Janssen Announces Submission to U.S. FDA for New DARZALEX® (Daratumumab)-Based Combination Regimen for Patients with Relapsed/Refractory Multiple Myeloma

On February 10, 2020 The Janssen Pharmaceutical Companies of Johnson & Johnson reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) seeking approval of DARZALEX (daratumumab) in combination with Kyprolis (carfilzomib) and dexamethasone (DKd) for relapsed/refractory multiple myeloma (Press release, Janssen Pharmaceuticals, FEB 10, 2020, View Source [SID1234554113]). The sBLA is supported by results from the Phase 3 CANDOR study, which compared treatment with DKd to carfilzomib and dexamethasone (Kd) in patients with multiple myeloma who relapsed after one to three prior lines of therapy.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"While we continue to make important strides in the treatment of multiple myeloma, unfortunately most patients will relapse at some point, so it is important that physicians have multiple treatment options and regimens for patients," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. "The results from the CANDOR study support the potential benefit of this DARZALEX-based combination regimen for patients with multiple myeloma who have relapsed from prior treatment."

Data from the Phase 3 CANDOR study were presented as a late-breaking abstract at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

About the CANDOR Study
CANDOR is a randomized, open-label Phase 3 study of DARZALEX (daratumumab), carfilzomib and dexamethasone (DKd) compared to carfilzomib and dexamethasone (Kd) alone. The study evaluated 466 relapsed or refractory patients with multiple myeloma who had received one to three prior lines of therapy from 120 global sites. Patients were treated until disease progression. The primary endpoint was progression free survival (PFS), and the key secondary endpoints were overall response rate, minimal residual disease and overall survival. PFS was defined as time from randomization until disease progression or death from any cause.

All patients received carfilzomib as a 30-minute intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter) and received 40 mg dexamethasone oral or IV weekly (20 mg/m2 for patients aged >75 years). In the treatment arm, DARZALEX 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and 16 mg/kg IV once weekly for the remaining doses of the first two cycles, then every two weeks for four cycles (cycles 3 to 6), and every four weeks thereafter.

CANDOR is an Amgen-sponsored study and is co-funded by Janssen Research & Development, LLC. For more information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT03158688.

About DARZALEX (daratumumab)
DARZALEX (daratumumab), the first monoclonal antibody for multiple myeloma approved anywhere in the world, is the only CD38-directed antibody approved to treat multiple myeloma.1 CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease.2 DARZALEX binds to CD38 and inhibits tumor cell growth causing myeloma cell death.3 DARZALEX may also have an effect on normal cells.3 DARZALEX is being evaluated in a comprehensive clinical development program across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.3,4,5,6,7,8,9,10 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant hematologic diseases in which CD38 is expressed, such as smoldering myeloma.11,12

In the U.S., DARZALEX received initial FDA approval in November 2015 as a monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double refractory to a PI and an immunomodulatory agent.13 DARZALEX received additional approvals in November 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.14 In June 2017, DARZALEX received approval in combination with pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior therapies, including lenalidomide and a PI.15 In May 2018, DARZALEX received approval in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT), making it the first monoclonal antibody approved for newly diagnosed patients with this disease.16 In June 2019, DARZALEX received approval in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma who are transplant ineligible.17 In September 2019, DARZALEX received approval in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for ASCT.18

In August 2012, Janssen Biotech, Inc. entered into a global license and development agreement with Genmab A/S, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.19 For the full U.S. Prescribing Information, please visit www.DARZALEX.com.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.20,21 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow. In 2020, it is estimated that 32,270 people will be diagnosed and 12,830 will die from the disease in the U.S.22 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.22

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

DARZALEX (daratumumab) is contraindicated in patients with a history of severe hypersensitivity (e.g., anaphylactic reactions) to daratumumab or any of the components of the formulation.

WARNINGS AND PRECAUTIONS

Infusion Reactions – DARZALEX can cause severe and/or serious infusion reactions, including anaphylactic reactions. In clinical trials, approximately half of all patients experienced an infusion reaction. Most infusion reactions occurred during the first infusion and were Grade 1-2. Infusion reactions can also occur with subsequent infusions. Nearly all reactions occurred during infusion or within 4 hours of completing DARZALEX. Prior to the introduction of post-infusion medication in clinical trials, infusion reactions occurred up to 48 hours after infusion. Severe reactions have occurred, including bronchospasm, hypoxia, dyspnea, hypertension, laryngeal edema, and pulmonary edema. Signs and symptoms may include respiratory symptoms, such as nasal congestion, cough, throat irritation, as well as chills, vomiting, and nausea. Less common symptoms were wheezing, allergic rhinitis, pyrexia, chest discomfort, pruritus, and hypotension.

Pre-medicate patients with antihistamines, antipyretics, and corticosteroids. Frequently monitor patients during the entire infusion. Interrupt infusion for reactions of any severity and institute medical management as needed. Permanently discontinue therapy if an anaphylactic reaction or life-threatening (Grade 4) reaction occurs and institute appropriate emergency care. For patients with Grade 1, 2, or 3 reactions, reduce the infusion rate when re-starting the infusion.

To reduce the risk of delayed infusion reactions, administer oral corticosteroids to all patients following DARZALEX infusions. Patients with a history of chronic obstructive pulmonary disease may require additional post-infusion medications to manage respiratory complications. Consider prescribing short- and long-acting bronchodilators and inhaled corticosteroids for patients with chronic obstructive pulmonary disease.

Interference with Serological Testing – Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX. Type and screen patients prior to starting DARZALEX.

Neutropenia and Thrombocytopenia – DARZALEX may increase neutropenia and/or thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to the manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. DARZALEX dose delay may be required to allow recovery of neutrophils and/or platelets. No dose reduction of DARZALEX is recommended. Consider supportive care with growth factors for neutropenia or transfusions for thrombocytopenia.

Interference with Determination of Complete Response – Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

Adverse Reactions – The most frequently reported adverse reactions (incidence ≥20%) were: infusion reactions, neutropenia, thrombocytopenia, fatigue, asthenia, nausea, diarrhea, constipation, decreased appetite, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, bronchitis, pneumonia, and upper respiratory tract infection.

DARZALEX in combination with lenalidomide and dexamethasone (DRd): The most frequent (≥20%) adverse reactions for newly diagnosed or relapsed/refractory patients were, respectively, infusion reactions (41%, 48%), diarrhea (57%, 43%), nausea (32%, 24%), fatigue (40%, 35%), pyrexia (23%, 20%), upper respiratory tract infection (52%, 65%), muscle spasms (29%, 26%), dyspnea (32%, 21%), and cough (30%, 30%). In newly diagnosed patients, constipation (41%), peripheral edema (41%), back pain (34%), asthenia (32%), bronchitis (29%), pneumonia (26%), peripheral sensory neuropathy (24%), and decreased appetite (22%) were also reported. In newly diagnosed patients, serious adverse reactions (≥2% compared to Rd) were pneumonia (15%), bronchitis (4%), and dehydration (2%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (56%), lymphopenia (52%), and leukopenia (35%). In relapsed/refractory patients, serious adverse reactions (≥2% compared to Rd) were pneumonia (12%), upper respiratory tract infection (7%), influenza (3%), and pyrexia (3%), and treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (53%) and lymphopenia (52%).

DARZALEX in combination with bortezomib, melphalan, and prednisone (DVMP): The most frequently reported adverse reactions (≥20%) were upper respiratory tract infection (48%), infusion reactions (28%), and peripheral edema (21%). Serious adverse reactions (≥2% compared to the VMP arm) were pneumonia (11%), upper respiratory tract infection (5%), and pulmonary edema (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (58%), neutropenia (44%), and thrombocytopenia (38%).

DARZALEX in combination with bortezomib and dexamethasone (DVd): The most frequently reported adverse reactions (≥20%) were peripheral sensory neuropathy (47%), infusion reactions (45%), upper respiratory tract infection (44%), diarrhea (32%), cough (27%), peripheral edema (22%), and dyspnea (21%). The overall incidence of serious adverse reactions was 42%. Serious adverse reactions (≥2% compared to Vd) were upper respiratory tract infection (5%), diarrhea (2%), and atrial fibrillation (2%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (48%) and thrombocytopenia (47%).

DARZALEX in combination with bortezomib, thalidomide, and dexamethasone (DVTd): The most frequent adverse reactions (≥20%) were infusion reactions (35%), nausea (30%), upper respiratory tract infection (27%), pyrexia (26%), and bronchitis (20%). Serious adverse reactions (≥2% compared to the VTd arm) were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (59%), neutropenia (33%), and leukopenia (24%).

DARZALEX in combination with pomalidomide and dexamethasone (DPd): The most frequent adverse reactions (>20%) were fatigue (50%), infusion reactions (50%), upper respiratory tract infection (50%), cough (43%), diarrhea (38%), constipation (33%), dyspnea (33%), nausea (30%), muscle spasms (26%), back pain (25%), pyrexia (25%), insomnia (23%), arthralgia (22%), dizziness (21%), and vomiting (21%). The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% of patients included pneumonia (7%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were neutropenia (82%), lymphopenia (71%), and anemia (30%).

DARZALEX as monotherapy: The most frequently reported adverse reactions (≥20%) were infusion reactions (48%), fatigue (39%), nausea (27%), back pain (23%), pyrexia (21%), cough (21%), and upper respiratory tract infection (20%). The overall incidence of serious adverse reactions was 33%. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%). Treatment-emergent Grade 3-4 hematology laboratory abnormalities (≥20%) were lymphopenia (40%) and neutropenia (20%).

ESSA Pharma Announces Multiple Abstracts Accepted for Presentation at Upcoming Medical and Scientific Symposia

On February 10, 2020 ESSA Pharma Inc. (Nasdaq: EPIX; TSX-V: EPI), a pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported that several abstracts on ESSA’s lead clinical candidate, EPI-7386, have been selected for presentation at upcoming medical and scientific symposia (Press release, ESSA, FEB 10, 2020, View Source [SID1234554112]). These presentations will provide further preclinical characterization of EPI-7386 including new preclinical data regarding safety studies, gene expression and combination data with antiandrogens.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium

Title: IND Candidate EPI-7386 as an N-terminal Domain Androgen Receptor Inhibitor in Development for the Treatment of Prostate Cancer

Abstract #:

142

Presenter:

Dr. Ronan Le Moigne

Session Title:

Prostate Cancer

Poster Board:

F22

Date:

Thursday, February 13, 2020

Time:

11:30am – 1:00pm PST

Location:

Moscone West Building, San Francisco, CA

American Association for Cancer Research Special Conference on Advances in Prostate Cancer Research

Title: The N-terminal Domain Inhibitor of the Androgen Receptor, EPI-7386, Targets Full Length and Splice Variant Driven Pathways

Presenter:

Dr. Nan Hyung Hong

Poster Session:

B

Date:

Saturday, March 14, 2020

Time:

12:30pm – 3:00pm MST

Location:

Grand Hyatt Denver, Denver, CO

2020 American Urological Association Annual Meeting

Title: The Preclinical Characterization and Development of EPI-7386, an N-terminal domain androgen receptor inhibitor, for the treatment of prostate cancer

Abstract #:

20-6346

Presenter:

Dr. Ronan Le Moigne

Session Title:

Prostate Cancer: Advanced IV

Moderated Poster:

MP79

Date:

Monday, May 18, 2020

Time:

9:30am – 11:30am EST

Location:

Walter E. Washington Convention Center, Washington, D.C.

Eisai to Present Latest on LENVIMA® (lenvatinib) at the 2020 Genitourinary Cancers Symposium

On February 10, 2020 Eisai reported the presentation of three abstracts at the 2020 Genitourinary Cancers Symposium (#GU20) in San Francisco from February 13-15 (Press release, Eisai, FEB 10, 2020, View Source [SID1234554111]). New data to be presented on lenvatinib (marketed as LENVIMA) include results from a Phase 2 trial evaluating the efficacy and tolerability of lenvatinib plus everolimus (LEN+EVE) in patients with non-clear cell renal cell carcinoma (nccRCC) who had not previously received chemotherapy for advanced disease, and an analysis of genomic biomarkers via whole exome sequencing and outcomes in patients with advanced renal cell carcinoma (RCC) who were treated with pembrolizumab plus lenvatinib in Study 111/KEYNOTE-146.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

A trials in progress poster on the LEAP-011 phase 3 study assessing the efficacy and safety of pembrolizumab plus lenvatinib, compared with pembrolizumab plus placebo in patients with advanced urothelial carcinoma (UC) will also be shared.

"We look forward to sharing new investigational information that expand our understanding of LENVIMA in advanced renal cell carcinoma," said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. "We are committed to deepening our understanding of our medicines and researching combinations for our patients."

This release discusses investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.

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

Abstract Name

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

Phase III study of first-line pembrolizumab
(pembro) plus lenvatinib (len) in patients (pts) with
advanced urothelial carcinoma (UC) ineligible for
platinum-based chemotherapy: LEAP-011.

Poster Session B

Abstract # TPS597 / Poster Board #N15

Friday, February 14, 2020

12:15-1:45 PM and 5:15-6:15 PM

Yohann Loriot, MD, PhD

A phase II study of lenvatinib plus everolimus in
patients with advanced non-clear cell renal cell
carcinoma (nccRCC): Study 221.

Poster Session C

Abstract # 685 / Poster Board G5

Saturday, February 15, 2020

7:00 AM-7:55 AM and 12:30 PM-2:00 PM

Thomas Hutson, DO, FACP, PharmD

Genomic biomarkers of response to
lenvatinib/pembrolizumab (Len/Pembro) in patients
with advanced renal cell carcinoma: Study 111.

Poster Session C

Abstract # 733 / Poster Board J9

Saturday, February 15, 2020

7:00 AM- 7:55 AM and 12:30 PM-2:00 PM

Chung-Han Lee, MD, PhD

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 lenvatinib, both as monotherapy and in combination with Merck’s anti-PD-1 therapy pembrolizumab.

About LENVIMA (lenvatinib) Capsules 10 mg and 4 mg

LENVIMA is indicated:

For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory 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)
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.

Please see Prescribing information for LENVIMA (lenvatinib) at View Source

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. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.

In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, 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 (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and urothelial cancer). The LEAP clinical program also includes a new basket trial targeting six additional cancer types (biliary tract cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma and ovarian cancer).

Sirnaomics’ siRNA Therapeutic Candidate, STP705, Granted Orphan Drug Designation By US FDA for Treatment of Hepatocellular Carcinoma

On February 10, 2020 Sirnaomics, Inc., a leading biopharmaceutical company in discovery and development of RNAi therapeutics, reported that the Office of Orphan Product Development division of the FDA has granted orphan drug designation to its leading therapeutic candidate, STP705, for the treatment of Hepatocellular Carcinoma (HCC) (Press release, Sirnaomics, FEB 10, 2020, View Source [SID1234554110]). This is the third such designation for this drug candidate, following the designation for Primary Sclerosing Cholangitis and Cholangiocarcinoma.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Sirnaomics lead product candidate, STP705 is a siRNA (small interfering RNA) therapeutic that takes advantage of the Company’s proprietary dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. Sirnaomics has opened Investigational New Drug (IND) applications under the jurisdiction of the US FDA and Chinese FDA for clinical studies for Non-melanoma skin cancers (NMSC), Cholangiocarcinoma (CCA), and Hypertrophic Scar (HTS) Reduction.

"We are very pleased to reach another significant milestone and very excited to develop our lead product candidate for treatment of HCC with tremendous unmet needs" stated Patrick Lu, PhD, President and CEO. "This third grant of orphan drug designation for STP705 to treat HCC further consolidates our long-term strategy positioning us to take advantage of the regulatory arbitrage by achieving approval in US and then moving to the large market in China."

"Receipt of the orphan drug designation for Hepatocellular Carcinoma is a very important step for Sirnaomics. It provides the pathway allowing us to develop STP705 in a devastating oncology disease for which there is currently no effective therapy," stated Dr. Michael Molyneaux, MD, MBA, Chief Medical Officer. "This orphan drug designation aligns with our mission to alleviate human suffering and target diseases with high unmet clinical need and we anticipate the start of our clinical study for HCC in the second half of 2020."

About STP705 (Cotsiranib)
Sirnaomics leading product candidate, STP705, is an siRNA (small interfering RNA) therapeutic which takes advantage of a dual-targeted inhibitory property and polypeptide nanoparticle (PNP)-enhanced delivery to directly knock down both TGF-β1 and COX-2 gene expression. The product candidate has received multiple IND approvals from both the US FDA and Chinese NMPA, including treatments of Cholangiocarcinoma, Non-Melanoma skin cancer and Hypertrophic Scar. STP705 has also received Orphan Drug Designation for treatment of Cholangiocarcinoma and Primary Sclerosing Cholangitis. Preclinical animal models using STP705, have demonstrated a dramatic improvement in T-cell penetration into tumors in the liver with single agent action as well as improvement in the efficacy of an anti-PD-L1 antibody checkpoint inhibitor in an HCC model. This effect may improve other immune checkpoint inhibitor efficacies in addition to those targeting the PD-1/PD-L1 axis.

About Hepatocellular carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults, and is the most common cause of death in people with liver cirrhosis. It occurs in the setting of chronic liver inflammation, and is most closely linked to chronic viral hepatitis infection (hepatitis B or C) or exposure to toxins such as alcohol or aflatoxin. Certain diseases, such as hemochromatosis and alpha 1-antitrypsin deficiency, markedly increase the risk of developing HCC. Metabolic syndrome and NASH are also increasingly recognized as risk factors for HCC. Worldwide, approximately 840,000 people are diagnosed with primary liver cancer each year and about 500,000 of the patients are in China, even though HCC is designated as an orphan drug indication by US FDA. Abundant literature has directly linked high level expression of TGF-β1 to liver epithelial to mesenchymal transition (EMT) and tumorigenesis. Inhibition of COX-2 is able to reverse the drug resistance to the chemo drug treatment of HCC and also increased CD4+ T cells within the tumor.

Arvinas Selects Certara to Advance Speed and Efficiency of Its Targeted Protein Degradation Research

On February 10, 2020 Certara, the global model-informed drug development and decision support leader, reported that its discovery research relationship with Arvinas has expanded to include a greater diversity of small molecule drug discovery projects and data sources. Arvinas’ current drug discovery focus areas include metastatic prostate cancer, locally-advanced or metastatic breast cancer, and neurodegenerative diseases (Press release, Arvinas, FEB 10, 2020, View Source [SID1234554109]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Arvinas is the pioneer and clinical-stage leader in the exciting new area of targeted protein degradation. Its proprietary PROTAC (proteolysis-targeting chimera) protein degraders are chimeric, modular small molecules, which harness the body’s natural protein disposal system, the ubiquitin‐proteasome system, to induce the degradation of disease‐causing proteins.

"Arvinas is employing Certara’s D360 scientific informatics platform to increase the speed and efficiency of its lead identification and optimization processes. D360 is specifically designed to allow scientific researchers to access, understand and share drug discovery data quickly," explained Dr. David Lowis, Senior Director of Product Management at Certara. "Medical research is moving so rapidly, especially in oncology, that gaining access to novel technology and fast, accurate drug discovery results will determine how quickly new medicines can be brought to patients."

"We need to be able to query, pivot and dive deep into our drug discovery data, and D360 is the best platform we have found for that," said Dr. Keith Hornberger, Director, Chemistry at Arvinas. "We have increased the number of data sources and complexity of data, which are now seamlessly integrated providing complete transparency to our end users. We currently have around 70 scientists using D360, running over 700 distinct D360 queries. Compared to our previous research informatics solution, D360 is saving us hundreds of hours annually on data analysis. That is an important contribution to our research."

"The Certara team is tenacious and resourceful. They always find a solution. That’s what has made our relationship so successful," added Dr. Hornberger.

Designed to meet clients’ specific research goals, D360 features small molecule discovery, biologics discovery, and pre-clinical toolkits for both large and small biopharmaceutical companies.