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TOPICS
UNDER DEVELOPMENT
In the News | Treatments | Improving Drug Development and Assessment |
The Essential Role of the NCI
 The treatments for lymphomas are often effective and can result in relatively high cure rates for some types of lymphoma and prolonged survival for indolent lymphomas.
But more work as needed as people still die and suffer from lymphoma. There remains an urgent need:
- to overcome resistance to treatments that can be primary (evident early) or acquired over time.
- for treatments with less short and long-term toxicities, both physical and financial.
- for biomarkers that can predict benefit from specific treatments, and who will experience unproductive toxicity
- for more effective protocols that help patients to become free of the disease and from the treatments.
As patient advocates, we have some thoughts as to how this might be accomplished:
Unsolicited Advice on Study Design:
the importance of Shared Infrastructure
The primary challenge limiting rapid progress against lymphoma and other cancer types is tumor heterogeneity. This might be described as the features of a tumor driving its behavior (including resistance or sensitivity to different treatments). These tumor features (such as genetic abnormalities) can vary within the same patient and among patients with the same diagnosis.
Tumor heterogeneity shows itself as no response to an treatment that is effective in other patients with the same diagnosis. Within the patient it shows itself a partial response, or a response to a treatment that is short lived.
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Focus on Biospecimen-based research. There's a need to account for tumor heterogeneity in clinical trials
This seems feasible today but only if the outcomes from the studied intervention (in a trial or as part of regular care) are systematically correlated with the features of the patients tumor specimen.
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Establish independent tumor registries
This to standardize the capture and analysis of biospecimens - and to share the results with all researchers.
An open source public utility is needed to guide and inform the most deserving clinical research carried out by public and industry sponsors. This would enable the reliable pooling of outcomes and clinical features across multiple trials. To validate predictive biomarkers size matters as does reproducibility by other groups.
Such registries can be available to patients at diagnosis -- even if not participating in a specific clinical trial - which will aid in learning from Big Data.
It will provide a high quality consent process that's efficient and transparent; and a sophisticated bioinformatics system (such as caBIG) that protects patient privacy and fosters public trust by describing its projects and reporting its finding to its partners: the patients who have contributed the tissue.
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Make use of information that arises from regular care: the so-called "Big data" initiative
Correlations with outcomes in regular practice will be most useful and reliable if the tissue capture and analytics are standardized and carried out as part of regular care.
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Patients contributions tumor samples when participating in trials
... has important potential benefits that needs to be incorporated into clinical trial design, but there are also pitfalls
Independent tumor registries that share data and are based on standard procedures will be needed to optimally support this important approach to personalized cancer research.
Institutional Review Boards (RBs) may disapprove study protocols that mandate biopsies, unless it is for the purpose of patient selection (integral to the study question) - as a way to select participants most likely to be helped by the study drug.
Mandating tumor sample can be a barrier to accrual depending on the competing choices available to the patient as part of regular care or a different clinical trial. There may be some patients who do not have tumors that can be safely resected. (Perhaps in such cases a provision could allow for participation without a biopsy.)
Understandably, few patients will consent to optional biopsies. Perhaps other tests on the sample can be done to “sweeten the pot” – such as to identify possible actionable mutations that might guide consideration of other studies (such as NCI MATCH) or off-label use. This might raise ethical concerns in IRB reviews, however, about “undue influence.”
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Experts Julia R. Pon1 and Marco A. Marra - On the importance of supportive infrastructure:
"The best predictors of treatment response, therefore, may not be the presence or absence of a single alteration, but rather signatures integrating multiple factors. Such predictive signatures may be identified by analyzing molecular correlates of treatment outcomes in routinely treated patients and in clinical trials.
However, obtaining and organizing such data will require significant forethought, interdisciplinary collaboration, and supportive infrastructure. Moreover, the incorporation of new biomarkers into clinical practice will require pathologists and oncologists to understand the utility and limitations of such tests. Overall, the utility of molecular markers does not end at obtaining a better understanding of cancer biology or at identifying new drug targets; the collection and evaluation of molecular signatures in clinical samples is needed for the continued improvement of patient outcomes."
Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma
Julia R. Pon1 and Marco A. Marra1 https://t.co/1vgm9l4YUE
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Make the consideration of clinical trials and participation in tissue registries ROUTINE
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Study approaches and concepts
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More Study Sequential Approaches with Curative Intent
Standard treatment + Study Drug-A designs ought to consider also the mechanism of action of the standard induction therapy - if it complements, or possibly works against, the mechanism of the study drug.
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Do Radioimmunotherapy-based research. RIT is an available induction therapy that is not widely prescribed. It may be superior to chemotherapy when is paired with an immunotherapy study drug because it has similar induction power but with less impact on effector cells that are needed to optimize immunotherapy.
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To minimize over-treating patients and related toxicity, including financial toxicity, there's a need test administration schedules for drugs given on an indefinite schedule – perhaps guided by clinical changes or changes to PCR-based Minimal Residual Disease (MRD) status over time.
The RESORT study of Rituximab is an example of an NCI-funded study - a finding that now spares patients from over-treatment and unproductive financial toxicity
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Consider the full range and classes of induction therapies that may have features that complement immunotherapy-- perhaps also describing the types, schedules, and doses that may be appropriate for different clinical circumstances.
The anticipated impact of induction therapy on effector cells seems an important consideration for the selection of induction therapies in general in combination immunotherapy trials.
Low or metronomic dosing of chemotherapy also comes to mind as an induction therapy that can elicit immune response and modulate the immune profile in ways that may promote immune rejection or prevent tumor escape.
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Study designs
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Establish think-tanks to develop creative concepts from independent researchers and advocates -- based on the full range of opportunities (whether feasible or not at this time). For example, study questions of importance to patients may not be important to industry.
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Randomized Controlled Trial (RCT) designs remain important, but are not always ethical or feasible
RCTs can be especially challenging to accrue for if the control treatment is perceived to be an undesirable choice, or when the compared protocols have very different types of risks, or when either or both protocol can be used off study.
Crossover provisions can sometimes mitigate the concern.
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Study or make use of novel study designs when traditional Randomized studies are not feasible or ethical.
Such as the Observation-enriched Randomized Controlled Trials (ORCT) -- giving patients a choice to be randomized or to choose the preferred study arm.
A design that includes an education component to explain why random allocation is reasonable and appropriate.
ORCT schema - at a glance: ORCT-schema.pdf
Full description: PCT-proposal-4-3-14.pdf
Such designs can be larger and will accrue faster. Here features of the tumor samples can help identify biomarkers that are specific to the drug received ... to identify features that may predict resistance or response to the study drug and to the standard control.
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Interpretation of single-arm studies may be aided by focusing study on patients having treatment-refractory disease (such as double-refractory).
In such population each patient can be the control (relative to the poor response to prior treatments). This is the apparent rationale for the accelerated approval path to conditional approvals by FDA.
Here the tissue samples in a narrowly defined group may be particularly helpful as a means to identify biomarkers for resistance to standard therapy and/or the response to the study drugs in high risk disease.
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Consider what is feasible in respect to study design based on the common clinical circumstances, such as:
• Watchful waiting – asymptomatic, indolent with low tumor burden
(novel approaches with low anticipated risks, or building on Rituximab monotherapy)
RCT design can be feasible – particularly with crossover
Patients may not be willing to take more risks, given the unknown and often low risk of the disease.
• Indolent lymphoma, previously untreated - all comer trial
(standard therapy + immunotherapy consolidation)
RCT could be feasible due to uncertainty about value of addition of any study drug on OS in this population
Can magnitude of improvement in PFS aid in interpretation? (Set a high bar)
Can serial MRD status could aid in interpretation earlier?
Patients may not be willing to take more risks, given the unknown and often low risk of the disease.
• Aggressive lymphoma, previously untreated
(standard therapy + targeted therapy or immunotherapy consolidation)
RCT feasible if standard is curative for most patients
Patients may be willing to take more risks, given the poor outcomes and toxicity of treatments that are needed if they relapse.
• Treatment-refractory, aggressive / including transformed
(novel combination therapy with potential to induce durable remissions )
CRs are the key endpoint, not ORR.
RCT not appropriate / feasible if standard approach is ineffective
Patients may be willing to take more risks, given the risk of the disease.
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Background on Approaches to Treatments
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Improved therapies will have greater specificity, more potency, and less toxicity;
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Can overcome bulky disease;
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Can selectively kill indolent lymphoma cells, that are not in cell cycle;
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Can induce and enhance active immunity - the way we naturally fight disease;
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Combine targeted therapies that may complement each other in order to minimize toxicity and prevent tumor escape;
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Rationally selected to match the differences in the disease by using genetic and metabolic profiling;
(please review information about the National Biospecimen Network an innovative blueprint for progress)
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Are less toxic, thus allowing patients with indolent lymphomas to safely receive treatment early and more regularly;
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Can be safely combined with existing treatments in order to cure indolent lymphomas, and more patients with aggressive disease.
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Address the role of the microenvironment:
(1) Altering the host environment in ways that silence or inhibit pro-survival signals concurrent with standard therapies.
(2) Focusing, and expanding immune surveillance against tumors.
(3) Turning off signals and inhibiting cells that contribute to drug resistance, depressed immunity and escape from immunity.
(4) Targeting tumors in ways that minimize damage to immunity, or that might enhance it.
(5) Sequencing therapies in ways that restore positive elements of the microenvironment in order to consolidate the response to treatments.
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Improving Drug Development and Assessment:
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Identify and validate biomarkers that predict prognosis and response to specific therapies -
So therapy can be tailored to meet the needs of patients who can have lymphomas with unique underlying biology.
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Evaluate better ways to assess response, such as for detection of minimal residual disease.
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Ensure that there are sufficient incentives for pharmaceutical companies to take the financial risks to
develop and test therapies for cancer.
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Consider reducing incentives to develop "me-too" drugs for conditions that
are not life-threatening.
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Ensure that the FDA considers factors such as lower toxicity and improvements in the quality of life benefits in the
assessment of new therapies.
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Encourage drug sponsors to properly account for and measure toxicities and quality of life in
clinical trials.
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Increase patient participation in clinical trials - an essential ingredient:
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Encourage drug sponsor to consult with informed patients and treating physicians
to help design clinical studies that are in harmony with patients survival goals.
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Educate the communities' doctors and patients about what studies are available, and which show promise for specific treatment settings.
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Encourage treating physicians to discuss all appropriate therapies, including investigational therapies,
during treatment consults.
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Ensure that tests associated with clinical trials are covered by government and / or insurance.
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Provide, when possible, predictive tests to determine who is more likely to benefit from an
investigational therapy and/or a standard therapy used as a pretreatment in studies.
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Encourage drug sponsors to test investigational bio- and immune-based therapies earlier in the course
of the disease, when they are more likely to provide benefit - especially for indolent lymphomas.
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Watch & wait should not be routine. Periods of stable disease provide an important
opportunity to test immune-based therapies and other more targeted therapies with safer toxicity profiles.
We must encourage drug sponsors, patients, and treating physicians to use this opportunity:
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Better immune competence |
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Less tumor burden |
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Less prior exposure to immune-suppressing or toxic treatments |
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Potential to improve quality of life |
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Potential to learn without precluding the use of standard treatments |
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The Essential Role of the National Cancer Institute (NCI):
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Ensure that funding of cancer research becomes a national priority.
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Encourage all cancer groups to work cooperatively in this effort.
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Encourage the NCI to carry out its promise to conduct translational research in order to validate
and clinically test promising new therapeutics.
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Ensure that gene-profiling technologies are fully funded and applied as quickly as possible.
We support the following rationale:
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Enables scientist to more rapidly identify the gene expressions that distinguish normal from
malignant cells and assist in the "development of molecularly targeted therapies that have specificity
and potency for defined cancer types."
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Enables scientists to link clinical behavior (how aggressive or indolent the cancer is likely to be)
to gene expression, and thus better advise patients about treatment selection and timing.
(Currently, the variable clinical course of patients given the same diagnosis stems, in part, from
the underlying molecular diversity among their tumors.)
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Enables identification of viral factors that may be present and may contribute to causing,
promoting, or maintaining malignant behavior of lymphoma cells.
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Enables scientists to discover how genes function in immune cells and apply that knowledge to
the treatment of numerous diseases.
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Enables retrospective testing to genetic expression with individual responses to treatments.
The potential benefits will enable researchers and/or doctors to:
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select treatments that are far more likely to benefit the patients
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spare patients from the side effects of ineffective treatments |
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identify patients in need of experimental approaches to treatment |
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reduce health costs by enabling rational treatment selection, instead of by wasteful trial and error |
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identify genes in tumors that lead to treatment resistance |
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select patients most likely to benefit from investigational drugs in clinical trials |
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“Presently we are overlooking effective treatments for some people, while administering ineffective and toxic treatments to others based on studies conducted with ill-defined aggregates of patients.” – DF.
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Enable testing of multiple samples from the same patient, in order to:
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identify changes to gene expression and other tumor characteristics in response to
treatments and over time. |
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identify changes to gene expression and other tumor characteristics that correlate to refractory
disease, or transformation to aggressive disease, or the lack thereof.
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Enable identification of tumor-associated antigens that can form the basis for therapeutic
cancer vaccines.
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Enable discovery of cells in the lymphoid microenvironment that may be promoting or inhibiting
lymphomas.
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Enable production of patient-specific therapeutics, such as cancer vaccines or therapeutic antibodies.
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Consider providing financial incentives to managers that bring new therapeutics to cancer patients,
and to scientist who make key discoveries to make this possible.
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Encourage clinical studies of the many promising therapeutics and adjuvants that are not of
commercial interest, such as:
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Combinations and sequences of agents that may complement one another.
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Immune-based strategies that have low toxicity on patients with indolent lymphomas.
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Natural compounds that have potential in combination with chemotherapies, such as fish oil and melatonin.
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Last, but NOT least:
Design compassionate use protocols in advance - anticipating the needs of patients who fail standard therapies, and are ineligible for clinical trials - so we can give patients every reasonable chance to survive, and also test new concepts in a timely manner.
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In the News
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Clinical impact of molecular features in diffuse large B-cell lymphoma and follicular lymphoma
Julia R. Pon1 and
Marco A. Marra1,2
https://t.co/1vgm9l4YUE
Conclusions
The molecular similarities of DLBCL and FL have provided insight into shared aspects of their pathogenesis and the potential of DLBCL and FL cases to respond to agents targeting alterations they have in common. Conversely, distinguishing lymphomas on the basis of cell-of-origin subtypes or the presence of other molecular features has proven biologically, prognostically, and therapeutically significant. However, the use of distinct treatment regimens for molecularly defined subtypes can become routine practice only if phase 3 clinical trials are designed in a manner that distinguishes the relevant subtypes. Neglecting to characterize predictive biomarkers decreases the efficiency with which treatment resources can be used and puts patients at risk of either not receiving a therapy that would have been effective or suffering side effects from an unnecessary treatment. Moreover, new therapies highly effective against cancers with certain molecular features may not be recognized as such if the relevant molecular data are not collected from clinical trials. Potentially ground-breaking new therapeutics may thus be overlooked.
Although it is logical to expect that an inhibitor of a particular protein will be most effective against lymphomas that are driven by the increased activity of that protein, identifying such cases may not be straightforward. Treatment response can be affected not only by multiple types of lesions affecting a given target but also by alterations affecting other components of the pathways in which that target acts. The best predictors of treatment response, therefore, may not be the presence or absence of a single alteration, but rather signatures integrating multiple factors. Such predictive signatures may be identified by analyzing molecular correlates of treatment outcomes in routinely treated patients and in clinical trials. However, obtaining and organizing such data will require significant forethought, interdisciplinary collaboration, and supportive infrastructure. Moreover, the incorporation of new biomarkers into clinical practice will require pathologists and oncologists to understand the utility and limitations of such tests. Overall, the utility of molecular markers does not end at obtaining a better understanding of cancer biology or at identifying new drug targets; the collection and evaluation of molecular signatures in clinical samples is needed for the continued improvement of patient outcomes.
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Medscape, free login required:
Time for 'Smaller and Smarter' Clinical Trials, Says ASCO http://bit.ly/1otMIHn
In many cases, however, targeted agents are being developed without a complete understanding of the drug's target and without a companion diagnostic tool to help in the selection of appropriate patients, he and his colleagues point out.
To address that issue, the working groups recommend that trial sponsors establish comprehensive biospecimen banks, with informed consent from patients, so that investigators can "ask scientific questions before and after trials are completed" that will facilitate the discovery and validation of biomarkers.
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