On January 14, 2019 CytRx Corporation (NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, reported that aldoxorubicin licensee NantCell, Inc., a private subsidiary of NantWorks, LLC, has dosed the first patient in the Phase 1b portion of a Phase 1b/2 clinical trial for patients with relapsed or refractory colorectal cancer (CRC) who have been previously treated with standard of care (SOC) therapy (Press release, CytRx, JAN 14, 2019, View Source [SID1234532646]). This is the fourth trial conducted by NantCell which will investigate high-affinity natural killer (haNK) cell therapy in combination with anti-cancer agents, including aldoxorubicin, in certain high unmet need cancer indications.

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"Among the most compelling recent medical advances has been the significant improvement in efficacy seen when immunotherapy is combined with chemotherapy, especially in high unmet medical need cancers such as non-small cell lung, pancreatic cancer and triple negative breast cancers," said Eric Curtis, CytRx’s President and Chief Operating Officer. "NantCell is leveraging this important emerging combination trend and to date has initiated four Phase 1b/2 clinical trials investigating their haNK cell therapy in combination with several anti-cancer agents, including aldoxorubicin. Aldoxorubicin targets and binds to serum albumin to concentrate drug inside solid tumors, maximizing efficacy and minimizing systemic toxicity. This newest clinical trial in relapsed or refractory CRC speaks to NantCell’s continued commitment to maximizing the clinical and commercial potential of targeting solid tumors with albumin binding aldoxorubicin for these patients with difficult to treat malignancies."

The trial titled "QUILT-3.071: NANT Colorectal Cancer (CRC) Vaccine: A Phase 1b/2 Trial of the NANT CRC Vaccine vs Regorafenib in Subjects With Metastatic CRC Who Have Been Previously Treated With Standard-of-Care Therapy," (NCT03563157) is a single-center, open-label, Phase 1b/2 clinical trial designed to evaluate the safety and efficacy of several combination therapies, including combinations with aldoxorubicin, in subjects with CRC who have progressed on or after SOC therapy. The primary endpoint for the Phase 1b portion of the trial is safety and if the study proceeds to phase 2, the primary endpoint for the Phase 2 portion of the trial is progression-free survival (PFS) and objective response rate (ORR), both by RECIST.

About Colorectal Cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is any cancer that affects the colon and the rectum. According to the Colorectal Cancer Alliance, CRC is the third most common type of cancer in the U.S., and the second leading cause of cancer death. The American Cancer Society estimates that approximately 140,000 new cases of CRC are expected to be diagnosed in the U.S. in 2018 and it will cause over 50,000 deaths in the same timeframe. CRC affects men and women of all racial and ethnic groups, and is most often found in people 50 years or older, however, incidence in those younger than 50 is on the rise.

On January 14, 2019 Array BioPharma Inc. (Nasdaq: ARRY) reported updated safety and efficacy results, including mature overall survival (OS), from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of BRAFTOVI (encorafenib), a BRAF inhibitor, MEKTOVI (binimetinib), a MEK inhibitor and ERBITUX (cetuximab), an anti-EGFR antibody, in patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) (Press release, Array BioPharma, JAN 14, 2019, View Source [SID1234532645]). The results showed that mature median OS was 15.3 months (95% CI, 9.6–not reached) for patients treated with the triplet. These data will be presented on Saturday, January 19 at the ASCO (Free ASCO Whitepaper) 2019 Gastrointestinal Cancers Symposium in San Francisco, California.

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Updated median progression-free survival (mPFS) and updated confirmed overall response rate (ORR) results for patients treated with the triplet in the safety lead-in remain the same, as previously reported, with 8 months mPFS (95% CI, 5.6-9.3) and a 48% ORR (95% CI, 29.4–67.5). Among the 17 patients who received only one prior line of therapy, the ORR was 62%.

A BRAF mutation is present in up to 15% of all patients with mCRC and V600 is the most common BRAF mutation. [1-5] BRAFV600E-mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no U.S. Food and Drug Administration (FDA)-approved therapies specifically indicated for this high unmet need population. [3-10]

"The mature median overall survival of 15.3 months demonstrated in the safety lead-in of the BEACON CRC trial is unprecedented in this patient population and, for context, represents a substantial improvement compared to the observed historical published benchmarks of approximately 4 to 6 months for median overall survival with current standards of care in patients with BRAF-mutant mCRC," said Axel Grothey, M.D., BEACON CRC trial lead investigator and Co-Chair of the National Cancer Institute’s Gastrointestinal Cancer Steering Committee, West Cancer Center, Memphis, TN. "These updated data further underscore the potential of this triplet for patients with BRAF-mutant mCRC who are in desperate need of effective new treatment options."

The triplet combination was generally well-tolerated with no unexpected toxicities. The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities continued to be lower than generally observed with ERBITUX in mCRC.

"We are delighted with the updated results from the BEACON CRC safety lead-in. Following consultations with the FDA and European Medicines Agency, we initiated an amendment to the BEACON CRC protocol to allow for an interim analysis based primarily on confirmed ORR and durability of response endpoints, which we believe could support an accelerated approval with positive results," said Victor Sandor, M.D., Chief Medical Officer, Array BioPharma. "We anticipate topline results from this interim analysis in the first half of this year. This timing allows for the subset of patients required for the interim analysis of ORR to achieve a response and for the durability of responses to be appropriately evaluated."

On August 7, 2018, Array announced that the FDA granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

BEACON CRC Safety Lead-In Data

Title:

Abstract #688: Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC)

Presenter:

Scott Kopetz, M.D., Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Date:

Saturday, January 19, 2019

Times:

7:00 – 7:55 a.m. and 12:15 – 1:45 p.m. Pacific Time

Location:

Poster N13; Moscone West Building

Following the presentation, the slides will be available as a PDF on the Publications section of the Array website.

Array will host an investor webcast presentation of the BEACON CRC safety lead-in data.

Investor Webcast:

Presenter:

Axel Grothey, M.D., BEACON CRC trial lead investigator and Co-Chair of the National Cancer Institute’s Gastrointestinal Cancer Steering Committee, West Cancer Center, Memphis, TN

Date:

Tuesday, January 15

Time:

9:00 a.m. Eastern Time

Toll-Free:

(844) 464-3927

Toll:

(765) 507-2598

Pass Code:

6774596

Webcast, including replay and conference call slides: View Source

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [11] In the U.S. alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. [12] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [1-5] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [1,10,13] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and median OS of 4 to 6 months. [3-9,14] BRAF V600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [15-17] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial. The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

BRAFTOVI + MEKTOVI have received regulatory approval in the United States, European Union, and Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information

The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Warnings and Precautions
New Primary Malignancies: Cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS trial, the most common laboratory abnormalities (≥20%, all Grades): included increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug Interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. [18,19] You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).

On January 14, 2019 Eisai Inc. reported the presentation of four abstracts at the 2019 Gastrointestinal Cancers Symposium (#GI19), taking place in San Francisco from January 17-19, 2019 (Press release, Eisai, JAN 14, 2019, View Source [SID1234532644]). The presentations feature the latest data from post-hoc analyses of the pivotal phase 3 REFLECT trial (Study 304) of lenvatinib (marketed as LENVIMA), an orally available kinase inhibitor discovered by Eisai, for the first-line treatment for unresectable hepatocellular carcinoma (HCC).

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Presentations of interest include:

An oral presentation on a landmark analysis of the relationship between overall survival (OS) and objective response (OR) in patients from REFLECT.
A poster presentation on a post-hoc analysis of responders from REFLECT who received first-line lenvatinib and subsequent anticancer medication during survival follow-up.
"Our data at this year’s GI Cancers Symposium provides important clinical insights—with the potential to better assess and further define the treatment paradigm for patients with unresectable HCC," said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. "At Eisai, the patients we serve are what fuel our drive to continue evaluating and exploring effective ways to approach difficult-to-treat cancers, and these data are one more example of our efforts to deliver on our commitment to patients."

Additionally, a needs assessment developed and conducted by the Association of Community Cancer Centers (ACCC) that identifies factors associated with delivery and coordination of care for patients with HCC in community settings will also be presented. This research was conducted via an unrestricted grant from Eisai.

The full list of Eisai presentations along with the time, location and presenter of each session is included below.

ABSTRACT NAME

SESSION

(All times are U.S. Pacific Standard Time)

Analysis of survival and objective response

(OR) in patients with hepatocellular

carcinoma in a phase 3 study of lenvatinib

(REFLECT)

Friday, January 18, 2019

Abstract No: 186

Masatoshi Kudo, MD, PhD

Oral Abstract Session

2:00 p.m. – 3:30 p.m.

Poster Sessions

11:30 a.m. – 1:00 p.m. and 5:30 p.m. – 6:30 p.m.

Subsequent anticancer medication following

first-line lenvatinib: A posthoc responder

analysis from the phase 3 REFLECT study in

unresectable hepatocellular carcinoma

Friday, January 18, 2019

Abstract No: 371

Arndt Vogel, MD, PhD

Poster Sessions

11:30 a.m. – 1:00 p.m. and 5:30 p.m. – 6:30 p.m.

Association between overall survival and

adverse events with lenvatinib treatment in

patients with hepatocellular carcinoma

(REFLECT)

Friday, January 18, 2019

Abstract No: 317

Max Sung, MD

Poster Sessions

11:30 a.m. – 1:00 p.m. and 5:30 p.m. – 6:30 p.m.

Safety and efficacy of lenvatinib by starting

dose based on bodyweight in patients (pts)

with unresectable hepatocellular carcinoma

(uHCC) in REFLECT

Friday, January 18, 2019

Abstract No: 316

Takuji Okusaka, MD, PhD

Poster Sessions

11:30 a.m. – 1:00 p.m. and 5:30 p.m. – 6:30 p.m.

Understanding practices and gaps in

multidisciplinary hepatocellular carcinoma

(HCC) care within the community oncology

setting

Friday, January 18, 2019

Abstract No: 390

Lorna Lucas, MSM

Poster Sessions

11:30 a.m. – 1:00 p.m. and 5:30 p.m. – 6:30 p.m.

In March 2018, Eisai and Merck (known as MSD outside the United States and Canada), through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab).

About LENVIMA (lenvatinib) capsules 10 mg and 4 mg

LENVIMA (lenvatinib) is a kinase inhibitor that is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with everolimus, for the treatment of patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
LENVIMA, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Important Safety Information

Warnings and Precautions

Hypertension. In DTC, hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In RCC, hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In HCC, hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.

Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.

Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.

Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3).

Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction.

Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%.

Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients.

Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome. Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events.

Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.

Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Wound Healing Complications. Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold for at least 6 days prior to scheduled surgery. Resume after surgery based on clinical judgment of adequate wound healing. Permanently discontinue in patients with wound healing complications.

Embryo-fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions

In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.

In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).

Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with RCC or DTC and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

No dose adjustment is recommended for patients with DTC or RCC and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC or RCC and severe hepatic impairment. Reduce the dose for patients with DTC or RCC and severe hepatic impairment.

For more information about LENVIMA please see available full Prescribing Information.

About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA (lenvatinib). Under the agreement, the companies will jointly develop and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA (pembrolizumab).

In addition to ongoing clinical studies of the LENVIMA and KEYTRUDA combination, the companies will jointly initiate new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program, which will evaluate the combination to support 11 potential indications in six types of cancer (bladder cancer, endometrial cancer, head and neck cancer, hepatocellular carcinoma, melanoma and non-small cell lung cancer). The LEAP clinical program also includes a new basket trial targeting six additional cancer types (biliary duct cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer). The LENVIMA and KEYTRUDA combination is not approved in any cancer types today.

On January 14, 2019 Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops and commercializes high quality medicines, reported that the first patient has been successfully dosed in a phase I clinical trial of anti-CD47 monoclonal antibody (IBI188) for patients with advanced malignancies (Press release, Innovent Biologics, JAN 14, 2019, View Source [SID1234532643]).

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The study is a phase I clinical study conducted in China to evaluate the safety, tolerability, and efficacy of IBI188 in the treatment of patients with advanced malignancies. The primary objectives are to evaluate the safety, tolerability, and phase II recommended doses of IBI188 as a monotherapy and in combination with other agents in subjects with advanced malignancy.

"CD47 is a ‘don’t eat me’ signal; the CD47-SIRPα mechanism is hijacked in many malignant tumors to escape immune mediated clearance. Based on the promising safety and efficacy data from literature, we hope to validate the therapeutic value of IBI188 monoclonal antibody in advanced malignancies," said Professor Jun Zhu, from the Beijing Cancer Hospital.

"IBI188 is a pivotal product in our pipeline of cancer immunotherapies. CD47 is an important component of a critical inhibitory immune pathway but is different from T cell check point inhibitors such as PD-1, PD-L1 and CTLA-4. CD47 targets macrophages and suppresses phagocytosis by interacting and activating the inhibitory receptor SIRPα. Anti-CD47 mono therapy and combination therapy has shown promising efficacy in several types of solid tumor and in refractory/relapsed non-Hodgkin Lymphoma. We are preparing to advance IBI188 into subsequent clinical trials in a variety of cancers once its safety, tolerability and the recommended phase II dose are confirmed. We hope our efforts will give more patients the opportunity for tumor control or even cure," said Michael Yu, Founder, Chief Executive Officer and Chairman of Innovent.

About IBI188

IBI188 is a fully human monoclonal antibody targeting CD47. In vitro and in vivo experiments have shown that IBI188 can bind to the CD47 antigen on the surface of tumor cells, block the CD47-SIRPα signaling pathway, inhibit the "Don’t Eat Me" signal, and promote the phagocytosis of tumor cells by macrophages, thereby exerting an anti-tumor effect. Innovent will launch several clinical trials to assess its safety and efficacy in multiple tumor types, including non-Hodgkin’s lymphoma and ovarian cancer.

About CIBI188A101

The CIBI188A101 study is a Phase I clinical study conducted in China to evaluate the safety, tolerability, and efficacy of IBI188 in the treatment of patients with advanced malignancies. The primary objectives are to evaluate the safety, tolerability, and phase II recommended doses of IBI188 as a monotherapy and in combination with other agents in subjects with advanced malignancy. The phase 1a study explores the priming and maintenance dose of IBI188 as monotherapy.

On January 14, 2019 Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on discovering and developing innovative immuno-oncology protein therapeutics, reported two upcoming presentations at the 2019 Gastrointestinal Cancer Symposium being held in San Francisco, January 17-19, 2019 (Press release, Five Prime Therapeutics, JAN 14, 2019, View Source [SID1234532642]). Data will be presented from the Phase 1/3 FIGHT Study evaluating bemarituzumab and mFOLFOX6 in advanced gastric/GEJ cancer. The study design of the randomized phase 2 study of cabiralixumab in combination with nivolumab and chemotherapy in advanced pancreatic ductal adenocarcinoma will also be presented. Here are the details of the two poster presentations:

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Title: Phase 1 Results from the Phase 1/3 FIGHT Study Evaluating bemarituzumab and mFOLFOX6 in Advanced Gastric/GEJ Cancer
Abstract Number: Board J1, Abstract #91
Poster Session: A – Cancer of the Esophagus and Stomach
Date & Time: Thursday, January 17, 19, 11:30-1pm and 5:30-6:30pm

Title: A Randomized Phase 2 Study of cabiralizumab (cabira) + nivolumab (nivo) ± chemotherapy (chemo) in Advanced Pancreatic Ductal Adenocarcinoma (PDAC)
Abstract Number: Board Q4 Abstract #TPS465
Poster Session: B – Pancreatic, Small Bowel, Hepatobiliary
Date & Time: Friday, January 18, 2019, 11:30-1pm and 5:30-6:30pm

The poster abstracts will be available on January 14, 2019 at 5:00 PM EST at the ASCO (Free ASCO Whitepaper) Meeting Library and the posters can be found on Five Prime Therapeutics’ Scientific Publications page after presentation at the conference.

About Bemarituzumab (FPA008)

Bemarituzumab is a first-in-class, isoform-selective, humanized monoclonal antibody in clinical development as a targeted immunotherapy for tumors that overexpress FGFR2b, a splice variant of a receptor for some members of the fibroblast growth factor (FGF) family. Bemarituzumab has been engineered for enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) to increase direct tumor cell killing by recruiting natural killer (NK) cells. Clinical results to date suggest that the specificity of bemarituzumab avoids the dose-limiting toxicities that have been seen with less selective pan-FGFR tyrosine kinase inhibitors that act on multiple FGFRs, including FGFR2.

In December 2017, Five Prime and Zai Lab announced a collaboration for the development and commercialization of bemarituzumab in Greater China. Zai Lab will manage the Phase 3 portion of the FIGHT trial in China.

About Cabiralizumab (FPA008)

Cabiralizumab is an investigational antibody that inhibits the CSF-1 receptor and has been shown in preclinical models to block the activation and survival of monocytes and macrophages. Inhibition of CSF1R in preclinical models of several cancers reduces the number of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment, thereby facilitating an immune response against tumors. Cabiralizumab is currently in clinical trials in oncology indications. Cabiralizumab is being developed under an exclusive worldwide license and collaboration agreement entered into with Bristol-Myers Squibb (BMS) in October 2015.