It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) will support a coordinating center for a network of cooperative agreements (see U01 FOA RFA-CA-17-001) that will conduct immunotherapy clinical trials in pet dogs with spontaneous tumors and perform laboratory correlative studies associated with the clinical trials. This FOA will work with the NCI Comparative Oncology Program (COP) of the NCI's Center for Cancer Research as an integral component and will provide statistical support; assist with the development and standardization of clinical protocols and laboratory immune monitoring assays; assist with the implementation of clinical studies in immunotherapy and combination agents including accrual to the trials; manage clinical and correlative data from all U01 sites and their collaborators including immune-related adverse events; facilitate the sharing of agents, specimens, and data; and create an ad hoc steering committee of required expertise--both inside and outside the U01 network, including the PD/PIs of the U01s, representatives of the COP and the NCI Project Collaborators --to ensure that the goals of the network are accomplished. The COP oversees the Comparative Oncology Trials Consortium--a network of 22 veterinary medical colleges that perform canine clinical trials.

Advances in Immunotherapy for Cancer Treatment: The past several years have seen an enormous advance in the use of immunotherapy approaches for cancer treatment in humans. In particular, the use of checkpoint inhibitor antibodies, such as anti-CTLA4 and anti-PD1, which bind to suppressor elements on immune cells and increase the magnitude and extent of effector cell immune responses, has achieved significant responses in patients with certain organ-site malignancies, such as melanoma, renal cell carcinoma, bladder cancer, and non-small cell lung cancer (NSCLC), with durable responses in a significant number of these patients. Initially, it was thought that the expression of PD-L1 on the surface of tumor cells could serve as a biomarker for responsiveness to anti-PD1 therapy, but several studies have shown that the correlations between expression and response are complex; the majority of patients with PD-L1-expressing tumors do not respond to PD-1/PD-L1 pathway blockade, while responses are occasionally seen in PD-L1 non-expressers. It is thought that sensitivity to PD-1 blockade in NSCLC depends primarily on a high non-synonymous mutation load in the tumor (generating neoantigens) and less on the expression of PD-L1 on the tumor surface although that does play some role.

Mutations and Susceptibility to Checkpoint Inhibitors: Certain mutations, such as mismatch repair defects in a subset of colon and other cancers, appear to predict susceptibility to the effects of checkpoint inhibitors, as shown by longer progression-free survival in patients with these mutations. The magnitude of T cell infiltration of tumor is also a factor, but not an independent biomarker. The specificity and affinity of the engagement of T cells with tumor cell neoantigens in the context of the patient’s HLA haplotype are probably important as well. However, the success of immunotherapy approaches has been difficult to predict.

Genetically-engineered/Humanized Animal Models: Animal models have been tremendously important tools in human cancer research. Immunocompetent mouse models, including syngeneic, transgenic, and genetically engineered mouse models (GEMMs), as well as a number of immunodeficient xenograft models, have been employed for decades. GEMMs carry many of the same mutations as do the corresponding human tumors and often develop tumors on a compressed timeline compared with the natural history of the human tumor; but these tumors do not in general replicate the genetic complexity of the human tumor, including its heterogeneity. GEMMs therefore are not optimal for testing the response of drugs and immunotherapeutic agents to be used in humans. Immune deficient models, including patient-derived xenografts (PDXs) carrying human primary tumors, have been used to predict patient response to drugs, but they lack an intact immune system and are therefore inadequate for testing the effect of immunotherapies.

More recently, humanized mouse models have been developed that accept and engraft human tissue, specifically human hematopoietic stem cells, and express human cytokine genes. However, a perfect humanized mouse model appropriate for immunotherapy studies would require specific human MHC class I and II elements to match those of the patients tumors; no such models are currently available.

Use and Advantages of Companion Animals (Pet Dogs) for Immunotherapy: Another approach to both targeted therapy and immunotherapy research is the use of companion animals, such as pet dogs. Canine patients with spontaneous tumors have a number of advantages over mice as therapeutic models. Briefly, the canine genome is similar to that of human; the complexity of canine tumors in terms of heterogeneity, their relationship to the tumor microenvironment, and the development of resistance to treatment are closely related to cancer in human patients; dogs are immunocompetent; dogs are relatively outbred compared with laboratory animals (although some breeds have greater susceptibility to certain forms of cancer); few standards of care and few agents are approved for the treatment of cancer in dogs, and therefore investigational agents can be considered even in early or minimal residual disease states; there is an established track record of responsiveness to known chemotherapeutic agents; for many cancers, dogs and humans share major cytogenomic aberrations in signaling pathways; and spontaneously-occurring cancers in pet dogs have been increasing as a result of increased life expectancy because of a higher standard and wider availability of quality veterinary medical care. It has been shown that canine PD-1 and PD-L1 genes are conserved among dog breeds and that the pathway is associated, as in humans, with T cell exhaustion that can be overcome with PD-1 or PD-L1 blockade.

Although it has not been demonstrated in dogs, it is probable that blockade of the PD-1/PD-L1 pathway will not result in a strong anti-tumor effect unless there is a high tumor mutational load or, in some cases, a few strong mutations that translate into the expression of neoantigens recognizable by the canine immune system. Mutations in human tumors do not necessarily parallel the equivalent mutations in canine tumors. For example, although both human and canine melanomas are similar in their activation of the AKT/mTOR pathway and other pathway dysregulation, B-raf mutations are rare in canine melanoma. Conversely, the frequency of BRAF mutations is higher in canine urothelial carcinoma and prostate cancer compared with human tumors. Identification of the specific somatic mutations in canine cancers and understanding why some mutations become tumor neoantigens important for effective immunotherapy will shed light on parallel mechanisms in human cancer.

The long-term objective of the NCI is to establish the suitability of canine models to study single and combination immunomodulating agents, ideally with molecularly targeted drugs, chemotherapy, or radiation, for the purpose of translating the canine findings to human studies.

For this FOA, the objective is to establish a Coordinating Center for the network of laboratory scientists and canine clinical trialists to study the anti-tumor effects, including mechanisms of action and immune-related adverse events, of immunotherapy agents and novel combinations of immunotherapy and other modalities in canine patients with spontaneous tumors. An essential goal of the network will be to determine whether or not canine cancer is a close model of human malignant disease, and if so, whether immunotherapy alone or in combination with other modalities in canine models will inform the design of therapies in humans.

This FOA is intended to solicit applications that propose to coordinate and govern the network of U01 awardees that will conduct:

(a) one or more clinical trials in canine patients with spontaneous tumors that will be treated with a single agent immune modifier or a combination of immunotherapy and one or more other agents (a second immune modifier, a molecularly targeted agent, chemotherapy, and/or radiation); and,

(b) one or more clinical correlative studies (using biopsy or surgical specimens and controls from the clinical trial) in the laboratory that seek to describe, characterize, and understand the cellular and molecular mechanisms that determine the anti-tumor response (or non-response) in dogs with spontaneous tumors that participate in the clinical trials.

The U24 Coordinating Center should provide research support by:

• Providing logistic infrastructure to support the activities of the Consortium awardees and the Steering Committee;
• Helping coordinate collaborative research efforts that involve multiple Centers;
• Helping to develop/implement the clinical studies in immunotherapy and therapeutic combinations;
• Assisting in the standardization of clinical and laboratory immune monitoring protocols;
• Managing clinical and correlative data from all sites--including immune-related adverse events;
• Working with the NCI to contribute data to a public access database;
• Providing statistical support;
• Facilitating sharing of agents, specimens, and data;
• Reporting progress in an annual report as required by the NCI.

The U24 Coordinating Center will act as the hub for the clinical and laboratory activities of the U01 network. Each U01 will involve both academic scientists who have had experience working with canine models, and veterinary oncologists who are associated with one of the veterinary medical institutions that may be part of the Comparative Oncology Trials Consortium (COTC) which is overseen by the NCI Center for Cancer Research's Comparative Oncology Program (COP). Industry partners may also participate in the U01 award.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Toby T. Hecht, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5683
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Outline the Specific Aims of the proposed Coordinating Center. A timeline of the initiation and completion of the aims may also be included.

Research Strategy: The applicants should provide a detailed description of how they will address:

• Development and implementation of canine immunotherapy and combination clinical trials which involve one or more components of the U01 network;
• Management of clinical and correlative data from all sites;
• Statistical support needed for both clinical and laboratory protocols;
• Facilitation of sharing agents, specimens, and data;
• Creation of an appropriate infrastructure to support the activities of the Consortium Steering Committee;
• Standardization of clinical and laboratory immune monitoring protocols.

Letters of Support: In some applications, applicants will include collaborations with industry partners or other laboratories that will provide assays or canine-specific or other agents for the canine clinical trial or correlative study. Letters of support from these entities will be required.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address both a Data Sharing Plan and a Resource Sharing Plan.

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

A primary objective of this FOA is to establish a Coordinating Center for the network of laboratory scientists and canine clinical trialists to study the anti-tumor effects of immunotherapy agents and novel combinations of immunotherapy and other modalities in canine patients with spontaneous tumors. While the CC will not directly produce scientific data, it is expected that it will facilitate information, data, model, and specimen sharing, administrative management, and additional research services as appropriate.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the proposed Center address the needs of the U01 research network that it will coordinate? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research network?

Specific to this FOA: Does the U24 application sufficiently address the tasks described in the scope of the FOA section under Network Structure?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing canine clinical and correlative study research across institutions? Do the investigators demonstrate significant experience with coordinating collaborative clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills, including statistical expertise; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA: If the applicant is an academic institution, is there a proven track record of working with veterinary medical colleges and industrial partners? If the applicant is a veterinary medical college, is there a proven track record of working with academic centers and industrial partners?

Innovation

Does the application propose novel organizational concepts, management strategies, or instrumentation in coordinating the research network the Center will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts, management strategies or instrumentation proposed?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research network the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the network, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the network is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the network? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

Specific to this FOA: Does the application have an approach to sharing specimens, assay protocols, and data? Does the application describe the means of partnering with the Comparative Oncology Program of the NCI to facilitate and augment the tasks of the U01s in both the canine clinical area and in the laboratory correlative study area? Does the application detail how statistical support will be provided to the network? Is there a plan for the creation of a Steering Committee and what is the vision for the operation of that committee for the network?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research network it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Specific to this FOA: If the U24 applicant is also a U01 applicant, will leading the network enhance the work of the U01 and the U01 network?

Protections for Human Subjects