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Aeglea BioTherapeutics Provides AEB1102 Program and Corporate Update

On May 23, 2017 Aeglea BioTherapeutics, Inc., (NASDAQ:AGLE) a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat rare genetic diseases and cancer, reported an AEB1102 program and corporate update (Press release, Aeglea BioTherapeutics, MAY 23, 2017, View Source [SID1234519276]). AEB1102, the company’s lead investigational molecule, is an engineered human enzyme designed to degrade the amino acid arginine and is being developed to treat two extremes of arginine metabolism.

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AEB1102 Program Update

Selection of Single Agent Solid Tumor Expansion Cohorts

Aeglea is currently conducting a Phase 1 clinical trial in cancer patients with advanced solid tumors to assess the safety, tolerability and pharmacokinetics of AEB1102, which has demonstrated clinical proof of mechanism. The trial is designed to include a dose escalation phase to determine maximum tolerated dose and an expansion phase to obtain additional single agent data in specific tumor types.

Aeglea has selected three single agent solid tumor expansion arms: cutaneous melanoma, uveal melanoma and small cell lung cancer, all of which have been shown in studies to demonstrate a dependence on arginine. The primary endpoint of the expansion arms is to assess safety in patients with specific tumor types. Secondary endpoints include assessment of pharmacokinetics, pharmacodynamics and clinical response. Each expansion arm will enroll up to 12 patients and are planned to initiate in the fourth quarter of 2017 or first quarter of 2018, following completion of the dose escalation phase.

Regulatory Update on Pediatric Dosing for Arginase 1 Deficiency Clinical Trial

In March 2017, the Company received an information request from the United States Food and Drug Administration (FDA) that additional data may be needed to support the inclusion of pediatric patients in the ongoing Phase 1/2 trial in Arginase 1 Deficiency. The Company recently received written feedback from the FDA based on supporting data provided in March and a follow-up meeting with the Agency in late April.

"Based on discussions with the FDA, we were unable to resolve a difference in opinion at this time on the data needed to support inclusion of pediatric patients. We anticipate continuing our dialogue with the FDA on this topic," said David Lowe, Ph.D., chief executive officer of Aeglea. "This results in a delay in our plan to initiate dosing in pediatric patients in the United States. We will continue to focus on our Phase 1/2 trial, which we expect to begin enrolling adult patients in the middle of 2017."

To date, Aeglea has received two Institutional Review Board (IRB) approvals for the Phase 1/2 protocol in the United States, and has an open Clinical Trial Application (CTA) in Canada which includes treatment of both adult and pediatric patients.

Aeglea names Aaron Schuchart to the position of chief business officer

Aaron Schuchart joined Aeglea as chief business officer on May 22, 2017 where he will be responsible for overseeing business development activities and facilitating corporate strategy.

"Aeglea’s Phase 1 clinical data in Arginase 1 Deficiency, along with encouraging preclinical data supporting a possible combination approach in cancer, highlights the potential of AEB1102 and puts us in a strong partnering position," said Mr. Schuchart. "Aeglea has a pipeline of exciting opportunities in rare disease and cancer and I look forward to working with the team to identify new business opportunities to maximize our impact in these areas."

Previously, Mr. Schuchart served as senior vice president of business development and strategic alliances at Coherus Biosciences where he played a role in growing the company from early platform stage to a fully integrated, late-stage clinical company. Prior to Coherus, Mr. Schuchart was head of business development and strategic planning at Novartis’ diagnostics division until its acquisition by Grifols. Earlier in his career, Mr. Schuchart served in various leadership roles at Mendel Biotechnology and Amgen. Mr. Schuchart holds a bachelor’s degree in accounting from Texas Tech University and an MBA from the UCLA Anderson School of Management.

About AEB1102

AEB1102 is an engineered human arginase I enzyme designed to degrade the amino acid arginine. Aeglea is developing AEB1102 to treat two extremes of arginine metabolism, including arginine excess in patients with Arginase 1 Deficiency, as well as some cancers which have been shown to have a metabolic dependency on arginine. In patients with Arginase 1 Deficiency, AEB1102 is intended for use as enzyme replacement therapy to restore the function of arginase 1 in patients and return elevated blood arginine levels to the normal physiological range. Aeglea is currently recruiting patients for its ongoing Phase 1/2 trial for the treatment of Arginase 1 Deficiency. Aeglea is also conducting two Phase 1 trials in cancer patients with advanced solid tumors and with hematological malignancies to evaluate the safety and tolerability of AEB1102. Data from these trials demonstrated that AEB1102 has the ability to reduce blood arginine levels, providing initial human proof of mechanism.

Data on LTX-315 has been accepted for poster presentation at ASCO 2017

On May 23, 2017 Lytix Biopharma reported that the poster "LTX-315, an oncolytic peptide converts immunogenically ‘cold’ tumors to ‘hot’ in a majority of patients with advanced or metastatic tumours: results from an ongoing phase I study" will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2017 (ASCO) (Free ASCO Whitepaper) (Press release, Lytix Biopharma, MAY 23, 2017, View Source [SID1234519275]). The poster includes safety, efficacy and immune data on 28 patients treated with LTX-315 monotherapy in advanced/metastatic tumours.

Poster Session: Developmental therapeutics-immunotherapy, June 5th 8-11.30AM EST.
Abstract number: 3085
The abstract can be found on: View Source

ORYX reports positive clinical evidence with oncolytic virus ParvOryx in combination with immuno-oncology drugs

On ay 23, 2017 ORYX, a translational medicine company focused on oncolytic virotherapy and cancer vaccines, reported positive findings from 16 patients treated with the oncolytic virus, ParvOryx, in combination with Avastin (bevacizumab) and with immune checkpoint inhibitors Keytruda or Opdivo under compassionate use programs (Press release, Oryx, MAY 23, 2017, View Source [SID1234519273]). These promising results have encouraged ORYX to prepare a controlled clinical study, which will be discussed with regulatory authorities.

Seven patients suffering from glioblastoma multiforme (GBM) who had experienced a second relapse following treatment with ParvOryx in a completed Phase I/IIa study were treated with ParvOryx plus Avastin following surgery. In the seven ParvOryx/Avastin-treated patients, median overall survival (mOS) was prolonged to 25.9 months compared to the ParvOryx monotherapy study mOS (15.9 months).

Additionally, nine GBM patients with either primary, diffuse primary, single recurrent or double recurrent GBM were treated with ParvOryx in combination with an immune checkpoint inhibitor alone (1) or in combination with Avastin and an immune checkpoint inhibitor (8) without prior surgery. All nine patients responded with objective tumor regression already after 6-8 weeks. The tumor load was reduced by 45-96% as measured by RANO (Response Assessment in Neuro-Oncology) criteria. Follow-up is ongoing.

Two patients relapsed (26 and 47 weeks) after virotherapy, while receiving constant treatment with Avastin and an immune checkpoint inhibitor. Treatment with ParvOryx together with the resumption of combination therapy with Avastin and the checkpoint inhibitor led to rapid regression of the tumor mass and disease control.

Dr. Michael Dahm, ORYX’s Chief Medical Officer, said: "Although these data are preliminary and uncontrolled, they are highly encouraging. We look forward to evaluating ParvOryx in combination with Avastin or with Avastin plus an immune checkpoint inhibitor in a controlled clinical trial setting."

About ParvOryx:

ParvOryx (Parvovirus H1) is a wild type rat oncolytic virus that infects and lyses tumor cells in a wide variety of cancers, including glioblastoma multiforme, pancreatic cancer, breast cancer, lung cancer, melanoma, lymphoma, pediatric tumors such as neuroblastoma and medulloblastoma, prostate cancer and renal cancer, as well as tumor stem cells. ParvOryx (parvus), the smallest among all oncolytic viruses, is able to pass the blood brain barrier. The special properties of ParvOryx allow for both intratumoral and intravenous administration as well as repeated application (boosters). Unlike other natural or modified oncolytic viruses currently under investigation, H-1PV does not affect normal cells and is not pathogenic for humans. The virus exerts a cytotoxic/oncolytic effect, resulting in dysregulation of cell transcription, cell cycle arrest, shut off of cell replication, activation of cellular stress response and induction of cell death. In addition, viral oncolysis induces a strong tumor-specific immune response leading to the recognition and elimination of minimal residual disease (bystander effect). ParvOryx can turn an immunogenic "cold" into a "hot" tumor by profoundly changing its microenvironment, making the tumor vulnerable to a variety of immuno-oncological approaches.

ParvOryx successfully completed a Phase I/IIa trial to treat glioblastoma multiforme in 18 patients with recurrent or progressive disease. A dose-escalation Phase I/IIa pilot study for the treatment of metastatic pancreatic cancer with ParvOryx monotherapy is currently ongoing, with topline data expected in Q4 2017.

FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for Adult and Pediatric Patients with Unresectable or Metastatic, Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient Cancer

On May 23, 2017 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved a new indication for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy (Press release, Merck & Co, MAY 23, 2017, View Source [SID1234519272]). KEYTRUDA is now indicated for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children, the recommended dose of KEYTRUDA is 2 mg/kg (up to a maximum of 200 mg) administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA (pembrolizumab) should be withheld or discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions; for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information below.

"The FDA’s approval of this new indication for KEYTRUDA further supports Merck’s commitment to helping people with difficult-to-treat cancers," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We are thankful to the researchers, as well as the patients and their families who helped make today’s approval possible."

Further details will be included in a news release to follow.

Selected Important Safety Information for KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA (pembrolizumab) can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA (pembrolizumab) for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

Most common adverse reactions (reported in ≥20% of patients) were fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea.

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

TG Therapeutics, Inc. Announces Successful Outcome from Pre-Planned Interim Analysis by Independent DSMB in the UNITY-CLL Phase 3 Trial

On May 23, 2017 TG Therapeutics, Inc. (NASDAQ:TGTX), reported that the independent Data Safety Monitoring Board (DSMB) of the UNITY-CLL Phase 3 trial has successfully completed a pre-specified interim analysis to assess the contribution of TG-1101 (ublituximab) and TGR-1202 in the combination regimen of TG-1101 plus TGR-1202 (Press release, TG Therapeutics, MAY 23, 2017, View Source [SID1234519270]).

In conducting the analysis, the DSMB reviewed efficacy data from approximately 50 patients per arm in the UNITY-CLL study who were eligible for at least one response evaluation. Based on the overall response rate data available, and in accordance with the statistical analysis plan in the study’s Special Protocol Assessment (SPA), the DSMB determined that contribution has been established and recommended the Company cease enrollment into the single agent arms. Accordingly, the study will now continue enrollment in a 1:1 ratio to only the two combination arms: the investigational arm of TG-1101 (ublituximab) plus TGR-1202 and the control arm of obinutuzumab plus chlorambucil. Additionally, the DSMB reviewed safety data from all patients on study (n > 270) as of the data cut-off date, including patients with both treatment naive and relapsed/refractory Chronic Lymphocytic Leukemia (CLL), and again identified no safety concerns in any treatment group (treatment naïve or previously treated) and recommended the continuation of the study without modification.

"We are extremely pleased that the DSMB has once again found no safety concerns that would require modifying the study. This is particularly comforting when we consider that the safety population now includes over 60 front-line CLL patients treated for more than 6 weeks with TGR-1202 alone or in combination with TG-1101. As most who have followed this area will recall, treatment naïve CLL patients appear to be exquisitely sensitive to the autoimmune mediated side effects of idelalisib, with approximately 50% experiencing Grade 3/4 liver toxicity by week 6 in a published study," stated Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer. Mr. Weiss continued, "We are also very pleased that, in accordance with our SPA, the DSMB has determined that contribution has been adequately demonstrated, enabling us to eliminate the single agent arms from continued enrollment. We are also excited to report that we continue to see strong interest in the study and enrollment remains robust. We continue to view the demand for this study as a strong indication of the need for alternative treatments for patients with CLL, even in the front-line setting. Given the current rate of enrollment, we are now targeting complete enrollment by year end, ahead of our previous guidance, which would put us in a position to report pivotal Overall Response Rate (ORR) data in the third quarter of 2018."

ABOUT UNITY-CLL PHASE 3 TRIAL

UNITY-CLL is a Global Phase 3 randomized controlled clinical trial in patients with Chronic Lymphocytic Leukemia (CLL) that includes two key objectives: first, to demonstrate contribution of each agent in the TG-1101 + TGR-1202 regimen, and second, to demonstrate superiority in Progression Free Survival (PFS) over the standard of care to support the submission for full approval of the combination. In addition, upon completion of enrollment, this trial will evaluate Overall Response Rate (ORR) for accelerated approval. The study initially randomized patients into four treatment arms: TG-1101 plus TGR-1202, TG-1101 single agent, TGR-1202 agent, and an active control arm of obinutuzumab plus chlorambucil. Pursuant to the Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA), an early interim analysis was conducted to assess contribution of each single agent which, upon success, allowed for early termination of both single agent arms.