On September 11, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported the U.S. Food and Drug Administration (FDA) has expanded the label for VENCLEXTA (venetoclax tablets) in combination with rituximab to include information about patients with previously-treated chronic lymphocytic leukemia (CLL) who achieved minimal residual disease (MRD)-negativity in the Phase 3 MURANO trial (Press release, AbbVie, SEP 11, 2018, View Source [SID1234529436]).

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MRD-negativity occurs when less than one CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow using sensitive analytical methods.1 More than half (53 percent [103/194]) of patients treated with the VENCLEXTA and rituximab combination achieved MRD-negativity (undetectable disease) after approximately nine months on therapy (three months after the last dose of rituximab), while 12 percent (23/195) of patients treated with the standard chemoimmunotherapy regimen of bendamustine plus rituximab achieved MRD-negativity.2

"With this label expansion for VENCLEXTA, physicians now have additional information on MRD-negativity, which is becoming an increasingly important goal when caring for their previously-treated CLL patients," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "VENCLEXTA plus rituximab is the first chemotherapy-free combination for previously-treated CLL that allows patients the ability to stop treatment after approximately two years. This label expansion is another important milestone in our efforts to advance care for patients with difficult-to-treat blood cancers."

In the MURANO study, the MRD-negativity rate was evaluated in patients who responded to treatment. The rate of MRD-negativity in patients with a complete response or complete response with incomplete marrow recovery (CR/CRi) at nine months on therapy (three months after the last dose of rituximab) was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.2

CLL is typically a slow-growing cancer of the bone marrow and blood in which white blood cells called lymphocytes become cancerous and multiply abnormally.3 In the U.S., CLL accounts for more than 20,000 newly diagnosed cases of leukemia each year.3

"CLL is a chronic, life-altering cancer marked by periods of remission and relapse, making it an emotional rollercoaster for patients. Many patients who enter remission worry that the disease will relapse," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO study and director of clinical haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The rates of MRD-negativity seen with VENCLEXTA plus rituximab are very encouraging. A goal in treating patients with CLL is to help them achieve the longest remission possible. MRD-negativity provides us with yet another potential tool for evaluating the effectiveness of new therapies."

VENCLEXTA, a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.4 In June 2018, the FDA approved, under priority review, VENCLEXTA in combination with rituximab for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.2 The addition of MRD-negativity data in these previously-treated CLL patients represents the second label expansion for VENCLEXTA in 2018.

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. 5,6,7,8

About the MURANO Study and MRD Results

A total of 389 patients with relapsed or refractory (R/R) CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized (1:1) MURANO study (NCT02005471). The study was designed to evaluate the efficacy and safety of VENCLEXTA in combination with rituximab (194 patients) compared with bendamustine in combination with rituximab (195 patients). The median age of patients in the trial was 65 years (range: 22 to 85 years).2

Efficacy in the U.S. was based on progression-free survival (PFS; the time people live without their disease worsening) as assessed by an Independent Review Committee (IRC). Median PFS with VENCLEXTA in combination with rituximab was not reached compared with 18.1 months for bendamustine in combination with rituximab (hazard ratio: 0.19; 95% confidence interval [CI]: 0.13, 0.28; P<0.0001). The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Additional efficacy endpoints included IRC-assessed response rate (defined as overall response rate [ORR], complete response [CR] plus complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS) and MRD-negativity).2

MRD was evaluated in patients who achieved a PR or better using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 10,000 lymphocytes. After nine months on therapy (three months after the last dose of rituximab), the MRD-negativity rate in peripheral blood was 53 percent (103/194) in the VENCLEXTA plus rituximab arm and 12 percent (23/195) in the bendamustine plus rituximab arm.2 The MRD-negativity rate in patients with a CR/CRi at this time point was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.

The most common adverse reactions (ARs; ≥20 percent) of any grade for VENCLEXTA in combination with rituximab were neutropenia (65 percent), diarrhea (40 percent), upper respiratory tract infection (39 percent), fatigue (22 percent), cough (22 percent) and nausea (21 percent). In the VENCLEXTA plus rituximab arm, discontinuation due to any ARs occurred in 16 percent of patients, dose reduction in 15 percent, and dose interruption in 71 percent. In the bendamustine plus rituximab arm, ARs led to treatment discontinuation in 10 percent of patients, dose reduction in 15 percent, and dose interruption in 40 percent. In the VENCLEXTA in combination with rituximab arm, neutropenia led to dose interruption of VENCLEXTA in 46 percent of patients and discontinuation in 3 percent, and thrombocytopenia led to discontinuation in 3 percent of patients. In the VENCLEXTA in combination with rituximab arm, fatal ARs that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab treatment were reported in 2 percent (4/194) of patients. Serious ARs were reported in 46 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent).2

About VENCLEXTA (venetoclax tablets) (U.S.)

VENCLEXTA is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA targets the BCL-2 protein and works to restore the process of apoptosis.2

VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.

In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.9 The FDA approved this indication under accelerated approval based on overall response rate.9 Based on the results of the MURANO study, VENCLEXTA was granted full approval in June 2018 for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy.2

Venetoclax is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

For more information, visit www.abbvie.com.

What is VENCLEXTA (venetoclax tablets)?
VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with or without 17p deletion, who have received at least one prior treatment.

It is not known if VENCLEXTA is safe and effective in children.

Important VENCLEXTA (venetoclax tablets) US Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your health care provider will do tests to check your risk of getting TLS before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your health care provider will do blood tests in your first 5 weeks of treatment to check you for TLS during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your health care provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome.

Tell your health care provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other, causing serious side effects.
Do not start new medicines during treatment with VENCLEXTA without first talking with your health care provider.
Before taking VENCLEXTA, tell your health care provider about all of your medical conditions, including if you:

Have kidney or liver problems.
Have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium
Have a history of high uric acid levels in your blood or gout
Are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during or after treatment with VENCLEXTA until your health care provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your health care provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your health care provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your health care provider right away.
Are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.
What should I avoid while taking VENCLEXTA?
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Low white blood cell count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your health care provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your health care provider right away if you have a fever or any signs of an infection while taking VENCLEXTA.
The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

The most common side effects of VENCLEXTA when used alone include low white blood cell count, diarrhea, nausea, upper respiratory tract infection, low red blood cell count, tiredness, low platelet count, muscle and joint pain, swelling of your arms, legs, hands, and feet, and cough.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your health care provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. Tell your health care provider if you have any side effect that bothers you or that does not go away.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

On September 11, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the publication of new patient-reported outcomes (PRO) data demonstrating that adding ERLEADA (apalutamide) to androgen-deprivation therapy (ADT) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who were at high-risk for development of metastases did not have a significant impact on individuals’ overall health-related quality of life (HRQoL) (Press release, Johnson & Johnson, SEP 11, 2018, View Source [SID1234529399]). These data from the pivotal SPARTAN study, in which ERLEADA significantly prolonged median metastasis-free survival (MFS), while preserving HRQoL, and delaying the decrease in HRQoL associated with symptomatic progression, were published today in The Lancet Oncology.

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"Prostate cancer treatment can often result in unwelcomed side effects that can impact or disrupt patients’ everyday lives," said Fred Saad, M.D., FRCS, Professor and Chairman of Urology, University of Montreal Hospital Center, and SPARTAN investigator and author of the study. "As clinicians, we want to monitor and measure the impact of new treatments to see if there is an effect on patients’ overall health and well-being. The fact that a treatment such as apalutamide can be added to current standard of care, prolonging metastasis-free survival without significantly impacting HRQoL, is a significant advance for patients with nmCRPC and for clinicians who treat them."

In February 2018, ERLEADA received U.S. Food and Drug Administration approval for the treatment of patients with nmCRPC, making it the first androgen receptor inhibitor approved for patients with this disease state in the U.S. The SPARTAN study was a Phase 3, randomized, double-blind, placebo-controlled multicenter study conducted in 1,207 patients with nmCRPC and a prostate-specific antigen (PSA) doubling time ≤10 months during
continuous ADT.

1 Patients were randomized 2:1 to receive ERLEADA in combination with ADT or placebo in combination with ADT.
1 All patients received a concomitant gonadotropinreleasing hormone (GnRH) agonist or had a bilateral orchiectomy. The primary endpoint of this study was MFS.

The Lancet Oncology publication includes prospective data from the treatment phase and the post-progression follow-up phase for the PRO exploratory endpoints as measured by the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and the EuroQol fivedimension, three-level (EQ-5D-3L) questionnaires.1 The FACT-P PRO questionnaire assessed prostate cancer symptoms, pain-related symptoms and overall HRQoL.

1 The EQ-5D-3L questionnaire evaluated mobility, self-care, usual activities, pain, discomfort, anxiety or
depression and health-state.

"Men with non-metastatic castration-resistant prostate cancer are at significant risk for developing metastases and dying from the disease. To date, this patient population has been understudied, and data on health-related quality of life in such men are scarce," said Andree Amelsberg, M.D., Vice President, Oncology Medical Affairs, at Janssen Scientific Affairs, LLC. "Patient-reported outcomes data are gaining importance as healthcare systems place greater emphasis on patient experience with treatment. Amongst men in this patient population, maintaining quality of life is an important endpoint. In this exploratory analysis of the SPARTAN results, we are pleased to see that patients reported they did not experience notable disruptive changes after ERLEADA was added to their standard of care."

About the SPARTAN Study
SPARTAN (NCT01946204) was a Phase 3, randomized, double-blind, placebo-controlled, multicenter study, that evaluated ERLEADA in combination with ADT in men with nmCRPC with a rapidly rising PSA (PSADT≤10 months).2 The SPARTAN study enrolled 1,207 patients

who were randomized 2:1 to receive either ERLEADA orally at a dose of 240 mg once daily in combination with ADT (n=806) or placebo once daily in combination with ADT (n=401). Study results were announced earlier this year at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Annual Meeting Cancers Symposium (ASCO GU), and published simultaneously in The New England Journal of Medicine. Warnings and Precautions include seizure, falls and fractures.2 In the SPARTAN study, the most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture and peripheral edema.2

About Non-Metastatic Castration-Resistant Prostate Cancer
Non-metastatic castration-resistant prostate cancer (nmCRPC) refers to a disease stage when the cancer no longer responds to medical or surgical treatments that lower testosterone, but has not yet been discovered in other parts of the body using a total body bone scan or CT scan.3 Features include: lack of detectable metastatic disease;3
rapidly rising prostate-specific antigen while on ADT and serum testosterone level below 50 ng/dL.4,5 Ninety percent of patients with nmCRPC will eventually develop bone metastases, which can lead to pain, fractures and spinal cord compression.6 The relative five-year survival rate for patients diagnosed at a distant stage prostate cancer is 30
percent.7 It is critical to delay the onset of metastasis in patients with nmCRPC.

About ERLEADA
ERLEADA (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.2 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer include apalutamide as a treatment option for patients with non-metastatic (M0) CRPC with a category 1 recommendation (especially for those with a PSA doubling time ≤10 months)*.8
Additionally, the AUA Guidelines for Castration-Resistant Prostate Cancer (CRPC) were recently updated to include apalutamide (ERLEADA) with continued androgen deprivation as a treatment option for patients with asymptomatic nmCRPC. It is included as one of the options clinicians should offer to patients with nmCRPC who are at high-risk for developing metastatic disease (Standard; Evidence Level Grade A)**.9

*Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer V.2.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed March 12, 2018. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application, and disclaims any responsibility for their application or use in any way.

**Standard: Directive statement that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be taken based on Grade A or B evidence.

**Evidence Level: A designation indicating the certainty of the results as high, moderate, or low (A, B, or C, respectively) based on AUA nomenclature and methodology.

INDICATION
ERLEADA (apalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer. ERLEADA IMPORTANT SAFETY INFORMATION2
CONTRAINDICATIONS
Pregnancy — ERLEADA (apalutamide) can cause fetal harm and potential loss of
pregnancy.

WARNINGS AND PRECAUTIONS
Falls and Fractures — In a randomized study (SPARTAN), falls and fractures occurred in 16% and 12% of patients treated with ERLEADA compared to 9% and 7% treated with placebo, respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for
fractures according to established treatment guidelines and consider use of bone targeted agents.

Seizure — In a randomized study (SPARTAN), 2 patients (0.2%) treated with ERLEADA experienced a seizure. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
ADVERSE REACTIONS

Adverse Reactions — The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.
Laboratory Abnormalities — All Grades (Grade 3-4)

• Hematology — anemia ERLEADA 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA 41% (2%), placebo 21% (2%)

• Chemistry — hypercholesterolemia ERLEADA 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA 32% (2%), placebo 22% (0.5%)

Rash — Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA treatment (5%) versus placebo (0.3%).

The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four percent of patients treated with ERLEADA received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA.Hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.

DRUG INTERACTIONS
Effect of Other Drugs on ERLEADA — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA on Other Drugs — ERLEADA is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration ERLEADA with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA and evaluate for loss of activity.
P-gp, BCRP or OATP1B1 substrates — Apalutamide is a weak inducer of P-glycoprotein (P- gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA and evaluate for loss of activity if medication is continued.

On September 11, 2018 Amgen (NASDAQ:AMGN) reported that it will present at the Bank of America Merrill Lynch Global Healthcare Conference at 9 a.m. GMT on Friday, Sept. 14, 2018, in London (Press release, Amgen, SEP 11, 2018, View Source;p=RssLanding&cat=news&id=2366942 [SID1234529392]). David W. Meline, executive vice president and chief financial officer at Amgen, will present at the conference. Live audio of the presentation can be accessed from the Events Calendar on Amgen’s website, www.amgen.com, under Investors. A replay of the webcast will also be available on Amgen’s website for at least 90 days following the event.

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On September 11, 2018 Blue Earth Diagnostics, a molecular imaging diagnostics company, reported the peer-reviewed publication of results from an investigational clinical trial ("LOCATE") evaluating the impact of 18F fluciclovine PET/CT imaging on patient management of biochemically recurrent prostate cancer after initial prostate cancer treatment and negative or equivocal findings on standard-of-care imaging (Press release, Blue Earth Diagnostics, SEPT 11, 2018, View Source [SID1234529390]). The LOCATE trial is a prospective, multi-center, open-label study (NCT02680041) conducted at 15 sites in the United States. Its primary endpoint measured the percentage of men with biochemical recurrence of prostate cancer following initial prior therapy whose treatment plan was changed following an 18F fluciclovine PET/CT scan.

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The manuscript, "The Impact of Positron Emission Tomography with 18F-Fluciclovine on the Management of Patients with Biochemical Recurrence of Prostate Cancer: Results from the LOCATE Trial," was accepted by The Journal of Urology and is now available online: The Journal of Urology (2018), doi:10.1016/j.juro.2018.08.050. The manuscript will also appear in an upcoming print issue. Lead authors are Gerald L. Andriole, Washington University School of Medicine, St. Louis, Mo.; Lale Kostakoglu, The Icahn School of Medicine at Mount Sinai, New York, NY; Albert Chau, Blue Earth Diagnostics, Oxford, UK; Fenghai Duan, Brown University, Providence, RI; Umar Mahmood, Massachusetts General Hospital, Boston, Mass.; David A. Mankoff, University of Pennsylvania, Philadelphia, Pa.; David M. Schuster, Emory University, Atlanta, Ga.; and Barry A. Siegel, Washington University School of Medicine, St. Louis, Mo. on behalf of the LOCATE Study Group.

Axumin (fluciclovine F 18 injection) is an FDA-approved molecular imaging agent for use in positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood levels of prostate specific antigen (PSA) following prior treatment. (For additional product information please see the end of this news release.)

The LOCATE trial prospectively evaluated 213 men with suspected recurrence of prostate cancer based on rising PSA levels (median PSA 1.00ng/mL) following previous curative-intent treatment, but with negative or equivocal findings on standard-of-care imaging. Overall, 18F fluciclovine PET/CT was positive in 57% of the evaluable patients. The study investigators used a questionnaire to document the patient’s intended treatment plan prior to 18F fluciclovine PET/CT and then to record if and how that plan was altered after reviewing the results of the scan with the patient. Results of the trial indicated that 59% (126/213) of patients had their clinical management changed when results of the 18F fluciclovine PET/CT imaging were included in the diagnostic work-up. Of those changes, 78% (98/126) were classified as "major" (i.e., a change in treatment modality) and 22% (28/126) were classified as "other" (i.e., a change within a treatment modality).

Of 128 patients whose original treatment plan was salvage radiation therapy (with or without androgen deprivation therapy (ADT)), 51% (65/128) had their treatment changed after 18F fluciclovine PET/CT. Of 60 patients originally planned to be treated with ADT, 75% (45/60) had their treatment changed to a non-systemic salvage treatment after 18F fluciclovine PET/CT. The specific treatment plan selected after the 18F fluciclovine PET/CT imaging results were available was based on the independent judgment of the study investigators, who utilized any other available confirmatory information. The clinical utility of 18F fluciclovine PET/CT to identify a particular course of treatment has not been established and clinical correlation, including potential histopathological evaluation of the suspected recurrence site, is recommended. Longer term follow-up is needed to confirm how incorporation of 18F fluciclovine PET/CT into therapy planning will affect outcomes. The safety profile of 18F fluciclovine in the LOCATE trial is consistent with that described in the approved U.S. Prescribing Information.

"We are extremely pleased that the results from the LOCATE study were so rapidly made available to the physician community through publication in the well-respected Journal of Urology," said Jonathan Allis, D. Phil., CEO of Blue Earth Diagnostics. "Blue Earth Diagnostics is focused on developing and commercializing innovative PET imaging agents for cancer. In line with that mission, the U.S.-based LOCATE study evaluated the utility of 18F fluciclovine PET/CT in providing physicians with actionable information for the management of men with recurrent prostate cancer."

"The LOCATE study evaluated men with biochemically recurrent prostate cancer, who had conventional imaging scans which were either negative or equivocal, and compared their treatment plans before and after 18F fluciclovine PET/CT to assess whether or not it impacted their management," said Gerald L. Andriole, MD, the Robert K. Royce Distinguished Professor and Chief of Urologic Surgery at Washington University School of Medicine in St. Louis and lead author on behalf of the LOCATE study group. "Results of the study showed that management plans were revised for 59% of patients, and that more than 75% of such revisions involved a change in treatment modality. The findings indicate that 18F fluciclovine PET/CT provides beneficial information for treatment planning in men with suspected biochemical recurrence of prostate cancer and merits further investigation of the long-term clinical outcomes following fluciclovine-guided patient management."

"The ability to determine the extent and location of recurrent prostate cancer can inform the clinical management plan for men with the disease. This is an important consideration for physicians and their patients, as up to 30% of patients with prostate cancer will develop local or distant recurrences within 10 years of radical prostatectomy or radiation therapy," said Lale Kostakoglu, MD, MPH, Professor of Radiology and Chief of Nuclear Medicine, Icahn School of Medicine at Mount Sinai, New York, NY and member of one of the LOCATE study group’s leading enrollment sites. "The LOCATE study demonstrated that imaging with 18F fluciclovine PET/CT can reveal the sites of disease recurrence in men with biochemically recurrent prostate cancer and, based on the pattern of recurrence together with the other available clinical information, this resulted in a change in management in 59% of the patients."

ABOUT THE LOCATE TRIAL

Blue Earth Diagnostics’ investigational LOCATE study ("The Impact of 18F Fluciclovine (FACBC) PET/CT (Positron Emission Computed Tomography) on Management of Patients with Rising PSA (Prostate-specific Antigen) After Initial Prostate Cancer Treatment"), is a U.S. multi-center study investigating the impact of 18F fluciclovine PET/CT imaging on the management of patients with rising PSA after initial prostate cancer treatment. The clinical utility of 18F fluciclovine PET/CT imaging was assessed by the change from initial management recommendation to the treatment plan after scanning with 18F fluciclovine PET/CT. Additional information about the LOCATE trial is available at: www.clinicaltrials.gov (NCT02680041).

U.S. Indication and Important Safety Information About Axumin*

INDICATION

Axumin (fluciclovine F 18) injection is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment.

IMPORTANT SAFETY INFORMATION

Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out recurrent prostate cancer and a positive image does not confirm its presence. The performance of Axumin seems to be affected by PSA levels. Axumin uptake may occur with other cancers and benign prostatic hypertrophy in primary prostate cancer. Clinical correlation, which may include histopathological evaluation, is recommended.
Hypersensitivity reactions, including anaphylaxis, may occur in patients who receive Axumin. Emergency resuscitation equipment and personnel should be immediately available.
Axumin use contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer. Safe handling practices should be used to minimize radiation exposure to the patient and health care providers.
Adverse reactions were reported in ≤ 1% of subjects during clinical studies with Axumin. The most common adverse reactions were injection site pain, injection site erythema and dysgeusia.
To report suspected adverse reactions to Axumin, call 1-855-AXUMIN1 (1-855-298-6461) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full U.S. Axumin prescribing information is available at www.axumin.com.

*This press release is intended to provide information about Blue Earth Diagnostics’ business in the United States. Please be aware that the approval status and product label for Axumin varies by country worldwide. Refer to the individual country product label for complete information or contact Blue Earth Diagnostics.

About Axumin (fluciclovine F 18)

Axumin (fluciclovine F 18) injection is a novel product indicated for use in positron emission tomography (PET) imaging to identify suspected sites of prostate cancer recurrence in men. Recurrence of prostate cancer is suspected by an increase in prostate specific antigen (PSA) levels following prior treatment. PET imaging with Axumin may identify the location and extent of such recurrence. Axumin was developed to enable visualization of the increased amino acid transport that occurs in many cancers, including prostate cancer. It consists of a synthetic amino acid that is preferentially taken up by prostate cancer cells compared with surrounding normal tissues, and is labeled with the radioisotope F 18 for PET imaging. Fluciclovine F 18 was invented at Emory University in Atlanta, Ga., with much of the fundamental clinical development work carried out by physicians at Emory University’s Department of Radiology and Imaging Sciences. Axumin was approved by the U.S. Food and Drug Administration in May 2016 following Priority Review, and is the first product commercialized by Blue Earth Diagnostics, which licensed the product from GE Healthcare. The molecule is being investigated by Blue Earth Diagnostics for other potential cancer indications, such as glioma.

About Prostate / Recurrent Prostate Cancer

Prostate cancer is the second leading cause of cancer death in men in the United States. While most primary prostate cancer can be successfully treated, the disease recurs in approximately one-third of patients. In some patients, recurrent disease is detectable only by a rise in prostate specific antigen (PSA) levels, yet the location of the recurrence cannot consistently be located by conventional imaging, potentially impacting subsequent management of these patients.

On September 11, 2018 OncoResponse, an immunotherapy company developing a portfolio of novel antibodies to high-value targets for the treatment of cancer, reported the completion of a $40 million series B equity financing (Press release, OncoResponse, SEPT 11, 2018, View Source [SID1234529389]). Participants in the round, which was led by RiverVest Venture Partners, included new investors Qatar Investment Authority (QIA) and Redmile Group, and existing investors Alexandria Venture Investments, ARCH Venture Partners, HT Family Office, Canaan Partners, Helsinn Investment Fund and William Marsh Rice University. The proceeds will be used to advance the company’s five drug candidates into preclinical and clinical development. All drug candidates were derived from OncoResponse’s discovery platform, which mines the immune systems of patients who have responded exceptionally well to cancer immunotherapies.

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"We are very pleased to add RiverVest, QIA and Redmile to our already strong syndicate of investors as we transition our company’s efforts from identifying drug candidates to developing them for patients," said Clifford J. Stocks, CEO of OncoResponse. "We now have several antibodies from our cancer patient-derived platform that are directed at modulating immunosuppression of the tumor microenvironment. This new capital will allow us to advance our programs through pre-clinical development and enable us to move our lead programs into clinical studies."

"Since its inception in October 2015, OncoResponse has done an excellent job leveraging its platform to rapidly screen and discover therapeutically relevant antibodies from patients with elite response to immunotherapy," said John McKearn, Ph.D., Managing Director of RiverVest Venture Partners. "We believe that their portfolio of unique drug candidates has the potential to help cancer patients, expanding the promise of immunotherapy."