The FDA granted the investigational new drug application for the ERK inhibitor ulixertinib (BVD-523) an immediate Expanded Access Program (EAP), according to an xCures press release.

The clinical stage biotechnology company, BioMed Valley Discoveries, is developing ulixertinib to treat patients with MAPK pathway aberrant cancer, including but not limited to KRAS, NRAS, HRAS, BRAF, MEK, and ERK mutations.

"xCures prospective real-world evidence generation capability transforms managed access programs such as the ulixertinib expanded access program by making them an efficient way for physicians and patients to gain access to promising therapies when clinical trials are not an option," Mika Newton, CEO of xCures, Inc., said in a press release.

The Expanded Access Program provides ulixertinib for compassionate use in patients with advanced cancer and a MAPK pathway-altered solid tumor(s). These patients have also exhausted all previously available lines of therapy.

The program collects data about a patient’s treatment to provide a complete and accurate case report to health authorities. These authorities use the data to “assess response to treatment, safety, tolerability, and quality-of-life.”

The Expanded Access Program involves the use of an unapproved drug for the treatment of patients with serious or life-threatening illnesses outside of a clinical trial setting.

"xCures' programs uniquely capture high-value evidence related to the safety and efficacy from this expanded set of patients," said Newton in a press release.

The best-in-class small-molecule inhibitor of extracellular signal-regulated kinase (ERK) family kinases (ERK1 and ERK2), ulixertinib, has demonstrated promising early efficacy for patients with “tumors harboring alterations in the MAPK pathway.”

According to xCures, this EAP is open across the United States to adolescent and adult patients with cancer who cannot access an open clinical trial to investigate ulixertinib.

xCures announces the launch of a Compassionate Use program for ulixertinib (BVD-523) [news release]. San Francisco, California. Published September 28, 2020. 

https://www.prnewswire.com/news-releases/xcures-announces-the-launch-of-a-compassionate-use-program-for-ulixertinib-bvd-523-301139076.html

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xCures recently announced that the FDA granted its IND immediate Expanded Access Program for the ERK inhibitor ulixertinib to treat patients with MAPK pathway aberrant cancer.

FDA Grants Expanded Access Program to Ulixertinib for MAPK Pathway Aberrant Cancer

The ataxia telangiectasia and Rad3-related (ATR) inhibitor BAY 1895344 showed promise in patients with a range of advanced, heavily pre-treated cancers, including breast, bowel, and prostate tumors in a dose-escalation portion of a first-in-human phase 1 clinical trial, according to the Institute of Cancer Research (ICR), the leader of the trial.

Importantly, the agent was also found to be well tolerated and stopped the growth of tumors in over half of patients treated.

“Our new trial shows that this promising new treatment is safe and can benefit some patients even with very advanced cancers,” study leader Johann S. de Bono, MRCP, PhD, MSc, professor of Experimental Cancer Medicine at the ICR and consultant medical oncologist at The Royal Marsden, said in a press release.

 “The new drug, which is currently known only by the code BAY 1895344, works by blocking a molecule called ATR which is involved in repairing DNA. It seems to be especially effective in patients whose tumors have defects in a gene called ATM which mean their ability to repair DNA is already weakened – suggesting that this could become a new form of targeted treatment.”

, intermittently dosed 22 patients with advanced solid tumors with 5 mg to 80 mg of BAY 1895344 twice daily from July 6, 2017 through June 17, 2018. Specifically, 18 patients received BAY 1895344 twice daily for 3 days on and 4 days off weekly and 4 patients received a less dose-intense variation of this schedule, consisting of 3 days on and 4 days off for 2 weeks followed by 1 week off.

At the time of data cut-off, the median duration of treatment was 64.5 days (range, 8-472) and 5 patients were ongoing with BAY 1895344 treatment. The most common reason for discontinuation was disease progression in 15 patients (68.2%); 2 patients (9.1%) discontinued due to adverse events (AEs).

The maximum tolerated dose was found to be 40 mg twice daily with 3 days on and 4 days off. Partial responses were achieved by 4 patients and stable disease by 8 patients. The median duration of response was 315.5 days. Responders had ataxia telangiectasia mutated (ATM) protein loss and/or deleterious ATM mutations and received doses 40 mg or greater twice daily.

AEs observed were manageable and reversible hematological toxicities. The most common all-grade treatment-emergent AEs were anemia (81.8% [all grade 3]), neutropenia (72.7% [grade 3/4, 54.5%]), and thrombocytopenia (45.5% [grade 3/4, 18.2%]). However, fatigue (68.2% [grade 2 requiring dose reduction, 4.5%; grade 3, 9.1%]) and nausea (50.0% [grade 3, 9.1%]) were also reported. Other nonhematological treatment-emergent AEs were of low frequency and were primarily grade 1 or 2.

Overall, BAY 1895344 was well tolerated with antitumor activity observed against cancers with certain DNA damage response (DDR) defects, including ATM loss. An expansion phase of the trial is ongoing in patients with DDR deficiency. Based on preclinical studies of BAY 1895344, clinical trials assessing combination regimens of the ATR inhibitor are also underway (NCT04095273; NCT04267939).

“It is very promising to see patients responding in an early-stage trial like this, and we are looking forward to further clinical trials to test the drug’s efficacy,” said de Bono.

1. Yap TA, Tan DSP, Terbuch A, et al. First-in-Human Trial of the Oral Ataxia Telangiectasia and Rad3-Related Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors. 

2. New drug targeting DNA repair shows promise in range of advanced cancers [news release]. Published September 28, 2020. Accessed September 29, 2020. https://www.icr.ac.uk/news-archive/new-drug-targeting-dna-repair-shows-promise-in-range-of-advanced-cancers

The ATR inhibitor BAY 1895344 appeared promising in patients with a range of advanced, heavily pre-treated cancers in a dose-escalation portion of a phase 1 clinical trial.

Phase 1 Study of BAY 1895344 Shows Promise in Advanced, Heavily Pre-treated Cancers

The FDA has issued the final guidance for certain labeling recommendations for breast implants in order to help improve the information available to patients and health care providers regarding the risks of breast implants.

The document is titled, “Breast Implants – Certain Labeling Recommendations to Improve Patient Communication.” The draft guidance of this document was issued in 2019.

“As new information has become available about the risks and complications of breast implants, it is critical that women have access to information they need to make informed decisions,” Binita Ashar, MD, director of the Office of Surgical and Infection Control Devices in the Center for Devices and Radiological Health, said in a press release. “After working with stakeholders, including patients, today we are recommending format and content changes to breast implant labeling so the information is presented in an easy to understand way. It is important that patients discuss the risks and benefits of breast implants with their health care provider and we hope that these labeling recommendations will help in facilitating these discussions.”

The General and Plastic Surgery Devices Advisory Panel was convened in 2019 to discuss the long-term benefits and risks of breast implants indicated for breast augmentation and reconstruction. The meeting covered a variety of important topics on breast implant safety, including characterization of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) incidence and risk factors, as well as methods for assessing systemic symptoms.

The panel then gave recommendations on these topics, including recommending that the FDA require a boxed warning in breast implant labeling and a standardized checklist as part of the informed consent process, revise the MRI screening recommendations for silent ruptures of silicone gel-filled breast implants, and improve transparency regarding materials present in breast implants. Additionally, the panel discussed the role of the patient device card in providing important information about a patient’s breast implant.

The final guidance now provides recommendations for manufacturers to incorporate a boxed warning and a patient decision checklist into the labeling for breast implants to better ensure certain information is received and understood by patients. The guidance also recommends updated and additional labeling information, including updates to the silicone gel-filled breast implant rupture screening recommendations, inclusion of an easy-to-find description of materials, and provision of patient device cards that were recommended at a panel meeting in March 2019.

According to the FDA, these labeling recommendations are intended to enhance, but not replace, discussions between doctors and patients to talk about the benefits and risks of breast implants that relate to individual patients.

In order to provide consistency with these labeling recommendations, the FDA has also updated the guidance, “Saline, Silicone Gel, and Alternative Breast Implants.” The agency indicated it will continue to work with professional medical societies, patient advocacy groups, and women’s health organizations to help ensure that risk information about these devices is properly disseminated to patients.

FDA Issues Final Guidance for Certain Labeling Recommendations for Breast Implants [news release]. FDA. Published September 28, 2020. Accessed September 29, 2020. https://www.fda.gov/news-events/press-announcements/fda-issues-final-guidance-certain-labeling-recommendations-breast-implants

The FDA issued the final guidance in order to help improve the information available to patients and health care providers about the risks of breast implants. 

FDA Issues Final Guidance for Certain Labeling Recommendations for Breast Implants

Telix Pharmaceuticals announced it has submitted a new drug application (NDA) to the FDA for TLX591-CDx (illumet), a radiopharmaceutical targeting prostate-specific membrane antigen (PSMA) intended for the imaging of prostate cancer using positron emission tomography (PET).

The NDA submission of the companion diagnostic includes clinical data from more than 600 patients obtained from both prospective and retrospective clinical studies performed either by Telix or in collaboration. In addition, the submission builds on definitive peer-reviewed clinical research conducted at leading academic centers including the University of California in Los Angeles, California, the Peter MacCallum Cancer Centre in Australia, and Heidelberg University Hospital in Germany.

“We are pleased to have achieved this significant milestone with the submission of the first commercial NDA for PSMA imaging in the United States. Telix has engaged with the FDA since July 2019, with valuable guidance resulting in what we believe to be a comprehensive submission,” Bernard Lambert, PhD, US president of Telix, said in a press release. “Subject to FDA approval, we look forward to bringing this product to market with our commercial partners to serve the needs of men living with prostate cancer.”

TLX591-CDx is a radiopharmaceutical for the imaging of metastatic prostate cancer. The imaging product comes in a “cold kit” to allow for the swift preparation of 68Ga-PSMA-11 injection, enabling rapid radiolabeling at room temperature with high radiochemical purity and production consistency. Moreover, it is compatible with the 68Ga generators that are already commercially available.

1. Telix Pharmaceuticals Submits New Drug Application to US FDA for Prostate Cancer Imaging Product [news release]. Melbourne, Australia and Indianapolis. Published September 24, 2020. Accessed September 28, 2020. https://www.globenewswire.com/news-release/2020/09/23/2098375/0/en/Telix-Pharmaceuticals-Submits-New-Drug-Application-to-US-FDA-for-Prostate-Cancer-Imaging-Product.html

2. Telix Pharmaceuticals. TLX591 PROSTATE CANCER. Telix Pharmaceuticals website. Published 2020. Accessed September 28, 2020. https://telixpharma.com/pipeline/tlx591/

TLX591-CDx (illumet) is a radiopharmaceutical targeting prostate-specific membrane antigen intended for the imaging of prostate cancer using positron emission tomography.

NDA Submitted for Prostate Cancer Companion Diagnostic, TLX591-CDx

suggest the possible utility of topical minoxidil, hair transplantation, and plastic surgical reconstruction in the treatment of persistent radiation-induced alopecia (pRIA) for patients with primary central nervous system (CNS) tumors or head and neck sarcomas.

“These findings may inform pretherapy counseling and efforts to identify preventive and therapeutic strategies, including randomized clinical trials in cancer survivors, for this burdensome sequela of a principal axis of cancer therapy,” the authors wrote.

In this retrospective cohort study, researchers evaluated 71 children and adults diagnosed with primary CNS tumors or head and neck sarcomas from 2 large tertiary care hospitals and comprehensive cancer centers. Of those included in the study, 64 (90%) had a CNS tumor and 7 (10%) had head and neck sarcoma.

Overall, alopecia severity was grade 1 in 40 of 70 patients (56%), with localized (29 of 54 [54%]), diffuse (13 of 54 [24%]), or mixed (12 of 54 [22%]) patterns. Further, the median (range) estimated scalp radiation dose was found to be 39.6 (15.1-50.0) Gy, with a higher dose (OR, 1.15; 95% CI, 1.04-1.28) and proton irradiation (OR, 5.7; 95% CI, 1.05-30.8) associated with greater alopecia severity (

< .001). In addition, the dose at which 50% of patients were estimated to have severe or grade 2 alopecia was 36.1 Gy (95% CI, 33.7-39.6 Gy).

“Our estimation of maximum scalp dose was limited in part because it did not directly consider the radiation field volume and involved scalp surface area; however, point approximation of scalp surface dose may be a convenient metric for use during treatment planning,” the authors explained.

Trichoscopic findings were analyzed in 28 of 71 patients (39%). The predominant trichoscopic features observed included white patches (57%), thin arborizing vessels (36%), and milky red areas (32%). Additionally, hair caliber was negatively correlated with the estimated scalp radiation dose in 15 patients with trichoscopy and radiotherapy treatment plans (Spearman correlation coefficient ρ = -0.624; 

 = .01). Ultimately though, the association between hair density and scalp radiation dose was not statistically significant (ρ = -0.381, 

“Larger, prospective studies would be better suited to deciphering the potential relevance of trichoscopy to pRIA prognosis and treatment allocation,” the authors noted.

Further, topical minoxidil, 5%, solution was prescribed to 53 patients (75%). In total, 28 of 34 evaluable patients (82%) responded to minoxidil treatment, with a median follow-up time of 61 weeks (95% CI, 41-97; IQR, 21-105; range, 7-226 weeks). Among 25 recipients of minoxidil with clinical images available, complete response occurred in 4 patients (16%), partial response in 13 patients (52%), stable alopecia in 7 patients (28%), and progression of alopecia in 1 patient (4%). In addition, 3 patients (4%) underwent a procedural intervention for pRIA, including 2 patients who received hair transplantation with partial and complete responses and 1 patient who underwent scalp expansion and plastic surgical reconstruction with a complete response.

“These findings suggest that topical minoxidil could have benefit in pRIA and that clinical trials are warranted to determine efficacy and tolerability for pRIA in cancer survivors,” the authors wrote.

Importantly, the researchers indicated that the retrospective study design and limited availability and analysis of radiotherapy treatment plans, standardized clinical photographs, and trichoscopy images were limitations of this study.

Phillips GS, Freret ME, Friedman DN, et al. Assessment and Treatment Outcomes of Persistent Radiation-Induced Alopecia in Patients With Cancer. 

These study findings suggested that topical minoxidil and procedural interventions may aid in the treatment of persistent radiation-induced alopecia among patients with primary central nervous system tumors or head and neck sarcomas.

Topical Minoxidil, Procedural Interventions May Benefit Persistent Radiation-Induced Alopecia

Journal of the National Comprehensive Cancer Network

 suggested that among clinical trials in which patients with non-small cell lung cancer (NSCLC) were treated with atezolizumab (Tecentriq), multiorgan immune-related adverse events (irAEs) were reported in 5.4%.

Given this finding, researchers indicated that future trial reporting should consider the incorporation of data on multiorgan toxicities in addition to single-organ specific toxicities.

“Multi-organ irAEs are under-recognized, under reported, and their pathophysiology is poorly understood,” lead researcher Ganessan Kichenadasse, MBBS, FRACP, of the Flinders Centre for Innovation in Cancer at Flinders University in Bedford Park, Australia, said in a press release.

 “We need a concerted international effort to improve our understanding and help identify predisposing factors and prevention strategies. Treating teams should be aware of the potential for irAEs which affect multiple organs and institute plans for recognizing and managing them.”

In order to determine the incidence, time of onset, and risk factors for multiorgan irAEs, researchers conducted a post hoc pooled analysis using individual patient data from atezolizumab monotherapy arms of 4 NSCLC clinical trials. From a total of 1548 patients identified, 730 irAE episodes were reported in 424 patients (27%). Skin irAEs were most often reported (42%), followed by laboratory abnormalities (27%) and endocrine (11.6%), neurologic (7.6%), and pulmonary (6.2%) irAEs.

Overall, 84 patients (5.4%) had multiorgan irAEs, including 70 with 2, 13 with 3, and 1 with 4 different organs affected. Moreover, “skin plus” or “laboratory plus” were the most commonly observed irAE multiorgan clusters.

Notably, patients with multiorgan irAEs were more likely to be white and have a good performance status, a lower baseline neutrophil-lymphocyte ratio, and a good or intermediate lung immune prognostic index score. In addition, multiorgan irAEs were also correlated with improved overall survival (HR, 0.47; 95% CI, 0.28-0.78; 

< .0001) but not with progression-free survival (HR, 0.92; 95% CI, 0.62-1.35; 

 = .74) compared with patients who had no irAEs.

“This study confirms that more than 1 organ, at the same time or sequentially, can be affected by immune-related adverse events from checkpoint inhibitor therapy,” Igor Puzanov, MD, MSci, FACP, professor of Medicine, director of the Early Phase Clinical Trials Program, and chief of Melanoma at Roswell Park Comprehensive Cancer Center, who was not involved in this study, said in the release. “This is worth noting for all practicing oncologists and other specialists taking care of patients who are receiving these therapies. The silver lining here is the seemingly improved overall survival we see among these patients.”

Importantly, researchers noted this analysis was a post hoc exploratory analysis and should therefore be considered hypothesis-generating and confirmed in other studies. Moreover, these data were specifically from lung cancer trials of atezolizumab, and it remains unclear whether a similar pattern of multiorgan irAEs occurs in other cancer types or with other immune checkpoint inhibitors.

1. Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich MJ. Multiorgan Immune-Related Adverse Events During Treatment With Atezolizumab. 

 Sheds Light on Multi-Organ Adverse Events from Immunotherapy [news release]. Plymouth Meeting, PA. Published September 8, 2020. Accessed September 16, 2020. https://www.eurekalert.org/pub_releases/2020-09/nccn-nri090420.php

This study found that among clinical trials in which patients with non-small cell lung cancer were treated with atezolizumab, multiorgan immune-related adverse events were reported in 5.4%.