Full Text CA-94-004

NEW THERAPEUTIC APPROACHES FOR BREAST CANCER

NIH GUIDE, Volume 22, Number 38, October 22, 1993

RFA:  CA-94-004

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Hormones 
  Gene Therapy+ 
  Immunotherapy 
  Monoclonal Antibodies 


National Cancer Institute

Letter of Intent Receipt Date:  December 3, 1993
Application Receipt Date:  February 17, 1994

PURPOSE

The Cancer Therapy Evaluation Program (CTEP), Division of Cancer
Treatment (DCT), National Cancer Institute (NCI) invites applications
for cooperative agreements for the development of novel approaches to
the treatment of breast cancer employing new agents, concepts, or
treatment strategies and to conduct Phase I/II clinical trials.

Awards will be made as cooperative agreements, which create an
assistance relationship with substantial NCI programmatic involvement
with the recipients during the performance of the project, as
outlined in this RFA.  The cooperative agreement mechanism is used
when the NCI wishes to stimulate investigator interest and proposes
to advise or assist in an important and opportune area of research.

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 RFA,
New Therapeutic Approaches for Breast Cancer, is related to the
priority area of cancer.  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

Applications may be submitted by domestic non-profit and for-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Applications can be
from single or multiple institutions (collaborating institutions,
consortia, cooperative groups).  Foreign institutions may participate
in Laboratory or Clinical Programs through sub-contract or consortium
arrangements.  Applications from minority individuals and women are
encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an "assistance" mechanism
(rather than an acquisition" mechanism), in which substantial NCI
scientific and/or programmatic involvement with the awardee is
anticipated during performance of the activity.  Under the
cooperative agreement, the NCI purpose is to support and/or stimulate
the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the
activity.  Details of the responsibilities, relationships and
governance of the study to be funded under cooperative agreement(s)
are discussed later in this document under the section "Terms and
Conditions of Award".

The total project period for applications submitted in response to
the present RFA may not exceed four years.  The anticipated award
date is September 1994.

Awards and level of support depend on receipt of a sufficient number
of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NCI, the award of grants
pursuant to this RFA is contingent upon the continuing availability
of funds for this purpose.  Because the nature and scope of the
research proposed in response to this RFA may vary, it is anticipated
that the size of an award will vary also.

This RFA is a one-time solicitation.  At this time, the NCI has not
determined whether or how this solicitation will be continued beyond
the present RFA.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for four years will
be committed to specifically fund applications submitted in response
to this RFA.  It is anticipated that five to seven individual awards
will be made.

RESEARCH OBJECTIVES

A.  Background

The incidence of breast cancer has been increasing and now accounts
for 32 percent of all carcinomas in women.  It is estimated that
there will be a total of 46,300 deaths from breast cancer and 183,000
breast cancers diagnosed in 1993.  Treatment during the past decade
has concentrated on attempts to optimize conventional
chemotherapeutic agents by varying drug dosage, schedule and
intensity.  Although there have been treatment advances, five-year
relative survival rates increased only three to four percentage
points in the 1980s over that observed for patients diagnosed in the
1970s.  With the dramatic increase in the diagnosis of in situ tumors
in the 1980s and '90s, new opportunities exist for the early
treatment of breast cancer.  For patients with the most advanced
stages of cancer, mortality rates have not improved and new
therapeutic strategies to treat such tumors are needed.  Therefore,
this RFA focuses on novel approaches to breast cancer treatment.

Recent advances in understanding the pathobiology of breast cancer
have furthered the development of a wide range of novel anti-cancer
therapeutic agents that will soon require clinical testing.  These
agents include new classes of cytotoxic agents derived from natural
products, as well as genetically engineered agents to act via
immune-stimulatory effects, or which are targeted specifically to
novel cancer cell targets, including surface receptors, signal
transduction molecules, transcriptional factors, and particular DNA
and RNA sequences.  Furthermore, mechanisms of action of these new
anti-cancer agents available for clinical study include not only the
mediation of anti-cancer effects through cytotoxic and immunologic
mechanisms, but also through growth inhibition by interruption of
specific oncogene-associated biochemical functions, inhibition of
protein synthesis through targeted toxins, biochemical reversal of
drug resistance, induction of differentiation and/or programmed cell
death (apoptosis), and through inhibition of tumor angiogenesis.  In
addition, new strategies to overcome resistance to conventional
cancer therapeutic approaches are also of interest.

One problem identified by clinical investigators is the lack of a
funding mechanism through which innovative investigator-initiated
approaches may be fostered to evaluate new agents or therapeutic
strategies in Phase I/II breast cancer clinical trials.
Collaborative interactions between clinicians and laboratory
scientists are essential features of these types of investigations.
Support is needed for toxicology and efficacy studies in preclinical
models, the preliminary clinical evaluations and the monitoring of
patients.  Thus, NCI proposes to create a mechanism for supporting
translational research that is aimed at bridging the gap between
basic research studies and phase III evaluation in the NCI Clinical
Trials Cooperative Groups.

Applications are expected to be multidisciplinary and may include
preclinical evaluation in in vitro or in vivo models.  Pilot clinical
studies and relevant laboratory studies needed to better understand
the mechanism of action of the therapeutic agents will be a necessary
part of the research plan.  It is expected that investigators should
be positioned to conduct or initiate a Phase II evaluation in breast
cancer by the end of the funding period.

B.  Objectives and Scope

The goals of this initiative are to:  (1) provide support for Phase
I/II trials of promising new therapeutic strategies for the treatment
of breast cancer; and (2) provide support for appropriate laboratory
programs that are necessary for the clinical development of the
therapeutic approach.  CTEP proposes to stimulate clinical research
relevant to breast cancer through the support of multidisciplinary
teams of basic and clinical investigators interested in performing
Phase I/II trials of innovative therapeutic strategies and in
conducting laboratory studies relevant to the clinical development of
the agents.  Scientific approaches should reflect the creativity and
capabilities of the investigators.  Applicants will form Breast
Cancer Treatment Groups (see Definitions) that consist of Clinical
and Laboratory Programs representing diverse scientific disciplines
under the leadership of a single Principal Investigator.

Applications should be focused on integrating clinical goals with
laboratory research areas.  The application should have a central,
common theme that should be the focus of the clinical studies and the
Group's efforts overall.  The Laboratory Programs must be relevant to
the clinical development of the new therapeutic agents or therapeutic
strategies proposed.  Preclinical Laboratory Programs may include the
identification and analysis of new analogs or agents relevant to the
clinical studies proposed; in vivo or in vitro models for evaluation
of therapeutic agents or strategies; or toxicology studies necessary
for submission of an Investigational New Drug (IND) application.
Laboratory Programs may also be designed to elucidate the mechanism
of action of the proposed therapeutic strategies; to provide
pharmacologic or immunologic monitoring of patients; or to perform
correlative studies relevant to the clinical behavior of breast
cancer tumors and/or their response to the therapeutic intervention.
Investigators are not limited to the above areas of laboratory
experimentation.

Clinical Programs should be designed to evaluate new therapeutic
agents or new therapeutic strategies for breast cancer.  Pilot
clinical trials may be included with the goal of initiating Phase II
evaluation of the therapy within the funding period.  Examples of new
clinical trials include:  (1) differentiating agents or apoptosis;
(2) novel growth factor or hormone-based therapies utilizing new
agents; (3) gene therapy and new therapies involving antisense or
ribozymes; (4) immunomodulatory approaches to breast cancer treatment
(such as vaccines); (5) targeted therapies including monoclonal
antibody therapy, radioimmunobiology, and the use of new
immunotoxins; (6) biologics in combination with drug or radiation
regimens; (7) new therapies combining endocrine manipulations with
chemotherapeutic agents; (8) treatment strategies for overcoming
hormone-, drug- or radiation-resistance of breast cancer; and (9)
treatment strategies based on novel mechanisms of action of defined
therapeutic agents (e.g., interference with signal transduction,
induction of immune response).  Investigators are not limited to the
above research areas.

SPECIAL REQUIREMENTS

A.  Study Organization

1.  Definitions

BREAST CANCER TREATMENT GROUP - A group consisting of Clinical and
Laboratory Programs representing diverse scientific disciplines that
join together under guidance and direction of a single Principal
Investigator and that function as a unit under the common goal of
bringing new therapeutic strategies for the treatment of breast
cancer to Phase II clinical evaluation.  In this RFA the terms,
Breast Cancer Treatment Group, BCTG, and "Group" are used
synonymously.

PRINCIPAL INVESTIGATOR -  The one person responsible to the applicant
institution for the scientific and technical direction of the
project. The Principal Investigator may lead one of the Laboratory or
Clinical Programs of the Group, and in addition, coordinate Group
activities scientifically and administratively.

CLINICAL PROGRAM - A research component of the overall group with the
expertise and experience to conduct clinical trials in the proposed
research area.  A minimum of one Clinical Program must be proposed.

LABORATORY PROGRAM - A research component of the overall group with
the expertise and experience to conduct laboratory studies relevant
to the therapeutic strategy proposed for clinical study.  A minimum
of one Laboratory Program be proposed.

PROGRAM LEADER - The director of each of the Laboratory or Clinical
Programs of the BCTG.

APPLICANT INSTITUTION - The organization to which a grant is awarded
and which is responsible and accountable to NCI for the use of the
funds provided and for performance of the grant-supported project.

NCI PROGRAM DIRECTOR - The extramural Program Director from the
Cancer Therapy Evaluations Program (CTEP), Division of Cancer
Treatment, National Cancer Institute who will be coordinating the NCI
interactions and administering and providing guidance for the overall
program within the NCI.

NCI COORDINATOR - The Senior Investigator, Medicine Section, Clinical
Investigations Branch, CTEP, DCT who interacts scientifically with
the Institutions.

IDB DRUG MONITOR - The Physician (Drug Monitor) from the
Investigational Drug Branch (IDB), CTEP, DCT who is assigned to each
agent to assist in the coordination of its development.

2.  Breast Cancer Treatment Group Organization

The composition of the BCTG is envisioned as follows:

a.  A Principal Investigator who is responsible for providing the
scientific and administrative leadership for the Group.

b.  One or more Clinical Programs, each headed by a Program Leader,
with demonstrated expertise in clinical research relevant to the
proposal and in the conduct of clinical trials.

c.  One or more Laboratory Programs, each headed by a Program leader,
each with demonstrated expertise in scientific disciplines necessary
to design and conduct the experiments necessary to achieve the
program's goals.

The Principal Investigator, in addition to coordinating Group
activities scientifically and administratively, may also be a Program
Leader.  All Program Leaders will be directly responsible to the
Principal Investigator.  The formation of the Group, the application
in response to this RFA, the overall management of the Group, and the
allocation of funds to the various Clinical and Laboratory Programs
based on performance and overall group needs at any given time will
be the responsibility of the Principal investigator and the applicant
institution in accordance with PHS policies.

The scientific makeup of the group's Clinical and Laboratory
Programs, and the specific disciplines represented, should depend on
the talents required to accomplish its scientific and technical
objectives as perceived by the Principal Investigator and Program
Leaders.  The major consideration in structuring a BCTG should be
bringing together the expertise necessary to evaluate and conduct
Phase II clinical studies on new agents, concepts, or treatment
strategies for breast cancer.

A BCTG may include members from a single institution or a number of
institutions, depending on the specific goals of the group.  The
multi-institutional approach may provide access to a wider range of
expertise.

Although a minimum of one Clinical and one Laboratory Program per
group is necessary, no limit on the number of Programs per BCTG is
stipulated. In preparing applications, however, prospective Principal
Investigators should be aware that effective, efficient cooperation
can be difficult in groups with more than a few Clinical and
Laboratory Programs.

B.  Terms and Conditions of Award

These special Terms of Award are in addition to, and not in lieu of,
otherwise applicable OMB administrative guideline, HHS grant
administration regulations at 45 CFR part 74 and 92, and other HHS,
PHS and NIH grant administration policy statements.

The administrative and funding instrument used for this program is a
cooperative agreement (U01), an "assistance" mechanism (rather than
an "acquisition" mechanism) in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated
during performance of the activity.  Under the cooperative agreement,
the NIH purpose is to support and/or stimulate the recipients's
activity by involvement in and otherwise working jointly with the
award recipient in a partner role, but it is not to assume direction,
prime responsibility, or a dominant role in the activity.  Consistent
with this concept, the dominant role and prime responsibility for the
activity reside with the awardee(s) for the project as a whole,
although specific tasks and activities in carrying out the studies
will be shared among the awardees and the NCI Coordinator.

1.  Awardee Rights and Responsibilities

It is the responsibility of the BCTG to develop the details of the
clinical and laboratory research design, including definition of
objectives and approaches, planning, implementation, analysis, and
publication of results, interpretations and conclusions of studies.
The BCTG shall, with CTEP assistance, develop Phase I and II
protocols for clinical cancer research in accord with the research
interests of the BCTG, abilities and goals, and submit them to CTEP
(either to the Letter of Intent (LOI) Coordinator or to the CTEP
Protocol and Information Office, the receiving office for all
protocols sent to CTEP) for review as appropriate prior to their
implementation.

a.  Membership in the Group

Group membership includes the Principal Investigator and the Program
Leaders.  In no case will changes of Principal Investigator or
Program Leaders be made without prior approval from the NCI. Such
approval may be sought either in the application for continuation
grant (PHS 2590 (rev. 9/91)) or during the course of the budget
period.  In the latter case, the procedure for requesting prior
approval is described in the "Methods for Grantees to Request
Approvals," PHS Grants Policy Statement, page 8-5.

b.  Protocol Development

It is anticipated that decisions in all BCTG activities will be
reached by consensus of the collaborating member institutions under
the leadership of the BCTG Principal Investigator.  The Principal
Investigator will designate a Protocol Chairperson for each proposed
study.  The Protocol Chairman is the scientific coordinator of the
protocol who is responsible for developing and monitoring the
protocol. The Principal Investigator will be responsible for
communication with the appropriate CTEP staff.

c.  Protocol Submission

The Principal Investigator will submit BCTG protocols to the CTEP
Protocol and Information Office in a timely fashion for review and
approval by NCI subject to negotiation with the awardees.  All
protocols should be preceded by a written Letter of Intent (LOI) from
the BCTG declaring interest in conducting a particular study.  The
LOI will describe the hypothesis to be investigated, the general
design of the contemplated trial, plus relevant information on
accrual capabilities to document feasibility.  The IDB Drug Monitor
will coordinate the NCI review and assure that the results of such
review are communicated to the Principal Investigator.  The Principal
Investigator will communicate the results of the NCI review of
protocols to the BCTG participating institutions.

d.  Quality Control

The awardee institution is responsible for ensuring that the group
establishes mechanisms for quality control of therapeutic and
diagnostic modalities employed in its trials.  These mechanisms will
be reviewed by the Head, Quality Assurance and Compliance Section
(QACS), Regulatory Affairs Branch (RAB), CTEP.

e.  Study Monitoring

The BCTG will establish mechanisms for study monitoring.  These
mechanisms will be reviewed by the Head, QACS, RAB, CTEP.  The BCTG
is responsible for assuring accurate and timely knowledge of the
progress of each study through:

1) establishing procedures for assigning dose level at the time a new
patient is entered, and assuring that the required observation period
has elapsed before beginning a higher dose level;

2) tracking and reporting of patient accrual and adherence to defined
accrual goals;

3) ongoing assessment of case eligibility and evaluability;

4) timely medical review and assessment of patient data;

5) rapid reporting of treatment-related morbidity (adverse drug
reactions) and measures to ensure communication of this information
to all parties;

6) interim evaluation and consideration of measures of outcome, as
consistent with patient safety and good clinical trials practice;

7) timely communication of results of studies;

8) an on-site monitoring program  (see BCTG Compliance with Federally
Mandated Regulatory Requirements); and

9) establishing data management support capabilities that assure that
data will be submitted via electronic transfer to the NCI's Clinical
Trials Monitoring Service (CTMS) when required (See BCTG Compliance
with Federally Mandated Regulatory Requirements).

f.  Data Management and Analysis

The BCTG will develop procedures to ensure that data collection and
management are:  (a) adequate for quality control and analysis; (b)
as simple as appropriate in order to encourage maximum participation
of physicians entering patients and to avoid unnecessary expense; and
(c) sufficient across the participating institutions.  These
procedures will be reviewed by the Chief, Biometrics Research Branch
(BRB), CTEP.

g.  BCTG Compliance with Federally Mandated Regulatory Requirements

The BCTG is responsible for establishing procedures for all
participating institutions to comply with FDA regulations for studies
involving investigational agents and OPRR requirements for the
protection of human subjects.  These procedures are:

1) methods for assuring that each institution where investigators are
conducting BCTG trials has a current, approved assurance on file with
the OPRR; that each protocol is reviewed and approved by the
responsible Institutional Review Board (IRB) prior to patient entry;
that each protocol is reviewed at least annually by the IRB so long
as the protocol is active; that each investigator is registered with
the Drug Management and Authorization Section (DMAS), CTEP, with a
current 1572 form on file; and that each patient (or legal
representative) gives written informed consent prior to entry on
study.

2) a system for assuring timely reporting of all serious and
unexpected toxicities to the IDB, CTEP according to CTEP guidelines
(mailed annually to all registered investigators).  This requires
reporting Adverse Drug Reactions (ADRs) by telephone to the IDB Drug
Monitor within 24 hours of the event and requires a written report to
follow within 10 working days.

3) an on-site monitoring program that assures that a sampling of
records at each participating institution is audited at least two
times during the cooperative agreement period.  The on-site audit
will address issues of data verification and compliance with
regulatory requirements for the protection of human subjects and
investigational agent accountability.  Any serious problems with data
verification or compliance with Federal regulations must be reported
to the Head, QACS immediately.  Otherwise, written reports must be
submitted within six weeks of each audit.  All audit schedules are to
be provided to the Head, QACS at least four weeks prior to the date
of the audit.

4) For the specific Phase I and Phase II trials that require
monitoring by the CTMS three times a year, information must be
provided via electronic transfer to the CTMS at two week intervals
and includes: notification of each patient entered onto a Phase I or
II protocol within the previous two week period, and all data
obtained on each registered patient within the previous two weeks as
specified by the NCI/DCT Standard Case Report Form and the individual
protocol.

5) implementation of the CTEP requirements described in the DCT
Investigators Handbook for storage and accounting for investigational
agents provided under DCT sponsorship.

h.  Progress Review

The BCTG will establish a mechanism for assessing performance of its
members, with particular attention to accrual of adequate number of
eligible patients onto consortium trials, timely submission of
required data, conscientious observance of protocol requirements,
authorship and participation in group leadership.  This mechanism
will include a procedure for recommending an adjustment of
institutional funds within the BCTG as appropriate for the level of
participation in group activities, including (but not limited to)
accrual.

i.  Attendance at Meetings

The Principal Investigator, Program Leaders, the NCI Coordinator, and
the NCI Program Director will meet periodically to review progress,
plan and design research activities, and establish priorities.  The
Principal Investigator will determine the frequency of meetings, and
will be responsible for scheduling the time and place of each
meeting.  The Principal Investigator and the NCI Coordinator should
plan at least one meeting per year in the Washington, DC area to
facilitate interaction with NCI staff.  The budget should include
funds for this meeting (see APPLICATION PROCEDURES).

No NCI staff member may chair group meetings.  A critical determinant
of group success will be the degree of communication among its
members.  Therefore, additional informal meetings among all
participants as well as regular telephone and written communication
is encouraged.

j.  Reporting Requirements

Reporting requirements will be in agreement with FDA regulations and
NCI procedures.  Annual progress reports will be submitted to the NCI
and will include, at a minimum, summary data on protocol performance
by the awardee and each participating institution.  In addition, data
summary reports will be requested prior to the due date of the annual
report to the FDA required of IND sponsors.  The types of reports
required are determined by CTEP at the time of protocol review.  They
are:  (1) Quarterly Data Updates (QDA) for late Phase I trials not
CTMS monitored; (2) Annual Data Updates (ADU) for late Phase I/Phase
II combination studies sent to Protocol Chairman to summarize
clinical data and progress; (3) The study summaries sent annually to
summarize clinical data for Phase II studies.  A system for providing
such information in a timely manner must be in place.

k.  Publication of Data

Timely publication of major findings is encouraged.  Publication or
oral presentation of work done under this agreement will require
appropriate acknowledgement of NCI support.  The NCI will have access
to all data generated under this cooperative agreement and may
periodically review the data.  The awardee will retain custody and
primary rights to the data consistent with current HHS, PHS, and NIH
policies.

2.  NCI Staff Responsibilities

The role of the CTEP staff as described throughout these terms of
cooperation is to assist and facilitate but not to direct research
activities.  This cooperative agreement is part of a larger program
of investigational agent development in the NCI.  Each of the CTEP
staff listed below has very specific and well defined
responsibilities in terms of investigational agent development and
the role of DCT as a drug sponsor as defined in CFR 21 Part 312.

The NCI will assist in the development and design of the Phase I and
Phase II protocols and will comment on the scientific rationale and
value of the study, the statistical requirements, and its
implementation.  NCI will advise the investigators of the nature and
results of relevant trials and laboratory studies being carried out
nationally or internationally, pointing out possible duplication of
effort.  NCI will provide information including relevant
pharmacokinetic and pharmacodynamic data concerning investigational
agents, availability, efficacy and toxicity of investigational new
agents supplied to the investigator(s) under an NCI IND.  NCI will
assist and advise the group on the IND application or will sponsor
the initial IND.

a.  CTEP as a Scientific Resource for NCI-supported Phase I and II
Clinical Trials Investigations

The NCI Coordinator will serve as a resource available to the BCTG
for specific scientific information with respect to treatment
regimens and clinical trial design.  The NCI Coordinator will assist
the BCTG as appropriate in developing information concerning the
scientific basis for specific trials and also will be responsible for
advising the BCTG of the nature and results of relevant trials being
carried out nationally or internationally.

b.  CTEP Assistance in Protocol Development

The protocol is the detailed written plan of a clinical experiment.
The protocol must be mutually acceptable to the PI and to the CTEP
Protocol Review Committee (PRC).  The PRC is chaired by the Associate
Director, CTEP, and is composed of professional staff of the DCT
including drug monitors, disease coordinators, regulatory staff,
pharmacy staff and ad hoc reviewers external to NCI when deemed
appropriate.

Communication at the various stages of protocol development is
encouraged as necessary to promote protocol development and
implementation.  A Drug Monitor is assigned to each agent to assist
in the coordination of its development.  All protocols should be
preceded by a written declaration of interest in conducting a
particular study from the Principal Investigator using the format
described in the GUIDELINES FOR SUBMITTING LOIs- Letter of
Intent/INVESTIGATIONAL DRUG TRIAL (available upon request from Ms.
Diane Bronzert at the address below).  The PRC will formally review
the LOI.  Following review, the IDB Drug Monitor will provide a
Program response to the BCTG and will address the following issues:
(a) the existence and nature of concurrent clinical trials in the
area of research, pointing out possible duplication of effort; (b)
information about additional investigational agents relevant to the
BCTG's research goals; (c) assistance in applying additional
government resources as outlined below; and (d) comments on the
scientific rationale and value of the proposed study, the design, the
statistical requirements.  If the study involves an NCI sponsored
investigational agent, the NCI Drug Monitor will also address the
following issues: (a) information including relevant pharmacokinetic
and pharmacodynamic data concerning investigational agents; and (b)
availability of investigational agents.  The LOI mechanism is
designed for preliminary review and is recommended to expedite
protocol development and implementation and to facilitate agreement
on study priority and design (see the DCT Investigator's Handbook, pp
32-35, available on request from Ms. Diane Bronzert at the address
listed under INQUIRIES, for further discussion of these mechanisms).

c.  CTEP Review of Proposed Protocols

BCTG protocols will be reviewed by the PRC which meets weekly.  NCI
reviews all protocols to insure they are within the peer reviewed and
awarded work scope.  All protocol approvals are subject to
negotiation with the awardees.  NCI will also review protocols for
safety considerations, as required by federal regulatory
requirements.  For NCI sponsored investigational agents, see the DCT
Investigational Handbook for further information regarding protocol
review procedures and considerations.   Following the review of the
protocol by the PRC, the NCI Coordinator will provide the BCTG with a
consensus review prepared by the IDB Drug Monitor.  The consensus
review describes recommended modifications and other suggestions, as
appropriate.

If a proposed protocol is disapproved, the specific reasons for lack
of approval will be communicated in writing by the NCI Coordinator to
the BCTG as a consensus review within 30 days of protocol receipt by
the NCI.  NCI will not provide investigational drugs or permit
expenditure of NCI funds for a protocol that it has not approved.
The NCI Drug Monitor will be available to assist the BCTG in
developing a mutually acceptable protocol, consistent with the
research interests, abilities and strategic plans of the BCTG and of
the NCI.

d.  CTEP Review of Quality Control and Study Monitoring

The Head, QACS, RAB, CTEP will review and provide advice, through the
NCI Coordinator, regarding mechanisms established by the BCTG for
quality control of therapeutic and diagnostic modalities employed in
trials using NCI-sponsored investigational agents.  (See Section 2A -
Awardee Rights and Responsibilities).  The Head, QACS will review the
BCTG procedures and policies for study monitoring including the
awardees' on-site monitoring program (See Section 9, CTEP Review of
Federally Mandated Regulatory Requirements).

e.  CTEP Review of Data Management and Analysis

The Chief, BRB, CTEP will review BCTG mechanisms for data management
and analysis.   (See Section 2A - Awardee Rights and
Responsibilities). When deemed appropriate, the Chief, BRB will make
recommendations to the BCTG, through the NCI Coordinator, to ensure
that data collection and management procedures are:  (a) adequate for
quality control and analysis; (b) as simple as appropriate in order
to encourage maximum participation of physicians entering patients
and to avoid unnecessary expense; and (c) sufficiently uniform across
the BCTG participants.

f.  CTEP Involvement in Protocol Closure

The NCI Coordinator will monitor protocol progress.  When a study
involves a NCI sponsored investigational agent, the Head, QACS and
the IDB Drug Monitor as well as the NCI Coordinator will monitor
protocol progress.  The NCI Coordinator or the IDB Drug Monitor may
request that a protocol study be closed to accrual for reasons
including:  (a) insufficient accrual rate; (b) accrual goal met; (c)
poor protocol performance; (d) patient safety and regulatory
concerns; (e) study results are already conclusive; and (f) emergence
of new information that diminishes the scientific importance of the
study question.  NCI will not provide investigational agents or
permit expenditures of NCI funds for a study after requesting closure
(except for patients already on-study).

g.  CTEP Involvement in Investigational New Drug Applications (INDs)

INDs for group trials may be held by the NCI, by a member of the
group, or by an appropriate third party (such as the drug
manufacturer, if not a member of the group).  The proposed IND
arrangements will be included in the initial application.  NCI will
be available to advise and assist in the IND application when a
member of the group will sponsor the initial IND.

The NCI will have the option to cross file or independently file an
IND on investigational drugs evaluated in the Phase I and II Clinical
Trials.  This would apply to drugs not developed in the NCI drug
development program.

When the NCI is to sponsor the initial IND or cross-file on an
existing IND for an agent to be studied by a group, the NCI
Coordinator will coordinate NCI assistance (e.g., facilitating the
completion of any necessary agreements between drug suppliers and
NCI, or advising the Principal Investigator of FDA-mandated specific
requirements and changes in requirements concerning investigational
drug management).  Investigators performing trials under Cooperative
Agreements will be expected to comply with all FDA monitoring and
reporting requirements for investigational agents.

Investigators performing NCI funded Phase I and II Clinical Trials
will be advised by the NCI Coordinator of potential studies that will
be relevant to new avenues of cancer therapy.  When this involves
investigational agents, the NCI Coordinator assisted by the Chief,
RAB, CTEP will advise the investigators of the specific clinical
information that will be needed from the clinical trials for that
information to be acceptable to the FDA for inclusion in a new drug
application (NDA).

h.  Use of Other NCI Resources in Support of BCTG Activities

Upon recommendation of the NCI Coordinator, the NCI may make limited
use of its contract based resources in support of group research
activities.  Use of such resources may be considered on an occasional
basis, at he NCI's discretion, within its budgetary and programmatic
constraints.

i.  CTEP Review of Federally Mandated Regulatory Requirements

The Head, QACS, through the NCI Coordinator, will advise the BCTG
regarding mechanisms to meet FDA regulatory requirements for studies
involving DCT-sponsored investigational agents and the Office for
Protection from Research Risks (OPRR) requirements for the protection
of human subjects by the BCTG institutions.  (See  RESPONSIBILITIES
OF AWARDEES, below)

For specific Phase I and II trials with NCI sponsored investigational
agents, the NCI has contracted for a Clinical Trials Monitoring
Service (CTMS) to document regulatory compliance, to maintain a
computerized data base and to produce periodic routine reports of the
results, and special reports as necessary.  For Phase I studies, CTEP
determines that the CTMS monitoring described above is necessary
using the following guidelines:  (a) Introduction of drug into humans
for the first time; (b) Early Phase I studies using a single agent;
(c) Concern for safety of patients; (d) PRC expresses concern with
excessive toxicity.  Phase II studies may also be monitored as noted
above if PRC expresses concern with excessive toxicity.  For these
trials, awardees may be visited by the CTMS contractor three times a
year.  The required biweekly data submissions to the CTMS are
described under RESPONSIBILITIES OF AWARDEES Section 7.d.

For Phase II trials with NCI sponsored investigational agents not
requiring the above described monitoring, NCI will delegate to the
awardee the task of providing an independent audit of each research
study.  The NCI's Clinical Trials Monitoring Service (CTMS)
contractor shall be used to conduct these audits.  The staff of QACS
will perform random audits of the awardee to assure that the awardee
is performing the delegated audit duties.  Audit schedules and final
audit reports will be provided to QACS, CTEP.  Institutional
responsibilities for monitoring are described below under
RESPONSIBILITIES OF AWARDEES Section 7.c.

j. Access to Data

The NCI will have access to all data generated under this cooperative
agreement and may periodically review the data.  Data must also be
available for external monitoring as required by NCI's Drug Master
File Agreement with the FDA relative to the responsibility of the NCI
as an IND agent sponsor.  The awardee will retain custody and primary
rights to the data consistent with current HHS, PHS and NIH policies.

k.  CTEP Review of Progress

Performance of each BCTG will be reviewed at least annually by the
NCI Coordinator on the basis of the information provided at the CTEP
sponsored meetings, in the annual progress reports and in the data
summary reports submitted to the IDB Drug Monitor or by CTMS reports.
In addition, periodic accrual information may be requested from the
BCTG by the NCI Coordinator for all active studies when deemed
appropriate.

Insufficient patient accrual or progress, or noncompliance with the
terms of award, including these Terms and Conditions of Award, may
result in a reduction of budget, withholding of support, suspension
or termination of the award.

3.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NCI
may be brought to arbitration.  An arbitration panel will be composed
of three members -- one selected by the BCTG, a second member
selected by NCI, and the third member elected by the two prior
selected members.  These special arbitration procedures in no way
affect the awardee's right to appeal an adverse action that is
otherwise appealable in accordance with PHS regulations at 42 CFR
Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN 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
women 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 women 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 women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  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
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects. Applicants/offerors 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 women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign consortium participants, the policy on inclusion of women
applies fully; since the definition of minority differs in other
countries, the applicant must discuss the relevance of research
involving foreign population groups to the United States'
populations, including minorities.

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
women 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 December 3, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and 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, the information
is helpful in planning for the review of applications.  It allows NCI
staff to estimate the potential review workload and to avoid conflict
of interest in the review.

The letter of intent is be sent to:

Ms. Diane Bronzert
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

APPLICATION PROCEDURES

A.  Method of Applying

The research grant application form PHS 398, (rev. 9/91) is to be
used in applying for cooperative agreements.  These forms are
available at most institutional offices of sponsored research; from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone (301) 435-0714; and from the NCI Coordinator
listed under INQUIRIES.  The RFA label available in the PHS 398
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 and the YES box must
be marked.

Because the Terms and Conditions of Award discussed above will be
included in all awards issued as a result of this RFA, it is critical
that each applicant include specific plans for responding to these
terms.  Plans must describe how the applicant will comply with staff
involvement.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

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

At the time of submission, two additional copies of the application
must also be sent to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by February 17, 1994.  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. The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction
addressing the previous critique.

B.  Organization of Application and Suggested Modifications of Form
PHS 398 (rev. 9/91)

This RFA requires the submission of a single application for the
proposed Breast Cancer Treatment Group.  An application representing
multiple programs may contain sections specific to each program;
however, all pages in an application must be numbered consecutively
from beginning to end.  A consolidated "Detailed Budget for the First
12-Month Budget Period" and a consolidated "Budget for the Entire
Proposed Project Period" for the entire BCTG should be included.
This should include the direct costs at the applicant institution and
both direct and indirect costs at participating institutions.  The
other budget pages should follow page 5.  List all key personnel for
the BCTG, including Biographical Sketches and Other Sources of
Support.

Because of the special requirements in this RFA, additional
suggestions regarding format and some modifications seem desirable to
provide a comprehensive yet readily reviewable application.

1.  The application should begin with an INTRODUCTORY SECTION.
Insert the INTRODUCTION after the Table of Contents.  This
INTRODUCTORY SECTION must describe the proposed BCTG as a whole with
respect to goals, objectives, and overall research plan.  In this
INTRODUCTORY SECTION, identify the Principal Investigator and Program
Leaders of each PROGRAM. It is important to discuss any prior
collaborative efforts among investigators in the group as well as
advantages expected from the group effort, e.g., how the projects are
mutually reinforcing, how collectively they will further the goals of
the proposed research, etc. The overall INTRODUCTORY SECTION should
be limited to 25 pages.

The INTRODUCTORY SECTION should also provide a separate "Detailed
Budget for the First 12-Month Period and a "Budget for the Entire
Proposed Project Period for Direct Costs" for the management and
coordination of group activities.  Each BCTG should anticipate the
need to attend at least one meeting per year in Bethesda, MD to
coordinate activities. Travel funds for the Principal Investigator
and the Program Leaders for each CLINICAL and LABORATORY PROGRAM
should be included in the budget.

Inasmuch as the Principal Investigator may also function as a Program
Leader for his/her CLINICAL or LABORATORY PROGRAM, parts of form PHS
398 that duplicate information provided in the section describing the
Principal Investigator's work need not be included in the
INTRODUCTORY SECTION.  The INTRODUCTORY SECTION should, however,
contain any additional information about the proposed Principal
Investigator or his/her institution as evidence of capability to
carry out the scientific and administrative duties required in this
RFA.

2.  Each application should clearly identify the CLINICAL and
LABORATORY PROGRAMS proposed, the proposed costs attributable to
each, and the relationship among the various programs.  Applicants
may organize their applications using the PHS 398 (rev. 9/91) format
for each CLINICAL PROGRAM and LABORATORY PROGRAM.  However, the face
page, Table of Contents, Checklist, and Biographical Sketches and
Other Support (if included elsewhere in the application) for the
individual PROGRAMS should be omitted.  A single face page should
apply to the entire application.  It is suggested that the title
"Principal Investigator" be reserved for the director of the overall
application.  The directors of the individual projects should be
referred to as "Program Leaders".  Under the Research Plan section,
describe the relevance of the PROGRAM to the primary theme of the
application and the collaborations with investigators within the BCTG
(limited to one page).  The 25-page limitation stipulated in the PHS
398 kit applies to each of the individual CLINICAL or LABORATORY
PROGRAMS.

A separate "Detailed Budget for the First 12-Month Budget Period", a
"Budget for the Entire Proposed Project Period", and a budget
justification for each PROGRAM must be included.  Often the various
research objectives necessary to reach the group's goals may need to
be phased in, at least in part, in sequential fashion.  In such
cases, the budgets for the individual CLINICAL and LABORATORY
PROGRAMS should, logically, reflect an appropriate change in relative
emphasis among objectives until an operational steady state situation
is attained.  Justification for phase-in budgets should also be
provided.

3.  The application will be reviewed as a whole as well as PROGRAM by
PROGRAM.  Therefore, prepare a detailed Table of Contents that will
enable reviewers to find specific information readily and number all
pages consecutively after the face page, which is page 1.

4.  Applications from institutions that have a General Clinical
Research Center (GCRC) funded by the NIH National Center for Research
Resources are requested to identify the GCRC as a resource for
conducting the proposed research.

C.  Minimal Requirements for Application

Applications must meet the requirements listed below.  Except for
item 1, each of these must be briefly addressed in the INTRODUCTORY
section of the application.  The INTRODUCTORY section may reference a
fuller discussion elsewhere in the application, provided that the
location of that discussion is clearly given in the INTRODUCTORY
section.

1.  Name a single Principal Investigator, who is an M.D., Ph.D., or
D.O., who will be responsible for the application, for group research
activities, and for the management of funds for the support of group
activities.

2.  Identify the applicant institution that will be responsible and
accountable to NCI for the use of the funds provided and for
performance of the grant-supported project.

3.  Describe the group's overall goals and, in the context of these
goals, describe how the group envisions the clinical development of
the agent(s) and/or regimen(s) to be tested.

4.  Provide a timetable detailing the research objectives for the
LABORATORY and CLINICAL PROGRAMS that will be investigated for each
year.  Due to the interdependence of the projects, it is expected
that some research and clinical studies will be phased in during the
grant funding period.  BCTGs may propose to conduct clinical trials
immediately and include the appropriate protocols for evaluation.  It
is anticipated that all BCTGs will have reached their goal of
initiating Phase II clinical evaluation by year 4.

5.  Provide, in the body of the application, a description of the
Investigational New Drug Application (IND) status of the agent(s)
proposed for study, including (in an Appendix) supporting
information. If an IND already exists for an investigational agent,
the IND number and the identity of the IND sponsor should be included
in the body of the application.

For any agent for which an IND does not exist, the application must
include enough information to demonstrate that an IND will be
obtained in a timely fashion.  This information should include:

o  a description of currently available preclinical data for the
agent;

o  a list of additional preclinical studies which remain to be done
in support of IND filing;

o  the anticipated date of IND filing;

o  Applicants proposing to conduct a trial without an IND must
demonstrate that all applicable FDA requirements will be met,
consistent with the above guidelines.

Include supporting documents (e.g., letters of agreement) in the
Appendix to the application.

6.  Supply of agent(s) for clinical trials.

Each application must describe the steps the applying group will take
to ensure adequate supplies of agents for the clinical trials
proposed.  Depending upon an applicant's particular circumstances,
such information may include a discussion of mechanisms of procuring
agents, timetables for production of agents, or evidence of industry
collaboration.  If possible, letters of support from pharmaceutical
companies should be included.

7.  If the BCTG expects to initiate clinical trials within the first
year, a draft or IRB approved clinical protocol should be included in
the Appendix.  For all proposed clinical protocols, provide detailed
evidence supporting the rationale for the protocol, including
literature citations, and emphasizing the results of work done by the
proposed group members.

If clinical protocols are not included with the application, the
Program Leader(s) of the Clinical Program(s) should include a
detailed description of future clinical studies and the proposed plan
for initiating clinical trials.

8.  Demonstrate that the group may expect sufficient patient accrual
to complete clinical trials in a timely fashion.

9.  Demonstrate that each component Clinical and Laboratory Program
is required for the attainment of the group's objectives.   Provide a
clear, concise plan that depicts the interrelationships among the
members of the group and the contribution of each to fulfillment of
group objectives.  This plan may be in narrative and/or diagrammatic
form; use the form which most clearly describes the group.  The name,
organization, and scientific discipline of the Principal
Investigator, Program Leaders, and other key personnel should be
included.

10.  Provide a plan to ensure the maintenance of close collaboration
and effective communication among members of the group, which will
include letters of commitment to this plan by all Program Leaders.
Include plans for scheduling group meetings, notifying group members
(including the NCI), and documenting and disseminating group meeting
proceedings.

11.  Demonstrate that the Principal Investigator and the Program
Leaders possess the necessary scientific skills and leadership
qualities to conduct the proposed research successfully; include
relevant research programs, experience in conducting clinical trials,
unique competencies, and pertinent publications.

12.  Demonstrate the competence of the Principal Investigator to
manage comprehensive research projects, and to coordinate and
integrate research activities of diverse Clinical and Laboratory
Programs.

13.  Describe how the group will comply with federally mandated
regulatory requirements, as outlined under the "SPECIAL
REQUIREMENTS", Terms and Conditions of Award.  This includes quality
control measures that will be used by the group and the capability to
conduct study monitoring.

REVIEW CONSIDERATIONS

A.  General Considerations

All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
the technical merit of the CLINICAL and LABORATORY PROGRAMS is
important, it will not be the sole criterion for selection of a
study.  Other considerations, such as the importance and timeliness
of the proposed study or clinical trials, the development of a
well-defined central research focus, the coordination and
interdependence of the individual PROGRAMS, and the cohesiveness and
multidisciplinary nature of the BCTG will be part of the evaluation
criteria.

B.  Review Procedures

Upon receipt, applications will be reviewed by the Division of
Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.
Applications that are judged non-responsive will be returned by the
NCI.  An application judged to be non-responsive to this RFA may be
submitted as an investigator initiated regular research grant (R01)
or program project grant (P01) at the next receipt date.  The
application would require modification in accordance with either the
R01 or P01 guidelines.  The new application would not be considered
an application for a Cooperative Agreement, nor would it be
considered a response to an RFA.  Questions concerning the relevance
of proposed research to the RFA may be directed to program staff
listed under 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 noncompetitive for award
and notify the applicant and institutional business official.  Those
applications judged to be both competitive and responsive will be
further evaluated, using the review criteria stated below, for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review will be provided by the National Cancer Advisory
Board.

C.  Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how best to meet the goals of the cooperative study and are
expected to address issues identified under SPECIAL REQUIREMENTS of
the RFA.

The review group will assess the scientific merit of the studies,
including:

1.  Extent to which the application addresses the goals and
objectives of the RFA.

2.  Scientific merit and originality of proposed research.

3.  Importance, timeliness, and clinical merit of the clinical
trials.

4.  Quality of data supporting the proposed clinical trial.

5.  Scientific and technical merit of the proposed laboratory
studies.

6.  Evidence that the Principal Investigator and the Program Leaders
possess the scientific skills and leadership qualities needed to
conduct the proposed research successfully; experience, competence,
commitment, and time availability of Principal Investigator, Program
Leaders, and other key personnel.

7.  Evidence of coordination and interdependence of the individual
Programs.  Adequacy of plans for effective intra-group communication
and for assuring group cohesiveness.  Evidence that each component
Clinical and Laboratory Program is required for the attainment of the
group's objectives, and that each has available the professional and
technical personnel to permit efficient and successful conduct of the
proposed research.

8.  Competence of Principal Investigator to develop, implement, and
manage comprehensive research programs, and to coordinate and
integrate research activities of diverse clinical and laboratory
programs.

9. Adequacy of existing physical facilities and resources of the
Principal Investigator and Program Leaders.

10.  Evidence that Clinical Programs are capable of completing the
clinical trial in a timely fashion, including evidence of adequate
patient accrual.

11.  Evidence of approval and commitment of institutions represented
by group members to group goals.

12.  Evidence that appropriate steps have been taken to insure the
protection of human subjects.

13.  Evidence that the applicant is in compliance with NIH policies
regarding the inclusion of women and minorities in clinical research
study populations (STUDY POPULATIONS section of this RFA).

The review group will critically examine the submitted budget and
will recommend an appropriate budget and period of support for each
approved application.

AWARD CRITERIA

Applications considered by the National Cancer Advisory Board will be
considered for award based upon (a) scientific and technical merit;
(b) availability of funds; (c) programmatic priorities; (d) how well
the BCTG meets the goals and objectives of the program as described
in the RFA; and (e) commitment to accept provisions outlined under
the "Special Requirements" Section 2, Terms and Conditions of Award.

Letter of Intent Receipt Date:             December 3, 1993
Application Receipt Date:                  February 17, 1994
Review by National Cancer Advisory Board:  September 1994
Anticipated Award Date:                    September 1994

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 strongly encouraged.  The program
staff welcome the opportunity to clarify any issues or questions from
potential applicants.

Direct inquiries regarding programmatic issues, and address the
letter of intent to:

Ms. Diane Bronzert
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Room 734
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663

Direct inquiries regarding fiscal matters to:

Ms. Carolyn Mason
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 242
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 59
FAX:  (301) 496-8601

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,
Part A (Public Law 78-410, as amended, Public Law 99-158, 42 USC 241
and 285) and administered under PHS grants policies and Federal
Regulations at 42 CFR Part 52 and 45 CFR Part 74 and 92.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review.

.

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