EpCAM has been shown to be overexpressed in non-muscle invasive bladder cancer (NMIBC) cells with minimal to no EpCAM expression observed on normal bladder cells. Eleven Biotherapeutics is currently conducting the Phase 3 VISTA trial, designed to support the registration of Vicinium for the treatment of NMIBC in patients who have previously received two courses of bacillus Calmette-Guérin (BCG) and whose disease is now BCG-unresponsive. Topline, three-month data from the trial are expected in mid-2018. Additionally, Eleven Biotherapeutics believes that Vicinium’s cancer cell-killing properties promote an anti-tumor immune response that may potentially combine well with immuno-oncology drugs, such as checkpoint inhibitors. The activity of Vicinium in BCG-unresponsive NMIBC is also being explored at the US National Cancer Institute in combination with AstraZeneca’s immune checkpoint inhibitor durvalumab.

On April 3, 2018 Pfizer Inc. (NYSE:PFE) and Allogene Therapeutics, Inc. (Allogene) reported that the two companies have entered into an asset contribution agreement for Pfizer’s portfolio of assets related to allogeneic chimeric antigen receptor T cell (CAR T) therapy, an investigational immune cell therapy approach to treating cancer (Press release, Pfizer, APR 3, 2018, https://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_allogene_therapeutics_enter_into_asset_contribution_agreement_for_pfizer_s_allogeneic_car_t_immuno_oncology_portfolio [SID1234525452]).

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Pfizer Inc. (NYSE:PFE) and Allogene Therapeutics, Inc. (Allogene) reported that the two companies have entered into an asset contribution agreement for Pfizer’s portfolio of assets related to allogeneic chimeric antigen receptor T cell (CAR T) therapy, an investigational immune cell therapy approach to treating cancer.

Pfizer views this agreement as an attractive opportunity to support the continued development of allogeneic CAR T therapy in a highly focused and skilled manner. Pfizer will continue to participate financially in the development of the CAR T portfolio through a 25 percent ownership stake in Allogene. Separately, Pfizer continues to have an 8 percent ownership stake in Cellectis through an equity agreement entered into in 2014. Allogene, a Two River portfolio company, was formed with Series A financing of $300 million from an investment consortium that includes TPG, Vida Ventures, BellCo Capital, the University of California Office of the Chief Investment Officer and Pfizer, among others. TPG, Vida Ventures, BellCo Capital and Pfizer will be represented on the Allogene Board of Directors. Closing is expected in the second quarter of 2018, subject to closing conditions.

"The allogeneic CAR T platform represents a potentially transformative approach to treating cancer, and we are very excited about what the future may hold for this area of research," said Robert Abraham, Senior Vice President and Group Head, Oncology Research & Development, Pfizer. "We believe that under the strong scientific, clinical development and regulatory expertise of Allogene’s leadership team, the portfolio of CAR T assets contributed by Pfizer will be well-positioned to rapidly advance into potential innovative new therapies, and ultimately to reach patients in need more quickly."

"While there is important work underway across the industry for next-generation autologous cell therapy, Allogene hopes to bring about the next revolution in the field with the successful development of allogeneic cell therapy and the potential for greater and faster patient access," said Belldegrun. "Under the direction of David Chang, an extraordinary scientist, physician and life sciences business executive with over 30 years of unprecedented experience in developing cancer treatments, Allogene is poised to potentially lead the development of one of the most exciting opportunities in our industry today."

"Last year, Kite’s anti-CD19 CAR T therapy became the first autologous CAR T treatment to be approved by the U.S. Food and Drug Administration for adult patients with aggressive non-Hodgkin lymphoma. Many believed the idea was rooted in science fiction, but science fiction became a reality," said Chang. "We believe that this partnership among leaders in the field – visionaries, industry forerunners, venture capitalists and researchers – has the potential to accelerate the development of allogeneic T cell therapy, making it a reality and forever changing how cancer is treated."

"Investing in innovation and R&D has long been a hallmark of who we are as investors, and for many years, we’ve been partnering with dynamic companies that are driving meaningful change in healthcare," said Todd Sisitsky, Managing Partner, TPG Capital. "We believe CAR T is one of the most exciting spaces within the pharmaceutical landscape today, and we are thrilled to partner with a best-in-class management team and industry leaders to invest in this potentially groundbreaking opportunity."

"As a pioneer of the allogeneic approach and expert in gene editing, the Cellectis team is excited by this agreement and eager to continue this groundbreaking work with Allogene’s experienced team, striving to accelerate the development of the portfolio and to continue along the path of making these treatments available to patients as soon as possible," said Dr. André Choulika, Cellectis CEO.

"I believe that the recognized expertise of the Allogene team in the field of CAR T will be of benefit to the development of UCART19, for which Servier is the sponsor of two clinical studies," commented Olivier Laureau, President of Servier Group. "The development of off-the-shelf allogeneic CAR T therapy in the field of oncology initiates a revolution that could potentially expand access of such innovative treatment to a larger number of oncologists and their patients."

Centerview Partners is acting as financial advisor to Pfizer, with Ropes & Gray LLP acting as its legal advisor. Cooley LLP is serving as legal counsel to Allogene, Vida Venture and TPG. Gibson Dunn & Crutcher LLP are also serving as legal counsel to TPG.

Allogeneic CAR T Cell Therapies

Allogeneic CAR T cell therapies have the potential to become the next advancement in one of the most powerful anti-cancer agents, eliminating the need to create personalized therapy from a patient’s own cells. These therapies are developed from cells of healthy donors and stored for "off-the-shelf" use in patients, simplifying manufacturing process and reducing waiting time for patients.

Allogene will receive from Pfizer the rights to 16 preclinical CAR T assets licensed from Cellectis and Servier and one clinical asset licensed from Servier, UCART19, an allogeneic CAR T therapy that is being developed for treatment of CD19-expressing hematological malignancies. In partnership with Servier, UCART19 is initially being developed in acute lymphoblastic leukemia (ALL) and is currently in Phase I. UCART19 utilizes TALEN gene editing technology pioneered and owned by Cellectis.

Allogene and Servier intend to initiate Phase 2 studies in 2019. Under the terms of the original development agreement, Allogene will have exclusive rights to develop and commercialize UCART19 in the United States, while Servier will retain exclusive rights for all other countries.

Pfizer’s Commitment to Immuno-Oncology

Immuno-Oncology (IO) is a key area of focus within Pfizer’s broad oncology portfolio, with research and development efforts spanning diverse modalities and mechanisms of action that tap into key immune system functions, harnessing the natural ability of the immune system to fight cancer. We believe that the future of IO lies in novel, biologically rational combinations based on unique tumor characteristics. We believe that Pfizer Oncology’s pipeline is in a strong position to help advance the next wave of IO science by developing new targeted therapies and IO combinations – areas in which Pfizer has a robust and proven legacy. We know that great science comes through collaboration, and we actively team up with strategic partners in IO who we believe will strengthen our portfolio and help speed innovative treatments to benefit more patients.

About Allogene Therapeutics

Allogene Therapeutics is a biotechnology company with a mission to catalyze the next revolution in cancer treatment through the development of allogeneic chimeric antigen receptor T-cell (CAR T) therapy directed at blood cancers and solid tumors. Founded and led by former Kite Pharma executives who bring unrivaled clinical development acumen in cell therapy, Allogene is well-positioned to further the potential of allogeneic cell therapy for patients.

Allogeneic CAR T therapies are engineered from cells of healthy donors and stored for "off-the-shelf" use in patients. This approach eliminates the need to create personalized therapy from a patient’s own cells, simplifies manufacturing, and reduces the time patients must wait for CAR T treatment. The Allogene portfolio includes 16 pre-clinical T cell therapy assets and UCART19, an allogeneic CAR T therapy currently in Phase 1 development for the treatment of acute lymphoblastic leukemia (ALL). Through its notable partnerships, Allogene leverages pioneering technology platforms, including TALEN gene editing technology, to progress its portfolio of immuno-oncology therapies. Allogene, with headquarters in San Francisco, California, is a Two River portfolio company formed with one of the largest Series A financings in biotechnology from an investment consortium that includes TPG, Vida Ventures, BellCo Capital, the University of California Office of the Chief Investment Officer and Pfizer, among others. For more information, please visit www.allogene.com, follow @AllogeneTx on Twitter and LinkedIn.

On April 3, 2018 Diffusion Pharmaceuticals Inc. (Nasdaq:DFFN) ("Diffusion" or "the Company"), a clinical-stage biotechnology company focused on extending the life expectancy of cancer patients using the novel small molecule trans sodium crocetinate (TSC) in conjunction with standard radiation and chemotherapy, reported 2017 financial results and provides a business update. Diffusion’s lead clinical trial program, the INvestigation of TSC Against Cancerous Tumors (INTACT) trial, is a Phase 3 study expected to enroll a total of 236 patients, with half in the treatment arm and half in the control arm (Press release, Diffusion Pharmaceuticals, APR 3, 2018, View Source [SID1234525158]). The design of INTACT is based on an almost four-fold increase in overall survival at two years demonstrated in inoperable GBM patients in the preceding Phase 2 study.

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"We began opening clinical sites for the INTACT trial in December as planned, and started enrolling and dosing patients in January while continuing to open more clinical sites," said David Kalergis, Chairman and Chief Executive Officer of Diffusion Pharmaceuticals. "We believe that the INTACT trial can provide a promising new treatment option for the thousands of patients who each year are newly diagnosed with inoperable GBM brain cancer and who, because of their poor prognosis, may be excluded from other clinical trials."

In January 2018 the Company conducted a public offering, raising gross proceeds of approximately $12.0 million from the sale of common stock and warrants. In conjunction with this capital raise, all the Company’s preferred stock was converted into common stock, eliminating the obligation for future dividend payments and certain restrictive provisions contained therein.

In January 2018 the Company, along with researchers from the University of California Los Angeles (UCLA) and the University of Virginia (UVA), presented an abstract at the International Stroke Conference in Los Angeles describing a Phase 2 trial design to test TSC for use in acute stroke. The planned Phase 2, randomized, double-blind, placebo-controlled trial calls for the administration of TSC by specially-trained Emergency Medical Technicians to ambulance-transported patients within two hours of the onset of a suspected acute stroke, potentially overcoming the current severe timing obstacle in the treatment of stroke patients. The trial, which has been named the Pre-Hospital Ambulance Stroke Trial – TSC (PHAST-T) is expected to commence in late 2018, subject to funding.

The Company further expanded its intellectual property portfolio in 2017, with the allowance of key patents that increased coverage of the therapeutic use of TSC and related compounds. The new areas include congestive heart failure, chronic renal failure, acute lung injury, chronic obstructive pulmonary disease and respiratory distress syndrome. Additional claims were also allowed relating to the treatment of a number of cancer types including brain and pancreatic, using TSC along with chemotherapy and radiation therapy.

Financial Results for the Year Ended December 31, 2017

We had cash and cash equivalents of $8.9 million as of December 31, 2017. Subsequent to the close of the year, on January 22, 2018 we closed an underwritten public offering of stock and warrants, raising approximately $12.0 million in gross proceeds.

We recognized $5.1 million in research and development expenses during 2017, compared with $7.3 million during 2016. This decrease was primarily attributable to a decrease of $1.3 million related to animal toxicology studies, a decrease of $0.9 million of pancreatic expenses, a decrease of $0.6 million related to stock-based compensation expense and a decrease of $0.3 million in manufacturing-related expenses. We also recognized a $1.0 million impairment charge upon our abandonment of future development efforts related to our RES-440 IPR&D asset in 2016. These decreases were offset by increases in GBM trial expenses of $1.6 million as we prepared for the Phase 3 clinical trial for TSC and increases in salaries and wages expenses of $0.2 million as a result of an increase in headcount. We currently expect our research and development expenses to increase significantly in future periods due to costs associated with our Phase 3 clinical trial for TSC, the Phase 2 trial for pre-hospital stroke therapy and overall efforts to advance the research and development of our technologies and product candidates.

General and administrative expenses were $6.2 million during 2017, compared with $11.1 million during 2016. The decrease was primarily due to a decrease of $3.2 million in professional fees incurred in 2016 in connection with preparations to operate as a public company and a $2.5 million decrease in non-cash litigation settlement fees, offset by increases in salary and wages and stock-based compensation expense of $0.4 million and $0.4 million, respectively, due to our increase in headcount.

In connection with the private placement of our Series A convertible preferred stock and common stock warrants in March 2017, we determined the warrants to be classified as liabilities and subject to remeasurement at each reporting period. As such, during 2017 we recorded a $22.1 million non-cash gain for the change in fair value of our common stock warrant liabilities, which was primarily attributable to the decrease in the market price for our common stock. We also recognized $10.2 million in excess fair value of the common stock warrants over the gross proceeds from our private placement and $2.9 million in placement agent commissions and other offering costs.

On April 3, 2018 Delcath Systems, Inc. (OTCQB:DCTH), an interventional oncology company focused on the treatment of primary and metastatic liver cancers, announces that Dr. Brian Steadman, Interventional Oncologist at the Southampton University Hospital will present a video training session at the Annual Meeting of the European Conference of Interventional Oncology (ECIO) (Press release, Delcath Systems, APR 3, 2018, View Source;p=RssLanding&cat=news&id=2340763 [SID1234525453]). Dr. Steadman will present an overview of the Percutaneous Hepatic Perfusion (PHP) procedure and potential indications of PHP Therapy, as well as review recent research. The session will be held Tuesday, April 24, 2018 at 3pm local time.

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The ECIO will be held in Vienna, Austria, April 22-25, 2018.

On April 3, 2018 AstraZeneca and Merck (NYSE:MRK), known as MSD outside the US and Canada, reported that the European Medicines Agency has validated for review the Marketing Authorization Application (MAA) for LYNPARZA (olaparib) for use in patients with deleterious or suspected deleterious BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been previously treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting (Press release, Merck & Co, APR 3, 2018, View Source [SID1234525159]).

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This is the first regulatory submission for a poly ADP-ribose polymerase (PARP) inhibitor in breast cancer in Europe. If approved, the identification of a patient’s BRCA status could become a critical step in the management of their disease alongside current consideration of their hormone receptor and HER2 status. The MAA is based on data from the randomized, open-label, phase 3 OlympiAD trial, which investigated LYNPARZA versus chemotherapy (physician’s choice of capecitabine, eribulin, or vinorelbine). In the trial, LYNPARZA significantly prolonged progression-free survival compared with chemotherapy, and reduced the risk of disease progression or death by 42 percent (HR 0.58; 95% CI 0.43-0.80; P=0.0009 median 7.0 vs 4.2 months).

In January 2018, LYNPARZA was approved by the U.S. Food and Drug Administration for use in the treatment of BRCA-mutated HER2-negative metastatic breast cancer, becoming the first PARP inhibitor to be approved beyond ovarian cancer. LYNPARZA is available in nearly 60 countries and has been used to treat more than 20,000 patients. AstraZeneca and Merck are working together to bring LYNPARZA to more patients across multiple cancers.

About OlympiAD

OlympiAD is a global, randomized, open-label, multi-center phase 3 trial of 302 patients, assessing the efficacy and safety of LYNPARZA tablets (300 mg twice daily) compared to physician’s choice of chemotherapy. 205 patients were randomized to receive LYNPARZA and 97 patients were randomized to receive chemotherapy.

Patients in the OlympiAD trial had germline BRCA-mutated, HER2-negative (hormone receptor-positive or triple-negative) breast cancer, and received LYNPARZA for treatment in the metastatic setting. Prior to enrollment, 71 percent of patients had received no more than two previous chemotherapy treatments for metastasized breast cancer and 28 percent of patients had received prior platinum-based chemotherapy. Also enrolled, were patients with HR+ breast cancer who had received at least one endocrine therapy (adjuvant therapy or therapy for metastatic disease) and had disease progression during therapy unless they had disease for which the endocrine therapy was considered inappropriate.

About Metastatic Breast Cancer

Progesterone receptors (PR), estrogen receptors (ER) and HER2 receptors may be expressed on breast cancer cells. A patient’s breast cancer will test either negative or positive for these three receptors. If a tumor tests positive for PR and/or ER, it is considered HR+. If a tumor tests negative for all three receptors, it is considered triple negative. These receptors indicate which hormones or other proteins may be promoting growth of the cancer.

Metastatic breast cancer (MBC) is the most advanced stage of breast cancer (Stage IV), and occurs when cancer cells have spread beyond the initial tumor site to other parts of the body outside of the breast and nearby lymph nodes.

Despite the increase in treatment options during the past three decades, there is currently no cure for patients diagnosed with MBC and only 26.9 percent of patients survive for five years after diagnosis. Thus, the primary aim of treatment is to slow progression of the disease for as long as possible, improving, or at least maintaining, a patient’s quality of life.

Breast cancer is the most common cancer in women, with an estimated 1.67 million new cases diagnosed worldwide in 2012 alone – one in four of all cancer cases. Approximately 30 percent of women who are diagnosed with early breast cancer will go on to develop advanced disease.

About BRCA Mutations

BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About LYNPARZA (olaparib)

LYNPARZA was the first in class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro trials have shown that LYNPARZA-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

LYNPARZA, which has the broadest clinical development program of any PARP inhibitor, is being investigated in a range of DDR-deficient tumor types.

The most frequently observed adverse reactions across clinical trials in patients receiving LYNPARZA monotherapy (≥10%) were nausea, vomiting, diarrhea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness and anemia.

LYNPARZA, the first poly ADP-ribose polymerase (PARP) inhibitor approved, was initially licensed as a capsule formulation. The new tablet formulation will reduce dosing from eight capsules twice daily to two tablets twice daily.

LYNPARZA is available in nearly 60 countries and has treated more than 20,000 patients globally. It has the broadest clinical development program of any PARP inhibitor, and AstraZeneca and Merck are working together to bring LYNPARZA to more patients across multiple cancers. In January 2018, LYNPARZA was approved by the U.S. Food and Drug Administration for use in metastatic breast cancer, becoming the first PARP inhibitor licensed beyond ovarian cancer.

Indications for LYNPARZA (olaparib) in the U.S.

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine treatment. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Important Safety Information for LYNPARZA (olaparib)

Contraindications

There are no contraindications for LYNPARZA.

Warnings and Precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA (olaparib) and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

Adverse Reactions—Maintenance Setting

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), and decreased appetite (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

Adverse Reactions—Advanced gBRCAm Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA (olaparib) for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue (including asthenia) (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), increase in mean corpuscular volume (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

Adverse Reactions—gBRCAm, HER2-Negative Breast Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

Drug Interactions

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA (olaparib) treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

Use In Specific Populations

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min). In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Dosing and Administration

To avoid substitution errors and overdose, do not substitute LYNPARZA tablets with LYNPARZA capsules on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Recommended tablet dose is 300 mg, taken orally twice daily, with or without food. Continue treatment until disease progression or unacceptable toxicity. For adverse reactions, consider dose interruption or dose reduction