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 canine clinical studies using immunotherapeutic agents and novel drug combinations (such as immune modulators, molecular targeted agents, chemotherapy, and/or radiation) together with laboratory correlative studies 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. The FOA will support a network of laboratories and canine clinical trial sites. The expectation for this program is that therapeutic agents, specimens, and laboratory and clinical protocols will be shared in order to standardize and validate data generated. A companion funding opportunity (see U24 funding opportunity RFA-CA-17-002) will support a coordinating center that will aid in the development, standardization, and conduct of the clinical and laboratory studies, as well as data management and statistical support across the funded U01 sites.

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.

An important 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.

The NCI's interest includes studies in canine B-cell lymphoma, osteosarcoma, melanoma, glioma, mammary cancer, and bladder cancer, but other canine cancers for which (1) sufficient accrual is assured, and (2) where preliminary data exists indicating that an immunotherapy approach will be successful, are acceptable for these studies.

For this FOA, the objective is to establish a 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 these studies 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:

• (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.

Studies may be based upon published or preliminary canine tumor sequence/neoantigen discovery data that might predict responsiveness to checkpoint inhibitors (of various types) and other immune modulators that have been shown to produce an anti-tumor response or to reduce or reverse the immunosuppressive tumor microenvironment.

Studies that use neoantigen data to combine specific antigenic vaccines with other agents in canine clinical studies and applications that create and test engineered T-lymphocytes in adoptive cell therapy studies in dogs are also responsive to this initiative. Agents used for proposed studies may be obtained from collaborating pharmaceutical companies that are developing and producing canine-specific immunotherapeutic agents, or from the investigator's own laboratory where agents such as antibodies, small molecules with immunomodulating effects, miRNAs, T cell therapies, and vaccines, are being developed. In all applications, attention should be paid to dosing, scheduling, and the character of immune-related adverse events in the overall effect of agents and combinations used in the clinical trials.

Studies that, in addition to a clinical trial, use specimens to compare the immunological response of subtypes of a particular canine cancer with similar subtypes of human cancer are also appropriate.

Applications should 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 are part of the Comparative Oncology Trials Consortium (COTC) which is overseen by the NCI Center for Cancer Research's Comparative Oncology Program (COP). However, participation of a COTC site is not mandatory, if a strong justification for involvement of a non-COTC site is provided. In addition, the application may also include industry partners that will provide materials, agents, and assays for the studies.

Once funded, a U01 awardee will be required (through a companion U24 Coordinating Center funding opportunity, RFA-CA-17-002, that includes NCI staff) to collaborate with other funded U01 holders in order to increase accrual, standardize clinical and laboratory protocols, and to share reagents and specimens as appropriate.

The trans-network activities of the awarded U01s will be coordinated and governed through the companion U24 Coordinating Center (see the companion RFA-CA-17-002) that will serve as a hub for the network. The network will be governed by a Steering Committee (for details see Section VI.2. Cooperative Agreement Terms and Conditions of Award. All U01 awardees must be willing to serve on the Steering Committee, which will communicate to the network and the NCI through periodic conference calls and, if necessary, through in person meetings.

• Applications that do not include a canine clinical trial and rely only on previously banked canine specimens.
• Applications that do not propose to conduct correlative studies associated with a canine clinical trial.
• Applications that are not willing or able to collaborate with other U01 holders or the U24 companion funding opportunity awardee.

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).

Applicants for U01 awards may also apply for the U24 Coordinating Center award (RFA-CA-17-002).

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: 240-273-5683
Email: hechtt@mail.nih.gov

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 project. A timeline of the initiation and completion of the aims may also be included.

Research Strategy: Describe in detail the proposed Research Project that includes (1) one or more canine clinical trials with spontaneous tumors 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 (2) one or more clinical correlative laboratory studies (using biopsy or surgical specimens from the clinical trial) 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. With respect to responders, correlations with the immunological mutational load (neoantigens) or specific mutations (e.g., mismatch repair and other mutations) would be valuable, as would evidence that combination modalities increase the immunological mutational load and make the subject more susceptible to immunotherapy.

The significance, including the scientific premise, of the proposed study as it relates to this funding opportunity announcement must be described. This should include (1) a description of earlier studies (published or not) that have led to the proposed clinical trial and (2) information or data from preliminary studies that addresses the feasibility of the project. The innovative aspects of the planned studies should be described, as well.

The approach proposed, including the canine clinical protocol(s) and the associated laboratory studies must be sufficiently and carefully detailed with rigor and transparency aspects addressed for:

• The experimental design and methods and how they will achieve robust and unbiased results;
• Relevant biological variables such as sex, age, weight, and underlying conditions of canine subject studied; and

Describe how the hypothesis and potential results of the proposed studies--both clinical and laboratory--address the long term goal of establishing the suitability of canine models to study immunotherapy agents and novel combinations of immunotherapy and other modalities; and establishing whether canine cancer research will inform the design of human cancer studies, particularly with respect to immunotherapy.

In applications that include multiple institutions (particularly in separate geographical areas), descriptions of the logistics involved in carrying out the proposed aims to completion within the project period (how tasks that require various and sequential expertise, and how information sharing will be coordinated) must be included.

It is important, as well, for this application to discuss how this U01 will make use of the Coordinating Center (U24) including the NCI element (the Comparative Oncology Program) in its role of facilitating the clinical studies including accrual, standardizing the clinical and assay protocols, sharing specimens, assays, and data as appropriate, and contributing to an ad hoc steering committee of expertise required of this network.

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. The appendix may include detailed protocols for canine clinical trials.

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 components of participating organizations, 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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: Will the research proposed in canines inform the design of human cancer studies, especially with respect to immunotherapy? Is the canine model suitable for studying immunotherapy approaches with single agents or combination agents or strategies?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Have the investigators from academic laboratories and those from veterinary medical colleges worked together in the past and established a track record of publishing studies together?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA: Are the innovations applied to canines with spontaneous tumors translatable to human cancer research?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Specific to this FOA: Will the scientific environment be suitable for forming a collaborative network and will the awardee share agents, specimens and protocols during the project period as appropriate and consistent with achieving the goals of the program?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Establishing a collaboration with a veterinary medical college and conducting one or more canine clinical immunotherapy trials (if the PD(s)/PI(s) are from an academic institution) or with an academic institution to conduct correlative studies associated with the canine clinical trials (if the PD(s)/PI(s) are from a veterinary medical college);
• Obtaining agents for study. In some cases, that will require purchasing the agent, collaborating with a pharmaceutical company that manufactures canine-specific immunomodulating agents or creating agents in the laboratory. Occasionally agents may be obtained from the NCI
• Working with the Coordinating Center (U24) to form a network with other U01 awardees to increase clinical accrual, and share data, specimens, and agents;
• Serving as a voting member on the Consortium Steering Committee;
• Adhering to the Steering Committee recommendations and policies (to the extent consistent with applicable grants regulation) to ensure that the goals of the network are accomplished; and
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The designated NCI Program staff members will have substantial involvement as Project Scientists in the awards under this FOA.

NCI Project Scientists will participate in the following activities:

• Assisting in avoiding unwarranted duplications of effort across the Network;
• Helping coordinate collaborative research efforts that involve multiple Centers;
• Monitoring the operations of the Centers and making recommendations on overall project directions;
• Reviewing the progress of individual Centers and specific activities shared among the Centers;
• Participating in the development and evaluation of trans-Network activities;
• Assisting the Network awardees as a liaison in stimulating their broader interactions with other NCI and NIH programs to disseminate results and outcomes and effectively leverage existing NIH/NCI resources and infrastructures (e.g., databases)

In addition, the members of the Comparative Oncology Program (COP) of the NCI Center for Cancer Research will have substantial roles as Project Collaborators.

NCI COP Project Collaborators will:

• Participate in the final design of collaborative canine clinical trials within the network;
• Assist in establishing Standard Operating Procedure for laboratory protocols and assays;
• Assist in ensuring sufficient accrual of canine subjects for study; and
• Assist in the distribution of reagents and specimens.

In addition, the NCI Program Director, acting as Program Official, will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NCI Program Official and Project Scientist may be the same person.

Areas of Joint Responsibilities

Steering Committee: A Steering Committee will serve as the governing body for the Consortium.

The Steering Committee will be composed of the following voting members:

• One representative from each U01 project award (a PD/PI or a designated senior investigator) who will have one vote;
• One representative from the U24 (a PD/PI or a designated senior investigator) who will have one vote; and
• NCI Project Scientists who will have one total vote.

The NCI COP Project Collaborators will act in an advisory capacity and participate in Steering Committee meetings as non-voting members.

The Chair of the Steering Committee will be selected from the representatives of all awardees.

The Steering Committee will meet periodically via online or phone conferences or in person, if necessary.

Primary responsibilities of the Steering Committee include, but are not limited to, the following activities:

• Establishing Consortium policies and procedures;
• Establishing policies and procedures for collaborative projects, and protocols;
• Developing guidelines for the collection and distribution of specimen reference sets for collaborative research; and
• Oversight of U01 awardees in multi-institutional trials and correlative studies with other U01 awardees coordinated by a U24 Coordinating Center.
• Serving as a hub for a broader outreach to the entire extramural research community investigating canine immunotherapy

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-710-0267

Toby T. Hecht, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5683
Email: hechtt@mail.nih.gov

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email:ncirefof@dea.nci.nih.gov

NCI Office of Grants Administration
National Cancer Institute (NCI)
Telephone: 240-276-6300
Email: Crystal.wolfrey@nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.