On September 30, 2019 Ayala Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company dedicated to developing targeted cancer therapies for people living with cancer, reported preliminary results from its ongoing Phase 2 ACCURACY study of lead investigational new drug candidate, AL101, in patients with recurrent/metastatic adenoid cystic carcinoma (ACC) with progressing disease and Notch activating mutations (Press release, Ayala Pharmaceuticals, SEP 30, 2019, View Source [SID1234539922]). The data were presented in a poster session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain.

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"ACC is a devasting rare cancer that affects more than 1,300 people in the U.S. annually. Currently, there is no standard drug therapy for ACC and new treatments are desperately needed. ACC with activating NOTCH mutations represent a particularly aggressive disease subtype that can be associated with a poorer prognosis," said Alan L. Ho., M.D., Ph.D., lead investigator in the ACCURACY study. "Ayala has taken the important step of attempting to personalize therapy for ACC patients by developing AL101, a drug designed to block NOTCH activation. It has been exciting to see the encouraging disease control rates and favorable safety profile emerging from the trial to date and I look forward to continuing to help further explore the clinical utility of AL101."

"We are very pleased by the initial data from our study as we have seen early signs of biological and clinical activity and a potentially strong safety profile from AL101 in this extremely difficult to treat patient population. AL101 has been well tolerated by ACC patients, most significantly in relation to diarrhea, which has traditionally been difficult to control with previous Notch pathway inhibitors," said Gary Gordon, M.D., Ph.D., Chief Medical Officer of Ayala. "Furthermore, we are encouraged by the 22% response rate and 61% disease control rate, as most ACC patients do not respond to treatment at all. To have observed some responses after only eight weeks on therapy is a noteworthy achievement."

AL101 is an investigational small molecule, gamma-secretase inhibitor that potently and selectively inhibits Notch 1, 2, 3 and 4. AL101 inhibits the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation.

Trial Design:
The ongoing Phase 2 ACCURACY clinical trial is a Simon 2-stage optimal design, noncomparative, open-label, single-arm, multi-center study to assess the clinical activity of AL101 using radiographic assessments in patients with recurrent/metastatic ACC with progressing disease and Notch activating mutations. Patients were treated with 4 mg of once-weekly IV AL101 and underwent radiographic assessments every eight weeks, with an end of study visit 30 days after the last treatment and long-term follow-up every three months thereafter. Stage 1 of the study has completed enrollment and Stage 2 is ongoing. A total of 38 patients were screened and 27 have been dosed with AL101.
As of August 31, 2019, 18 of the 27 patients dosed with AL101 and had at least one pre-dosing and one post-dosing radiological evaluation. Seven patients are currently undergoing dosing and have not yet had a post-dosing radiological evaluation. Two patients began treatment, but discontinued prior to the first post-dosing radiological evaluation due to non-treatment related adverse events (AEs) and are considered to be non-evaluable for efficacy.

Preliminary Safety Results:
At the time of the cut off for data collection, treatment-related AEs were reported in ≥ 15% in patients dosed with AL101. The most common AEs included nausea (59%), diarrhea (56%, most reports were Grades 1 and 2 with one Grade 3 and zero Grade 4 events reported), fatigue (13%), cough (including productive cough) (11%), vomiting (9%), and epistaxis (6%).
Investigators reported Grade 3 AEs in three patients who experienced nausea, diarrhea and hypophosphatemia. Three treatment-related serious adverse events (SAEs) were observed, including two episodes of infusion reaction in one patient and one case of keratoacanthoma. There were two on-study, non-treatment related deaths.

Preliminary Efficacy Results:
Data presented at ESMO (Free ESMO Whitepaper) were from 18 patients with recurrent/metastatic ACC with progressing disease and Notch activating mutations treated with AL101 as of the data collection cut-off date of August 31, 2019. Based on RECIST 1.1 or modified MDA Bone Response Criteria, at the time of the cut-off date for data collection, four patients achieved a partial response (PR, 22%), seven patients achieved stable disease (SD, 39%), for a disease control rate of 61% and seven patients had progressive disease (PD, 39%).

About AL101
AL101 is an investigational small molecule, gamma-secretase inhibitor that potently and selectively inhibits Notch 1, 2, 3 and 4. AL101 inhibits the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. It has the potential to inhibit tumor growth as demonstrated by three Phase 1 studies conducted by Bristol-Myers Squibb. AL101 is currently in a Phase 2 clinical trial in adenoid cystic carcinoma (ACC), as well as planned Phase 2 clinical trials for triple-negative breast cancer (TNBC) and T-Cell acute lymphoblastic leukemia (T-ALL).

About Adenoid Cystic Carcinoma (ACC)
ACC is a rare malignancy of the salivary glands, accounting for about 10% of all salivary gland tumors with an annual incidence of 1,300 in the U.S. There is currently no approved standard of care for patients with recurrent/metastatic ACC and as a result, patients undergo surgery and radiation therapy, with recurring disease treated by chemotherapy. ACC is an immunologically "cold" tumor that is refractory to chemotherapy (ORR 8%-11%), with a recurrence rate of about 60% after initial surgery.

About the Notch Signaling Pathway
The Notch signaling pathway functions as a mediator of short-range cell to cell communication and plays a fundamental role in a variety of tissue types. The gain or loss of Notch signaling aspects has been associated with a wide range of disorders, developmental syndromes and cancers, both hematological and solid tumors. The Notch pathway is involved in several hallmarks of cancer including: cellular proliferation, survival, migration, invasion, epithelial to mesenchymal transition and drug resistance, increased angiogenesis and metastasis. The Notch pathway has been determined to be an oncogenic driver of ACC and its dysregulation plays a key role in tumorigenesis and correlates with a distinct pattern of metastasis and a poor prognosis.

On September 30, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed results from the Phase III PROfound trial in 387 men with metastatic castration-resistant prostate cancer (mCRPC) who have a mutation in their homologous recombination repair (HRRm) genes and whose disease had progressed on prior treatment with new hormonal agent (NHA) treatments (e.g. abiraterone or enzalutamide) (Press release, AstraZeneca, SEP 30, 2019, View Source [SID1234539921]).

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The trial was designed to analyse men with HRRm genes in two cohorts: the primary endpoint was in those with mutations in BRCA1/2 or ATM genes and then, if Lynparza (olaparib) showed clinical benefit, a formal analysis was performed of the overall trial population of men with HRRm genes (BRCA1/2, ATM, CDK12 and 11 other HRRm genes; key secondary endpoint).

Results showed a statistically significant and clinically meaningful improvement with Lynparza in the primary endpoint of radiographic progression-free survival (rPFS), improving the time men with BRCA1/2- or ATM-mutated mCRPC lived without disease progression or death to a median of 7.4 months vs. 3.6 months for those treated with abiraterone or enzalutamide. Lynparza reduced the risk of disease progression or death by 66% (equal to a hazard ratio of 0.34) for these men.

The trial also met the key secondary endpoint of rPFS in the overall HRRm population, where Lynparza reduced the risk of disease progression or death by 51% (equal to a hazard ratio of 0.49) and improved rPFS to a median of 5.8 months vs. 3.5 months for abiraterone or enzalutamide.

The results were presented during the Presidential Symposium at the 2019 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) congress in Barcelona, Spain (Abstract #LBA12_PR).

Results also showed a trend at this interim analysis time point for improvement in overall survival (OS), another key secondary endpoint, in the two groups. Lynparza extended OS to 18.5 months vs.15.1 months for abiraterone or enzalutamide in men with BRCA1/2- or ATM-mutated tumours, despite that at this interim analysis 81% of patients on NHA crossed over to Lynparza at progression. A similar trend in OS was observed at this interim analysis in the overall HRRm population with a median of 17.5 months’ OS for men treated with Lynparza vs. 14.3 months for abiraterone or enzalutamide (analysis at 41% data maturity).

José Baselga, Executive Vice President, Oncology R&D, said: "Results from PROfound demonstrate that, in addition to providing substantial benefit as a precision medicine for men with metastatic castration-resistant prostate cancer with BRCA-mutated tumours, Lynparza is effective beyond just BRCA in tumours with mutations in other genes associated with homologous recombination repair. PROfound validates the concept of PARP sensitivity across multiple genes associated with homologous recombination repair in this disease and marks the first positive Phase III trial using a molecular biomarker to identify men for targeted treatment for metastatic castration-resistant prostate cancer. We are working with global health authorities to bring Lynparza to these patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "The results from the Phase III PROfound trial are a testament to MSD and AstraZeneca’s lasting commitment to patients with cancer. The trial met the primary endpoint in men with metastatic castration-resistant prostate cancer that progressed on prior hormonal therapy, a notoriously difficult-to-treat disease. The benefit seen in patients beyond just those with BRCA mutations underscores the potential value of genomic testing in prostate cancer."

Maha Hussain, one of the principal investigators of the PROfound trial and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, said: "We have seen advances in the treatment over the last 15 years for men with metastatic castration-resistant prostate cancer. However, to date treatments for this state of disease continue to use ‘one size fits all’ approaches overlooking the genomic make-up of the tumour and how it could inform treatment decisions to better personalise care and impact outcomes. I am thrilled by the PROfound results and Lynparza’s clinically meaningful benefit which offers the potential of a molecularly targeted treatment for this patient population with advanced disease. I am confident we are now entering a new era of personalised care and precision medicine for metastatic castration-resistant prostate cancer."

Summary of resultsi

Cohort A

(BRCA1/2 or ATM)

Cohort A+B ii

(Overall HRRm)

Lynparza

n=162

pcNHA

n=83

Lynparza

n=256

pcNHA

n=131

rPFS

Median, months

7.4

3.6

5.8

3.5

% progression-free at 6 months

59.8

22.6

49.7

23.7

% progression-free at 12 months

28.1

9.4

22.1

13.5

Hazard ratio (95% CI)

0.34 (0.25-0.47)

0.49 (0.38-0.63)

p-value

<0.0001

<0.0001

Confirmed ORR

Patients with response (%)

33.3

2.3

21.7

4.5

Odds ratio (95% CI)

20.86 (4.18-379.18)

5.93 (2.01-25.40)

p-value

<0.0001

0.0006 (nominal)

Time to pain progression iii

Median, months

NR

9.92

Hazard ratio (95% CI)

0.44 (0.22-0.91)

p-value

0.0192

OS (interim) iv

Median, months

18.5

15.1

17.5

14.3

Hazard ratio (95% CI)

0.64 (0.43-0.97)

0.67 (0.49-0.93)

p-value

0.0173

0.0063 (nominal)

NR, not reached; ORR, objective response rate; pc, physician’s choice
i Assessed by blinded independent central review (BICR)
ii Cohort B included patients with any 1 of 12 other HRR mutations
iii Time to pain progression in Cohort A was a secondary endpoint included in the formal testing hierarchy
iv Interim analysis was done at 38% (Cohort A) and 41% (Cohort A+B) data maturity; Alpha spend at interim was 0.01; statistical significance not reached

The safety and tolerability profile of Lynparza in the PROfound trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were anaemia (47%), nausea (41%), fatigue/asthenia (41%), decreased appetite (30%) and diarrhoea (21%). Grade 3 or above AEs were anaemia (22%), pulmonary embolism (4%), fatigue/asthenia (3%), vomiting (2%), dyspnoea (2%), urinary tract infection (2%), decreased appetite (1%), diarrhoea (1%) and backpain (1%). 16% of patients on Lynparza discontinued treatment due to AEs.

AstraZeneca and MSD are also exploring additional trials in prostate cancer, including the ongoing Phase III PROpel trial, testing Lynparza as a 1st-line therapy in mCRPC, in combination with abiraterone.

About PROfound

PROfound is a prospective, multicentre, randomised, open-label, Phase III trial testing the efficacy and safety of Lynparza versus new hormonal agents (e.g. abiraterone or enzalutamide) in patients with mCRPC who have progressed on prior treatment with new hormonal anticancer treatments and have a qualifying tumour mutation in one of 15 genes involved in the HRR pathway, including among them BRCA1/2, ATM and CDK12.

About metastatic castration-resistant prostate cancer

Prostate cancer is the second-most common cancer in men, with an estimated 1.3 million new cases diagnosed worldwide in 2018 and is associated with a significant mortality rate.1 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.2 mCRPC occurs when prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.2 Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.3 Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.3 Despite an increase in the number of available therapies for men with mCRPC, five-year survival remains low.3

About HRR gene mutations

HRR is a DNA repair process that allows for high-fidelity, error-free repair of damaged DNA, in the form of double-strand breaks and inter-strand crosslinks (amongst others).4,5 The inability to properly repair DNA damage leads to genomic instability and contributes to cancer aetiology.5 Deficiency in HRR leads to a compromised ability to repair damaged DNA, and is a feature of cancer cells that is a target for PARP inhibitors, such as Lynparza. PARP inhibitors block DNA damage repair by trapping of PARP bound to DNA single-strand breaks which leads to replication fork stalling causing their collapse and the generation of DNA double-strand breaks which in turn lead to cancer cell death.4

About Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer, regardless of BRCA status. It is approved in the US, the EU, Japan and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 43 countries, including the US and Japan, for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally-advanced breast cancer. Regulatory reviews are underway in other jurisdictions for ovarian, breast and pancreatic cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 25,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as one of AstraZeneca’s four Growth Platforms focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On September 30, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported data from the global Phase 3 ClarIDHy trial of TIBSOVO (ivosidenib) in previously treated cholangiocarcinoma patients with an isocitrate dehydrogenase 1 (IDH1) mutation in a Presidential Symposium at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) (Press release, Agios Pharmaceuticals, SEP 30, 2019, View Source [SID1234539920]). Results from the ClarIDHy trial demonstrated a statistically significant improvement in progression-free survival (PFS) by independent radiology review of 2.7 months among patients randomized to TIBSOVO compared with 1.4 months among placebo patients (hazard ratio [HR] 0.37; 95% CI [0.25, 0.54], p<0.001). The safety profile observed in the study was consistent with previously published data.

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"Advanced cholangiocarcinoma is an aggressive disease oftentimes characterized by rapid progression following multiple lines of therapy, and there are no currently approved treatments," said Ghassan Abou-Alfa, M.D., medical oncologist at Memorial Sloan Kettering Cancer Center, who presented the data at ESMO (Free ESMO Whitepaper). "The ClarIDHy study is the first randomized trial in previously treated IDH1 mutant cholangiocarcinoma patients and demonstrates that TIBSOVO provides significant improvement in PFS compared to placebo, while also showing a favorable trend in overall survival. These critical data also provide strong justification for genomic testing in cholangiocarcinoma patients where a targeted therapeutic approach may provide benefit."

"Since we began clinical trials of TIBSOVO in solid tumors five years ago, we have hoped to provide benefit to cholangiocarcinoma patients who desperately need new treatment options. The results of the ClarIDHy trial help to establish the role that this targeted therapy may play in the treatment paradigm for patients with an IDH1 mutation," said Chris Bowden, M.D., chief medical officer at Agios. "Moving forward, we’re focused on submitting our supplemental new drug application for previously treated IDH1 mutant cholangiocarcinoma patients by the end of the year."

ClarIDHy Phase 3 Trial
The ClarIDHy trial is a global, randomized Phase 3 trial in previously treated IDH1 mutant cholangiocarcinoma patients who have documented disease progression following one or two systemic therapies in the advanced setting. Patients were randomized 2:1 to receive either single-agent TIBSOVO 500 mg once daily or placebo with crossover to TIBSOVO permitted at the time of documented radiographic progression per RECIST 1.1. As of the January 31, 2019 data cutoff, 185 patients were randomized, with 124 patients in the TIBSOVO arm and 61 patients in the placebo arm. Thirty-five patients randomized to placebo (57.4%) crossed over to open-label TIBSOVO upon radiographic disease progression and unblinding.

Efficacy Results
Efficacy data as of the data cut-off showed:

Median progression-free survival (PFS) for patients randomized to TIBSOVO was 2.7 months compared to 1.4 months with placebo (hazard ratio [HR]=0.37; 95% CI [0.25, 0.54], p<0.001) as assessed by independent radiology review. PFS benefits were observed across all subgroups analyzed.

The estimated PFS rate was 32% at six months and 22% at 12 months for patients randomized to TIBSOVO, while no patients randomized to placebo were free from progression beyond these timepoints as of the data cut-off.

In the TIBSOVO arm, 2% of patients achieved a partial response and 51% had stable disease, compared to 28% with stable disease in the placebo arm.

Median overall survival (OS) based on 78 events was 10.8 months for patients randomized to TIBSOVO compared to 9.7 months for placebo patients (HR=0.69; 95% CI [0.44, 1.10], p=0.06). Using the rank-preserving structural failure time (RPSFT) method to reconstruct the survival curve for the placebo subjects as if they never crossed over to TIBSOVO, the median OS with placebo adjusts to 6 months (HR=0.46; 95% CI [0.28, 0.75], p<0.001).

Safety Results
A safety analysis conducted for all patients as of the data cut-off demonstrated:

Less than half of patients experienced a Grade 3 or above treatment-emergent adverse event (TEAE) in either arm (46.2% with total TIBSOVO [includes patients who crossed over from placebo to TIBSOVO] vs. 35.6% on placebo), with the most common being ascites (7.7% total TIBSOVO vs. 6.8% placebo).

TEAEs leading to discontinuation were more common with placebo compared with total TIBSOVO (8.5% vs. 5.8%).

TEAEs leading to dose reductions (2.6% vs. 0%) and interruptions (26.3% vs. 16.9%) were more common with total TIBSOVO relative to placebo.

The most common TEAEs of any grade for total TIBSOVO were nausea (32%), diarrhea (29%) and fatigue (24%).

TIBSOVO is not approved in any country for the treatment of patients with advanced cholangiocarcinoma.

Conference Call Information
Agios will host a conference call and live webcast with presentation slides today at 1 p.m. ET /7 p.m. CET to discuss the data from the ClarIDHy study. To participate in the conference call, please dial 1-877-377-7098 (domestic) or 1-631-291-4547 (international) and refer to conference ID 5209309. The live webcast can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

About Cholangiocarcinoma
Cholangiocarcinoma (CC) is a rare cancer of the bile ducts within and outside of the liver. Cases that occur within the liver are known as intrahepatic cholangiocarcinoma (IHCC) and those that occur outside the liver are considered extrahepatic. Mutations in IDH1 occur in up to 20% of IHCC cases. Current treatment options for localized disease include surgery, radiation and/or other ablative treatments. There are no approved systemic therapies for cholangiocarcinoma and limited chemotherapy options are available in the advanced setting. Gemcitabine-based chemotherapy is often recommended for newly diagnosed advanced or metastatic disease.

About TIBSOVO (ivosidenib)

TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

Adult patients with relapsed or refractory AML.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).

In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).

In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).

DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.
Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.
Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

On September 30, 2019 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology (I-O) company with a pipeline of immune checkpoint antibodies, adoptive cell therapies1 and cancer vaccines, reported that Jennifer Buell, PhD, Chief Operating Officer of Agenus, present an update on Agenus’ progress and host one-on-one meetings with investors at the 2019 Cantor Global Healthcare Conference on October 4th, 2019 at the InterContinental New York Barclay Hotel (Press release, Agenus, SEP 30, 2019, View Source [SID1234539919]).

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The presentation will be webcast live and may be accessed by visiting the "Events & Presentations" page within the Investors section of the Agenus website www.agenusbio.com or by using the link below. A replay of the webcast will be available on the Agenus website following the conference.

Date: Friday, October 4, 2019

Time: 8:20 A.M. ET

Webcast: View Source

On September 30, 2019 Thermo Fisher Scientific Inc. (NYSE: TMO), the world leader in serving science, reported that it will release its financial results for the third quarter of 2019 before the market opens on Wednesday, October 23, 2019, and will hold a conference call on the same day at 8:30 a.m. EDT (Press release, Thermo Fisher Scientific, SEP 30, 2019, View Source [SID1234539917]).

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During the call, the company will discuss its financial performance, as well as future expectations. To listen, call (877) 273-7122 within the U.S. or (647) 689-5496 outside the U.S. You may also listen to the call live on the "Investors" section of our website, www.thermofisher.com. The earnings press release and related information can be found in that section of our website under "Financial Results." A replay of the call will be available under "Webcasts and Presentations" through Friday, November 8, 2019.