A recent START webinar titled Malignant Hematology: Advancing Treatment in Blood Cancers, provided an in-depth look into the current advancements and challenges in treating hematological malignancies. Moderated by Dr. Andrew Sochacki, Associate Director for Hematology and Clinical Research at START Midwest, the session brought together leading experts to discuss myeloid malignancies, lymphoid malignancies, plasma cell disorders, and the promise of cellular therapies.

The panel comprised:

• Daniel Morillo, a hematologist & clinical investigator specializing in lymphomas and multiple myeloma at START Madrid FJD.
• Gala Vega, a hematologist at START Madrid FJD focusing on Phase I clinical trials in hematologic malignancies.
• Kathryn Bradford and Dr. Nikki Daskalakis, clinical leaders from Johnson & Johnson.
• Hugo Otones, a seasoned professional in pharmaceutical industry operations in Jannsen.

Tackling Myeloid Malignancies: A Comprehensive Approach

The panel started discussing how Acute Myeloid Leukemia (AML) and other myeloid malignancies present unique challenges due to their aggressive progression. Patients often require swift enrollment in clinical trials, demanding innovative strategies from sponsors and investigators.

Dr. Morillo highlighted the critical need for a diverse portfolio of trials to accommodate patients at varying stages of disease. “It’s not easy to include these kinds of patients because they progress very quickly,” he explained. “We need a robust portfolio of trials open at the same time, and we need to work with our sponsors to know when a slot might be open in an escalation or expansion trial,” he added, which was echoed by Dr. Bradford.

Trial Design and Enrollment: Balancing Broad Inclusion and Future Therapies

Broad inclusion criteria play a critical role in trial design, noted Dr. Bradford. “It’s important to strike a balance between broad inclusion and maintaining a robust evaluation framework. This approach ensures trials are generalizable while paving the way for future combination therapies,” she said.

Dr. Daskalakis noted how sponsors spend significant efforts and use preclinical data and modeling to identify a starting dose that is very likely to be efficacious and benefit the patient right away. The panelists also addressed the challenge of using combination therapies in myeloid trials. With a lack of valid animal or in vitro models to generate robust preclinical data, sponsors turn to biomarkers to identify patients who could potentially benefit from a combination treatment, noted Dr. Bradford.

Using Molecular Stratification and NGS for Trial Inclusion

Dr. Bradford also highlighted the role of molecular stratification in helping identify patients who may not qualify under traditional classifications but could benefit from targeted therapies. “I can give you a specific example with myeloid diseases, we have a menin inhibitor where we are enrolling patients, but the menin pathway is not really active in (Myelodysplastic Syndromes) MDS versus AML. But with some of our AML therapies, for example, the bispecifics with CD33 was something that we evaluated in both MDS and AML.

The integration of Next-Generation Sequencing (NGS) panels has transformed how patients are identified and enrolled. Dr. Gala Vega shared her team’s experience: “At START Madrid, as soon as we receive results from NGS, we inform the clinical team, ensuring timely identification and enrollment of eligible patients,” she explained.

Overcoming Eligibility Challenges

Keeping patients eligible from diagnosis to trial enrollment remains a significant challenge. Dr. Bradford highlighted the importance of managing drug washout periods, balancing patient safety without compromising eligibility. She also emphasized the need to ensure immune cell populations are not depleted or compromised during the washout period when using immune-targeting agents.

Dr. Andrew Sochacki expanded on these strategies, highlighting the role of continuous clinical assessments. “One thing that has been helpful is monitoring MRD (Minimal Residual Disease). You often have an inkling that relapse is pending. This allows us to position patients for trials on the near horizon,” he noted.

Advancing Treatments in Lymphoid Malignancies

Dr. Daniel Morillo highlighted the improved treatment landscape for lymphoid malignancies in recent years. “Over the past decade, we’ve seen overall response rates in lymphomas rise from 10% to 30%, and with therapies like CAR T-cells and bispecific antibodies, these rates have climbed as high as 60%,” he shared.

Critical Role of Biomarkers in Lymphoid Trials

Biomarker discovery has been pivotal in shaping the progress in lymphoid malignancy treatment, in identifying targets for disease as well as disease surveillance and response monitoring, said Dr. Bradford.

The experts underscored the availability of timely, reliable clinical data in driving understanding of biomarkers, but also recognized the practical challenges. Fresh biopsies provide the most accurate data, but logistical challenges often require reliance on archival samples, which may not reflect the patient’s current disease state, Dr. Daskalakis explained. “When you see something interesting with clinical data or we need to understand resistance, that motivates all of us to dig deeper, from a biomarker perspective,” she said.

Trial Design and Execution: Collaboration at the Core

A significant aspect of the discussion centered on collaboration between sponsors and investigators in ensuring effective trial design and execution. Dr. Nikki Daskalakis emphasized the value of engaging investigators early in the process. “There’s no substitute for the expertise of our physician collaborators in terms of their knowledge of the disease, and the practicality of conducting a proposed study in the target population. I think it’s crucial for investigators to have a very strong voice in what we do, so that we can partner together in the execution.”

Regular meetings between sponsors and investigators were identified as critical for trial quality and overall study success. These forums allow stakeholders to navigate the many variables that emerge during trials, “When we open these cohorts, there are many variables you’re deciding at a given time. You can be altering the dose interval. If this is an immune cell engager, there could be target doses and step-up doses. It’s a forum to talk through different considerations.” Dr. Bradford said.

Dr. Gala Vega emphasized how close communication enabled early detection of toxicities in some recent trials she had been involved in. “We started to see toxicities that initially weren’t seen. We could adjust doses, start early treatment to identify toxicities, and progress to phase two,” she shared.

Dr. Nikki Daskalakis highlighted the learning curve, particularly for managing toxicities in first-in-human studies, “Because you’re seeing them in real time, we really rely on the investigator and set discussions to understand what’s happening and implement your experience globally,” she noted.

Strategic Site Selection

Site selection remains a critical element of trial execution. Hugo Otones outlined the criteria sponsors prioritize: “One of the main drivers is the degree of dedication and collaboration between the sites and the sponsors,” he explained. Regulatory adaptability is also a significant factor, especially in regions like Europe with complex frameworks. “Strong communication and responsiveness is always the tipping point to finalize the study strategies,” he concluded.

When selecting sites for a malignant hematology study, several factors play a role. With CAR T-cell trials, in particular, there is an emphasis on site readiness and manufacturing facilities. As Hugo Otones explained, “The operational feasibility and proximity to manufacturing facilities are often decisive factors in site selection for CAR T-cell therapies.” These trials also require robust infrastructure and expertise in handling complex therapies, which further narrows the pool of eligible sites.

START network was highlighted as a preferred partner for sponsors, and praised for its deep expertise and global reach. “What I really appreciate about START is that it’s a network across different disease areas with disease expertise, but also phase-one expertise. The START network has always been a partner of choice for us because of their deep phase-one expertise, but also their network within different countries,” said Dr. Nikki Daskalakis.

Additionally, the panel discussed the unique dynamics between large and small centers in site selection. Larger centers provide access to a broader patient population and often have advanced infrastructure, making them ideal for initiating complex trials. However, smaller centers can offer faster site activation and more personalized care, which can be advantageous for certain studies. Sponsors carefully weigh these factors to ensure trials meet both scientific and logistical goals.

Insights from the Q&A Session

Leveraging AI in Clinical Trials

Artificial intelligence was identified as a transformative tool for optimizing clinical trials at various stages. Dr. Bradford noted: “AI can assist in target identification, molecule design, and dose optimization to enhance trial efficiency. One exciting opportunity is leveraging AI to learn from other clinical trials to get better versions that optimize for faster escalation while preserving safety checkpoints.”

Dr. Andrew Sochacki elaborated on the role of AI in response assessment, stating: “Uniformity in response assessment is a significant challenge. Leveraging AI to integrate imaging, laboratory, and biopsy data can provide a comprehensive view of patient outcomes.”

Addressing the Disparity in Disease Coverage

The panel acknowledged a paradox in the field—numerous therapies exist, yet many disease areas remain underserved. Dr. Nikki Daskalakis emphasized the importance of early inclusion: “We always work to include diverse disease types early in trial development to address unmet needs in smaller populations.”

Dr. Kathryn Bradford added: “Focusing on establishing proof of relevance in larger populations first can create pathways for smaller indications to be studied effectively later.” The panel agreed that collaborative efforts and innovative trial designs are necessary to address these gaps.

Dr. Nikki Daskalakis discussed strategies to enhance inclusivity: “Viewing diseases on a spectrum, like MDS to AML, allows us to design trials that account for different expressions of a target and expand access.” This approach broadens the potential impact of emerging therapies.

Investigator-initiated trials (IITs) were highlighted as a crucial mechanism for studying smaller, less-funded disease areas. These trials allow investigators to leverage existing safety data and explore novel targets, generating meaningful insights that can broaden the scope of therapeutic applications. “IITs provide investigators with the flexibility to explore hypotheses and focus on unmet needs,” added Dr. Vega.

The panel concluded with the panelists agreeing that fostering close collaborations between sponsors and investigators help dissolve silos between sponsors and investigators, creating a cohesive strategy for advancing therapies in underserved patient populations.

Listen to the full broadcast of the webinar here: https://startresearch.wistia.com/medias/p9wg9mldqu.