Carisma Therapeutics Announces a $53 Million Series A Financing to Develop Novel CAR Macrophage Cellular Immunotherapy

On June 27, 2018 Carisma Therapeutics Inc., formerly CARMA Therapeutics, a privately-held biotechnology company focused on the development of macrophage-based immunotherapeutics, reported the close of a $53 million Series A financing to further expand its technology platform and rapidly drive its programs toward clinical development (Press release, Carisma Therapeutics, JUN 27, 2018, View Source [SID1234527485]). The financing was led by AbbVie Ventures and HealthCap and includes existing seed investors IP Group, Penn Medicine and Grazia Equity. Carisma is also proud to welcome new investors Wellington Partners, TPG Biotech, MRL Ventures Fund and Agent Capital.

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Carisma Therapeutics’ discovery and development efforts are focused on their proprietary CAR-Macrophage platform – the first technology to combine antigen recognition with the effector function of macrophages. The proposed dual mechanism of action includes the ability to directly kill targeted cells and the ability to leverage antigen-presenting cell biology to mount an adaptive immune response. Initial applications for therapeutic candidates will be in the treatment of solid tumors. Other potential applications include the disruption of protein aggregates in multiple disease states. The company anticipates initiating clinical development in 2019.

The Carisma management team is led by Steven Kelly, CEO, who brings nearly 30 years of diverse drug development and commercialization experience at a variety of biotechnology and pharmaceutical companies. The team also includes Dora Mitchell, PhD as Head of Operations and Daniel Cushing, PhD heading development. Carisma is continuing to build its team and currently recruiting a CSO and a CMO.

Founded by Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology in Penn’s Abramson Cancer Center, and Michael Klichinsky, PharmD, a PhD candidate in Systems Pharmacology and Translational Therapeutics, in partnership with the UPstart Program of the Penn Center for Innovation at the University of Pennsylvania, Carisma Therapeutics raised its incubation financing and began operations last summer. The company’s founders will be joined on the Scientific Advisory Board by Drs. Carl H. June, Lisa M. Coussens, Reinhard Andreesen and S. Jane Flint.

"Carisma’s programs combine the unique effector function of macrophages with advances in CAR technology to create a revolutionary approach to adoptive cellular therapy," commented CEO, Steven Kelly. "We are thrilled about the composition of our financing syndicate, which brings varied and deep experience in cell and gene therapy to further support our research and development efforts."

The company’s Board of Directors will be comprised of Margarita Chavez, JD, Managing Director of AbbVie Ventures; Jacob Gunterberg, Partner of HealthCap; Regina Hodits, PhD, Managing Partner of Wellington Partners; Steven Kelly, CEO; Eran Nadav, PhD, Senior Advisor of TPG Biotech; Althea Stillman, PhD, Associate Director at IP Group Inc.; and Bruce Peacock, Chairman.

Trovagene Announces Preliminary Clinical Data from First Dosing Cohort Demonstrating Durable Treatment Effect of PCM-075 in Combination with Cytarabine or Decitabine in Patients with Relapsed or Refractory AML

On June 27, 2018 Trovagene, Inc. (NASDAQ: TROV), a clinical-stage oncology therapeutics company, developing targeted therapeutics for the treatment of hematologic and solid tumor cancers, reported preliminary clinical data from the first dosing cohort showing a treatment effect with PCM-075 in combination with low-dose cytarabine (LDAC) or decitabine, as measured by decreases in leukemic cells in both peripheral blood and bone marrow in patients in its ongoing Phase 1b/2 trial in relapsed or refractory Acute Myeloid Leukemia (AML) (Press release, Trovagene, JUN 27, 2018, View Source [SID1234527483]).

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Both blood and bone marrow samples were obtained from patients with relapsed or refractory AML enrolled in the Phase 1b/2 trial prior to, and at timepoints following administration of PCM-075, in combination with cytarabine or decitabine. In the first dose level, seven patients were treated with PCM-075 at 12 mg/m2 in combination with either LDAC or decitabine. One patient was not evaluable for safety due to rapid disease progression. Among the other 6 patients, no dose-limiting toxicities (DLTs) were observed that would prohibit further escalation of the PCM-075 dosing. Three patients exhibited substantial reductions in the percentage of both circulating leukemic cells within the blood and leukemic cells within the bone marrow. Two of these three patients continued on treatment in the second cycle and further decreases in circulating leukemic cells in the blood and within the bone marrow were observed. One patient had a decrease in his bone marrow blasts from 96% to 40% at the end of cycle 2 and has continued on treatment in cycle 3. The next dose level cohort of PCM-075 at 18 mg/m2 in combination with LDAC or decitabine is currently enrolling and dosing patients.

In addition, Translational Control Tumor Protein (TCTP), which is uniquely phosphorylated by PLK1, was used to evaluate PLK1 inhibition by PCM-075. Data presented by Trovagene at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) showed that PCM-075 decreases phosphorylated TCTP (pTCTP) in AML cell lines. In these same cell lines pTCTP levels were unaffected by treatment with either LDAC or decitabine.

PLK1 inhibition in the Phase 1b/2 AML trial is being assessed in patients 3-hours following administration of PCM-075 in combination with LDAC or decitabine, when PCM-075 levels are expected to be at their peak concentration (Cmax). Significant reductions in PLK1, as measured by pTCTP levels, were observed in the circulating blood cells in four of six patients treated with PCM-075 in combination with cytarabine or decitabine. Three of these four patients also had significant reductions in circulating blast cells during the treatment cycle.

"While we are still quite early in the trial, these data points are encouraging from both a safety and efficacy standpoint," said Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine, Department of Medicine, and Yale Cancer Center, Yale School of Medicine, Yale University, a leading investigator on the trial. "There were no dose limiting toxicities seen in the first cohort and treatment was generally well tolerated. We know that treatment with decitabine or low-dose cytarabine in patients with relapsed or refractory AML is rarely effective, and the rare patients who do respond usually require several cycles of therapy to do so. Seeing substantial blast reductions in blood and bone marrow achieved in several patients in the first one to two cycles at this first dose level of PCM-075, combined with significant reductions in PLK1 activity as measured by pTCTP levels, potentially suggests synergistic clinical activity with the combination therapy. We remain excited to see how our patients will do as we go to higher dose levels of PCM-075."

"In addition to the preliminary clinical data from our first dose cohort, we are encouraged by the additional pharmacodynamic data for patients in our Phase 1b/2 AML trial," said Dr. Mark Erlander, Chief Scientific Officer of Trovagene. "This is the first time we have observed a change in PLK1 status in patients during treatment with PCM-075 in combination with either LDAC or decitabine."

About the PCM-075 Phase 1b/2 Acute Myeloid Leukemia Trial

The Phase 1b/2 trial (NCT03303339) is a multi-center, open-label trial to evaluate the safety and efficacy of PCM-075 in combination with standard-of-care chemotherapy in AML patients who are ineligible for intensive induction therapy or whose disease is relapsed or refractory. In Phase 1b dose-escalation segment of the trial, the primary objective is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), using a traditional 3+3 design. In Phase 2 the MTD or RP2D will be administered to 32 patients to evaluate preliminary antitumor activity and to continue to evaluate the safety and tolerability of PCM-075 in combination with standard-of-care chemotherapy. This trial is being led by Hematologist Jorge Cortes, M.D., Deputy Department Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine, Department of Medicine, and Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT. Nine clinical sites are currently activated in the U.S. and recruiting patients.

About PCM-075

PCM-075 is a highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple hematologic and solid tumor cancers. Separate studies with other PLK inhibitors have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia (AML) where response rates up to 31% were observed when used in conjunction with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate. A Phase 1 open-label, dose escalation safety study of PCM-075 has been completed in patients with advanced metastatic solid tumor cancers and published in Investigational New Drugs. The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) in this trial was 24 mg/m2. Trovagene has an ongoing Phase 1b/2 clinical trial with PCM-075 in AML that was accepted by the National Library of Medicine (NLM) and is now publicly viewable on www.clinicaltrials.gov. The NCT number assigned by clinicaltrials.gov for this study is NCT03303339. PCM-075 has been granted Orphan Drug Designation by the FDA for the treatment of patients with AML. Trovagene is enrolling a Phase 2 trial of PCM-075 in combination with Zytiga (abiraterone acetate) and prednisone in metastatic Castration-Resistant Prostate Cancer that was accepted by the National Library of Medicine (NLM) and is now publicly viewable on www.clnincaltrials.gov. The NCT number assigned by clinicaltrials.gov for this study is NCT03414034.

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3), is orally available, has a 24-hour drug half-life with reversible on-target hematologic toxicities. Trovagene believes that targeting only PLK1 with reversible on-target activity and an improved dose/scheduling protocol can significantly improve on the long-term outcome observed in previous studies with a PLK inhibitor in AML.

PCM-075 has demonstrated synergy in preclinical studies with over 10 chemotherapeutic and targeted agents used in hematologic and solid tumor cancers, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins. Trovagene believes the combination of its targeted PLK1 inhibitor, PCM-075, with other compounds, has the potential for improved clinical efficacy in Acute Myeloid Leukemia (AML), metastatic Castration-Resistant Prostate Cancer (mCRPC), Non-Hodgkin Lymphoma (NHL), Triple Negative Breast Cancer (TNBC), as well as other hematologic and solid tumor cancers.

Medicenna Announces March 31, 2018 Year-End Results and Provides Update on Clinical Program

On June 27, 2018 Medicenna Therapeutics Corp. ("Medicenna" or the "Company") (TSX: MDNA, OTCQX: MDNAF), a clinical stage immunotherapy company, reported its operational and financial results for the year ended March 31, 2018 (Press release, Medicenna Therapeutics, JUN 27, 2018, View Source [SID1234527482]).

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"We are quite pleased with the progress we have made this year," said Fahar Merchant, PhD, Chairman, President and CEO. "We are past the mid-stage of the Phase 2b clinical trial of MDNA55 in patients with recurrent glioblastoma (rGBM), a uniformly fatal form of brain cancer, and have seen early signs of tumor response and impressive overall survival rate at 6 months (OS-6) of 90 percent following a single treatment with low doses of MDNA55. With exceptional drug distribution and a desirable safety profile to date, we plan to treat the remaining patients before the end of 2018 at the higher maximum tolerated dose with an option for repeat treatment in patients showing benefit. We have also accelerated the development of MDNA109, the only CD122 biased high-affinity IL-2 in development, designed to selectively stimulate cancer-fighting T and natural killer (NK) cells and expect to have a long-acting lead candidate in the next six months. Finally, we graduated to the main board of the TSX and listed on the OTCQX. We have laid the groundwork for success in fiscal 2018 and look forward to achieving key milestones in fiscal 2019."

Program updates for the year ended March 31, 2018 are as follows:

MDNA55

On October 10, 2017, results from the Cancer Prevention and Research Institute of Texas (CPRIT) funded on-going Phase 2b rGBM study were presented at the 2017 Congress of Neurological Surgeons (Boston, MA) demonstrating successful delivery in brain cancer patients and a reassuring safety profile for MDNA55 as well as a substantially higher proportion of the target tissue being covered than in similar previously conducted trials. In some cases, close to 100 percent of the tumor and the 1cm margin around it (at risk for tumor spread) had been successfully covered.

In November, further drug distribution and safety data were presented at the Annual Meeting of the Society for Neuro-Oncology (San Francisco, CA) on the first 15 patients in the study confirming earlier results presented at the 2017 Congress of Neurological Surgeons.

On May 2, 2018, Medicenna announced that half the patients in the ongoing Phase 2b study of MDNA55 in recurrent glioblastoma had been recruited and that the data to date demonstrated solid safety results and early signals of efficacy based on the findings of the Safety Review and Clinical Advisory Committees, comprised of key opinion leaders and study investigators. Following the recruitment milestone, the protocol was amended to implement optimal methodologies for treatment of the remaining patients, including more personalized dosing based on tumor load, incorporation of advanced imaging to more reliably measure treatment responses, and the ability to administer a second dose of MDNA55 where appropriate.

On April 27, 2017 we announced the issuance of a US Patent related to our lead clinical candidate MDNA55. U.S. Patent 9,629,899, issued to the U.S. Department of Health and Human Services and licensed exclusively to Medicenna, covers the combination of MDNA55 with other anti-cancer therapeutic agents.
Superkine Platform

MDNA109 is an IL-2 Superkine licensed from Stanford University and has been engineered to make existing cancer therapies work for more people. By selectively boosting the cancer fighting T and NK cells, it can dramatically improve the anti-tumor activity of treatments such as checkpoint inhibitors, cancer vaccines, CAR-T therapies and oncolytic viruses. New long-acting variants of MDNA109 have shown promising early pre-clinical results in aggressive models of melanoma when administered sub-cutaneously (under the skin) potentially allowing convenient once weekly or bi-weekly treatments as opposed to daily intravenous (IV) infusions.

The U.S. Patent & Trademark Office issued Medicenna a patent related to the Company’s Superkine platform. U.S. Patent 9,738,696, issued to the Board of Trustees of the Leland Stanford Junior University ("Stanford") and licensed exclusively to Medicenna, covers the composition of engineered IL-4 Superkines.
Operational Highlights

On August 1, 2017, the Company announced the graduation of its common shares to the main board of the TSX, the premier stock exchange in Canada.

On September 21, 2017, the Company appointed William W. Li, MD, an experienced oncology drug development expert, to its Board of Directors.

On October 18, 2017, the Company’s common shares were listed on the OTCQX, a segment of the OTC marketplace reserved for high-quality non-U.S. companies, under the symbol, "MDNAF."
Annual Financial Results

Net loss for the year ended March 31, 2018 was $7,465,452, compared to a net loss of $7,631,265 for the year ended March 31, 2017. The decrease in net loss in the year ended March 31, 2018 compared with the year ended March 31, 2017 was primarily a result of one-time costs incurred in the prior year including a liquidity payment and a non-cash listing expense of $1,784,414 resulting from the reverse takeover transaction completed in the year ended May 31, 2017. These decreases from the prior year were offset by increased spending on the Phase 2b clinical trial of MDNA55 as well as increased costs incurred on the pre-clinical pipeline, specifically MDNA109 during the year ended March 31, 2018.

Research and development expenses for the year ended March 31, 2018 were $5,090,146, compared to $4,229,110 for the year ended March 31, 2017. The increase is primarily due to costs associated with the initiation of discovery and pre-clinical activities associated with the Superkine programs including MDNA109 as well as the development of MDNA57 (second generation MDNA55). In addition, clinical costs increased significantly in the current year due to patient treatment and related expenses in the Phase 2b clinical trial of MDNA55 for which the first patient was treated in April 2017. These increases were partially offset by reduced costs associated with the manufacture, testing and stability studies of MDNA55 drug product, as well as lower licensing, patent legal fees and royalty expense due to the one-time liquidity payment discussed above.

General and administrative expenses for the year ended March 31, 2018 were $2,334,684, compared to $1,684,671 for the year ended March 31, 2017. The increase is primarily due to higher stock-based compensation expense, fees associated with the graduation of Medicenna’s common shares from the TSX Venture exchange to the main TSX Board, the OTCQX listing, investor relations activities and fees paid to the Board of Directors. The noted increases are partially offset by lower salary and benefit costs in the year ended March 31, 2018 due to severance costs incurred in the prior year as well as lower legal, professional and finance expenses in the year ended March 31, 2018 due to costs related to the reverse takeover transaction incurred in the prior year.

Medicenna had a cash balance of $3,938,734 at March 31, 2018.

Outlook

The Company will focus on completing patient enrollment for its Phase 2b clinical trial for MDNA55 in the fourth quarter of calendar 2018 and expects top-line clinical results in early 2019. Medicenna also plans to select a MDNA109 lead candidate with extended half-life characteristics.

Array BioPharma Announces FDA Approval of BRAFTOVI™ (encorafenib) in Combination with MEKTOVI® (binimetinib)

On June 27, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported that the U.S. Food and Drug Administration (FDA) has approved BRAFTOVI capsules in combination with MEKTOVI tablets for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test (Press release, Array BioPharma, JUN 27, 2018, View Source [SID1234527481]). BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

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"We are thrilled with the approval of BRAFTOVI + MEKTOVI, which help fill a critical unmet need for patients with advanced BRAF-mutant melanoma, a serious and deadly type of skin cancer," said Ron Squarer, Chief Executive Officer, Array BioPharma. "As presented at ASCO (Free ASCO Whitepaper), BRAFTOVI + MEKTOVI is the first targeted treatment to demonstrate over 30 months median overall survival in a Phase 3 trial. These products represent a new standard of care for BRAF-mutant melanoma patients and we sincerely thank the patients and dedicated researchers who participated in our clinical program."

BRAFTOVI + MEKTOVI are now available to order through select specialty pharmacies in the U.S. market.

"Despite recent advances, there remains a significant unmet need for treatments that are both effective and well-tolerated for patients with BRAF-mutant melanoma," said Keith T. Flaherty, M.D., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School. "Now, physicians and patients have the option to consider treatment with BRAFTOVI + MEKTOVI, which has been shown to delay disease progression, improve overall survival and is generally well-tolerated."

"Nearly half of patients diagnosed with metastatic melanoma test positive for the BRAF mutation," said Valerie Guild, Co-Founder and President of the AIM at Melanoma Foundation. "Today’s approval is welcome news for the melanoma community as it arms BRAF-mutant late-stage melanoma patients with an important new targeted treatment in their fight against this devastating disease."

The approval of BRAFTOVI + MEKTOVI is based on results from the Phase 3 COLUMBUS trial, which demonstrated the combination doubled median progression-free survival (mPFS) compared to vemurafenib, alone (14.9 months versus 7.3 months, respectively [HR (0.54), (95% CI 0.41-0.71), p<0.0001]). Only 5% of patients who received BRAFTOVI + MEKTOVI discontinued treatment due to adverse reactions.

The most common adverse reactions (≥25%) in patients receiving BRAFTOVI + MEKTOVI were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.

As announced in February 2018, BRAFTOVI + MEKTOVI reduced the risk of death compared to treatment with vemurafenib 960 mg daily [hazard ratio (HR) of 0.61, [95% CI 0.47, 0.79, p <0.001] in the planned analysis of overall survival (OS) from the COLUMBUS trial. Median OS was 33.6 months for patients treated with the combination, compared to 16.9 months for patients treated with vemurafenib as a monotherapy. These positive results add to the growing body of clinical evidence supporting the BRAF/MEK inhibitor combination therapy and Array and its partners are working to formally submit these results with global regulatory authorities.

Array BioPharma is committed to providing access and reimbursement support to all patients. Array offers a $0 copay for eligible, commercially-insured patients. For more information about treatment of BRAFTOVI in combination with MEKTOVI, visit www.braftovimektovi.com.

The full prescribing information for BRAFTOVI can be found here:
View Source

The full prescribing information for MEKTOVI can be found here:
View Source

About BRAF-mutant Metastatic Melanoma
Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumors. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates. [1, 2] There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF. There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations, a key target in the treatment of metastatic melanoma. [1, 3, 4, 5]

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, thyroid 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.

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 and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America.

BRAFTOVI + MEKTOVI are not approved outside of the U.S. The European Medicines Agency (EMA), as well as the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are currently reviewing the Marketing Authorization Applications submitted by Pierre Fabre, and Japan’s Pharmaceuticals and Medical Devices Agency has accepted the Manufacturing and Marketing Approval applications submitted by Ono Pharmaceutical Co, Ltd.

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomized, open label Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared to vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAFV600 mutation. All secondary efficacy analyses, including overall survival, are descriptive in nature. Over 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the trial.

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.

Warnings and Precautions
New Primary Malignancies: 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. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or BRAFV600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy: 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. The 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.

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.

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. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). 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 ophthalmic evaluation at regular intervals and for any visual disturbances.

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). 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 periodically and as clinically indicated.

QTc Prolongation: 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. Nonhormonal 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.

Merck to Hold Second-Quarter 2018 Sales and Earnings Conference Call on July 27

On June 27, 2018 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that it will hold its second-quarter 2018 sales and earnings conference call with institutional investors and analysts at 8:00 a.m. EDT on Friday, July 27 (Press release, Merck & Co, JUN 27, 2018, View Source [SID1234527479]). During the call, company executives will provide an overview of Merck’s performance for the quarter.

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Investors, journalists and the general public may access a live audio webcast of the call on Merck’s website at View Source A replay of the webcast, along with the sales and earnings news release and supplemental financial disclosures, will be available at www.merck.com.

Institutional investors and analysts can participate in the call by dialing (706) 758-9927 or (877) 381-5782 and using ID code number 6975606. Members of the media are invited to monitor the call by dialing (706) 758-9928 or (800) 399-7917 and using ID code number 6985606. Journalists who wish to ask questions are requested to contact a member of Merck’s Media Relations team at the conclusion of the call.