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Advanced breast, non-small cell lung, colorectal, genitourinary, pancreatobiliary gastrointestinal, upper aerodigestive tract, gynecological, melanoma, unknown primary, and rare carcinomas; as well as patients who are phase I trial candidates

Philippe Bedard, MD

Substantial progress has been made in the treatment of cancer through the use of targeted therapies, but what works for one patient might not work for another patient. Certain drugs are now being developed that target specific molecules in the body that are believed to be part of the disease.

Biomarkers are specific characteristics of the cancer that may help provide prognostic information (i.e. how well patients will be regardless of the treatments given) or help predict sensitivity or resistance to a specific treatment.

The study will collect archival tumor samples (previously collected biopsy or surgical tumor samples) to provide biomarker data about a patient's cancer, in order to help their physicians to identify which clinical trials of molecularly targeted therapies may be most appropriate for the patient in the future.

The increasing appreciation and identification of specific somatic mutations and other genetic aberrations that drive cancers leave us on the threshold of a new era of "personalized cancer medicine", in which specific biomarkers will be used to direct targeted agents only to those patients deemed most likely to respond. The potential medical, scientific and economic benefits of such a personalized approach to cancer therapy are immense and self-evident. Yet despite some important advances, only a limited number of approved targeted agents have had their approvals predicated on specific biomarkers of sensitivity or resistance.

The premises behind personalized cancer medicine include: i) genetic aberrations exist in human malignancies; ii) a subset of these aberrations, often present across multiple cancer types, have functional relevance as "hallmarks" or "drivers" for oncogenesis and tumor progression; iii) such genetic aberrations are potentially "druggable" targets; and iv) there are tolerable medicinal compounds that can effectively modulate such targets. A key requirement of this new, personalized approach to anti-cancer therapy is that specific patients must be matched to a particular drug or combination of drugs. Molecular profiling of tumors to identify somatic mutations and/or other genetic aberrations are examples of enrichment strategies to assist in matching patients to drugs or treatments that have gained increasing interest in the oncology community.

The present protocol seeks to provide molecular profiling data to the treating physician for patients with advanced breast, non-small cell lung, colorectal, genitourinary, pancreatobiliary gastrointestinal, upper aerodigestive tract, gynecological, melanoma, unknown primary, and rare carcinomas, as well as patients who are phase I trial candidates, in order to help identify which standard regimens or clinical trials of molecularly targeted therapies may be most appropriate for the individual patient.

Archival tumor tissue

1 tube of whole blood

Integrated Molecular Profiling in Advanced Cancers Trial

Genotyping assays including: AKT1, HRAS, AKT2, JAK2, AKT3, KIT, BRAF, KRAS, CDK, MEK1, CTNNB1, MET, EGFR, NOTCH1, ERBB2, NRAS, FGFR1, PDGFRA, FGFR2, PIK3CA, FGFR3, RET, FGFR4, SMO, STK11

Including utilization of information for standard regimens or clinical trials of molecularly targeted therapies.

Princess Margaret Hospital, Canada

University Health Network, Toronto

Head and Neck Neoplasms

Patients with advanced, incurable solid tumors receiving standard palliative treatment(s) will have archival tumor specimens requested and used for targeted next generation sequencing (NGS) testing. Blood samples and additional archival tumor specimens will be collected for banking and future research purposes.

Samanta Del Rossi

Han (Jenny) Zhang

Kendra Christink

John Hilton, MD

Lillian Siu, MD

Substantial progress has been made in the treatment of cancer through the use of targeted therapies, but what works for one patient might not work for another patient. Certain drugs are now being developed that target specific molecules in the body that are believed to be part of the disease.

Biomarkers are specific characteristics of the cancer that may help provide prognostic information (e.g. how well patients will be regardless of the treatments given) or help predict sensitivity or resistance to a specific treatment.

The study will collect archival tumor samples (previously collected biopsy or surgical tumor samples) to provide biomarker data about a patient's cancer, which may help their physicians to identify which clinical trials of new drug treatments may be most appropriate for the patient in the future and may also guide the use of approved treatments that may potentially benefit the patient.

Another goal of this study is to develop a province-wide registry of targeted gene sequencing testing results that will be made available to cancer researchers. Additional tumour tissue and blood samples collected from all study participants will also be stored in a biobank at the Ontario Institute for Cancer Research for future research.

The study will also look at linking data from this study to other health care databases to further collect information about the health care the patients received, including medical tests, clinic visits, or procedures both before and after participating in this study. Having more information about patient health to relate to the DNA sequences may provide new insights into cancer and its treatment.

A recent survey of clinical genetic testing laboratories for cancer diagnostics by the Molecular Oncology Advisory Committee for Cancer Care Ontario identified disparities in access and use patterns for next generation sequencing (NGS) across the province of Ontario. All fourteen responding laboratories indicated that NGS instruments were either currently being used for clinical testing, were in the validation stage, or that they were planning to purchase NGS instruments within the near future. Respondents were uncertain about what tests should be performed, how costing and reimbursement would be addressed by the provincial funding agency (e.g. individual tests vs. panels), and how to deal with informatics issues from NGS testing, such as storage, variant interpretation, and utilization over the long term.

Given the increasing use of multi-gene somatic mutation testing in routine clinical cancer care (e.g. KRAS, NRAS, BRAF mutations in colorectal cancer, EGFR mutation and ALK translocation in non-small cell lung cancer, and BRAF, NRAS, and cKIT mutations in malignant melanoma), there is a need to expand the infrastructure for NGS panel testing in clinical laboratories. With a single payer provincial health care system, there is also an opportunity to develop a provincial-wide registry of NGS panel-based testing results and repository of genomically-characterized and clinically-annotated tumor tissues and blood samples to accelerate the development of additional "omic"-based tests for clinical use.

This study will enroll patients with advanced, incurable solid tumors at selected Ontario hospitals receiving standard palliative treatment(s). Archival formalin-fixed paraffin embedded (FFPE) tumor tissue will be requested and undergo targeted panel sequencing. An additional FFPE tissue sample will be requested at the same time for future research purposes. Patients will also be asked to provide blood samples for future research. A selected number of genes will be annotated in a research report provided to their treating oncologist. In addition to the clinically reported variants, targeted NGS testing results for all tested genes will be captured in a clinical research database that can be accessed by the treating oncologist in a secure web-based portal.

Following the reporting of targeted DNA sequencing results into the web-portal, remaining tumor DNA will be stored in the clinical testing laboratories. Blood samples collected at the time of consent and additional FFPE research blocks or slides collected for research will be transferred to a centralized biorepository maintained by the Ontario Tumour Bank (OTB) for more comprehensive analysis at the Princess Margaret (PM)-Ontario Institute for Cancer Research (OICR) Translational Genomics Laboratory (TGL). Blood will undergo standard germline DNA extraction and plasma processing for future circulating tumor DNA (ctDNA) and RNA (ctRNA) isolation at the PM-OICR TGL. Selected patient samples will be further characterized at the PM-OICR TGL for test development, additional sequencing, or discovery research.

All patients will be asked to provide permission for data-sharing with other cancer researchers. The consent will also include a provision for review of patient health records through review of patient charts or administrative databases (i.e. Cancer Care Ontario New Drug Funding Program, Provincial Cancer Registry, etc.) to obtain addition information about time on drug treatments and survival.

Archival tumor tissue 2 tubes of whole blood

Ontario-wide Cancer TArgeted Nucleic Acid Evaluation

Targeted gene sequencing results, along with limited clinical information that does not identify the patient as an individual, such as age, partial date of birth (year, month), gender, cancer type, and pathology information related to the samples tested, and survival time will be sent to centralized scientific databases or shared with collaborating researchers.

Data from this study can be shared through two types of databases: open-access or controlled-access. An open-access database is publicly accessible and contains limited clinical information and analyses of samples. A controlled-access database contains more detailed clinical information, such as relevant past medical history and the results of prior and ongoing cancer treatments, and analyses of samples, but is only accessible to researchers who sign agreements defining how data may be used. All data will be stripped of all personal identifying information.

Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Immunomodulating Agents

Patients with a histological or cytological diagnosis of advanced solid tumors who are currently on immune checkpoint inhibitors will have archival tumor specimens requested and used for whole exome sequencing (WES) of tumor DNA. 3 tubes of blood at a single time point will be collected for ctDNA analysis and germ line DNA analysis (to study normal variants) using next generation sequencing.

Patients with a histological or cytological diagnosis of advanced solid tumors who are candidates for a phase I, II, or III clinical trial testing immune checkpoint inhibitors (ICIs) or planning to have treatment with ICIs or other immunological therapy as standard of care will have image-guided fresh tumor core needle biopsy at a maximum of 3 time points: 1) prior to commencement of immune checkpoint inhibitors, 2) when disease response to therapy is confirmed using radiology RECIST 1.1 criteria and/or immune related response criteria, and 3) when radiological disease progression is confirmed by using RECIST 1.1. Blood samples for ctDNA analysis will be collected at the commencement of immunotherapy and every 6-12 weeks thereafter until radiological disease progression is confirmed.

Two part prospective study to:

1. investigate the feasibility of performing ultra-deep sequencing of plasma derived circulating tumor DNA (ctDNA) in individual patients with advanced solid tumors who are currently being treated with immune checkpoint inhibitors (ICIs) and
2. obtain fresh tumor biopsies and serial blood samples to investigate the clonal evolution of tumors under the selection pressure of ICIs.

This feasibility study will be conducted in two parts.

The first part is mainly designed to investigate the feasibility of performing ultra-deep sequencing of plasma derived circulating tumor DNA (ctDNA) in individual patients with advanced solid tumors who are currently being treated with immune checkpoint inhibitors (ICIs). Patients' archival tumors will be requested and used for whole exome sequencing (WES) of tumor DNA. Blood samples at a single time point will be collected for ctDNA analysis and germ line DNA analysis (to study normal variants) using next generation sequencing.

The second part is designed as a prospective research study in which patients will have tumor and blood samples collected at serial time points to investigate the clonal evolution of tumors under the selection pressure of ICIs. Patients will have image-guided fresh tumor core needle biopsy at a maximum of 3 time points:

1. prior to commencement of ICIs, and
2. when disease response to therapy is confirmed by standard radiology RECIST 1.1 criteria and/or immune related response criteria, and
3. when radiological disease progression on therapy is confirmed by RECIST 1.1 criteria.

Patients who have disease response to immunotherapy could have up to 3 fresh tumor biopsies (all 3 time points) when those who do not respond to therapy will only have one biopsy (1st time point). For patients who will have a mandatory on treatment biopsy as part of a separate clinical trial (within which they are receiving ICIs) at time points different from this study, investigators will request one extra core tumor material for research use within SPECIAL if it is feasible and safe judged by a staff radiologist. Blood samples for ctDNA analysis will be collected at commencement of treatment and every 6-12 weeks thereafter ideally coinciding with radiological tumor assessments whenever possible until radiological disease progression is confirmed using RECIST 1.1 criteria. Normal genomic DNA derived from peripheral mononuclear cells (PBMC) will be extracted from one tube of whole blood collected at baseline to study normal variants. Blood samples for studying changes in immune cells repertoire and immune related amino acids, peptides, proteins and their metabolites in peripheral circulation will be collected at baseline, 6-12 weeks after starting treatment coinciding with the 1st radiological tumor assessment and at the time of radiological disease progression. Imaging parameters for radiomic imaging analysis will be derived from patients' routine CT scans. Fresh tumor biopsies will be used for genomic profiling to study the tumors' mutation spectrum by WES and level of gene expressions. PBMC DNA will be analysed by WES to study normal variants. Mutation profiling of ctDNA will be performed using next generation DNA sequencing approaches.

Genomic data derived from tumor, ctDNA and PBMC DNA analyses will be used to explore tumor clonal architecture and study clonal selection or tumor evolution under selection pressure induced by ICIs or other immunological therapies.

Changes in radiomic imaging signatures during treatment with immune checkpoint inhibitors and their correlation with genomic signatures will also be examined.

Using blood samples collected at baseline, at the time of 1st radiological tumor assessment and at the time of disease progression, dynamic changes in immune cells repertoire and immune related amino acids, peptides, proteins and their metabolites in the peripheral circulation of patients during treatment with ICIs will also be explored.

Part 1: Archival tumor tissue, 3 tubes of whole blood Part 2: Fresh tumor tissue, 5 tubes of whole blood at baseline, serial tubes of whole blood

Selection Pressure and Evolution Induced by Immune Checkpoint Inhibitors and Other Immunologic Therapies

Study title	NCT ID	Conditions	Eligibility	Organization
Integrated Molecular Profiling in Advanced Cancers Trial	NCT01505400	Breast Cancer Non-small Cell ... Colorectal Canc... Genitourinary C... Pancreatobiliar... Upper Aerodiges... Gynecological C... Melanoma Cancer... Rare Cancers Unknown Primary...	18 Years -	University Health Network, Toronto
Ontario-wide Cancer TArgeted Nucleic Acid Evaluation	NCT02906943	Breast Cancer Lung Cancer Colorectal Canc... Melanoma Gynecological C... Genitourinary C... Pancreatobiliar... Gastrointestina... Head and Neck C... Rare Cancer Unknown Primary...	18 Years -	University Health Network, Toronto
Ontario-wide Cancer TArgeted Nucleic Acid Evaluation	NCT02906943	Breast Cancer Lung Cancer Colorectal Canc... Melanoma Gynecological C... Genitourinary C... Pancreatobiliar... Gastrointestina... Head and Neck C... Rare Cancer Unknown Primary...	18 Years -	University Health Network, Toronto
Selection Pressure and Evolution Induced by Immune Checkpoint Inhibitors and Other Immunologic Therapies	NCT02724488	Head and Neck C... Melanoma	18 Years -	University Health Network, Toronto

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