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Tag: Clinical Trial

  • Three early-phase clinical studies show promising initial data for patients with lymphoma, gastric cancers

    Three early-phase clinical studies show promising initial data for patients with lymphoma, gastric cancers

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    Three early-phase clinical studies presented by researchers from The University of Texas MD Anderson Cancer Center at the American Association for Cancer Research (AACR) Annual Meeting 2024 show promising initial data for patients with lymphoma, gastric or gastroesophageal junction cancers, and specific molecularly selected tumors. The studies were featured in a clinical trials minisymposium highlighting novel agents and emerging therapeutic strategies. Information on all MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR.

    Novel combination with evorpacept demonstrates promising results for patients with B-cell non-Hodgkin lymphoma (Abstract CT037)

    Data from an investigator-initiated Phase I trial of the novel CD47 blocker evorpacept (ALX148) in combination with lenalidomide and rituximab (R2), presented by Paolo Strati, M.D., assistant professor of Lymphoma and Myeloma, showed promising early results for patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

    While historical complete response rates (CRRs) with R2 monotherapy are 30%, the new combination achieved an 80% CRR with an overall response rate of 90%. After a median follow-up of 16 months, the one-year progression-free survival rate was 70% and one-year overall survival rate was 90%.

    Previous work from Strati demonstrated that specific white blood cells known as SIRPα+ macrophages may mediate resistance to the R2 combination, leading to the hypothesis that adding evorpacept to the R2 combination could have synergistic results. Blocking CD47 prevents the ‘don’t eat me signal’ that results from the interaction of SIRPα and CD47.

    The addition of evorpacept to R2 seems to significantly increase the efficacy of these therapies, with no synergistic toxicity, in patients with indolent B-cell lymphomas. We look forward to continuing studies with this novel combination in order to bring effective options to our patients in need.”


    Paolo Strati, M.D., assistant professor of Lymphoma and Myeloma

    The trial included 20 patients with four different types of B-cell non-Hodgkin lymphoma, 18 of whom had indolent, or slow-growing, disease. All patients previously received an anti-CD20 monoclonal antibody, and 73% received prior chemotherapy.

    The most common grade 3 or higher adverse events were consistent with those typically seen with R2 therapy, such as neutropenia, infections, elevated liver enzymes, skin rash and anemia, and were not increased by the addition of evorpacept. No dose-limiting toxicities were observed, and the recommended Phase II dose was identified.

    A Phase II study investigating the efficacy of this combination in previously untreated patients is now enrolling.

    This study was funded by ALX Oncology, the Leukemia & Lymphoma Society Scholar in Clinical Research Award, the Gilead and Kite Scholar Award and the Andrew Sabin Family Fellowship Program. 

    Antibody-drug conjugate SKB264 shows potential for durable responses in heavily pretreated patients with advanced gastric or gastroesophageal junction cancers (Abstract CT038)

    Preliminary data from a Phase I/II study evaluating the antibody-drug conjugate (ADC) SKB264, presented by Jordi Rodon, M.D., Ph.D., associate professor of investigational cancer therapeutics showed that pretreated patients with gastric or gastroesophageal junction cancers could have durable responses and potentially longer overall survival with SKB264 monotherapy.

    Of the 41 patients able to be evaluated for response, SKB264 achieved an objective response rate of 22%, a disease control rate of 80.5%, and a median duration of response of 7.5 months.

    “It is interesting to note the change in antitumor activity and safety profile that results from changing payloads and linkers, even among ADCs aiming at the same target,” Rodon said. “One of the big results of this trial is that, by using a different linker-payload combination, we did not see the interstitial lung diseases associated with other ADCs.”

    SKB264 is an ADC that targets TROP2, a factor associated with poor prognosis in advanced gastric cancers. It uses a novel linker to connect the antibody with the payload, a belotecan-derivate topoisomerase I inhibitor.

    Forty-eight patients were evaluable for safety, with a follow-up of at least nine weeks at the data cutoff. All received previous therapy, with 50% having received multiple prior lines of therapy. Treatment-related adverse events higher than grade 3 were seen in 52.1% of patients, with the most common being anemia, decreased white blood cell or neutrophil counts, and neutropenia. Only 18.8% of patients had to decrease dosage, and 33.3% had to delay dosing due to adverse events. No adverse events led to discontinuation of the trial or death.

    Based on these results, a Phase III global study currently is being planned to evaluate SKB264 in comparison to the current standard of care in patients with at least three prior lines of therapy in gastric or gastroesophageal junction adenocarcinomas.

    This study was funded by Klus Pharma and Merck & Co. (MSD). 

    Combining PARP and PI3K inhibitors shows encouraging results in Phase Ib trial for molecularly selected patients (Abstract CT042) 

    Results from a biomarker-driven, tumor-agnostic Phase Ib trial of copanlisib plus olaparib showed the combination was safe and well tolerated, with a clinical benefit in 36% of molecularly selected patients who had advanced cancers harboring PIK3CA hotspot, PTEN, or DNA damage response (DDR) mutations. 

    Trial results were presented by Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics, and vice president and head of clinical development in the Therapeutics Discovery division. 

    Of 22 patients able to be evaluated for efficacy, six achieved partial responses and two achieved stable disease for at least six months. Notably, a patient with advanced triple-negative breast cancer with PIK3CA H1047R, PTEN and ARID1A mutations achieved a confirmed radiological partial response and was on trial for 42 months with minimal side effects. 

    Preclinical studies had shown potential for the combination of PI3K and PARP inhibition in cancers with DDR and PI3K pathway alterations, prompting this investigator-initiated trial conducted through National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP), which partnered the pan-PI3K inhibitor copanlisib with the PARP inhibitor olaparib. 

    The trial enrolled 28 patients, representing 12 cancer types and 11 mutation types. Ten patients had more than one qualifying mutation. This was a heavily pretreated patient population, with 61% having received three or more prior lines of therapy. The combination was safe and generally well tolerated, with the most common adverse events of any grade being mucositis, nausea, diarrhea and vomiting. 

    “We observed promising antitumor activity in patients with a range of cancers with different DDR and/or PI3K pathway alterations, which may serve as novel predictive biomarkers of response,” Yap said. “Comprehensive translational analyses of longitudinally collected patient samples from the clinical trial are currently ongoing.” 

    This study was funded and sponsored by the National Cancer Institute, part of National Institutes of Health. MD Anderson led the study with participation from the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) (4UM1CA186688-07). AstraZeneca Pharmaceuticals and Bristol-Myers Squibb Company provided support to this study through Cooperative Research and Development Agreement between NCI and each company.

    Source:

    University of Texas M. D. Anderson Cancer Center

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  • Deciphering cancer plasticity:Insights from MSK research

    Deciphering cancer plasticity:Insights from MSK research

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    About 90% of deaths from cancer are a result of metastasis -; that is, from cancer’s ability to spread from an initial primary tumor to seed new tumors throughout the body, often in the lungs, liver, and brain.

    And metastasis relies on cancer cells’ ability to adapt to different tissue environments throughout the body by gaining improper access to a variety of playbooks stored in our genetic code -; including gene programs that are generally available only during early stages of human development.

    Today, researchers at Memorial Sloan Kettering Cancer Center (MSK) are using innovative approaches like single-cell sequencing technology and sophisticated computational tools to illuminate cancer cells’ ability to take on new traits. And they’re applying those findings toward treating or preventing metastasis.

    In a plenary presentation at the 2024 American Association for Cancer Research (AACR) Annual Meeting, Dana Pe’er, PhD, Chair of the Computational and Systems Biology Program at MSK’s Sloan Kettering Institute, highlighted three recent research collaborations between her lab and other labs at MSK that have shed new light on the ability of cancer cells to adapt and spread.

    “It’s not genetic mutations that are critical here, but the ability to access gene programs that normally are associated with other cell types -; including early developmental and embryonic programs that should not be accessed by adult cells,” Dr. Pe’er said in a recent interview. “We call this ability for cells to run new programs ‘plasticity.’ So cancer doesn’t reinvent the wheel; it exploits gene programs that exist for other biological purposes.”

    In general, she notes, plasticity isn’t a bad thing. It’s important for early development and for regeneration after injury. And the body also has built-in barriers to limit the scope of plasticity so that cells can’t just run amok.

    But in cancer, these cells can wreak havoc because they’ve lost these natural barriers.”


    Dr. Dana Pe’er, Howard Hughes Medical Institute Investigator

    Plasticity in colorectal cancer

    In the first study Dr. Pe’er presented at AACR, she teamed up with MSK physician-scientist Karuna Ganesh, MD, PhD, to look at the differences in gene programs active in the primary tumors and metastatic tumors of patients with advanced colorectal cancer. Samples of both types of tumors were collected at the same time from 31 patients -; the largest cohort of its kind -; some of whom had undergone chemotherapy and some of whom had not.

    They also created organoids from the patients’ cells -; three-dimensional clusters of cells that act more like human tissue than traditional laboratory cell cultures.

    The study found that primary tumor cells largely run programs still associated with intestinal cells, while metastases often shed their heritage as intestinal cells and take on the characteristics of squamous cells or of neuroendocrine cells, which helps them invade and survive in new tissue contexts and makes them more resistant to treatment. The team also found that chemotherapy exacerbates these transformations. The findings were published as a preprint on bioRxiv in August 2023.

    “The metastatic organoids were very different from the primary tumor organoids,” Dr. Pe’er says. “And it matters what environment they’re in, too. If you put the metastatic organoids into the liver of a mouse, they will adapt their identity in ways that primary tumor organoids are not able to -; so they’re a lot more plastic.”

    The team additionally found that a gene known as PROX1 restricted the ability of cells from the primary tumor to stray too far from their lineage as intestinal cells. But when this factor is removed, the cells gain access to many more types of cell lineages -; which scientists call noncanonical. (For reasons that aren’t fully understood, metastatic cells that lose the restrictions imposed by Prox1 are already primed to go in these noncanonical directions.)

    “I call it a mix-and-match buffet,” Dr. Peer says. “Metastatic cells have this awesome power to combine gene programs across many different types of cells, endowing them with new abilities that allow them to adapt themselves to take advantage of different conditions and environments throughout the body.”

    Plasticity in pancreatic cancer

    The second study Dr. Pe’er presented looked at about a dozen metastases collected from a single patient with pancreatic cancer, who donated their body for research under MSK’s Last Wish Program. A collaboration with physician-scientist Christine Iacobuzio-Donahue, MD, PhD, Director of the David M. Rubenstein Center for Pancreatic Cancer Research at MSK, the research used advanced single-cell and computational approaches to look at the differences in active gene programs in genetically identical cancer cells -; called clones -; that had spread to different locations in the body. The findings of the study have not yet been published.

    “What we see is that these clones are able to adapt to the pressures and metabolic demands of very different environments,” Dr. Pe’er says. “And we see that they’re able to access different gene programs that allow them to thrive in different places, different organs.”

    Moreover, even genetically different cancer cells tend to adapt to specific situations by accessing the same gene programs.

    “The big question of a cancer cell is, ‘Are you plastic or not?’ And once you are, you can acquire all these different traits. The environment is what really determines what traits will be most advantageous,” she says.

    For example, the research showed that cells that metastasize to the peritoneum -; the tissue that lines the abdominal cavity -; are able to adapt their metabolism to take advantage of the lipid-rich environment and exploit it as an energy source, she notes.

    Moving plasticity research from the lab to the clinic

    Lastly, Dr. Pe’er highlighted a third collaboration -; this time with neuro-oncologist Adrienne Boire, MD, PhD, a member of MSK’s Human Oncology and Pathogenesis Program -; which showed how plasticity can be turned against cancer cells.

    The research led to a clinical trial for patients with leptomeningeal metastasis, which is when cancer has spread to the fluid and tissues of the spinal cord and brain. The team showed that cancer cells were able to survive in this challenging environment by reprogramming themselves to outcompete other cells for iron; this fuels their growth while also preventing immune defenders in the area from getting enough iron.

    “It’s an elegant solution on the part of the cancer cell,” Dr. Boire says. “It’s really unique biology that allows them to win the competition.”

    Based on that discovery, doctors at MSK are now determining whether a drug called deferoxamine could be an effective treatment for leptomeningeal metastases by helping to remove iron from the cerebrospinal fluid.

    “The plasticity of these cells allowed several patients with several different cancers to overexpress the same two genes that are typically only expressed in myeloid cells,” Dr. Pe’er says. “And the cells not only got aberrant access to these gene programs, but they also expressed the genes at 100 times the levels seen in their normal counterparts.”

    By injecting the study drug into the spinal fluid, the idea is to prevent the cancer cells from getting the iron they need to thrive. And so far, Dr. Pe’er told the audience, initial results from the trial have been extremely promising.

    Only at a place like MSK

    “The ultimate goal, though we’re not there yet, would be to be able to target plasticity directly -; to restore some of the biological barriers or inhibit plasticity with drugs,” Dr. Pe’er says.

    And MSK is uniquely poised to pursue that aim, with strong collaborations between laboratory and clinical research; a high volume of patients that provides a wide variety of clinical samples from a wide variety of cancers, including rare ones; access to state-of-the art sequencing tools combined with some of the world’s top computational expertise; and a significant number of physician-scientists who focus both on caring for patients and finding new ways to treat their disease.

    “Not every cancer center would see enough patients with leptomeningeal metastasis to set up a clinical trial like this,” Dr. Pe’er notes. “Or have someone like Dr. Boire, who not only cares for patients with metastasis to the central nervous system but who also runs a lab dedicated to studying the underlying molecular mechanisms.”

    Source:

    Memorial Sloan Kettering Cancer Center

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  • Pioneering vaccine strategy promises to outmaneuver antimicrobial resistance

    Pioneering vaccine strategy promises to outmaneuver antimicrobial resistance

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    In a recent study published in the journal Npj Vaccines, researchers presented the method of Reverse Vaccine Development, which provides an opportunity to determine the correlates of protection in the early stages of clinical trials for vaccines against pathogens that are resistant to antimicrobial agents to prevent problems such as significant phase-III clinical trial failures, loss of investment in vaccine development, and populations being exposed to ineffective vaccines.

    Perspective: Reverse development of vaccines against antimicrobial-resistant pathogen. Image Credit: Kateryna Kon / ShutterstockPerspective: Reverse development of vaccines against antimicrobial-resistant pathogen. Image Credit: Kateryna Kon / Shutterstock

    Background

    The development of antimicrobial resistance in pathogens is rapidly becoming a public health concern of the same or possibly higher magnitude as malaria or human immunodeficiency virus (HIV). However, the process of developing vaccines is tedious and expensive, and in the case of antimicrobial-resistant pathogens, it is made worse by inadequate information on correlates of protection.

    In the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the process of vaccine development was significantly accelerated by the discovery of antibodies that could bind to the spike protein of the virus, preventing it from binding to the host angiotensin-converting enzyme-2 receptor. This discovery also indicated that neutralizing antibody titers could be used as correlates of protection since they indicated the clinical efficacy of the vaccine.

    For most antimicrobial-resistant pathogens, the mechanisms through which vaccines can protect the host remain unknown. While immunomics, proteomics, and genomics are being extensively used to develop vaccines against antimicrobial-resistant pathogens, the dearth of information on correlates of protection continues to present the risk of jeopardizing late-stage clinical trials.

    About the study

    In the present study, the researchers presented a method of Reverse Vaccine Development, a new paradigm for vaccine development that requires information on the efficacy of the vaccine and the immune responses to be generated much earlier in the vaccine development process so that the correlates of protection can be identified early on instead of closer to phase III trials. They also implemented this paradigm to evaluate a vaccine against the antimicrobial bacteria Staphylococcus aureus.

    The process is called Reverse Vaccine Development since the order of information procurement on vaccine efficacy is reversed as compared to the typical procedure of vaccine development. This information is obtained from populations that are already experiencing a high incidence of antimicrobial-resistant pathogenic infections instead of the population that will eventually get vaccinated.

    Paradigm clinical trial design (phase 1/2) in Reverse Vaccine Development: S. aureus vaccine in subjects at high risk of SSTI.

    Paradigm clinical trial design (phase 1/2) in Reverse Vaccine Development: S. aureus vaccine in subjects at high risk of SSTI.

    Given that animal models have not been unreliable in vaccine development against antimicrobial-resistant pathogens, using high-risk populations helps compare the immune responses of unprotected and protected individuals, which can provide data on correlates of protection.

    The efforts to develop vaccines against S. aureus have yielded four candidate vaccines that target various antigens and use four different protection mechanisms. Based on the results from animal model studies and in-vitro assays, the vaccines were advanced to phase I and II clinical trials. The vaccines passed the safety assessments and elicited satisfactory antibody titers. However, the phase III efficacy trials for these vaccines failed, indicating a lack of adequate information on correlates of protection.

    To circumvent such problems, the researchers in this study applied the paradigm of Reverse Vaccine Development to design a randomized, observer-blinded, placebo-controlled phase I and II trials to assess the immunogenicity, safety, and efficacy of the candidate vaccine developed against S. aureus by GSK.

    Results

    The study discussed how Reverse Vaccine Development differs from the traditional vaccine development process by beginning in phase I or II trials that evaluate the efficacy, immunogenicity, and safety of the vaccine instead of efficacy evaluation in phase III trials. This ensures that potential problems associated with correlates of protection are identified early in the vaccine development process and do not result in the failure of the vaccine towards the end stages when considerable resources have been invested in the process.

    Phase I safety trials with and without adjuvant are often conducted if the vaccine is being developed for the first time for humans, and based on the results of the phase I safety assessments, the trial proceeds into phase II to evaluate the efficacy and immunogenicity. Comparing the immune responses elicited by the vaccine among unprotected and protected groups can help identify correlates of protection, which can then be used to formulate, schedule, and facilitate vaccine efficacy assessments in the general populations and refine the vaccine dosage.

    The researchers discussed in detail the various parameters that need to be evaluated when correlates of protection are being explored. These included serology, cellular responses, immunological signals, transcriptional profiles, memory immune cell responses, and background immunity.

    Conclusions

    To summarize, the study described a novel vaccine development paradigm that involves conducting phase I and II trials in populations that are at high risk of contracting the target antimicrobial-resistant pathogen to understand the correlates of protection before the development process progresses to phase III trials and risks failure. This method could circumvent grave problems in vaccine development, such as exposure to inefficacious vaccines and the loss of resource investment.

    Journal reference:

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  • Lurie Children’s Hospital administers first gene therapy for Duchenne muscular dystrophy in Illinois

    Lurie Children’s Hospital administers first gene therapy for Duchenne muscular dystrophy in Illinois

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    On March 27, 2024, Ann & Robert H. Lurie Children’s Hospital of Chicago treated its first patient with ELEVIDYS (delandistrogene moxeparvovec-rokl), the first gene therapy for Duchenne muscular dystrophy – a rare, genetic disease characterized by progressive muscle damage and weakness. Lurie Children’s is the first in Illinois to administer this treatment after ELEVIDYS received U.S. Food and Drug Administration (FDA) approval in June 2023.

    Developed by Sarepta Therapeutics, ELEVIDYS is approved for the treatment of Duchenne muscular dystrophy (DMD) in ambulatory patients aged 4 through 5 years with a confirmed mutation in the DMD gene.

    Our team at Lurie Children’s has had encouraging experience with this gene therapy for Duchenne through our active participation in clinical trials. Over the past two years, we have treated three boys with DMD with ELEVIDYS as part of a larger clinical trial, and it’s gratifying to see that their muscle strength and function stabilized. Without gene therapy, we would expect to see ongoing deterioration in muscle function in these boys. This therapy is not a cure, and unfortunately it cannot reverse previous muscle damage, but we anticipate that we can slow down the disease enough for science to step in and offer new treatments. This is the beginning of a very exciting journey.”


    Nancy Kuntz, MD, Director of Muscular Dystrophy Association Care Center at Lurie Children’s and Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine

    Duchenne occurs in approximately one in every 3,500-5,000 newborn males worldwide. It is caused by mutations in the dystrophin gene that lead to a lack of dystrophin protein, which acts as a shock absorber when muscles move. The first subtle signs of DMD may appear during infancy. Muscle weakness becomes increasingly noticeable between the ages of 3 and 5 years with the diagnosis being typically made around those ages. Most children living with Duchenne use a wheelchair by age 13 years. The leading causes of death in individuals with Duchenne are respiratory or cardiac failure, which typically occurs when patients are in their mid-20s/30s.

    Mason Flessner, now an energetic 6-year-old, was one of the clinical trial participants at Lurie Children’s who received ELEVIDYS about eight months ago. He now is able to run faster, climb stairs more easily and even jump – something he couldn’t do previously. His little brother, 3-year-old Dawson, who also has Duchenne, is waiting until he is old enough to qualify for gene therapy.

    “ELEVIDYS has been life-changing for Mason, and it has given us hope and optimism that Duchenne is no longer a fatal diagnosis,” said Dan Flessner, Mason’s father. “Thanks to research, gene therapy now gives us a pathway to a cure. With so much progress already, it’s not a pipedream anymore.”

    ELEVIDYS is administered as a one-time intravenous infusion. The gene therapy addresses the root genetic cause of Duchenne by delivering a gene that codes for a shortened form of dystrophin to muscle cells, known as ELEVIDYS-dystrophin. Because dystrophin gene is the largest known human gene, scientists engineered a shortened version of the gene that could fit inside current gene therapy delivery technologies and still retain key functional information. The therapy’s accelerated approval is based on an increase in ELEVIDYS-dystrophin protein expression in skeletal muscle cells.

    “Across the country, since the FDA approval, ELEVIDYS has only been administered a few times and we’re very excited to be the first site in Illinois to administer it,” said Abigail Schwaede, MD, one of the neuromuscular physicians on Mason’s care team at Lurie Children’s and Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. “This treatment has enormous potential to improve the quality of life and long-term outcomes for boys with Duchenne muscular dystrophy.”

    Source:

    Ann & Robert H. Lurie Children’s Hospital of Chicago

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  • New model predicts kidney injury risk in cancer patients on cisplatin

    New model predicts kidney injury risk in cancer patients on cisplatin

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    In a recent study published in the BMJ, researchers created and validated a model to predict severe acute kidney injury in patients receiving cisplatin using data from various cancer centers.

    Study: Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study. Image Credit: crystal light / ShutterstockStudy: Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study. Image Credit: crystal light / Shutterstock

    Background

    Cisplatin remains a key chemotherapy agent for numerous cancers. However, it poses a high risk of causing cisplatin-associated acute kidney injury (CP-AKI), limiting further treatment options and increasing toxicity risks. Identifying those at high risk for CP-AKI is vital for adjusting treatment and improving clinical trial participant selection. Despite its widespread use, current research on CP-AKI risk factors is limited by small sample sizes and inconsistent definitions of kidney injury. Further research is needed to enhance CP-AKI risk prediction and create targeted prevention methods, ensuring safer treatment plans for patients undergoing cisplatin therapy.

    About the study 

    In the present multicenter cohort study, adults were treated with intravenous cisplatin at six major academic cancer centers across the United States (US), including Memorial Sloan Kettering Cancer Center and Massachusetts General Hospital. They were examined to identify risk factors for CP-AKI. The study focused on individuals over 18 years old receiving their first dose of cisplatin between 2006 and 2022, excluding those with end-stage kidney disease or missing baseline serum creatinine values. Data were collected on various patient characteristics and laboratory values to analyze outcomes related to serum creatinine level, kidney replacement therapy, and survival post-cisplatin treatment.

    The primary outcome was CP-AKI, defined as a significant increase in serum creatinine or the need for kidney replacement therapy within 14 days of the first cisplatin dose, indicating moderate-to-severe kidney injury. Secondary outcomes included alternative CP-AKI definitions and major adverse kidney events within 90 days. 

    The study used multivariable logistic regression to identify predictors of CP-AKI and developed a simple risk model to enhance clinical decision-making. Statistical analyses assessed model calibration, discrimination, and validation, comparing it with previous models and conducting additional analyses on CP-AKI severity and its impact on survival. Patient feedback was also gathered through surveys and focus groups, emphasizing the importance of the study’s findings for individuals considering cisplatin treatment.

    Study results 

    The present study initially examined 34,122 patients treated with intravenous cisplatin across six institutions, narrowing down to 11,766 in the derivation cohort and 12,951 in the validation cohort after exclusions. An examination of baseline characteristics revealed notable similarities between both cohorts, although with variations in the prevalence of conditions such as hypertension, diabetes mellitus, congestive heart failure, and cirrhosis, which were more common in the validation cohort. Conversely, chronic obstructive pulmonary disease was more prevalent in the derivation cohort. Additionally, the median dose of cisplatin administered was higher in the derivation cohort compared to the validation cohort.

    In terms of the study’s secondary outcomes, the primary model demonstrated consistent discrimination across five additional analyses. Particularly, the model’s concordance (C) statistic, an indicator of its discriminative ability, remained stable at 0.75 even after excluding patients who only had serum creatinine follow-up within four days post-cisplatin administration. This exclusion involved 1,581 out of 36,483 patients, representing 4.3% of the total. 

    When adjustments were made for the first two secondary outcomes, the model exhibited C statistics of 0.71 and 0.74, employing a more liberal and stricter definition of CP-AKI, respectively. Its ability to discriminate was further highlighted in secondary analyses, where it consistently surpassed three earlier models in forecasting CP-AKI.

    The model was more effective in identifying patients at risk for major adverse kidney events within 90 days of treatment, achieving a C statistic of 0.79, which was significantly better than previous models. There was a direct correlation between the severity of CP-AKI and reduced survival rates at both 90 days and one year, underscored by a significant log-rank test (P<0.001) and an adjusted hazard ratio of 4.63 for stage 3 acute kidney injury compared to no acute kidney injury. This highlighted the severe impact of CP-AKI severity on survival. Additionally, a higher stage of CP-AKI was consistently associated with an increased likelihood of experiencing major adverse kidney events within a 365-day period, emphasizing the long-term risks linked to CP-AKI.

    Conclusions 

    To summarize, in the significant study, this innovative score, which incorporates nine readily available variables, effectively differentiates patients at varying risk levels for CP-AKI. Notably, the study identified novel risk factors for CP-AKI, including hypomagnesemia. It highlighted the association between CP-AKI severity and decreased survival rates, underscoring the importance of accurate risk prediction for improving patient care and outcomes in cisplatin therapy.

    Journal reference:

    • Gupta S, Glezerman I G, Hirsch J S, et al. Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study, BMJ  (2024), doi:10.1136/bmj-2023-077169, https://www.bmj.com/content/384/bmj-2023-077169

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  • Stem cell therapy safe and potentially beneficial for spinal cord injury patients

    Stem cell therapy safe and potentially beneficial for spinal cord injury patients

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    A Mayo Clinic study shows stem cells derived from patients’ own fat are safe and may improve sensation and movement after traumatic spinal cord injuries. The findings from the phase 1 clinical trial appear in Nature Communications. The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

    In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function. The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

    This study documents the safety and potential benefit of stem cells and regenerative medicine. Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients.”


    Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study

    No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

    In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

    The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

    Stem cells’ mechanism of action not fully understood

    In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

    Participants’ stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients’ lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

    Although it is understood that stem cells move toward areas of inflammation -; in this case the location of the spinal cord injury -; the cells’ mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants’ MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

    The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. One unexpected outcome of the trial was that two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment.

    Two of three patients with complete injuries of the thoracic spine -; meaning they had no feeling or movement below their injury between the base of the neck and mid-back -; moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers’ understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

    “In spinal cord injury, even a mild improvement can make a significant difference in that patient’s quality of life,” Dr. Bydon says.

    Research continues into stem cells for spinal cord injuries

    Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

    Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the World Health Organization.

    An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

    “For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy,” Dr. Bydon says. “Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients.”

    Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

    Source:

    Journal reference:

    Bydon, M., et al. (2024). Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial. Nature Communications. doi.org/10.1038/s41467-024-46259-y.

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  • Research suggests booster doses may be necessary for monkeypox immunity

    Research suggests booster doses may be necessary for monkeypox immunity

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    New research to be presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2024) in Barcelona, Spain (27-30 April) shows that even in men who receives two doses of mpox vaccine intradermally, their level of antibodies to the virus falls to low or zero within the first few months if they have not received a previous smallpox vaccine.

    The authors, who include Dr Klara Sonden, deputy state epidemiologist of the of Public Health Agency of Sweden and affiliated to Karolinska Institute, Stockholm, Sweden, says that their study shows that booster vaccination may be needed long-term for such individuals, and that scientific evidence is needed for the background to any decisions.

    Since May 2022, an mpox outbreak has emerged globally, spreading mainly among men who have sex with men (MSM). It was classified as a Public Health Emergency of International Concern (PHEIC). In Sweden, a vaccine against smallpox based on the live Modified Vaccinia Virus Ankara (MVA-BN), has been offered intradermally to risk groups. Intradermal administration means 0.1 ml in the skin, one-fifth of the dose needed for subcutaneous administration. This was used as a dose-saving strategy as supplies were initially limited.

    The vaccine has been shown to be efficacious in studies using real-world data from the 2022 and onward outbreak among MSM, with limited number of breakthrough infections and milder disease reported when breakthrough infections occur so far. The aim of this cohort study was to assess dynamics of, and factors affecting neutralizing antibodies against mpox virus (MPXV) following MVA-BN vaccination.

    A total of 100 MSM attending the sexual health clinic “Venhälsan”, Stockholm, Sweden, eligible to receive the vaccine MVA-BN were included in the study. Following the initial serum sample drawn before dose 1, serum samples were further collected before dose 2, and 28 days and three months after the second dose. These samples were tested to establish titers (levels) of MPXV-neutralising antibodies. Titers were compared in individuals with or without previous smallpox vaccination and patients with past natural infection were included as positive controls.

    10 individuals were of uncertain status regarding smallpox vaccination (due to being born in many different countries in the time period 1977-1980 when vaccination was de-escalated globally) and 23 individuals were previously smallpox vaccinated. The other 67 individuals had no history of smallpox vaccination.

    A total of 312 samples from four time points from the 100 individuals included in the study were analyzed. In addition to the study population, anonymized age and sex matched controls from blood donors were included as negative controls (n=20) and previously MPXV-infected individuals as positive controls (n=20). The controls gave one blood sample each.

    Within the study group, previous smallpox vaccination was associated with significantly higher antibody titers, and 15/23 of these individuals had pre-existing neutralising antibodies (ie, the B-cell memory was still present thanks to their previous smallpox vaccination).

    Among those without prior smallpox vaccination, fewer than half of the group showed any detectable neutralizing antibodies at all 28 days after the second vaccination, with those who did exhibit responses having a median titer (standard unit of measurement of antibodies) of 20. In contrast, for previously vaccinated individuals, the median titer 28 days after a single dose of the MVA-BN vaccine was 40.

    The authors say: “Our findings corroborate other studies showing that mpox vaccination results in neutralising antibodies only in a proportion of vaccinees, and that a significant decline occurs already during the first month post-vaccination Immunity after previous MPXV infection mounts a higher and more robust neutralising response. In conclusion, the findings merits the study of booster doses.“

    They continue: “Our results indicate a rapid decline in neutralising antibodies after two doses and are in line with other recent studies. These results, together with the continued spread of mpox in MSM populations in Europe has prompted the consideration of a booster dose. Such a recommendation needs to be based on scientific evidence. However, as far as we know, no clinical trial has studied or is studying a 3rd MVA-BN dose (from an analysis of clinicaltrials.gov March 2024), but a booster dose is common practice for inactivated vaccines. The MVA-BN is a live, non-replicating vaccine and therefore likely equivalent to an inactivated vaccine. Studies are essential to inform public health policy, and the largest STI clinic in Sweden is planning to perform a randomised clinical trial of a booster dose with immunological parameters as the primary outcome in the comparison with those who have had the two doses of the regular full 0.5 subcutaneous dose (sc) (0.5ml), two doses of the dose-saving intradermal dose (id) (0.1ml), or one dose sc/one dose id, and those with no booster dose.”

    They add that despite this, the Mpox cases in Sweden have been few and mostly imported during 2023 (12 cases) and 2024 (5 cases) and the vast majority have been among unvaccinated individuals. Data collection is ongoing regarding the occurrence of breakthrough infections in Sweden. Breakthrough cases have been reported in the scientific literature among individuals that have received different vaccination strategies (i.e. sc/sc, id/sc, id/id) (Hazra et al).

    The results presented here indicate that long-term protective immunity might need a booster dose for its maintenance. Since the current situation regarding mpox in Sweden is stable with minimal transmission any change in policy should be backed by results from clinical trials. Currently we will focus on finding unvaccinated individuals who are at risk of getting mpox and offer them vaccination, and we believe that this as well as the previously administered vaccinations will contribute to lowering the risk for new outbreaks of mpox in Sweden in future.”


    Dr. Klara Sonden, deputy state epidemiologist

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  • Delaying surgical inguinal hernia repair in preterm infants reduces risks

    Delaying surgical inguinal hernia repair in preterm infants reduces risks

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    Delaying surgical inguinal hernia repair in preterm infants until after discharge from the neonatal intensive care unit (NICU) appears to reduce the likelihood of serious adverse events, according to researchers at UTHealth Houston. 

    A study led by first and corresponding author Martin L. Blakely, MD, MS, MMHC, professor of surgery and pediatrics with McGovern Medical School at UTHealth Houston, analyzed the safety of early versus late surgical repair for preterm infants born with an inguinal hernia. The findings were published today in the Journal of the American Medical Association (JAMA). 

    The biggest question we wanted to answer was, ‘Should we let these little babies go home to grow before we repair their inguinal hernia, or should we do it now?’ It’s a very common condition in preterm infants, but they also have other health concerns. If the inguinal hernia is not repaired before NICU discharge, they face health risks, but at this age they are somewhat fragile and general anesthesia can be hard on them.” 


    Martin L. Blakely, MD, MS, MMHC, professor of surgery and pediatrics with McGovern Medical School at UTHealth Houston

    An inguinal hernia is a visible bulge in the groin area. It affects 30% of preterm infants. 

    Researchers conducted the first randomized clinical trial addressing this neonatal surgical question across 39 trial sites in the U.S. from September 2013 to April 2021. Of the 338 infants in the trial, 172 received early surgical repair and 166 underwent a late surgical repair.

    In the early repair strategy, infants underwent inguinal hernia repair before being discharged from the NICU. In the late repair strategy, hernia repair was planned after discharge and after 55 weeks’ postmenstrual age. Postmenstrual age accounts for gestational age (weeks of development prior to birth) and age in weeks after birth. Postmenstrual age is a commonly used age measure for preterm infants according to the American Academy of Pediatrics.

    Results of the trial showed a 97% probability that infants who underwent a later surgical repair experienced fewer adverse events. Researchers also found that more than 10% of the hernias in the late repair group went away, and none of these infants required surgery. Later repair also allows the infant to be discharged more quickly from the NICU.

    “These findings will likely result in changes of clinical practice across the country. Until now, physicians have not had data to back up their decision to hold off on surgical repair. For years, there have been questions about what is best. Now we have solid data that later is better for most preterm infants,” Blakely said.

    A future focus will be to study the uptake of the research findings in clinical practice, he added.

    Additional UTHealth Houston authors include Kevin P. Lally, MD, MS; Jon E. Tyson, MD, MPH; and Claudia Pedroza, PhD.

    Source:

    University of Texas Health Science Center at Houston

    Journal reference:

    HIP Trial Investigators., (2024). Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial. JAMA. doi.org/10.1001/jama.2024.2302.

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  • UC researchers open Phase 2 clinical trial to test new combination treatment for glioblastomas

    UC researchers open Phase 2 clinical trial to test new combination treatment for glioblastomas

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    A multidisciplinary team of University of Cincinnati Cancer Center researchers have opened a Phase 2 clinical trial to test a new combination treatment for glioblastomas (GBM), the most deadly form of brain tumors. 

    The team, led by UC’s Pankaj Desai, PhD, and Trisha Wise-Draper, MD, PhD, has been awarded a Catalyst Research Award from the Dr. Ralph and Marian Falk Medical Research Trust to move the trial forward. 

    Study background 

    Difficult to diagnose at early stages, GBMs are aggressive brain tumors that become symptomatic once the tumor is substantial. Current treatments include immediate surgery to safely remove as much tumor as possible, radiation and chemotherapy, but the tumor often recurs or becomes resistant to treatments. The average patient survives no more than 15 months after diagnosis. 

    Drug-based treatments for GBMs face an additional challenge known as the blood-brain barrier, which only allows certain compounds into the brain based on their physical and chemical properties. 

    The research team is focused on the use of a drug called letrozole that has been used for more than 20 years as a treatment for breast cancer. The drug targets an enzyme called aromatase that is present in the breast cancer cells and helps the cells grow. 

    Early research in Desai’s lab found that aromatase was present in brain tumor cells, making letrozole a potential new treatment for GBMs. 

    Phase 0/1 trial results 

    To bring letrozole from Desai’s lab to patients’ bedsides, he collaborated with Wise-Draper and neuro-oncologists and neurosurgeons at UC’s Brain Tumor Center to launch a Phase 0/1 clinical trial. 

    “In the academic setting, we are very good at doing molecular research that enhances our understanding of the mechanism of disease and preclinical characterization of efficacy, safety and other aspects of drug development research,” said Desai, professor and chair of the Pharmaceutical Sciences Division and director of the drug development graduate program in UC’s James L. Winkle College of Pharmacy. “But you can’t translate this into a clinical trial without a Phase 1 clinical trial expert like Dr. Wise-Draper and the experts at the Brain Tumor Center.” 

    The researchers published the results of the Phase 0/1 trial March 26 in Clinical Cancer Research, a journal of the American Association for Cancer Research.

    Letrozole was safe up to the highest dose, and there were no safety concerns in the Phase 0/1 trial. The biggest conclusion is that it was safe and that we could reach what we felt was going to be the effective dose based on Dr. Desai’s preclinical work.” 


    Trisha Wise-Draper, MD, PhD, section head of Medical Oncology and professor in the Division of Hematology/Oncology in UC’s College of Medicine

    The research team collected tumor tissues from patients enrolled in the Phase 0/1 trial and found that letrozole was crossing the blood-brain barrier when they analyzed the samples in Desai’s lab. 

    “We can categorically show that in humans the drug actually crosses and reaches the brain tumor at concentrations that we believe are likely to be most efficacious,” Desai said. 

    Phase 2 trial design 

    Since GBMs are aggressive and complicated tumors, Desai said most likely new effective treatments will be combinations of drugs instead of one single drug. 

    In the Phase 2 trial, patients will be given letrozole in combination with a chemotherapy drug called temozolomide that is already approved as a GBM treatment. Desai said preclinical research in his lab and input from Brain Tumor Center collaborators, including neuro-oncologist and former UC faculty member Soma Sengupta, suggested this combination treatment could be more effective than letrozole alone. 

    A total of 19 patients with recurrent GBM who are no longer eligible for additional surgery will be enrolled in the first stage of the trial. The results from this trial will guide the design of future larger Phase 2 trials.

    The team estimates it will complete enrollment within two years, and two patients have already been enrolled. 

    Collaboration and funding support 

    Wise-Draper and Desai have worked together on various research projects for nearly 15 years and said this project would not be moving forward without the varied expertise each team member brings. 

    “I think collaboration with multidisciplinary teams is critical to be able to have the expertise and all the components you need, including biostatistics, pharmacokinetics, clinical, basic science and neuro-oncology expertise,” Wise-Draper said. “The future of all science is team science. No one really can do everything on their own anymore because we’re all too specialized.” 

    “Only academic centers with integrated scientific and clinical expertise are able to move their molecules from the research bench to clinical trials,” Desai added. “It takes a lot of persistence, ups and downs, highs and lows of funding, but we have been supported by a very strong team of people. It’s a journey that has taken a while and a lot of hard work by a number of people, and we’re in a very exciting stage.”

    Early-stage support for the preclinical and clinical trial studies was provided by the UC Brain Tumor Center, where investigators from UC’s colleges of Medicine, Pharmacy, Engineering and Applied Science and Cincinnati Children’s Hospital collaborate on brain tumor research.

    UC’s Brain Tumor Center provided direct support for the completion of the Phase 0/1 trial and some of the correlative mechanistic studies that will continue during the Phase 2 trials using funds raised in the annual Walk Ahead for a Brain Tumor Discoveries fundraiser. 

    The Falk Catalyst Award provides up to $350,000 in seed funding to support translational research projects, which the researchers said was crucial in opening the new trial. 

    “Oftentimes the funding is somewhat limited for initial clinical trial development compared to many other more early-stage studies that you can do,” Desai said. “So that gap is filled by foundations like the Falk Medical Research Trust, and that really is very helpful and plays a critical role in accelerating clinical development.”

    “It would not be possible if we didn’t have the funding to be able to bring this combination into patients that desperately need new treatment options,” Wise-Draper said. 

    As the clinical trial progresses, the team is also collaborating to find other drugs to combine with letrozole to treat GBMs, funded by a $1.19 million National Institutes of Health/National Institute of Neurological Disorders and Stroke grant. The team is already preparing a proposal for larger confirmatory Phase 2 studies and expanding the opportunities for cutting-edge brain tumor clinical trials in Cincinnati. 

    Desai said the ongoing research includes additional collaboration from experts including David Plas, PhD, Biplab DasGupta, PhD, and Tim Phoenix, PhD (molecular/cancer biology); Gary Gudelsky, PhD (neuro-pharmacology) Rekha Chaudhary, MD, and Lalanthica Yogendran, MD (neuro-oncology); Mario Medvedovic, PhD (bioinformatics and genomics); and Shesh Rai, PhD (biostatistics). Many graduate students, postdoctoral fellows and the clinical trials support staff also provide essential support for the project.

    Source:

    Journal reference:

    Desai, P. B., et al. (2024) A Phase 0/1 Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-23-3341.

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  • Viroclinics-DDL changes name to Cerba Research

    Viroclinics-DDL changes name to Cerba Research

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    Viroclinics-DDL (referred to herein as Cerba Research, the Netherlands) a world-leading vaccine and antiviral specialty laboratory providing research and clinical trial solutions rooted in virology, proudly announces changing its name to Cerba Research as of the 1st of April 2024. This branding step was an expected move after the Viroclinics-DDL teams had joined Cerba Research in 2022, now operating as one company well-positioned in the entire value chain of research and clinical trials.  

    Viroclinics-DDL, with its three specialty laboratory and office locations in the Netherlands, and an extensive partner laboratory network worldwide, has been part of the Cerba Research group since early 2022. By fully entering into the Cerba Research brand now, the company underscores its collective focus and dedication to the advancement of clinical research together.  

    The name change of Viroclinics-DDL to Cerba Research marks a natural step forward in the company’s mission to accelerate the development of life-saving therapies and improve patient outcomes; uniquely positioning Cerba Research to offer a broader portfolio of research and clinical trial solutions spanning virology, oncology, cell & gene therapy, and beyond.  

    The Netherlands business unit combines the strengths and capabilities of existing specialty laboratory services with Cerba Research’s unique global footprint, which includes Africa, USA, Europe, Asia Pacific, and Australia to provide end-to-end support throughout the drug development lifecycle across the globe; from pre-clinical research and biomarker discovery to clinical trial management and epidemiological studies. 

    For more information about Cerba Research and its comprehensive portfolio of research and clinical trial solutions, please visit www.cerbaresearch.com. 

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