Andrew Zupnick, PhD

	The latest generation of oncology treatments is entering the market faster than ever before, owing much to the emergence of precision medicines and tumor immunotherapies.

	This shifting landscape poses complex challenges for sponsors as they design clinical trials. For instance, what does a pharma company do if a competing drug is approved mid-development? Proactive drug developers can adapt by building flexibility into their clinical trial protocols. Below, we offer strategies based on our observations both closely watching and actively managing over 

	Among those excited about these new therapies is the U.S. Food and Drug Administration (FDA). Over the past several years, the federal agency has significantly quickened its pace for approving drugs, particularly for those that address an unmet need or confer a significant benefit. The first approval for an oncology product under the FDA’s Breakthrough Therapy designation, which can greatly reduce review times and overall time to market, was for ibrutinib in 

. The trend continued in 2014, with nearly all of the oncology drugs approved by the FDA falling under some type of expedited designation or status, such as Breakthrough Therapy, Priority Review, Fast Track, and Orphan Drug.

	The very next year, the FDA approved 33 drugs in oncology, setting a record high. This brisk pace of approval has made a substantial impact on the standard of care, which has shifted frequently based on emerging clinical data. Practice guidelines for lung cancer, for example, have been 

 this year alone, according to the National Comprehensive Cancer Network.

	The accelerated approvals are taking place in part because the more recently sanctioned drugs create fewer harmful side effects. Patients are now able to receive more lines of therapy and investigators have more metrics available to determine clinical efficacy. As a result, the FDA has relaxed its view on endpoints to demonstrate a drug’s safety and effectiveness. The agency is now more open to embracing measures other than standard survival endpoints as indicators that a drug works and is safe in clinical trials. A non-small cell lung cancer drug, 

 based on Phase 2 trial results showing an overall response rate for more than half of patients over seven months.

	Another accelerating factor is that the FDA has shown a willingness to approve based on single-arm cohorts of larger Phase 1 or Phase 2 trials. 

 based on a 182-patient single-arm bladder cancer cohort from a larger Phase 1/2 multi-arm trial.

	In response to the FDA’s rapid approvals, pharma sponsors need to quickly generate enough evidence to satisfy FDA requirements. Innovative protocol designs are becoming more prominent in this regard. For example, one can conduct a “basket trial” that tests a new therapy across a variety of tumor types by enrolling patients based on their genetic mutations rather than tumor histology. This concept was validated via the 

 in microsatellite instability-high or mismatch repair deficient solid tumors. It was the first approval based on a common biomarker rather than the location in the body where the tumor originated.

	In another innovative design, “umbrella trials” allow researchers to test multiple indications and combinations for a given therapy, with the potential to spin any arm off as its own registrational component. Each therapeutic arm is based on different molecular characteristics of the subjects’ cancers. These complex approaches are attractive because they link protocol design to personalized medicine approaches, making it possible to explore multiple indications with similar genotypes simultaneously and observe sizeable effects in small populations.

	Although this strategy of using innovative, aggressive study designs speeds up clinical trials, there are risks and trade-offs involved. First, an overly complex clinical trial may not produce enough convincing statistics and require additional studies to demonstrate efficacy. Beyond that, these types of studies are likely to incur additional costs in trial implementation and burden for the clinical sites and their staff. Most importantly, patient safety should remain the number-one priority, so building appropriate safety measures into any clinical trial may save a lot of time with regulatory oversight.

	A major challenge for sponsors planning clinical trials today is to keep up with the latest changes to the standard of care and anticipate future shifts to the competitive landscape while their trials are in progress. To increase their chances of success, sponsors need to design their clinical trial protocols with a degree of adaptability.

	For example, sponsors can speed up patient recruitment by adjusting language describing inclusion/exclusion criteria to be less strict. This will allow them to cast a wider net and facilitate easier patient recruitment. However, the downside is that a more heterogeneous population may have ramifications for data quality and statistical efficacy.
	 
	In some indications, there is no single, accepted standard of care, or there may be a pending approval which could shift the standard. Therefore, in trials where a new drug is combined or compared with the existing standard of care, and that standard may change, researchers may elect to allow investigators to choose from a list of comparator drugs that have a similar mechanism of action. This decision needs to be considered carefully, as it too might have statistical and logistical implications. Such a move may affect trial timeline, especially if the approval of an agent in an indication does not rapidly become the new standard of care.

	Depending on the stage of one’s clinical trial, sponsors might be able to complete crucial portions of the study while presuming the new therapy eventually will become generally available or reimbursed. Without definitive information to guide choices, sponsors can design protocols knowing that changes are likely to take place. Sponsors prefer to avoid making cost- and time-intensive critical amendments to their protocols, but such changes are sometimes necessary and must be used judiciously.

	Finally, many drug developers are adding multiple arms to their trials. Novella Clinical recently worked with a sponsor that added an arm to study its drug candidate as a second-line of therapy after noticing a competitor was closer to first-line approval. This strategy took advantage of a potential gap in treatment options, removing the chance of directly competing for a rare patient population and speeding the potential time-to-market as approved second-line therapies are minimal. It also left the window open to compete head-to-head against the first-line therapy later.

 are underway in the United States. To bring new cancer therapies to market successfully, many pharma companies benefit from the insight and guidance provided by an oncology-focused clinical research organization that understands the space and its nuances. Despite a competitive and ever-evolving landscape, this is an exciting time for pharma companies to do their part in advancing therapies that will shape the course of cancer treatment for years to come.

	To design flexible clinical trials that adapt to shifting standards of care, pharma sponsors can:  

 PhD, is Vice President, Oncology Strategy, with 

Articles

Due to a shifting landscape because of faster drug approvals, this article offers strategies for sponsors to design clinical trials.

The Impact of Faster Drug Approvals on Oncology Clinical Trial Design

	The former drummer of the rock band Poison was recently declared cured of oral cancer after undergoing experimental immunotherapy at the UC San Diego Moores Cancer Center. Rikki Rockett joins a growing list of cancer survivors who are testaments to the power of immunotherapy, which was named by the American Society of Clinical Oncology (ASCO) as its Advance of the Year for 2016 and what some are calling the biggest breakthrough in cancer treatment since the invention of chemotherapy.

	Behind the high-profile news stories-including that of former US President Jimmy Carter-more work must be done to ensure every patient who can benefit from these life-saving drugs receives them. Despite some incredible successes, not all patients respond to immunotherapies or to the same degree, the reasoning for which is still under investigation. Immuno-oncology drugs act by harnessing the body’s immune system to attack cancer, a new modality that requires new thinking about how to measure safety and efficacy during clinical trials. Many traditional clinical trial parameters common to chemotherapy or even the newer wave of targeted therapies must be revisited for their application to immunotherapies. Also, conventional clinical response criteria do not take into consideration differences between response patterns to cytotoxic agents and immunotherapies; immunotherapy-treated tumors don’t always shrink at the same rate as with chemotherapy. So, the trial could stop and then, months later, patients respond. 

	Small and mid-sized biopharmaceutical companies play significant, pioneering roles in creating new immunotherapies. However, because such sponsors typically have limited resources, they often require outsourcing support to plan, launch and manage clinical investigations. Smaller sponsors usually only have budget for one trial so they need to get things right the first time. For these reasons, Novella recently hosted a 

 on mastering immuno-oncology clinical trials for smaller biopharmaceuticals. Two topics generated the most discussion:

		Dose-escalation strategies and how best to measure response

	Below, we summarize our thoughts around these two topics.

	A well-written protocol can guide clinical investigators and trial staff as they adapt to this new class of treatment. Effective protocol design is particularly important because of the emerging popularity of testing a novel therapy in combination with an investigational or recently approved immunotherapy within the same protocol.

	For early phase studies, safety and pharmacokinetics remain primary endpoints. Sponsors need to ensure the drug is finding its target in vivo, and identify the optimal dose that balances safety and efficacy. Here’s what’s new: early phase studies are more commonly including efficacy endpoints such as overall response rate and progression-free survival as secondary or exploratory measures. Detecting efficacy as early as possible can better inform future development; or, in some cases, allow a drug candidate to proceed straight to approval (as was the case in 2014 for pembrolizumab’s initial approval in melanoma).

	In late phase programs, overall survival remains the gold standard, but it has been displaced as a primary endpoint in many cases to help reduce the time needed to get breakthrough therapies onto the market and into the hands of the patients that need them most. Surrogate endpoints (e.g., progression-free survival, response rate, and response duration) are becoming more relevant for initial drug approval, as evidenced by nearly all recent immuno-oncology approvals. Other endpoints specific to the drug’s indication or mechanism of action may also be selected, such as the normalization of cancer markers. It remains important to discuss plans early with the FDA and other regulatory bodies, as they are motivated to expedite the approval of truly breakthrough medicines (as evidenced by the FDA’s Breakthrough Therapy Designation and EMA’s PRIME designations).

Trials in combination with checkpoint inhibitors

	One of the most significant advances in oncology drug development has been the emergence of checkpoint inhibitors [LH6]. It’s this class of drugs that Rockett’s physicians used to treat his cancer. Two challenges in particular in managing checkpoint inhibitor trials sponsors face are patient enrollment and access to study drugs. 

	The biggest hurdle is enrolling patients. Because many sponsors are developing new drugs in combination with checkpoint inhibitors, there is a significant number of potentially competing trials that will shrink your patient recruitment pool. Many new combination trials exclude patients who have been exposed to prior checkpoint inhibitor treatment, making meeting enrollment targets more difficult as use of the marketed products becomes more prevalent, especially in the United States. Shifting standards of care to use checkpoint inhibitors in earlier lines of therapy further diminish the population of patients available for checkpoint inhibitor-involved studies. Finally, the potentially eligible patient pool at a specific clinical trial site may be reduced due to study protocols that require enrolling a discreet population of patients with rare biomarkers, thus creating more risk to enrollment timelines.  

	Combination trials also require accessing the checkpoint inhibitors, which can pose a risk to timely study completion and a large expense to the sponsor. For trials recruiting patients outside the approved label and/or outside the United States, it is generally expected that the sponsor will provide, or at least pay for in some respect, the checkpoint inhibitor.  

Best case scenarios for a master protocol

	The concept behind a master protocol-or all-in-one designs-is the design of a common experimental plan across several candidate drugs that screens patients for various biomarkers and assigns them to the most likely effective drug trials, or looks to match various subtypes of a specific cancer with the best combinations of a number of viable drug options. While master protocol studies are most likely to help expand the labeling of approved drugs, they are less likely to be used in early to mid-phase studies to establish proof-of-concept and confirm basic efficacy.

	ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study is a non-randomized clinical trial that aims to describe the performance of commercially available, targeted anticancer drugs prescribed for treatment of patients with advanced cancer that has a potentially actionable genomic variant. TAPUR’s goals are to collect data on clinical outcomes to help expand the indications of approved drugs, to get real-world practice experience in targeted therapy, to spread the word about targeted therapy in clinical practice, and to expand our knowledge of genomic profiling tests. As another example, the I-SPY program is seeking to confirm the efficacy of new treatments for breast cancer, allowing multiple drugs to be tested in an adaptive way.

	Determining the ideal dosing protocol for the best patient response can be novel territory for investigators using immunotherapeutic agents. Determining the maximum tolerated dose may not apply to immuno-oncology drugs because they display response at dose levels below where toxicity may be observed. Also, measuring patient response is a known challenge for immunotherapies.

Best practices for measuring disease progression

	To account for the effects of the immune system in response to immunotherapy, especially in solid tumors, we follow the irRECIST guidelines. This criteria combines the best of immune-related response criteria developed by Memorial Sloan Kettering Cancer Center researchers with that of RECIST 1.1 (Response Evaluation Criteria in Solid Tumors). The aim of irRECIST is to improve reproducibility and inter-rater reliability, and it has become a standard measure of tumor response measurement in immuno-oncology.  

	Specifically, we’ve adapted the standard measurement of response, i.e., serial radiological assessment of tumors, to confirm whether an increase in tumor size actually reflects tumor growth or is in fact an immune response within the tumor, known as a “flare effect.”

When to assess total tumor burden volumetrically

	Clinicians routinely measure baseline tumor volume as a quantitative measure of treatment response as studies have shown it is a good predictor of survival.

	Today, assessing treatment effectiveness involves both clinical assessment and cross-sectional, two-dimensional imaging. Although a CT[LH8] scan is effective in measuring tumor response to treatment, defining tumor boundaries can be difficult, and two-dimensional measurement may not always be reflective of true disease response or progression. Using magnetic resonance technology to assess 3D tumor volume has been shown to have an acceptable rate of inter-rater agreement, and may evolve into a more common standard for tumor response assessment.  

	The classic 3+3 Phase I trial design for determining maximum tolerated dose is still the most frequently used strategy, particularly for first-in-human studies in oncology patients. However, new models that seek to minimize the number of patients treated at sub-optimal doses are emerging. 

	Accelerated titration designs, which combine features from traditional 3+3 and model-based design, enroll one patient per dose (e.g. a single patient cohort), starting at the lowest dose. This dose is escalated until the patient experiences a Grade 2 toxicity, whereupon 3+3 rules apply. 

	Another design is pharmacologically guided dose escalation in which plasma drug concentrations are used to direct dose escalation. When the target area under the curve is reached, or if dose-limiting toxicities (DLT) occur, titration reverts to 3+3. 

	Pediatric studies typically use a rolling six design. Two to six patients can be enrolled concurrently based on current enrollment numbers and evaluability for safety assessment. The ability to use dosing data from adult studies makes this possible.  

	Finally, continual reassessment models use statistical methods to assess safety and dose escalation, where the probability of a DLT is revised with every patient who enters the study. Stopping rules such as DLT incidence are put in effect.  

is the Vice President, Oncology Division with 

Immunotherapy drugs have led to successes in the oncology space as the list of cancer survivors continues to grow. However, more work must be done to ensure that all patients who can benefit from these life-saving drugs receive them.

FAQs for Immunotherapy Trials

Conducting successful clinical trials in hematological malignancies requires an understanding of a rapidly evolving treatment paradigm that is increasingly nuanced, complex, and patient-directed. Just as the underlying differences in biology and prevalence between blood cancers and solid tumors necessitates differences in treating patients, so, too, do they demand differences in clinical trial expertise and conduct. Sponsors developing hematological oncology therapies must capitalize on the principles and infrastructures shared by solid tumor oncology trials while adapting endpoints, study designs and considering patients' experiences to address the particular challenges related to investigating candidate treatments for blood-based cancers. This article examines the nuances of effectively and successfully conducting hematological oncology clinical trials.

	In the United States, someone is diagnosed with a blood cancer every four minutes, and every 10 minutes, these malignancies result in a death.

 Despite this incidence, the three most common forms of blood-based cancers-leukemia, lymphoma, and myeloma-comprised only an estimated 9% of all new cancers and 9% of all cancer deaths in 2013 in the U.S.

 In comparison, the three most common U.S. solid tumor cancers-breast, lung, and colon cancer-together accounted for an estimated 34% of new cancer patients and 43% of cancer deaths in 2013.

(See Figure 1). Globally, leukemia, multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma collectively accounted for only 6.5% of all cancer patients in 2012, excluding non-melanoma skin cancer.


	Figure 1. Blood-based cancers comprised only an estimated 9% of all new cancer cases and 9% of all cancer deaths in 2013 in the U.S.

	Despite a smaller incidence within the total oncology patient population, the global market for hematological cancer drugs reached an estimated $18.7 billion in 2012, with a projected target of at least $28.8 billion by 2017, equating to a compound annual growth rate of 9%.

	The growing hematological oncology therapy market will be fueled by the success of some of the more than 3,000 medicines in development for cancers.

 Driven in part by the application of new scientific knowledge and technologies to isolate and study the biology of malignant cells, a significant portion of hematological cancer medicines can truly be called novel. Of the 818 hematological oncology investigational projects underway, 627 had the potential to be first-in-class medicines, according to a January 2013 assessment.

	The ongoing research investment in understanding the fundamental biology of hematological malignancies will produce an enhanced and refined understanding of cancer pathologies in general as well as increasing the number of targeted therapies for blood cancers and enabling truly personalized treatments. Therefore, sponsors that ensure careful design and precise execution of their hematological oncology clinical trials will yield data that can inform, and perhaps significantly impact the greater oncology community.

	As an example, several years ago, Novella Clinical was approached by a biotech company to help rescue a pair of pivotal Phase III trials for its CXCR4 antagonist in development for hematopoietic stem cell transplantation. The sites participating in the trial had nearly shut down, refusing to submit any further patient data due to the supporting contract research organization (CRO) overwhelming them with nonsensical queries. Simply put, the data and clinical management teams did not understand that, fundamentally, these patients are incredibly sick, and an "abnormal" lab value can be "normal" in this setting. For example, one would expect neutropenia or thrombocytopenia to occur following a transplant, and should not necessarily query lab data showing out of "normal" range white blood cell or platelet counts.

	Novella was brought in to leverage its hematological oncology expertise in data management and biostatistics to rebuild the clinical database, clean up a substantial amount of the queries and help perform the analysis to support a new drug application (NDA). Ultimately, Novella turned the trial around and Mozobil(r) (plerixafor) for stem cell mobilization in NHL and MM patients was approved.

	A hematological oncology trial is fundamentally different than a solid tumor study. Patient access alone is more difficult, as evidenced by the incidence rates previously mentioned. Researchers should evaluate a hematological oncology study design relative to the feasibility of successfully enrolling and executing the trial and, if deficient, be able to offer modifications or alternative approaches that will lead to successful enrollment. To do so, they first need to understand the pathology, clinical manifestations, and current treatment guidelines of the specific hematological cancer under study to fully comprehend all aspects of the most appropriate trial design. Sponsors and their partners must consider how these cancers influence the selection and precise use of terminology in defining important study parameters, of appropriate trial endpoints, and of data management technologies, as well as the selection and experience of patients.

 The correct clinical research use of terminology associated with hematological cancers requires familiarity and understanding. This defining process can present a notable learning curve for sponsors, trial staff, or partners.


	Table 1. A patient-screening comparison.

	For example, if a tumor forms in the lung, it is considered lung cancer, which has various subtypes, and if it spreads to other parts of the body, it is still called metastatic lung cancer. In contrast, bone marrow can be the starting location for several distinct cancers, many of which have their own subtypes and some of which can change and develop with time into a new cancer.

	Other classification systems define leukemia by the speed at which it develops, either chronic (slow) or acute (more quickly), as well as by the type of white blood cell affected, usually lymphoid or myeloid cells. Similarly, NHL is comprised of a large group of lymphocytic cancers divided into aggressive (fast-growing) and indolent (slow-growing) types that occur from either B-cells or T-cells. Classifying NHL is challenging not only because there are many subtypes, but also because of the methods used to determine the subtype. The World Health Organization (WHO) devised a system that not only uses cell morphology but also includes assessments of cell genetics and surface protein receptors.

	Recently, the most significant advance to clinical trial design, and an early glimmer into the potential of personalized medicine, is the need to identify patients with specific biomarkers before the patient can be considered eligible for study participation. Depending on the frequency of the marker used as entrance criteria, or even whether the marker is tested as standard of care at a given institution, the population of potential patients may be significantly reduced and necessitate a consequently large increase in screenings of patients. For example, adding the criteria that acute myeloid leukemia (AML) cancer patients be positive for a FLT3-internal tandem duplication (ITD) mutation reduces the patient population to just 25% of all de novo (first line) AML patients.

 A sponsor must be knowledgeable of the bigger picture presented by the competitive hematological oncology treatment landscape, including current treatment guidelines and clinical practices. To appropriately drive development strategy in hematological oncology, a sponsor also must understand how to assess an investigational treatment's effect on the underlying disease, not just the patient's symptoms, so as to discern efficacy and safety comparative to current practices. Such evaluations will involve complex assessments using intricate endpoints that may involve counts of white blood cells, neutrophils, myeloblasts, myleocytes, as well as bone marrow measures, the spleen and the liver, among others.

	In addition, understanding the investigational therapy is critical. As more and more therapies have the potential to be first-in-class, such as antibody-drug conjugates or mutationally-selective inhibitors, potential clinical trial sites will likely have little to no experience with these new treatments. This knowledge gap can be addressed with appropriate site staff training before and during the trial. Study-specific training often is not just about the therapy but also the processing of complex and sensitive lab samples and the use and measurement of specific targeted endpoints, such as biomarkers.

 The determination of endpoints differs significantly between solid tumor and hematological oncology. Most solid tumor cancer trials rely on the Response Evaluation Criteria in Solid Tumors (RECIST) to define a participant's improvement/response, worsening/progression or stability. In contrast, the very nature of blood-based cancers requires that treatment trials rely on different measurements to determine treatment-related changes and disease progression, which can add more complexity to trial design, conduct and assessment.

	Overall survival (OS) remains the gold standard when evaluating cancer treatment effectiveness. However, progression-free survival (PFS) is the most commonly used surrogate endpoint for trials involving advanced cancers.

 Other progression-related OS surrogate endpoints include disease-free or event-free survival, response rate or objective response rate and time to progression.

	The smaller, single-arm design used in many hematological oncology trials usually precludes using time-to-event endpoints to reliably interpret treatment effects

 and determine OS. Therefore, these trials measure event-free survival, remission rates, duration of response, as well as laboratory measures of biological activity. Major molecular response endpoints also are not uncommon in hematological oncology trials but require great specificity in determining what to measure and the techniques involved, based on the disease under study and whether it is acute or chronic. In the care setting of patients with chronic myeloid leukemia (CML), for example, a polymerase chain reaction (PCR) assay can evaluate molecular responses, namely measures of transcription levels of a specific fusion protein. Such molecular measures are now being adapted to the research setting. For example, entry criteria in CML trials using treatment-free remission as an endpoint require that patients achieve deep, molecular response levels.

	Hematological oncology trials also take advantage of technological developments to measure survival, particularly imaging, to provide greater specificity. For example, the 2011 biologics license application (BLA) submitted to the FDA for brentuximab vedotin was the first to use the agency's response criteria for lymphoma drugs, set forth in 2007,

 which included FDG-PET (18F-fluorodeoxyglucose positron emission tomography) scans in the response assessments. The FDA considered PFS acceptable as an endpoint to confirm clinical benefit because an OS endpoint would not likely occur within a reasonable time frame. The BLA used data from two single-arm studies, both designed to show superiority using PFS as a primary endpoint and OS as a secondary endpoint. The FDA used these data to grant accelerated approval of the biologic for patients with Hodgkin's lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and for patients with relapsed systemic anaplastic large-cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

	As companies create a development strategy for a compound, the choice of endpoints is very important. Often, sponsors need to strike a balance between FDA-supported endpoints, cost, time, and other endpoints, markers or measures that can quantify or qualify an efficacy signal but may not meet regulatory stringency. Designing trials accurately, understanding appropriate endpoints and measuring response using the correct technology are keys to trial success.

 Whether in-house or through a partner, clinical research associates (CRAs) need to understand the significance and implications of blood count shifts as well as of transfusions and dosing timing. In the seriously ill patient populations of most hematological oncology trials, certain blood counts are expected to fluctuate because of their disease. For example, anemia in these patients can affect both drug activity and toxicities, so monitoring the anemia and its treatment in trials is important. When hemoglobin counts drop below a certain level, patients require a blood transfusion, which will raise the hemoglobin count. However, the hemoglobin count may also rise after a patient receives a treatment dose. An experienced CRA will know if such fluctuations are prompted by the transfusion, the dosage or the disease state.

 Many pharmaceutical and biotechnology companies are pursuing compounds that target hematological malignancies, and combined with an inherently rare patient pool, this naturally causes competition for investigator and institution participation, patient enrollment and key opinion leader relationships. Moreover, the world of hematological oncology specialists is even smaller than that of solid tumor specialists, making competition that much more intense. For a global trial, the rarity of some hematological oncology diseases can result in a lack of knowledgeable investigators or inconsistencies in standards of care from region to region. These variations can limit regional or country-specific options in site selection, which can have implications for trial conduct and regulatory clearance plans.

	While the 2012 ASCO National Census of Oncology Practices found more than 70% of all responding practices reported offering a hematological oncology specialty for patients, only 26% of all practice types participated in clinical trials.

 A mere 11.3% of responding practices defined themselves as academic, with either teaching or research activities,

 making it clear that highly knowledgeable and experienced oncologists and hematologists practicing in community settings represent a significant source of referrals for clinical trials. However, at smaller community-based sites, a sponsor may need to offer more significant trial management support.

	Consider patients' experiences. Sponsors of hematological oncology studies need to take several patient needs into consideration when recruiting, enrolling, and retaining patients. The trial's educational materials must not only clearly transmit information about potential treatment benefits and risks regarding their disease but also must include the potential impact study participation may have on one's quality of life, such as the number of clinic visits, blood draws, and radiographic studies as common in lymphoma.

	Additionally, trial teams must be aware that patients with hematologic cancers have disparate potential viewpoints that set them apart from solid tumor patients and that might impact enrollment and retention strategies. Some patients with lymphoma or leukemia, for example, have a chronic clinical course that extends for years, even decades. These patients are frequently interested in the potential a trial can offer, but want the confidence that an investigative therapy is likely effective and will not interfere with their lifestyle. They usually are less concerned about the pace of a trial and more concerned about invasive procedures, such as repeat biopsies or bone marrow exams, because of their risks.

	The opposite is true for patients with acute hematological cancers such as acute leukemia. Time is highly important to them, and they seek immediately available clinical trials and "instant" therapies they perceive as offering the potential for life extension, even if trials involve more invasive interventions, multiple clinical visits, or radiographic studies. These patients find trials requiring long evaluations and limited chances to participate unappealing, but readily accept coming to the clinic frequently to confirm an investigative therapy is working.

	The better a hematological oncology trial can address the treatment agendas of individual patients, the more success the study will have in recruitment and completion.

	General patient rarity (most of these indications can be classified as orphan) combined with limited treatment specialists and centers, an intense competing trial landscape, and the potential for shifting standards of care both over time and across global regions makes proper site selection that much more critical to a study's success right out of the gate. Disease terminology, classification, and trial endpoints/response assessments are highly complex and can even morph over time, highlighting the need for an active knowledge base in this space when designing the trial and when assigning the study team. Finally, the differences between the potential speed of progression within an indication (e.g., acute vs. chronic leukemia) and the resulting impact of invasive or frequent procedures on a patient's willingness to participate in a given trial should be taken into account when designing the protocol.

	Ultimately, the future looks bright for hematological oncology treatment with so many novel drugs and personalized approaches in development; a thorough understanding of the potential challenges in implementing clinical trials in this complex space will help speed the process to bring new therapies to patients in need.

, is senior director, oncology division, at Novella Clinical Inc., email: 

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http://www.bccresearch.com/pressroom/phm/global-market-hematological-disorder-drugs-diagnostics-expected-reach-$64.7-billion-2017

	5. PhRMA, "The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients," January 2013. Page 2. Accessed at 

	6. Long G, Works J. "Innovation in the Biopharmaceutical Pipeline: A Multidimensional View." Analysis Group, January 2013, page 9 and 13. Accessed at 

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. Accessed atFLT3-ITD acute myeloid leukemia 

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Successful conduct of hematological malignancy trials requires addressing several unique complexities.

Overcoming Challenges in Hematological Cancer Trials

Conducting successful clinical trials in hematological malignancies requires an understanding of a rapidly evolving treatment paradigm that is increasingly nuanced, complex and patient-directed. Just as the underlying differences in biology and prevalence between blood cancers and solid tumors necessitates differences in treating patients, so, too, do they demand differences in clinical trial expertise and conduct. Sponsors developing hematological oncology therapies must capitalize on the principles and infrastructures shared by solid tumor oncology trials while adapting endpoints, study designs and considering patients' experiences to address the particular challenges related to investigating candidate treatments for blood-based cancers. This article examines the nuances of effectively and successfully conducting hematological oncology clinical trials.

	In the United States, someone is diagnosed with a blood cancer every four minutes and every 10 minutes; these malignancies result in a death.

 Despite this incidence, the three most common forms of blood-based cancers-leukemia, lymphoma and myeloma-comprised only an estimated 9% of all new cancers and 9% of all cancer deaths in 2013 in the United States.

 In comparison, the three most common US solid tumor cancers-breast, lung and colon cancer-together accounted for an estimated 34% of new cancer patients and 43% of cancer deaths in 2013.

  Globally, leukemia, multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL) and Hodgkin's lymphoma collectively accounted for only 6.5% of all cancer patients in 2012, excluding non-melanoma skin cancer.

	Despite a smaller incidence within the total oncology patient population, the global market for hematological cancer drugs reached an estimated $18.7 billion in 2012, with a projected target of at least $28.8 billion by 2017, equating to a compound annual growth rate of 9%.

	As an example, several years ago, Novella Clinical was approached by a biotech company to help rescue a pair of pivotal Phase III trials for its CXCR4 antagonist in development for hematopoietic stem cell transplantation. The sites participating in the trial had nearly shut down, refusing to submit any further patient data due to the supporting CRO overwhelming them with nonsensical queries. Simply put, the data and clinical management teams did not understand that, fundamentally, these patients are incredibly sick, and an “abnormal” lab value can be “normal” in this setting. For example, one would expect neutropenia or thrombocytopenia to occur following a transplant, and should not necessarily query lab data showing out of “normal” range white blood cell or platelet counts. 

	Novella was brought in to leverage its hematological oncology expertise in data management and biostatistics to rebuild the clinical database, clean up a substantial amount of the queries and help perform the analysis to support a new drug application (NDA). Ultimately, Novella turned the trial around and Mozobil® (plerixafor) for stem cell mobilization in NHL and MM patients was approved. 

	A hematological oncology trial is fundamentally different than a solid tumor study. Patient access alone is more difficult, as evidenced by the incidence rates above. Researchers should evaluate a hematological oncology study design relative to the feasibility of successfully enrolling and executing the trial and, if deficient, be able to offer modifications or alternative approaches that will lead to successful enrollment. To do so, they first need to understand the pathology, clinical manifestations and current treatment guidelines of the specific hematological cancer under study to fully comprehend all aspects of the most appropriate trial design. Sponsors and their partners must consider how these cancers influence the selection and precise use of terminology in defining important study parameters, of appropriate trial endpoints and of data management technologies as well as the selection and experience of patients.

. The correct clinical research use of terminology associated with hematological cancers requires familiarity and understanding. This defining process can present a notable learning curve for sponsors, trial staff or partners.

A sponsor must be knowledgeable of the bigger picture presented by the competitive hematological oncology treatment landscape, including current treatment guidelines and clinical practices. To appropriately drive development strategy in hematological oncology, a sponsor also must understand how to assess an investigational treatment's effect on the underlying disease, not just the patient's symptoms, so as to discern efficacy and safety comparative to current practices. Such evaluations will involve complex assessments using intricate endpoints that may involve counts of white blood cells, neutrophils, myeloblasts, myleocytes, as well as bone marrow measures, the spleen and the liver, among others.

The determination of endpoints differs significantly between solid tumor and hematological oncology. Most solid tumor cancer trials rely on the Response Evaluation Criteria in Solid Tumors (RECIST) to define a participant’s improvement/response, worsening/progression or stability. In contrast, the very nature of blood-based cancers requires that treatment trials rely on different measurements to determine treatment-related changes and disease progression, which can add more complexity to trial design, conduct and assessment.

 and determine OS. Therefore, these trials measure event-free survival, remission rates, duration of response as well as laboratory measures of biological activity. Major molecular response endpoints also are not uncommon in hematological oncology trials but require great specificity in determining what to measure and the techniques involved, based on the disease under study and whether it is acute or chronic. In the care setting of patients with chronic myeloid leukemia (CML), for example, a polymerase chain reaction (PCR) assay can evaluate molecular responses, namely measures of transcription levels of a specific fusion protein. Such molecular measures are now being adapted to the research setting. For example, entry criteria in CML trials using treatment-free remission as an endpoint require that patients achieve deep, molecular response levels.

	Hematological oncology trials also take advantage of technological developments to measure survival, particularly imaging, to provide greater specificity. For example, the 2011 biologics license application (BLA) submitted to the FDA for brentuximab vedotin was the first to use the agency's response criteria for lymphoma drugs, set forth in 2007,x which included FDG-PET (

F-fluorodeoxyglucose positron emission tomography) scans in the response assessments. The FDA considered PFS acceptable as an endpoint to confirm clinical benefit because an OS endpoint would not likely occur within a reasonable time frame. The BLA used data from two single-arm studies, both designed to show superiority using PFS as a primary endpoint and OS as a secondary endpoint. The FDA used these data to grant accelerated approval of the biologic for patients with Hodgkin’s lymphoma after failure of autologous stem cell transplantation (ASCT) or of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates, and for patients with relapsed systemic anaplastic large-cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

	As companies create a development strategy for a compound, the choice of endpoints is very important. Often, sponsors need to strike a balance between FDA-supported endpoints, cost, time and other endpoints, markers or measures that can quantify or qualify an efficacy signal but may not meet regulatory stringency. Designing trials accurately, understanding appropriate endpoints and measuring response using the correct technology are keys to trial success.

Whether in-house or through a partner, clinical research associates (CRAs) need to understand the significance and implications of blood count shifts as well as of transfusions and dosing timing. In the seriously ill patient populations of most hematological oncology trials, certain blood counts are expected to fluctuate because of their disease. For example, anemia in these patients can affect both drug activity and toxicities, so monitoring the anemia and its treatment in trials is important. When hemoglobin counts drop below a certain level, patients require a blood transfusion, which will raise the hemoglobin count. However, the hemoglobin count may also rise after a patient receives a treatment dose. An experienced CRA will know if such fluctuations are prompted by the transfusion, the dosage or the disease state.

Many biopharmaceutical and pharmaceutical companies are pursuing compounds that target hematological malignancies, and combined with an inherently rare patient pool, this naturally causes competition for investigator and institution participation, patient enrollment and key opinion leader relationships. Moreover, the world of hematological oncology specialists is even smaller than that of solid tumor specialists, making competition that much more intense. For a global trial, the rarity of some hematological oncology diseases can result in a lack of knowledgeable investigators or inconsistencies in standards of care from region to region. These variations can limit regional or country-specific options in site selection, which can have implications for trial conduct and regulatory clearance plans.

 found more than 70% of all responding practices reported offering a hematological oncology specialty for patients, only 26% of all practice types participated in clinical trials.x  A mere 11.3% of responding practices defined themselves as academic, with either teaching or research activities,

Sponsors of hematological oncology studies need to take several patient needs into consideration when recruiting, enrolling and retaining patients. The trial’s educational materials must not only clearly transmit information about potential treatment benefits and risks regarding their disease but also must include the potential impact study participation may have on one’s quality of life, such as the number of clinic visits, blood draws and radiographic studies as common in lymphoma.

	The opposite is true for patients with acute hematological cancers such as acute leukemia. Time is highly important to them, and they seek immediately available clinical trials and "instant" therapies they perceive as offering the potential for life extension, even if trials involve more invasive interventions, multiple clinical visits or radiographic studies. These patients find trials requiring long evaluations and limited chances to participate unappealing, but readily accept coming to the clinic frequently to confirm an investigative therapy is working.

	General patient rarity (most of these indications can be classified as orphan) combined with limited treatment specialists and centers, an intense competing trial landscape, and the potential for shifting standards of care both over time and across global regions makes proper site selection that much more critical to a study’s success right out of the gate. Disease terminology, classification and trial endpoints/response assessments are highly complex and can even morph over time, highlighting the need for an active knowledgebase in this space when designing the trial and when assigning the study team. Finally, the differences between the potential speed of progression within an indication (e.g., acute vs. chronic leukemia) and the resulting impact of invasive or frequent procedures on a patient’s willingness to participate in a given trial should be taken into account when designing the protocol. 

, PhD, is the senior director, oncology division, at Novella Clinical Inc.; email: 

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Conducting successful clinical trials in hematological malignancies requires an understanding of a rapidly evolving treatment paradigm that is increasingly nuanced, complex and patient-directed.

Andrew Zupnick, PhD

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