Exceptional Responders Initiative: Questions and Answers

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1.  What is the purpose of the Exceptional Responders Initiative?

The National Cancer Institute (NCI) has embarked on the Exceptional Responders Initiative (ERI) to understand the molecular underpinnings of exceptional responses to treatment, primarily via chemotherapy, in cancer patients. Exceptional responders are patients who have a unique response to treatments that are not effective for most other patients. For this initiative, exceptional responders will be identified among patients enrolled in early-phase clinical trials in which fewer than 10% of the patients responded to the treatments being studied; patients who were treated with drugs not found to be generally effective for their disease; patients who were treated in later-phase clinical trials of single agents or combinations; and even patients who were treated with established therapies. In this pilot study, malignant tissue (and normal tissue, when possible) and clinical data will be obtained from a group of exceptional responders and analyzed in detail. The goal is to determine whether certain molecular features of the malignant tissue can predict responses to the same or similar drugs. The study also has an optional survey of complementary and alternative medicines, lifestyle changes, and additional medical conditions and their medications that may help to clarify the exceptional response.

2.  What are the eligibility requirements for this study?

Exceptional responders are patients who meet the following criteria:

  • Received a treatment in which fewer than 10% of patients had a complete response or a durable (lasting at least 6 months) partial response based on clinical trial data or extensive historical experience in the context of the patient’s tumor type.
  • Achieved either a complete response (CR) or a partial response (PR) with duration of at least 6 months as defined by RECIST (Response Evaluation Criteria in Solid Tumors) criteria for solid tumors or response criteria as defined where RECIST is not commonly used.
  • Sustained a complete or partial response for at least three times longer than the median duration of response from literature resources for that treatment.

Other requirements include:

  • The patient, if still living, must have given appropriate consent for future research on their tumor tissue. If a patient is deceased, their tissue can be used for genomic analysis, unless a previous consent indicated their tissue could not be used for further research.
  • Available tumor tissue was collected prior to administration of the drug to which the exceptional response occurred. Ideally this would be just prior to treatment, but any prior tissue will be acceptable. The amount of tissue needs to be either a core biopsy or larger; fine needle aspirations will not provide enough tissue for analysis
  • If available, blood or other biospecimens could undergo germline (non-cancerous) genomic sequencing to help clarify if molecular abnormalities seen in tumor are also seen in normal (germline) tissue.
  • Tumor treatment history, other than the drug to which the exceptional response occurred, will be collected if possible.

3.  In order to be eligible, did the patient need to be treated on a clinical trial?

No. The Exceptional Responders study does not require that patients were treated on a clinical trial. If the patient was treated on a clinical trial, the overall percentage of patients who responded to the therapy should be 10% or less of all patients (e.g., less than 10% had a complete response, or less than 10% had a partial response lasting at least 6 months). The study also accepts cases from patients that were treated with any treatment (except local treatments like surgery and radiation therapy), but the case must have a documented response to that treatment that would not be expected to occur in more than 10% of similarly treated patients (i.e., the same disease symptoms and the same drug). Because a response needs to be documented, adjuvant treatments are generally not applicable.

4.  Was an initial feasibility study conducted?

As a proof of principle, experts in NCI’s Cancer Therapy Evaluation Program (CTEP) searched a phase 2 trial database over a period of 10 years (2002–2012) for cases that experienced exceptional responses. About 100 cases were identified to demonstrate that the types of cases needed for the ERI did exist, and in sufficient numbers to establish this initiative.

Investigators believe that obtaining successful exome-sequencing results and deep targeted sequencing and mRNA sequencing, if possible, from about 100 cases will provide sufficient information about the likelihood of finding promising discoveries. The exome regions of the genome are the protein-coding regions. The sample size was based on 95% confidence intervals (i.e., the estimate is 95% reliable) for various measures of feasibility and success. The investigators have also allowed enough flexibility to add additional cases through other means as appropriate.. The results are not expected to meet rigorous statistical standards but to indicate whether this line of investigation has promise.

5.  What are the criteria for the study, including determining the minimum and maximum number of cases that will be examined in the ERI?

This is an exploratory study. The investigators may examine up to 300 cases to see if they would be able to acquire useable data on 100 cases. At this point, feasibility seems assured. Some attrition is expected. The path going from exceptional responder case identification to usable genomic sequencing data requires several steps:

  • Identify cases and confirm they meet the exceptional responder definition
  • Determine whether appropriate informed consent to use the specimens is already in place or can be obtained
  • Determine whether archived tumor tissue can be located
  • Determine whether the tumor tissue is of sufficient quality and quantity to use in genomic tests
  • Determine if interpretable sequencing data can be obtained

If there is interpretable genomic sequencing data, researchers will determine if the results yield any interesting biological clues. Thus, all of these steps could cause a substantial reduction in the “useable” sample size.

6.  How will molecular testing be performed?

DNA and RNA will be isolated from tissues submitted to the ERI and will undergo whole-exome sequencing and/or mRNA sequencing. Whole-exome sequencing is used to analyze the exons of thousands of genes simultaneously using advanced sequencing techniques. The exome comprises only 1% of the human genome, yet it houses as many as 85% of disease-related mutations. As a research tool, exome sequencing is a powerful way to investigate common and rare genetic variations that play a role in complex human diseases.

Cases with sufficient nucleic acids will undergo additional analyses (e.g., deep targeted sequencing, microRNA sequencing, promoter methylation analysis, single-nucleotide polymorphism genotyping and/or whole genome sequencing). Each case will be annotated with demographic and clinical information, along with sufficient follow-up information, to correlate molecular profiles with response. Both retrospective and prospective specimen collections will be considered.

7.  Was there a particular case that prompted this initiative?

Yes. In the case that sparked this initiative, mutations in genes called TSC1 and NF2, which result in a loss of function (the genes are defective and don’t produce an active protein product), were detected in a patient with a form of bladder cancer. This person had a complete response that lasted more than two years in a clinical trial of everolimus, an agent targeting a molecular pathway that is regulated by the TSC1 and NF2 genes. Separately, investigators sequenced tumors from 96 other individuals with high-grade bladder cancer, and found five additional TSC1 gene mutations. They then sequenced tumors from 13 patients with bladder cancer who had received everolimus, and found that three of four patients with TSC1 gene mutations had some tumor shrinkage in response to receiving everolimus, whereas eight of nine patients whose tumor progressed did not have such a mutation (Ref: Iyer, et al. Genome Sequencing Identifies a Basis for Everolimus Sensitivity. Science. Oct 12, 2012. Vol. 338, No. 6104, pg. 221). This example demonstrates how exceptional responders could help identify novel or known molecular abnormalities that are likely to be predictive of response to agents with targets in a relevant biological pathway.

In subsequent workshops and discussions, it was obvious that all clinicians have seen a few exceptional responders.

8.  How can researchers and physicians submit cases for review or consideration?

The ERI protocol has been reviewed and approved by the NCI Adult Central Institutional Review Board (CIRB) – Early Phase Emphasis and is  accessible on the Clinical Trials Support Unit (CTSU) public website (www.ctsu.org). Institutions that are participating in the NCI Adult CIRB will be able to accept CIRB approval for this study.

Investigators who have tissue from a potential exceptional responder should send an email to NCIExceptionalResponders@mail.nih.gov. The email should include a short description of the case, the response observed and its duration, as well as the treatment associated with the exceptional response. This should be sent without patient identifiers. Also needed are: information about whether tissue collected before the exceptional response is available; whether informed consent was given to use tissue for research; and the patient’s vital status.

An NCI panel will review the information submitted within a month . If the case is provisionally accepted, the investigator will be asked to obtain IRB approval (either local IRB or accept the NCI CIRB approval), execute a material transfer agreement (MTA) with the Biospecimen Core Resource facility, provide clinical data, submit the tumor tissue (and non-tumor tissue, if available), and execute a contract to receive reimbursement. The investigator will also be asked to submit patient and clinical data to Medidata Rave, a Web-based clinical data management system used for capturing, managing, and reporting clinical research data. This system will allow investigators to record patient information (visit, lab, and adverse event data) using forms that are customized for the study. The proposer of the exceptional responder case is invited to be part of the Analysis Working Group for that case.

It is understood that “ideal” tissue may not be available, so the initiative will accept specimens as small as a core biopsy. Snap (quickly) frozen tumor is best for genomic studies. If only formalin-fixed, paraffin-embedded tissue is available, providing it in block-form is preferred. Tissue of any age is acceptable. Unfortunately, fine-needle aspirations will not be eligible, because they do not provide enough tissue for analysis. 

Specimens cannot be accepted directly from patients. Patients who believe they may be exceptional responders should contact their physicians or clinical trialists to see if they can assist in submitting tissue for consideration.

9.  When will the molecular characterization data be available?

Processing of the tissues to obtain nucleic acids will take place at the Biospecimen Core Resource facility and is expected to take approximately 30 days. Whole-exome sequence characterization at the Genome Sequencing and Characterization Center is expected to take 120 days. Thirty days after the relevant information is deposited in the data center, it will be made available through a controlled access mechanism. Controlled access will be provided via the database for Genotypes and Phenotypes (dbGaP). Investigators will be able to apply for access by submitting a Data Access Request to the Exceptional Responders Data Access Committee through the dbGAP. More information on this process is available at http://www.ncbi.nlm.nih.gov/gap.

10.  Where can I obtain more details about this initiative?

The trial number is NCT02243592. More information is available in the protocol summary.

  • Updated: May 17, 2017

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