Molecular Profiling in Tissue Samples From Patients With Cancer Who Are Exceptional Responders to Treatment

PRIMARY OBJECTIVES:

I. To identify molecular indicators in malignant tissues from patients who were exceptional
responders on clinical trials or standard systemic treatments using whole exome and/or
targeted deep sequencing, as well as potentially other sequencing and other molecular
characterization methods (if adequate tissue exists).

II. To explore associations between the identified molecular indicators and the putative
mechanism of action of the treatment received by the patient.

III. To test the feasibility of identifying "exceptional responders", obtaining the relevant
tumor and normal tissue and clinical data, and performing whole exome and/or targeted deep
sequencing on these samples.

OUTLINE:

Previously collected tissue samples are analyzed via whole exome sequencing and/or targeted
next generation sequencing (NGS) assay deep sequencing. Cases for which sufficient nucleic
acid amounts are available will undergo additional analyses including whole genome
sequencing, messenger ribonucleic acid (RNA) (mRNA)-sequencing, micro (miRNA) sequencing,
promoter methylation analysis, and single nucleotide polymorphism (SNP) analysis.

Inclusion Criteria:

- Documented exceptional response, defined as patients meeting the following criteria:

- Complete response to a regimen in which complete response is expected in < 10% of
similarly treated patients

- Partial response (PR) > 6 months in a regimen in which PRs > 6 months are
expected in < 10% of patients with similar disease treated with same or similar
regimen

- Complete response (CR) or PR of unusual duration, such that the internal review
committee considers it to be an exceptional response; examples below:

- PR of duration > 3 x the median expected PR duration (in cases where PR is
expected in > 10% of patients with the same disease treated with the same
regimen)

- CR or duration > 3 x the median expected CR duration (in cases where CR may
be seen in > 10% of patients with same disease treated with same regimen)

- The observed duration of CR (or PR) is longer than expected for 90% of
patients with same disease treated with same regimen

- Note: it is not required that the patient be enrolled on a clinical trial when
the exceptional response was observed

- 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

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

- Patient must meet consent criteria; this requires: (i) current exceptional responder
(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

- Tumor sample available that meets study requirements

- 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 National Cancer Institute (NCI) will provide investigators
with a letter for the collaborator amending their existing agreement to allow for the
case to be submitted

- 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

- Tumor tissue amount must be at least a core biopsy, and meet minimum specimen
requirements

- Encouraged: normal tissue sample: (optional): blood or other specimen source for
germline sequencing

- The tumor samples and clinical data submitted to the Exceptional Responders Database
in database in Genotypes and Phenotypes (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 Cancer Therapy
Evaluation Program (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
Intellectual Property (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; Note: as
stated above, the patient does not need to have been enrolled on a clinical trial to
be eligible for the exceptional responders study

Exclusion Criteria:

- Patient's response did not meet criteria for an exceptional response

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

- Patient?s duration of response is not > 3 x expected median length of response

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

- Patient refused consent for use of tissue for research activities included in the
exceptional responders study

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