Molecular Profiling of Tumors From Cancer Patients Who Are Exceptional Responders

The Exceptional Responders Initiative is a pilot study to investigate the underlying
molecular factors associated with exceptional treatment responses of cancer patients to drug
therapies. The goal is to discover underlying molecular features that can be further
investigated as potential molecular features that are predictive of benefit to a particular
drug or class of drugs. Study researchers will examine molecular profiles of tumors from
patients either enrolled in a clinical trial for an investigational drug(s) and who achieved
an exceptional response relative to other trial participants, or who achieved an exceptional
response to a non-investigational chemotherapy or approved targeted agent that is not
expected. An exceptional response is defined as achievement of either a) a complete
response, or b) a partial response of at least 6 months duration in a trial or treatment
where the overall response rate is < 10%, or a response of exceptionally long duration.

This pilot project will successfully characterize approximately 100 cases of tumor tissue
and, when available, case-matched germline DNA. All samples will undergo whole exome
sequencing, and/or targeted NGS assay deep sequencing. Cases for which sufficient nucleic
acid amounts are available will undergo additional analyses (e.g. whole genome sequencing,
messenger RNA (mRNA)-sequencing, micro (miRNA) sequencing, promoter methylation analysis,
single nucleotide polymorphism (SNP) analysis, etc). Each case will be annotated with
demographic and clinical information, along with follow-up information minimally sufficient
to enable correlations between the molecular profiles and the drug responses. Cases will be
deidentified prior to tissue being sent. All data will be de-identified and placed in a
controlled-access database so other investigators may use them to gain new insights.

Clinically-annotated tissue specimens meeting the acceptance criteria will be provided by
clinical cancer investigators or practitioners who choose to participate in the Exceptional
Responders Initiative. Specimens will be sent to a Biospecimen Core Resource (BCR), which
will perform quality control on the tissues, and will use established standard operating
procedures to isolate nucleic acids. The nucleic acids will be shipped to a sequencing and
characterization center at Baylor to perform designated sequencing and analysis and to
Foundation Medicine Inc when enough tissue is available, for targeted deep sequencing on an
analytically validated cancer panel. These findings, as well as contributed molecular
profiling performed outside this effort (if possible), and correlated to exceptional
responses will be made available to the broader cancer research community via a
controlled-access database.

- INCLUSION CRITERIA:

1. Documented exceptional response. Reports of radiologic scans or other evidence
documenting response will be submitted for review. Cases where response is not
assessable (e.g. adjuvant treatment) will not be eligible because the outcome
can not be attributed to a specific treatment.

2. Treatment history must be available, for prior treatment and for the drug to
which the exceptional response occurred.

3. Patient must meet consent criteria detailed in section VII.2.0. This requires:
(i) current ER consent by a living participant not lost to follow-up, (ii) prior
consent for future research by a participant not known to be deceased, but lost
to follow-up, or (iii) if patient is deceased and did not decline to participate
in research at the time of tissue removal for any tissue that would be used in
this study, then no consent is required.

4. Tumor sample available that meets study requirements.

5. Required tumor samples MUST exist and be able to be submitted. Investigators
wishing to submit samples must not have made agreements that would prohibit the
free use of data from such samples. The NCI will provide investigators with a
letter for the collaborator amending their existing agreement to allow for the
case to be submitted.

5.1 Tumor tissue from prior to administration of the drug to which the
exceptional response occurred is required. Ideally this sample will have been
collected just prior to treatment, but other prior tissue will be considered.
Tissue may be fresh frozen or formalin-fixed paraffin embedded

5.2 Tumor tissue amount must be at least a core biopsy, and meet minimum
specimen requirements as described below in METHODS.

6. Encouraged: Normal tissue sample: (optional): Blood or other specimen source for
germline sequencing.

7. The tumor samples and clinical data submitted to the Exceptional Responders
Database in dbGaP will need to have appropriate agreements in place to allow for
the submission. The Exceptional Responders Database can accept clinical data and
samples from cases enrolled on a CTEP sponsored clinical trial and cases that
were not enrolled on any clinical trial. If the response occurred on a trial
that was not CTEP-sponsored, there are existing agreements between the
submitting site and the pharmaceutical company. If existing agreements do not
allow for the submission of sample and clinical data, the NCI will provide the
investigators with a letter that allows the tissue to be used for the
Exceptional Responders study if signed by the appropriate collaborator. The
letter modifies the existing agreement to include the CTEP IP Option language
that would allow the case to be submitted to the Exceptional Responders
Database. If the existing agreement cannot be modified and the letter cannot be
signed, the proposed case will not be accepted.

EXCLUSION CRITERIA:

Cases or tissue meeting these requirements will not be accepted into this study:

1. Patient's response did not meet criteria for an exceptional response

1.1 Patient's treatment regimen is expected to lead to CR or durable PR in > 10% of
patients.

1.2 Patient s duration of response is not > 3x expected median length of response.

1.3 Response not evaluable or not able to be attributed to systemic treatment
(e.g.adjuvant treatment)

2. Patient refused consent for use of tissue for research activities included in the
Exceptional Responders study.

3. Tumor sample from prior to the exceptional response is not available, or does not
meet quality metrics.