Full Text CA-93-10

SMALL GRANTS FOR CLINICAL TRIALS IN AIDS MALIGNANCIES

NIH GUIDE, Volume 22, Number 1, January 8, 1993

RFA:  CA-93-10

P.T. 34

Keywords: 
  AIDS 
  Cancer/Carcinogenesis 
  Clinical Trial 


National Cancer Institute

Letter of Intent Receipt Date:  February 1, 1993
Application Receipt Date:  April 23, 1993

PURPOSE

The Cancer Therapy Evaluation Program of the Division of Cancer
Treatment at the National Cancer Institute (NCI) invites small grant
applications for innovative therapeutic studies in Acquired
Immunodeficiency Syndrome (AIDS) malignancies.  The studies should be
restricted to pilot or phase I or II trials with approximately 5 to
30 patients/trial.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Small Grants for Clinical Trials in AIDS
Malignancies, is related to the priority area of cancer and AIDS.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202/783-3238).

ELIGIBILITY REQUIREMENTS

Domestic for-profit and non-profit organizations, governments and
their agencies are eligible to apply.  Foreign institutions are not
eligible to apply.  Applications can be from single institutions or
multiple institutions (collaborating institutions, consortia,
cooperative groups).  New and experienced investigators are
encouraged to apply.  Applications from minority individuals and
women are encouraged.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) small grants mechanism (R03).  The small grants research
program provides limited funds (maximum of $48,000 direct costs per
year) for short-term (up to two years) research projects.  The R03
grants are non-renewable.  Future competing renewals (type 2s) must
be prepared and submitted as traditional research grant applications
(R01s) to be considered along with other non-solicited investigator
initiated applications reviewed by the Division of Research Grant
(DRG) study sections.  Responsibility for the planning, direction,
and execution of the proposed research will be solely that of the
applicant.  Awards will be administered under PHS grants policy as
stated in the Public Health Service Grants Policy Statement, DHHS
Publication No. (OASH) 90-50,000, revised October 1, 1990.

This RFA is a one-time solicitation for FY 93.  Applications received
after the deadline receipt date will be returned.

FUNDS AVAILABLE

Approximately $750,000 in total costs per year for two years will be
committed to fund applications submitted in response to this RFA.
This funding level is dependent on the receipt of a sufficient number
of applications of high scientific merit.  The direct cost for each
R03 is limited to $48,000 per year.  Thus it is anticipated that ten
awards will be made in FY 93.  The total project period for
applications submitted in response to the RFA may not exceed two
years.  The earliest feasible start date for the initial awards will
be September 30, 1993.  Although this program is provided for in the
financial plans of the NCI, the award of R03 grants pursuant to this
RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

Congenital and acquired states of immunodeficiency increase the
incidence of high-grade B cell non-Hodgkin's lymphoma (NHL), Kaposi's
sarcoma, and certain types of epithelial malignancies. Individuals
infected with human immunodeficiency virus (HIV) have a marked
increase in the appearance of intermediate and high-grade B cell NHL
and Kaposi's sarcoma, and show trends for an increased incidence for
Hodgkin's disease, anogenital dysplasia and cancer, and basal cell
carcinoma, compared to age-matched controls.  On October 22, 1992,
the Center for Disease Control proposed the addition of invasive
cervical cancer in HIV-infected individuals to the AIDS Surveillance
case definition.

The tumors in HIV-infected individuals are generally aggressive and
insufficiently sensitive to conventional therapy.  The median
survival of HIV-associated NHL is less than one year and is only two
months for primary central nervous system lymphoma.  Clinical
observations suggest that Hodgkin's disease, anogenital dysplasia and
cancer, and basal cell carcinoma, have a different natural history
and therapeutic outcome compared to the disease in the general
population.  The dramatic growth rate of the tumors, combined with
the problems of myelosuppression and opportunistic infections, have
made treatment extremely difficult.  As children and adults with
HIV-infection are surviving longer due to improved retroviral and
opportunistic infection treatment, the incidence of the malignancies
are expected to rise.

Research into the pathogenesis of these tumors in the context of HIV
has shed light on potential interactions of cytokines, HIV, other
viral co-factors (i.e., human papilloma virus in squamous cell cancer
of the anogenital region, and EBV in the high-grade primary central
nervous system lymphomas), and oncogenes.  Based on the current
information on the potential interactions in the formation of these
tumors, and the lack of effective, standard regimens, the NCI is
encouraging investigators to apply novel therapies or innovative
approaches in pilot or phase I or II clinical trials.

Research Goals And Scope

The aim of this RFA is to stimulate pilot, phase I, or phase II
therapeutic clinical trials in AIDS malignancies so that new
treatment strategies and new agents are moved more rapidly into the
clinic.  The ultimate goal of the NCI is to provide more effective
management and treatment for HIV-associated malignancies in children
and adult men and women.

The project will fund single or groups of institutions to perform
innovative therapeutic studies in AIDS malignancies.  The studies
should be restricted to pilot, phase I, or II trials, with
approximately 5 to 30 patients/trial.  Examples of potential clinical
studies to consider:  (1) combinations of interferon-alpha and/or
retinoic acid in anogenital dysplasia or cancer (recent report by
Lippman and associates of a 68 percent response rate in patients with
cutaneous squamous cell cancer, and a 50 percent major response rate
in patients with locally advanced squamous cell cancer of the
cervix); (2) angiogenesis inhibitors in Kaposi's sarcoma; (3) immune
modulating therapy with IL-4 (and subsequent down-regulation of IL-6,
which may have some role in the development of NHL or Kaposi's
sarcoma), anti-B4 blocked ricin immunoconjugate in NHL, or anti-sense
to potential viral cofactors such as HPV in Kaposi's sarcoma.  The
investigators are not limited to the above studies, and any
innovative therapies with appropriate rationale are sought.

Although the major purpose of these grants is to facilitate rapid
testing of novel agents or innovative approaches, tumor tissue or
other relevant biologic fluid collection is strongly encouraged for
ongoing or future investigations of laboratory correlates.  The
interchange of ideas and tumor tissue between the recipients of the
grants will be encouraged.  The research plan should be focused on
the clinical trial proposed.  Laboratory studies addressing
correlative issues to the clinical trials may be included but are not
necessary.  Clinical studies must involve human subjects and be
designed to ultimately improve cancer treatment.  The clinical
studies must be based on a strong rationale and preclinical data
should support the underlying hypothesis.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF FEMALES AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
females in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and females in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If females or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.  As Kaposi's sarcoma occurs
predominantly in men, the lack of female participation should be
rationally explained.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in the Research
Plan, 1-4, AND summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from females and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
females or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 1, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the names and addresses of the Principal Investigators, the
names of other investigators and key personnel, the participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.

The letter of intent is to be sent to Dr. Roy S. Wu at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The PHS 398 (rev 9/91) research grant application form is to be used
in applying for this RFA.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 496-7441; and from the NCI Program Director named below.

The RFA label available in the PHS 398 research grant application
form must be affixed to the bottom of the face page.  Failure to use
this label could result in delayed processing of the application such
that it may not reach the review committee in time for review.  In
addition, the RFA number and title must be typed on line 2a of the
face page of the application form.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator must be included with
the application.

Submit the signed, typewritten original application, including the
Checklist, and three signed, exact photocopies of each R03.  The
photocopies must be clear and single sided.

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of each
application to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
Bethesda, MD  20892

Applications must be received by April 23, 1993.  If an application
is received after that date, it will be returned.  The Division of
Research Grants (DRG) will not accept any application in response to
this announcement that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Review Procedure

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.
Applications that are judged to be non-responsive will be returned to
the applicant by the NCI.  Applications judged to be non-responsive
to this RFA may be submitted as an investigator initiated regular
research grant (R01) or as a project within a program project grant
(P01) at the next receipt date.  The application would require
modification in accordance with R01 or P01 guidelines.  The revised
application would not be considered an application for a small grant
nor would it be considered a response to another RFA.  Questions
concerning the responsiveness of proposed research to the RFA may be
directed to program staff (see INQUIRIES).

Applications may be triaged by an NCI peer review group on the basis
of relative competitiveness.  The NCI will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical review by an
appropriate peer review group convened by the Division of Extramural
Activities, NCI.  Institutional Review Board (IRB) approval must have
been received and the date of approval provided to NCI prior to peer
review.  If this information is not provided prior to peer review,
the application will be withdrawn from competition by the NCI and
returned to the applicant without review.  The second level of review
will be provided by the National Cancer Advisory Board.

Review Criteria

The factors considered in evaluating the scientific merit of each
application will be:

o  Extent to which the proposed research addresses the goals of the
RFA;

o  Scientific, technical, or medical significance and originality of
proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Research or clinical experience, training, time availability, and
qualifications of the investigators involved;

o  Adequacy of plans for effective collaboration among laboratory,
clinical, and statistical investigators;

o  Adequacy of the available resources and environment (e.g.,
facilities, equipment, statistical resources; patient population);

o  Adequacy of the mechanisms for quality control, study monitoring,
data management and reporting, and data analysis;

o  Adequacy of provisions for the protection of human subjects;

o  Adequacy of the plans for inclusion of females and minorities.

The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the proposed research.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.  In addition to
the technical merit of the application, the NCI will consider how
well the applicant institution meets the goals and objectives of the
program as described in the RFA, availability of resources, and study
populations.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be responsive are encouraged and may be directed to
NCI Program Directors at the addresses below.  The NCI Program
Directors welcome the opportunity to clarify any issues or questions
from potential applicants.

For technical information:

Dr. Roy S. Wu
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

For business information:

Ms. Joan Metcalfe
Grants Management Specialist
National Cancer Institute
Executive Plaza South, Room 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 28
FAX:  (301) 496-8601

Applicants who use express mail or a courier service are
advised to follow the carrier's requirements for showing a street
address.  The addresses for the Executive Plaza North and the
Executive Plaza South are:

Executive Plaza North              Executive Plaza South
6130 Executive Boulevard           6120 Executive Boulevard
Rockville, MD  20852               Rockville, MD  20852

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No 93.395, Cancer Treatment Research.  Awards are made
under the authorization of the Public Health Service Act, Title IV
Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as
amended, Public Law 99-158, 42 USC 285a) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR
Part 74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency
review.

.

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