On May 15, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that the global Phase 3 ClarIDHy trial of TIBSOVO (ivosidenib) in previously treated cholangiocarcinoma patients with an isocitrate dehydrogenase 1 (IDH1) mutation met its primary endpoint (Press release, Agios Pharmaceuticals, MAY 15, 2019, View Source [SID1234536382]). Treatment with TIBSOVO demonstrated a statistically significant improvement in progression-free survival (PFS) by independent radiology review compared with patients who received placebo. The safety profile observed in the study was consistent with previously published data.

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A full analysis of the ClarIDHy trial will be submitted for presentation at the European Society for Medical Oncology Congress taking place in Barcelona, Spain from September 27-October 1, 2019. The company plans to submit a supplemental new drug application for TIBSOVO in previously treated IDH1 mutant cholangiocarcinoma by the end of 2019.

"Advanced cholangiocarcinoma is a life-threatening disease with no currently approved treatment options," said Chris Bowden, M.D., chief medical officer at Agios. "The data from the ClarIDHy Phase 3 trial demonstrate the clinically significant benefit of TIBSOVO in patients with this challenging disease who harbor the IDH1 mutation. We are committed to working with regulators to bring this potential treatment option to patients as quickly as possible. We thank the patients and physicians who participated in the ClarIDHy study, without whom this important advancement would not be possible."

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. As of the January 31, 2019 data cutoff, 185 patients were randomized.

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.
The primary endpoint of the trial is PFS as evaluated by independent radiology review with secondary endpoints including investigator evaluated PFS, safety and tolerability, overall response rate, overall survival, duration of response, PK/PD and quality of life assessments.
The study was designed with 96% power to detect a hazard ratio of 0.5 for PFS (TIBSOVO vs. placebo), with a one-sided alpha of 0.025.
Thermo Fisher Scientific is providing next-generation sequencing to detect IDH1 mutations for all tumor samples as inclusion criteria for enrollment in the study and will develop and commercialize the validated companion diagnostic.
TIBSOVO is not approved in any country for the treatment of patients with advanced cholangiocarcinoma.

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.

Please see full Prescribing Information, including Boxed WARNING.

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 metastatic disease.

On May 15, 2019 MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), reported that Geoffrey O’Brien, JD/MBA, Vice President and Executive Officer, will present a corporate overview at the 20th Annual B. Riley FBR Institutional Investor Conference on Wednesday, May 22, 2019 at 11:30 am at the Beverly Hilton Hotel in Beverly Hills, California (Press release, MediciNova, MAY 15, 2019, View Source [SID1234536437]). MediciNova will be available for one-on-one meetings at this conference and investors may request a one-on-one meeting through B. Riley FBR

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On May 15, 2019 SELLAS Life Sciences Group, Inc. (Nasdaq:SLS) ("SELLAS" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapies for a broad range of cancer indications, reported financial results for the quarter ended March 31, 2019 (Press release, Sellas Life Sciences, MAY 15, 2019, View Source [SID1234536326]).

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"Throughout 2019, as we have been progressing the review of strategic alternatives, we also have been continuing to advance our novel cancer immunotherapy clinical pipeline and are excited to be presenting data on one of our clinical candidates, nelipepimut-S (NPS), at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting," said Angelos Stergiou, MD, ScD h.c., President and Chief Executive Officer of SELLAS

American Society of Clinical Oncology 2019 Annual Meeting

Sellas will present immunologic response data from the NPS/Trastuzumab Study will be presented at the upcoming ASCO (Free ASCO Whitepaper) Annual Meeting being held May 31 – June 4, 2019 in Chicago, IL. Details for the presentation are as follows:

Title: Immunologic responses in triple-negative breast cancer patients in a randomized phase IIb trial of nelipepimut-S plus trastuzumab versus trastuzumab alone to prevent recurrence
Presenter: Jessica Campf, MD, San Antonio Military Medical Center
Abstract Number: 556
Poster Session: "Breast Cancer – Local/Regional/Adjuvant"
Date and Time: June 2, 2019, 8:00 am – 11:00 am CDT
Location: Hall A, McCormack Place, Chicago, IL

First Quarter 2019 and Recent Highlights

Galinpeptimut-S (GPS)
— In February 2019, the Company announced that Richard Maziarz, M.D., Medical Director of the Adult Blood and Marrow Stem Cell Transplant & Cellular Therapy Program at the Knight Cancer Institute and Professor of Medicine at Oregon Health and Science University (OHSU), and Roisin O’Cearbhaill, M.D., Assistant Attending Physician in Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC), will serve as co-principal investigators of the Company’s Phase 1/2 open-label, non-comparative, multicenter, multi-arm study of GPS in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab) in patients with selected WT1-positive advanced cancers, including both hematologic malignancies and solid tumors. The study is assessing the efficacy and safety of the combination, with exploratory long-term follow-up for overall survival and safety.
— In April 2019, the Company announced an agreement with MSKCC to conduct an investigator-sponsored clinical trial of GPS in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, nivolumab, in patients with malignant pleural mesothelioma (MPM). The Phase 1 open-label clinical study will enroll patients with MPM who harbor relapsed or refractory disease after having received frontline standard of care multimodality therapy with study drug provided by both SELLAS and Bristol-Myers Squibb.
Nelipepimut-S (NPS)
— In February 2019, the Company announced preliminary immune response data from an analysis of the patterns of induction of NPS-specific T-cell responses over time in a subgroup of patients with triple-negative breast cancer (TNBC) from the prospective, randomized, single-blinded, controlled Phase 2b independent investigator-sponsored clinical study of the combination of trastuzumab (Herceptin) +/- NPS targeting HER2 low-expressing breast cancer patient cohorts (the NPS/Trastuzumab Study). CD8+ cytotoxic T-lymphocytes (CTLs) from peripheral blood samples from study patients with TNBC were measured using specifically designed NPS-specific dextramers in a flow cytometry-based assay in duplicate. In 64 evaluable TNBC patients (39 in the NPS plus trastuzumab arm; 25 in the trastuzumab alone arm) across a median of four time-points (including baseline), NPS + trastuzumab administration generated up to 3-fold higher frequencies of NPS-specific CTLs compared to trastuzumab alone. CTL frequencies were higher among non-recurrent patients compared with those who recurred, on either arm
— In March 2019, SELLAS announced previously unreported disease free survival (DFS) data from the NPS/Trastuzumab Study. In the 97-patient TNBC cohort, the DFS landmark rate at 24 months for patients treated with NPS plus trastuzumab (n=53) was 92.6% compared to 70.2% for those treated with trastuzumab alone (n=44), a clinically and statistically significant improvement. In the intent-to-treat (ITT) population (all HER2 low-expressing breast cancer patients; n=275), and over the 24-month post-randomization follow-up period, the DFS landmark rate was in favor of the combination arm (89.8%) versus trastuzumab alone (83.8%).
Corporate
— In February 2019, the Company announced that it engaged Cantor Fitzgerald & Co. to act as its strategic and financial advisor in conducting a review of strategic options. This strategic review is ongoing and there can be no assurance that this process will result in a transaction.
— In the first quarter and early in the second quarter of 2019, the Company received aggregate gross proceeds of $3.5 million from the exercise of warrants from a holder pursuant to a Warrant Exercise Agreement which reduced the exercise price of certain outstanding warrants from $2.10 to $1.10 and provided for the issuance to the holder of new warrants on a share-for-share basis in an amount equal to the number of existing warrants that are cash exercised by the holder prior to May 31, 2019.

First Quarter 2019 Financial Results

R&D Expenses: Research and development expenses were $1.9 million for the first quarter of 2019, as compared to $1.8 million for the first quarter of 2018. The $0.1 million increase was primarily attributable to a $0.4 million increase in outsourced clinical and regulatory consulting related to our ongoing discussions with the U.S. Food and Drug Administration for further development of the combination of NPS plus trastuzumab in TNBC and a $0.2 million increase in licensing fees. These increases were partially offset by a $0.3 million decrease in clinical expenses due to the completion of the Phase 2b trial of NPS in combination with trastuzumab in 2018 and a $0.2 million decrease in personnel related expenses due to reduced headcount.

G&A Expense: General and administrative expenses were $2.5 million for the first quarter of 2019, as compared to $3.9 million for the first quarter of 2018. The $1.4 million decrease was due to a $0.6 million decrease in legal fees, a $0.2 million decrease in accounting and audit fees, a $0.2 million decrease in outsourced consulting, a $0.2 million decrease in public company costs and a $0.2 million decrease in other expenses. These decreases were driven by our focus on reducing expenses as we explore a wide range of strategic alternatives.

Net Loss: Net loss attributable to common stockholders was $5.0 million for the first quarter of 2019, or a basic and diluted loss per share attributable to common stockholders of $0.22, as compared to a net loss attributable to common stockholders of $10.0 million for the first quarter of 2018, or a basic and diluted loss per share attributable to common stockholders of $1.67.

Cash Position: As of March 31, 2019, cash and cash equivalents totaled approximately $2.6 million. Cash and cash equivalents as of March 31, 2018 totaled approximately $5.4 million. Net cash used in operating activities for the quarter was $5.0 million, compared to $5.4 million for the quarter ended March 31, 2018. During the first quarter, SELLAS received net proceeds of $2.2 million from the exercise of certain warrants. SELLAS received an additional $1.1 million from the exercise of warrants subsequent to March 31, 2019.

Keytruda and Herceptin are registered trademarks of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, N.J., USA, and Genentech, Inc., respectively, and are not trademarks of SELLAS. The manufacturers of these brands are not affiliated with and do not endorse SELLAS or its products.

On May 15, 2019 Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company), a biopharmaceutical company focused on developing and commercializing medicines seeking to improve the survival and quality of life of cancer patients, reported a poster highlighting dose modification data from the Phase 3 DUO study evaluating COPIKTRA (duvelisib) in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies (Press release, Verastem, MAY 15, 2019, View Source [SID1234536359]). The poster, entitled "Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial," will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting, taking place May 31 – June 4, 2019, in Chicago. COPIKTRA, an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, received approval from the U.S. Food and Drug Administration (FDA) for this same indication in September 2018.

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"Duvelisib is a potent oral dual inhibitor of PI3K-delta and -gamma with robust activity in patients with CLL/SLL after at least two prior therapies," commented Ian Flinn, MD, PhD, Director, Lymphoma/CLL Program at Sarah Cannon Research Institute and lead investigator of the DUO study. "These new data demonstrate that dose modifications may be used to manage treatment-emergent adverse events (TEAEs) while allowing patients to remain on therapy, and that dosing interruptions of a median 15 days do not appear to negatively impact response to Duvelisib or progression-free-survival (PFS)."

"Notably, these data also show that when adverse events of special interest (AESIs) occur, they tend to show up in the first few months of treatment, then the proportion of patients experiencing AESIs decreases," said Robert Forrester, President and Chief Executive Officer of Verastem Oncology. "We look forward to sharing these data with the scientific and medical communities at ASCO (Free ASCO Whitepaper) this year."

Effect of Dose Modification on Response to COPIKTRA in Patients with Relapsed or Refractory CLL/SLL in the Phase 3 DUO Study

The randomized, multicenter, open-label, Phase 3 DUO study, compared COPIKTRA versus ofatumumab in 319 adult patients with CLL (n=312) or SLL (n=7) after at least one prior therapy. The study randomized patients with a 1:1 ratio to receive either COPIKTRA 25mg twice daily until disease progression or unacceptable toxicity, or ofatumumab, an approved standard of care treatment for use in CLL/SLL, for 7 cycles. This analysis examined dose modification patterns and their impact on response to COPIKTRA. Dose interruptions (DI) or dose reductions (DR) to 15mg, 10mg or 5mg twice daily were permitted per study protocol to manage TEAEs. Responses were assessed per an Independent Review Committee (IRC).

Among the 158 COPIKTRA-treated patients in the DUO study, the median duration of exposure was 11.6 months, versus 5.3 months for patients treated with ofatumumab. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n=118), median time to first response on COPIKTRA was 1.9 months and the estimated median duration of response was 11.1 months. Median time to first DI was 3.9 months and median duration of DI was 15 days (range 1 to 133 days). Response to COPIKTRA was improved or maintained in most patients evaluated for response who had at least one DI for >1 week (84%) or >2 weeks (82%) followed by at least 3 weeks on COPIKTRA. In a landmark analysis, median PFS was similar in patients with DI and those without DI for >1 week (17.8 versus 16.3 months) or >2 weeks (17.8 versus 16.3 months) within the first 3 months. The median time to DR after a complete response or partial response was 5.6 months (n=25) and median duration was 3.4 months. Median time to onset across AESIs after starting COPIKTRA ranged from 2.2 to 4.3 months. Median time to resolution was within 4 weeks across AESIs. Proportions of patients experiencing AESIs were stable or decreased over time after 3-6 months: 0-3 months, 64%; >3-6 months, 63%; >6-9 months, 47%; >9-12 months, 52%, and seldom led to discontinuation of COPIKTRA (≤10%). These findings support the thesis that DI or DR can be useful in effectively managing TEAEs with COPIKTRA and that DI of >1-2 weeks or more do not appear to significantly impact response to COPIKTRA or PFS.

A PDF copy of this poster presentation will be available here following the conclusion of the presentation.

Details for the ASCO (Free ASCO Whitepaper) 2019 presentation is as follows:

Title: Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial

Lead author: Ian Flinn, Sarah Cannon Research Institute

Session: Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia

Poster Board#: 277

Abstract #: 7523

Location: McCormick Place, Hall A

Date and Time: Monday, June 3, 8:00 – 11:00 a.m. CT

Important Safety Information

WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

See full prescribing information for complete boxed warning

Fatal and/or serious infections occurred in 31% of COPIKTRA-treated patients. Monitor for signs and symptoms of infection. Withhold COPIKTRA if infection is suspected.
Fatal and/or serious diarrhea or colitis occurred in 18% of COPIKTRA-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold COPIKTRA.
Fatal and/or serious cutaneous reactions occurred in 5% of COPIKTRA-treated patients. Withhold COPIKTRA.
Fatal and/or serious pneumonitis occurred in 5% of COPIKTRA-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS

Infections: Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N=442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold COPIKTRA until infection has resolved. Resume COPIKTRA at the same or reduced dose.

Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA and following completion of treatment with COPIKTRA until the absolute CD4+ T cell count is greater than 200 cells/μL. Withhold COPIKTRA in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.

Cytomegalovirus (CMV) reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold COPIKTRA until infection or viremia resolves. If COPIKTRA is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.

Diarrhea or Colitis: Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).

Advise patients to report any new or worsening diarrhea. For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e., up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents, continue COPIKTRA at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting COPIKTRA at a reduced dose.

For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e., > 6 stools per day over baseline), withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart COPIKTRA at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA. Discontinue COPIKTRA for life-threatening diarrhea or colitis.

Cutaneous Reactions: Serious, including fatal (2/442; <1%), cutaneous reactions occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months) with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).

Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue COPIKTRA at the current dose, initiate supportive care with emollients, antihistamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold COPIKTRA for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or antihistamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart COPIKTRA at a reduced dose. Discontinue COPIKTRA if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue COPIKTRA. In patients with SJS, TEN, or DRESS of any grade, discontinue COPIKTRA.

Pneumonitis: Serious, including fatal (1/442; <1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving COPIKTRA 25 mg BID (N=442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months. The median event duration was 1 month, with 75% of cases resolving by 2 months.

Withhold COPIKTRA in patients with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation, and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on COPIKTRA at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids and resume COPIKTRA at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue COPIKTRA. For severe or life-threatening non-infectious pneumonitis, discontinue COPIKTRA and treat with systemic steroids.

Hepatotoxicity: Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, of patients receiving COPIKTRA 25 mg BID (N=442). Two percent of patients had both an ALT or AST > 3 X ULN and total bilirubin > 2 X ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).

Monitor hepatic function during treatment with COPIKTRA. For Grade 2 ALT/AST elevation (> 3 to 5 X ULN), maintain COPIKTRA dose and monitor at least weekly until return to < 3 X ULN. For Grade 3 ALT/AST elevation (> 5 to 20 X ULN), withhold COPIKTRA and monitor at least weekly until return to < 3 X ULN. Resume COPIKTRA at the same dose (first occurrence) or at a reduced dose for subsequent occurrences. For grade 4 ALT/AST elevation (> 20 X ULN), discontinue COPIKTRA.

Neutropenia: Grade 3 or 4 neutropenia occurred in 42% of patients receiving COPIKTRA 25 mg BID (N=442), with Grade 4 neutropenia occurring in 24% of all patients. Median time to onset of grade ≥3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.

Monitor neutrophil counts at least every 2 weeks for the first 2 months of COPIKTRA therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold COPIKTRA in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, then resume COPIKTRA at same dose for the first occurrence or at a reduced dose for subsequent occurrences.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Conduct pregnancy testing before initiating COPIKTRA treatment. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.

ADVERSE REACTIONS

B-cell Malignancies Summary

Fatal adverse reactions within 30 days of the last dose occurred in 8% (36/442) of patients treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%).

Adverse reactions resulted in treatment discontinuation in 156 patients (35%) most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain and anemia.

CLL/SLL

Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with COPIKTRA and in 4% (7/155) of patients treated with ofatumumab. Serious adverse reactions were reported in 73% (115/158) of patients treated with COPIKTRA and most often involved infection (38%; 60/158) and diarrhea or colitis (23%; 36/158). COPIKTRA was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash. The most common adverse reactions with COPIKTRA (reported in ≥20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.

DRUG INTERACTIONS

CYP3A Inducers: Coadministration with a strong CYP3A inducer may reduce COPIKTRA efficacy. Avoid coadministration with strong CYP3A4 inducers.
CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dose to 15 mg BID when coadministered with a strong CYP3A4 inhibitor.
CYP3A Substrates: Coadministration of COPIKTRA with sensitive CYP3A4 substrates may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the coadministered sensitive CYP3A substrate.
Please see the full Prescribing Information, including BOXED WARNING, and patient Medication Guide found on www.COPIKTRA.com.
About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes and are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. The symptoms of CLL/SLL include a tender, swollen abdomen and feeling full even after eating only a small amount. Other symptoms can include fatigue, shortness of breath, anemia, bruising easily, night sweats, weight loss, and frequent infections. However, many patients with CLL/SLL will live for years without symptoms. There are approximately 200,000 patients in the US affected by CLL/SLL with nearly 20,000 new diagnoses this year alone. While there are therapies currently available, real-world data reveals that a significant number of patients either relapse following treatment, become refractory to current agents, or are unable to tolerate treatment, representing a significant medical need. The potential of additional oral agents, particularly as a monotherapy that can be used in the general community physician’s armamentarium, may hold significant value in the treatment of patients with CLL/SLL.

About COPIKTRA (duvelisib)

COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase (PI3K), and the first approved dual inhibitor of PI3K-delta and PI3K-gamma, two enzymes known to help support the growth and survival of malignant B-cells. PI3K signaling may lead to the proliferation of malignant B-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.1,2,3 COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two prior therapies and relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. COPIKTRA is also being developed by Verastem Oncology for the treatment of peripheral T-cell lymphoma (PTCL), for which it has received Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.4 For more information on COPIKTRA, please visit www.COPIKTRA.com. Information about duvelisib clinical trials can be found on www.clinicaltrials.gov.

On May 15, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that data from its isocitrate dehydrogenase (IDH) programs will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting being held May 31-June 4, 2019 in Chicago (Press release, Agios Pharmaceuticals, MAY 15, 2019, View Source [SID1234536383]).

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The accepted abstracts are listed below and are available online on the ASCO (Free ASCO Whitepaper) conference website: View Source

Oral Presentation:

Title: A phase 1, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: Results from cohort 1
Date & Time: Monday, June 3, 2019 from 2:15-2:27 p.m. CT
Oral Abstract Session: Central Nervous System Tumors
Abstract: 2003
Location: S102
Presenter: Ingo K. Mellinghoff, M.D., Memorial Sloan Kettering Cancer Center

Poster Presentations:

Title: Ivosidenib (IVO; AG-120) in IDH1-mutant newly diagnosed acute myeloid leukemia (ND AML): Updated results from a phase 1 study
Poster Session Date & Time: Monday, June 3, 2019 from 8:00-11:00 a.m. CT
Poster Session: Hematologic Malignancies – Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract: 7028
Poster Board: 403
Poster Location: Hall A
Author: Gail J. Roboz, M.D., Weill Medical College of Cornell University

Title: Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML)
Poster Session Date & Time: Monday, June 3, 2019 from 1:15-4:15 p.m. CT
Poster Session: Hematologic Malignancies – Leukemia, Myelodysplastic Syndromes, and Allotransplant
Abstract: 7011
Poster Board: 386
Poster Location: Hall A
Author: Courtney D. DiNardo, M.D., University of Texas MD Anderson Cancer Center