AIDS-ASSOCIATED MALIGNANCIES CLINICAL TRIALS CONSORTIUM

Release Date:  July 9, 1998

RFA:  CA-98-010

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  October 21, 1998
Application Receipt Date:  November 18, 1998

PURPOSE

The Cancer Therapy Evaluation Program (CTEP) of the Division of Cancer Treatment
and Diagnosis (DCTD) at the National Cancer Institute (NCI) invites applications
from single institutions or consortia of institutions for cooperative agreements
(U01) to participate or to continue to participate in the activities of the AIDS-
associated Malignancies Clinical Trials Consortium (AMC).  For the past 3 years,
the AMC has designed, developed and performed clinical trials using novel agents
or innovative approaches in patients with AIDS-associated malignancies.  The NCI
is seeking talented scientists from academic, non-profit and for-profit research
organizations who will interact with other members of the Consortium and with
CTEP in a concerted way in order to further conceive, create, and evaluate new
approaches to therapy of AIDS-associated malignancies.  The AMC will consist of
the awardees funded under this solicitation, and a separately funded Operations,
Statistics and Data Management Center.  Scientific approaches taken by the
Consortium will continue to be broad and will reflect the creativity and
capabilities of team participants.  Clinical trials using conventional cytotoxic
chemotherapy regimens alone would not be performed within the Consortium.  The
potential exists for expanding to phase III studies and applicants should
consider relevant phase III questions as appropriate.  The purpose of the
proposed awards is to continue to stimulate cooperative efforts to improve
treatment and to develop more effective therapies for AIDS-associated
malignancies.

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), Aids-
Associated Malignancies Clinical Trials Consortium, is related to the priority
areas of cancer and AIDS.  Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary Report:  Stock
No. 017-001-00473-1) through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Domestic and Canadian for-profit and non-profit organizations, public and
private, such as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal government are
eligible to apply.  Foreign institutions other than Canadian are not eligible to
apply but can participate as subcontractors/collaborating institutions.  Thus,
applicants are encouraged to enlist foreign institutions that meet the Office for
Protection from Research Risks (OPRR) requirements as collaborators, because
their contributions in scientific input and patient access might be highly
desirable for the development and conduct of the larger clinical trials. 
Canadian institutions are included because many of them are members of the NCI
Clinical Trials Cooperative Groups and the National Institute of Allergy and
Infectious Diseases (NIAID) AIDS Clinical Treatment Units.  Applications may
consist of one or several institutions that can include, but are not limited to,
the NCI Clinical Trials Cooperative Groups, the NIAID AIDS Clinical Treatment
Units, or a coalition between a Cancer Center and collaborating institutions. 
New and experienced investigators are encouraged to apply.  Applications with
racial/ethnic minority individuals, women, and persons with disabilities as
Principal Investigators are encouraged.

Each applicant as a Clinical Trials Member must demonstrate the ability to
recruit a minimum of 30 patients per year and the willingness to accrue patients
onto four to six different clinical trials.  It is anticipated that the AMC will
perform four to six clinical trials involving approximately 200 patients with
different AIDS-associated malignancies per year.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program will be a
cooperative agreement (U01), an "assistance" 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, primary 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."

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.  If
it is determined that there is a sufficient continuing program need, the NCI will
either invite recipients of awards under this RFA to submit competitive
continuation cooperative agreement applications for review or re-issue the RFA
for re-competition.  If the NCI does not continue the program, awardees may
submit grant applications through the usual investigator-initiated grants
program.

FUNDS AVAILABLE

Approximately $3,000,000 in total costs per year for five years will be committed
to fund applications submitted in response to this RFA. It is anticipated that
10 to 13 awards for Clinical Trials Members of the AMC will be made. Awards and
level of support depend on receipt of a sufficient number of applications of high
scientific merit.  Because of the variation in numbers of patients to be accrued,
it is anticipated that the size of awards will vary also. It is anticipated that
the award for each Clinical Trials Member will be approximately $150,000 direct
costs per year.  There will be a fund within the Operations, Statistics and Data
Management Center to reimburse institutions that accrue above and beyond the
basal level within these awards.  The support provided to the Clinical Trials
Members in years two to five will be performance based and may be adjusted by NCI
staff should accrual to clinical trials be minimal or unacceptably low.  The
total project period for each application submitted in response to the RFA may
not exceed five years.  The earliest anticipated award date is August 1, 1999. 
Although this program is provided for in the financial plans of the NCI, awards
pursuant to this RFA are contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

With the introduction of highly active antiretroviral therapies (HAART) and more
effective treatment of opportunistic infections, the overall survival of patients
infected with the human immunodeficiency virus (HIV) is increasing.  The impact
of HAART on the incidence and course of AIDS-associated malignancies is being
assessed, with early information reported at the NCI-sponsored Second National
AIDS Malignancy Conference in April 1998 showing a decreased incidence of KS and
perhaps of primary central nervous system lymphoma.  Longer term follow-up and
systematic evaluation are critical, particularly as compliance and access to
complex, expensive, multi-agent HAART might be very problematic, and as drug
resistance to some of these newer anti-retroviral therapies emerges.  The impact
of HAART on the other malignancies affecting patients with HIV infection has not
been reported, and it is not known at this time whether these malignancies may
become an increasing cause of morbidity and mortality.

Conventional treatment for these malignancies has only been modestly effective. 
The median survival of HIV-associated NHL is less than one year and only 2 months
for primary central nervous system lymphoma.  Kaposi's sarcoma is an AIDS-
defining illness in 10 to 20% of HIV infected individuals and has been found at
death in over 50% of the patients.  In addition to its disfiguring complications,
it can lead to significant morbidity and to mortality due to GI and pulmonary
complications in a significant proportion of patients.  Conventional therapy in
KS has been palliative.  Several studies have suggested that anogenital
dysplasias and cancer in the HIV infected population may be more biologically
aggressive and resistant to conventional therapeutic approaches.  Research into
the pathogenesis of these HIV-associated tumors has focused on potential
interactions of cytokines, HIV, and other viral co-factors.  The oncogenic roles
of human papilloma virus in squamous cell cancer of the anogenital region and
Epstein-Barr virus (EBV) in the high-grade primary central nervous system
lymphomas have been well documented in cancer patients.  Recent studies have
shown that EBV is also associated with leiomyosarcomas in pediatric AIDS
patients.  A new human herpesvirus (HHV-8/KSHV) has been proposed as a viral
factor in the etiology and biology of AIDS-associated Kaposi's sarcoma.  The
unique DNA sequence of this virus has been shown to be present in over 90% of
AIDS-KS lesions, in a type of diffuse B-cell lymphoma called body cavity-based
lymphoma, which invades the pleural and peritoneal cavities, and in Castleman's
disease, a multicentric angiolymphoproliferative hyperplasia that often presents
with KS.  Numerous other studies have also pointed to dysregulation of cytokines
and to angiogenesis as being significant in the pathogenesis of KS.  New clinical
research opportunities exist with the development of differentiation agents,
monoclonal antibodies, angiogenesis inhibitors, cytokines and growth factor
modulators, and of new approaches to gene therapy and immunomodulating therapy. 
Furthermore, the widespread use of  potent protease inhibitors to suppress HIV
replication has brought into question the effects of these protease inhibitors
on the metabolism of anti-tumor agents in AIDS patients with malignancies and,
vice versa, the impact of chemotherapy on the use of protease inhibitors for the
treatment of the underlying AIDS infection.  Based on the current information on
the potential interactions in the formation of these tumors, the lack of
effective, standard regimens for the treatment of AIDS-associated malignancies,
and the lack of data on drug-drug interactions, the NCI wants to continue to
encourage investigators to apply novel therapies or innovative approaches in
pilot or phase I and II clinical trials.

The AMC was formed on September 30, 1995, from the successful applicants who
responded to the NCI solicitation, "AIDS-Associated Malignancies Clinical Trials
Consortium" (RFA CA-95-009).  Thirteen Clinical Trials Members and one
Operations, Statistics and Data Management Center were funded by cooperative
agreement awards (U01).  The Clinical Trials Members themselves are composed of
multi-centered consortiums with a total of 38 participating institutions.  This
structure of the AMC allowed for multidisciplinary interactions to conceive and
develop the critical scientific questions, flexibility in applying complex
laboratory assessments, and greater access to patient populations.  This
structure also facilitated enhanced interactions with other NIH funded
investigators and resources in the areas of AIDS and malignancies (i.e., AIDS-
Associated Malignancies Bank, AMB; NCI Clinical Trials Cooperative Groups; the
NIAID AIDS Clinical Treatment Units).  The leveraging of resources with the AMB
resulted in the quality control and storage of AMC specimens at AMB sites at no
cost to the AMC and facilitated the conduct of laboratory studies that could
elucidate the mechanism of action of therapeutic interventions as well as the
effects on the underlying virus and immune system.  The Review and Evaluation
Panel of the AMB provided the external peer review of the laboratory proposals
from the AMC and from other extramural scientists made in response to a request
for proposals.  The AMB also received excess specimens obtained from AMC clinical
trials, which can be made available to the research community at large. The AMC
and the NCI-sponsored Clinical Trials Cooperative Groups have worked together to
develop complementary research agendas and work collaboratively to smooth the way
from pilot to larger phase clinical trials. There are extensive interactions
between AMC and the NIAID AIDS Clinical Trial Groups, particularly in the area
of virology and immunology. These interactions with other funded entities
leveraged the current support provided to the AMC and utilized the best available
expertise in conducting the clinical and laboratory studies.

Some examples of the protocols that have been open to patient accrual include:
A pilot study of 5-azacytidine given as a 7-day continuous infusion in HIV
patients with relapsed and/or refractory EBV-associated malignancies (AMC #001);
Phase II trial of 9-cis-retinoic acid in AIDS-Kaposi's sarcoma (AMC #002); Low-
dose interleukin-2 in AIDS lymphoma (AMC #003/CALGB9550); Phase I/II trial to
determine the safety, tolerance and anti-tumor effects of ritonavir and
interferon-alpha-2b combined with nucleoside reverse transcriptase inhibitors in
patients with HIV-related Kaposi's sarcoma (AMC #004); and Pilot study of the
effects of combination chemotherapy (modified CHOP) and triple antiretroviral
therapy on pharmacokinetics, pharmacodynamics, viral load and clinical outcome
in the treatment of AIDS-related non-Hodgkin's lymphoma (AMC #005). Laboratory
studies are associated with each of these protocols.

Objectives and Scope

The purpose of this RFA is to support the Clinical Trials Members of the AMC and
to continue to stimulate cooperative efforts to design and develop clinical
trials using novel agents or innovative approaches in patients with AIDS-
associated malignancies.  Each application may consist of one or more
institutions.  The NCI is seeking talented scientists from academic, non-profit,
and for-profit research organizations who will interact with other members of the
Consortium and with CTEP in a concerted way to conceive, create, and evaluate new
approaches to therapy of AIDS-associated malignancies.  Scientific approaches
taken by the Consortium will continue to be broad and will reflect the creativity
and capabilities of team participants.  Clinical trials using conventional
cytotoxic chemotherapy regimens alone would not be performed within the
Consortium.  In the case of pilot, phase I, or phase II clinical trials,
laboratory studies to monitor patients (e.g., pharmacokinetics, pharmacodynamics)
or to measure a particular biological response (e.g., imaging) that may provide
information relevant to the interpretation of the success or failure of the
therapy administered are encouraged and will be included in the protocol(s) to
be created by the Consortium.  Tissue specimens or biological fluids will be
collected by the Clinical Trial Members for use in laboratory studies or donation
to the AMB.  The potential exists for expanding to phase III studies should the
initial efforts with this project prove successful and relevant phase III
questions are appropriate.  If the Consortium decides to perform phase III
clinical studies, the NCI Clinical Trials Cooperative Groups and the NIAID AIDS
Clinical Treatment Units will be asked to participate.

It is anticipated that the AMC will perform four to six clinical trials involving
approximately 200 patients with different AIDS-associated malignancies per year. 
Thus, each Clinical Trials Member applicant must demonstrate the ability to
recruit a minimum of 30 patients per year in one or more varieties of AIDS-
associated malignancies and the willingness to accrue patients onto four to six
different clinical trials.  Applicants should describe areas of clinical and
laboratory expertise that would serve as a basis for the development of clinical
protocols in specific malignancies by the Consortium.  Incumbent Clinical Trials
Members must document their past progress and accomplishments, including the
actual numbers of patients in the various malignancies enrolled onto the clinical
trials sponsored by the AMC.

In the period immediately following the award of funds, NCI will sponsor a
meeting at which the Principal Investigators of each awarded U01 and NCI staff
will meet to discuss the operational features of the Consortium.  The ideas for
clinical trials provided in the cooperative agreement applications as well as
ideas generated de novo after the formation of the Consortium will be presented,
discussed and prioritized.  Protocols will then be created, reviewed by the
Steering Committee, and submitted to the NCI for review and approval, both to
ensure that they are within the scope of peer review and for safety
considerations, as required by Federal regulations.  The NCI will consult with
NIAID on issues involving antiretroviral therapy and infectious diseases, as is
the current practice.  Such high priority clinical trials will begin after
receiving final NCI approval.

The Consortium will be formed for the purpose of:  (1) sharing expertise of
researchers in several disciplines, (2) conducting joint exploratory phase I and
phase II clinical trials of novel agents or innovative approaches in order to
provide adequate patient populations and timely completion with the potential of
expanding to phase III clinical trials, (3) developing and conducting larger
national or international randomized clinical trials in treatment and/or
prevention should relevant questions arise, and (4) providing tumor tissue and
relevant biological fluids to the recently funded AMB.

SPECIAL REQUIREMENTS

Definitions

AIDS-ASSOCIATED MALIGNANCIES CLINICAL TRIALS CONSORTIUM - The consortium of
Clinical Trials Members and the Operations, Statistics and Data Management Center
which has been awarded separate cooperative agreements (U01s).

AWARDEE - The organization to which a cooperative agreement is awarded and which
is responsible and accountable to NCI for the use of funds provided and for
performance of the cooperative agreement-supported project.

CLINICAL TRIALS MEMBER - The institution or group of institutions that submits
an individual cooperative agreement application for conducting clinical trials
as part of the AIDS-Associated Malignancies Clinical Trials Consortium.

CTEP PROTOCOL REVIEW COMMITTEE - A committee composed of the professional staff
of the CTEP, additional consultants from other NCI divisions, and chaired by the
Associate Director, CTEP, that reviews and approves every protocol involving DCTD
investigational drugs or studies that have any NCI support (funding) and use an
investigational agent.

DISCRETIONARY FUND - A fixed amount of money ($400,000) given to the Operations,
Statistics and Data Management Center to hold, manage and allocate according to
the instructions of the Steering Committee.  Appropriate uses may include funding
for laboratory studies, shipment of samples, providing clinical data to the AMB,
and supplementing existing budgets for patient accrual and auditing of clinical
trials.

NCI COORDINATOR - The Deputy Director, DCTD, who interacts scientifically with
the Applicant/Awardee Institutions.

NCI PROGRAM DIRECTOR - The CTEP extramural grants Program Director, who will
coordinate DCTD's interactions and administer and provide guidance for the
overall program within the NCI.  He/she is available for consultation during
preparation of applications as well as the duration of research conducted through
this cooperative agreement.  He/she serves in a back-up role for the NCI
Coordinator.

OPERATIONS, STATISTICS AND DATA MANAGEMENT CENTER -  The administrative unit that
coordinates all the Consortium activities.  Responsibilities include
administrative management, coordination of protocol development and submission,
study conduct, quality control and protocol performance monitoring, statistical
analyses, adherence to requirements regarding NCI drug accountability and FDA,
OPRR, and HHS regulations, and protocol and institutional performance reporting. 
Statistical responsibilities include experimental design, participation in study
planning and coordination, collection and analysis of patient and laboratory
data, data management and analysis, data monitoring, and reporting of data.  The
Center may be separate from the sites for the Clinical Trials Members, or may be
located at the same site as a Clinical Trials Member.

PRINCIPAL INVESTIGATOR (PI) - The single individual designated by the awardee
institution who is responsible for the scientific and technical direction of the
project.

PROTOCOL CHAIRPERSON - The person who is responsible for the development,
coordination and monitoring of a specific clinical protocol.

STEERING COMMITTEE -  A committee composed of the PIs, the NCI Program Director
and NCI Coordinator that will be the main oversight body of the AIDS-Associated
Malignancies Clinical Trials Consortium.

STEERING COMMITTEE CHAIRPERSON - A member of the Steering Committee (cannot be
the NCI Program Director or the NCI Coordinator) elected by the Steering
Committee who will coordinate the activities of the Consortium with the
Operations, Statistics, and Data Management Center, and chair the biannual
meetings of the Consortium (after the first meeting, which will be convened by
the NCI) to be held at the NCI.  The chairperson shall prepare and distribute the
agendas for each meeting.

Terms and Conditions of Award

The following terms and conditions will be incorporated into the award statement
and provided to the institutional official at the time of award.  These special
Terms of Award are in addition to and not in lieu of otherwise applicable OMB
administrative guidelines, HHS grant administration regulations in 45 CFR part
74 and 92, and other HHS, PHS and NIH grant administration policy statements.
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, primary
responsibility, or a dominant role in the activity.  Consistent with the above
concept, the dominant role and primary 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 Program Director and NCI Coordinator.  The NCI Program Director will
coordinate DCTD's interactions and administer and provide guidance for the
overall program within the NCI.  He is available for consultation during
preparation of the applications as well as for the duration of research conducted
through this cooperative agreement.  He will serve in a back-up role for the NCI
Coordinator scientifically.  The NCI Coordinator will interact scientifically
with the awardee institutions.

Under the cooperative agreement, a relationship will exist between the recipients
of these awards and the NCI, in which the performers of the activities are
responsible for the requirements and conditions described below and agree to
accept program assistance from the NCI Program Director and/or the NCI
Coordinator in achieving project objectives.  Failure of an awardee to meet the
performance requirements, including these special terms and conditions of award,
or significant changes in the level of performance, may result in a reduction of
budget, withholding of support, suspension and/or termination of the award.

A.  Awardee Rights and Responsibilities.

Each Clinical Trials Member Awardee is responsible for:

1.  Participating in the AIDS-Associated Malignancies Clinical Trials Consortium
as evidenced by participating in research design and protocol development,
including definition of objectives and approaches, by optimal patient accrual to
studies, and by following and implementing the operating procedures of the
Consortium.

2.  Participant recruitment (a minimum of 30 patients/yr) and follow-up, data
collection, quality control, interim data and safety monitoring, final data
analysis and interpretation, and publication of results.  Failure to accrue the
minimum number of patients may result in a reduction in or withholding of future
year support.

3.  Serving as Protocol Chairs.  For each specific clinical protocol, a single
Protocol Chairperson (if the P.I. does not assume this role) shall function as
the scientific coordinator for that protocol.  He/she will assume responsibility
for the development of the protocol and monitoring the protocol during the review
process as well as during the actual performance of the clinical trial.  It is
the responsibility of the Protocol Chairperson to obtain approval from the
Steering Committee prior to submitting any proposed letters of intent, concepts,
protocols and modifications to the Operations, Statistics and Data Management
Center for processing.

4.  Implementing the core data collection method and strategy collectively
decided upon by the Steering Committee.  It is the responsibility of each
awardee/site to ensure that data will be submitted in a timely way to the central
Operations, Statistics, and Data Management Center.

5.  Implementing the procedures established by the Operations, Statistics, and
Data Management Center to meet Federal regulatory requirements, especially in the
area of NCI-sponsored investigational agents.

6.  Performing laboratory studies that are specified in the NCI-approved
protocols and collecting tumor tissue and biological fluids for the AMB.

7.  Cooperating in the reporting of the study findings.  The NCI will have access
to and may periodically review all data generated under an award.  Where
warranted by appropriate participation, plans for joint publication of pooled
data and conclusions with the NCI are to be developed by the Steering Committee,
as applicable.  NIH policies governing possible co-authorship of publications
with NCI staff will apply in all cases.  In general, to warrant co-authorship,
NCI staff must have contributed to the following areas:  (a) design of the
concepts or experiments being tested, (b) performance of significant portions of
the activity, and (c) preparation and authorship of pertinent manuscripts.  The
awardee(s) will retain custody of and have primary rights to the data developed
under these awards, subject to Government rights of access consistent with
current HHS, PHS and NIH policies.

B.  NCI Staff Responsibilities

It is expected that the dominant role and primary responsibility for the activity
will 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 Program Director and NCI Coordinator.  The Program Director
and the NCI Coordinator will be the contact points for all facets of scientific
interaction with the awardee(s).  Two NCI staff are required to  coordinate
activities, expedite progress and provide advice to the awardee on specific
scientific and/or analytic issues in addition to programmatic issues.

NCI Program Staff Responsibilities will include:

1.  Interacting with the PI(s) on a regular basis to monitor study progress. 
Monitoring may include:  regular communications with the PI and staff, periodic
site visits for discussions with awardee research teams, observation of field
data collection and management techniques, quality control, fiscal review, etc.,
as well as attendance at Steering Committee, Data and Safety Monitoring
Committee, and related meetings.  The NCI retains, as an option, the right to
periodic external review of progress.

2.  Convening the first meeting of and subsequent participation in the Steering
Committee that oversees the AIDS-Associated Malignancies Clinical Trials
Consortium.  The NCI Program Director and NCI Coordinator will be full
participants and voting members of the Steering Committee and, if applicable,
subcommittee(s).

3.  Serving as a resource with respect to other ongoing NCI activities that may
be relevant to the protocol to facilitate compatibility and avoid unnecessary
duplication of effort.

4.  Substantial involvement by assisting in the design and coordination of
research activities for awardees as elaborated below:

a.  Providing advice in the management and technical performance of the
investigations;

b.  Coordinating clearances for investigational agents held by NCI. The NCI may
reserve the right to crossfile or independently file an Investigational New Drug
Application form with the FDA;

c.  Coordinating activities among awardees by assisting in the design,
development, and coordination of a common research or clinical protocol and
statistical evaluation of data; in the preparation of questionnaires and other
data recording forms; and in the publication of results.  Assistance in protocol
development at the minimum will include providing information regarding: (1) the
existence and nature of concurrent clinical trials in the area of research,
pointing out possible duplication of effort, (2) pharmacodynamic data concerning
investigational agents, (3) availability of investigational agents, and (4)
therapy for underlying HIV infection and other infectious diseases (NIAID will
be NCI's consultant);

d.  Reviewing and approving protocols to ensure that they are within the scope
of peer review and are safe, as required by Federal regulations.  Final drafts
of protocols approved by the Steering Committee will be reviewed by the CTEP
Protocol Review Committee (PRC), which will meet weekly.  The PRC will be chaired
by the Associate Director, CTEP, or his/her designee and is composed of the
professional staff of the CTEP and additional consultants from other NCI
divisions.  The NCI Coordinator will provide the Protocol Chairperson via the
Operations, Statistics and Data Management Center, with a consensus review that
describes recommended modifications and other suggestions as appropriate.  The
major considerations relevant to protocol review include: (1) the strength of the
scientific rationale supporting the study, (2) the medical importance of the
question being posed, (3) the avoidance of undesirable duplication with other
ongoing studies, (4) the appropriateness of study design, (5) a satisfactory
projected accrual rate and follow-up period, (6) patient safety, (7) compliance
with federal regulatory requirements, (8) adequacy of data management, and (9)
appropriateness of patient selection, evaluation, assessment of toxicity,
response to therapy and follow-up.

If a proposed protocol is disapproved, the specific reasons for lack of approval
will be communicated to the Protocol Chairperson and the Steering Committee 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 PRC has not approved.  The NCI Coordinator will be available to assist the
Protocol Chairperson and the Steering Committee in developing a mutually
acceptable protocol, consistent with the research interests, abilities and
strategic plans of the Consortium and of the NCI;

e.  Monitoring protocol progress and involvement in protocol closure.  The NCI
Program Director and NCI Coordinator will monitor protocol progress and may
request that a protocol study be closed to accrual for reasons including:  (a)
accrual rate insufficient to complete study in a timely fashion, (b) accrual
goals met early, (c) poor protocol performance, (d) patient safety and regulatory
concerns, (e) study results that are already conclusive, and (f) emergence of new
information that diminishes the scientific importance of the study question.  The
NCI will not permit further expenditures of NCI funds for a study after
requesting closure (except for patients already on-study);

f.  Reviewing and providing advice regarding the establishment of mechanisms for
quality control and study monitoring.  For specific phase I/II trials with NCI-
sponsored agents, the NCI will arrange for the 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 II trials
with NCI-sponsored investigational agents not requiring the above described
monitoring, NCI will delegate to the Operations, Statistics and Data Management
Center awardee the task of providing an independent audit of each research study. 
The CTMS shall be used to conduct these audits.  Random audits by NCI staff will
be performed to assure that the awardee is performing the delegated audit duties.

5.  Making recommendations to the Steering Committee on the allocation of monies
from the Discretionary Fund.

C.  Collaborative Responsibilities

In addition to the interactions defined above, NCI Staff and Awardees shall share
responsibility for the following activities:

1.  Service on the Steering Committee.  The Steering Committee has primary
responsibility to design research activities, establish priorities, develop and
provide preliminary approval of protocols (prior to submission to NCI and final
NCI approval), develop manuals, questionnaires and other data recording forms,
establish and maintain quality control among awardees, review progress, monitor
patient accrual, coordinate and standardize data management, and cooperate on the
publication of results.  Major scientific decisions regarding the core data will
be determined by the Steering Committee.  The Steering Committee will also
authorize spending of money from the Discretionary Fund and allocate the funds
to Clinical Trial Members based on scientific and administrative needs and
priorities.  Appropriate uses may include funding for laboratory studies,
shipment of samples and providing clinical data to the AMB, and supplementing
existing budgets for patient accrual and auditing of clinical trials.  The PI of
the Operations, Statistics and Data Coordinating Center, with the help of the
Steering Committee Chairperson, will document actions taken and progress made in
written reports to the NCI Program Director and will provide periodic
supplementary reports to designated NCI staff upon request.

The Steering Committee will be composed of all PI(s), including the PI of the
Operations, Statistics and Data Coordinating Center, the NCI Program Director and
the NCI Coordinator.  An initial meeting of the Steering Committee will be
convened early after award by the NCI Program Director and NCI Coordinator.  The
final structure of the Steering Committee will be established at the first
meeting.  The NCI will have one vote on the Steering Committee or any of its
subcommittees, despite the fact that two NCI staff members (Program Director and
NCI Coordinator) may serve on such committees.  The Steering Committee usually
will meet twice yearly.

A Steering Committee Chairperson, not one of the NCI representatives, will be
selected by a vote of the members during the initial meeting of the AIDS-
Associated Malignancies Clinical Trial Consortium.  The Chairperson shall
function as a liaison between the NCI program staff and the Consortium, as well
as a liaison between the Clinical Trial Members and the Operations, Statistics,
and Data Management Center.  He/she is responsible for coordinating the Committee
activities, preparing meeting agendas, and scheduling and chairing meetings.

2.  Service on Data and Safety Monitoring Committee and Ad Hoc Monitoring
Committees.  The major emphasis of the Consortium is on exploratory phase I and
phase II trials.  However, the AMC should have the capability to expand to phase
III trials should the initial results with the early phase trials prove promising
and appropriate phase III questions exist.  Phase III trials will require an
independent Data and Safety Monitoring Committee established by the Steering
Committee.  The Data and Safety Monitoring Committee will review interim results
periodically and report to the Steering Committee and the NCI.  In all other
studies, exploratory phase I and phase II trials, where warranted, the NCI
Program Director and NCI Coordinator will facilitate, and the awardee shall allow
for, interim data and safety monitoring through ad hoc committees established by
the Operations, Statistics, and Data Management Center.

D.  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 awardee, 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.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

Investigators proposing research involving human subjects should read the "NIH
Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (59 FR
14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.  This
policy applies to all initial (type 1) applications submitted for receipt dates
after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by October 21, 1998, a letter of
intent that includes a descriptive title of the proposed research, name, address,
and telephone number of the Principal Investigator, identities of other key
personnel and participating institutions, and 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 allows the NCI staff to estimate the potential
review workload and to avoid conflict of interest in the review.

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

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev 5/95) is to be used in applying
for these awards.  These forms are available at most institutional offices of
sponsored research; from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/435-0714, Email: GrantsInfo@nih.gov; and
from the NIH program administrator listed under INQUIRIES.

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.

It is critical that applicants clearly describe plans to accommodate stated
criteria and staff involvement as listed in the Terms and Conditions of Award,
and in the Review Criteria section.

Investigators applying to be a Clinical Trials member should provide
documentation of all of the following:

o  ability to meet the minimum requirement of accruing 30 patients with AIDS-
associated malignancies per year by documenting the number of HIV-infected
patients seen at their institutions, the number of patients for each AIDS-
associated malignancy available for accrual, the number of AIDS patients with
malignancies who actually enrolled in clinical trials, and the plans for outreach
to women/minority/children populations;

o  commitment to accrue patients to clinical trials being performed through the
Consortium and acknowledgment that those clinical trials have the highest
priority, and detailing other competing studies (e.g., pharmaceutical-sponsored)
in similar patient populations;

o  Documentation of the actual number of patients with AIDS-associated
malignancies accrued to clinical trials sponsored by the AMC by incumbent
Clinical Trials Members;

o  ability and history of conducting and monitoring phase I and phase II trials
with specific documentation of such trials;

o  expertise in specific therapeutic modalities, specific laboratory and imaging
methodologies, and data management;

o  availability of appropriate facilities and equipment including clinical,
computer and data management, laboratory facilities and facilities for handling
and storing patient specimens;

o  clinical expertise in disease-specific issues in the AIDS-malignancies they
wish to study, which may include, but are not limited to, AIDS-associated NHL,
KS, and anogenital dysplasias and cancer;

o  clinical expertise in infectious disease(s) for patient care;

o  willingness to provide clinical data and tumor tissue and relevant biological
fluids to the AMB;

o  willingness to collaborate with other Clinical Trials Members of the
Consortium and with CTEP, and to prioritize and to participate in the clinical
trials that will be run by the Consortium;

o  provide a discussion of the types of clinical studies/trials, for which the
investigators have expertise, that could be run through the Consortium.  The
investigators would have the option to describe the monitoring of patients using
laboratory assays or imaging techniques and whether or not their institution has
the expertise to perform such monitoring;

o  state the applicant's area of scientific expertise in AIDS-associated
malignancies, discuss and document the expertise (funded grants, publications,
etc.), and describe how the applicant would bring this expertise into the
Consortium;

o  describe the unique contributions that could be made by the applicant to the
Consortium.  Incumbent Clinical Trials Members must document progress and
contributions.

The applicants for Clinical Trials Member should request funds for clinical
studies including monies for the efforts expended in the performance of the
clinical trials necessary to accrue a minimum of 30 patients/year, and monies for
quality control of data and travel for two meetings per year at the NCI.

The RFA label available in the PHS 398 (rev. 5/95) must be affixed to the bottom
of the face page of the application.  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 title and number must be
typed on line 2 of the face page of the application form and the YES box must be
marked.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20850 (for express/courier service)

Applications must be received by November 18, 1998.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
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.

REVIEW CONSIDERATIONS

Review Method

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NCI.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  Applications that
are complete and responsive to the RFA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by the NCI in
accordance with the review criteria stated below.  As part of the initial merit
review, all applications will receive a written critique and may undergo a
process in which only those applications deemed to have the highest scientific
merit will be discussed, assigned a priority score, and receive a second level
of review by the National Cancer Advisory Board.

Review Criteria

All applications will be judged on the basis of the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA as listed under Review
Criteria.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

o  Significance.  The significance of the program overall and its potential to
advance scientific knowledge in the field.

o  Approach.  The adequacy and quality of the experimental approaches proposed
in the projects and the overall design of the project including: progress and
contributions made by Incumbent Clinical Trials Member; adequacy of plans for
recruitment and retention of subjects; extent of potential contributions to the
AMC in scientific and clinical approach; and adequacy of plans to provide tumor
tissue, biological fluids and relevant clinical data to the AMB.

o  Innovation.  The degree to which the overall program applies novel concepts
and innovative approaches.

o  Investigators.  The qualifications and experience of the Principal
Investigator and other key personnel to meet the requirements for participation
listed under APPLICATION PROCEDURES; the ability to design, conduct, monitor and
analyze phase I and II clinical trials; and the ability to perform studies to
monitor patients using laboratory assays or imaging techniques that would be
relevant to AIDS-associated malignancies as documented by publications or
previous funding.

o  Environment.  Scientific, organizational and administrative environment. 
Documentation by Incumbent Clinical Trials Members of the actual numbers of
patients accrued to AMC clinical trials or demonstration of availability of and
access to sufficient numbers of evaluable patients for the conduct of phase I and
II clinical trials; and adequacy of existing physical facilities and resources
of the organization.

As part of the scientific and technical merit evaluation of the research plan,
reviewers will be instructed to address the adequacy of plans to include both
genders, minorities and their subgroups, and children as appropriate for the
scientific goals of the research, and the adequacy of provisions for protection
of human subjects.

AWARD CRITERIA

Applications recommended by the National Cancer Advisory Board will be considered
for award based upon (a) technical merit of the application as reflected in the
priority score, (b) availability of resources and study population, and (c)
availability of funds.  Furthermore, the applicant organization must indicate a
commitment to accept provisions outlined under the SPECIAL REQUIREMENTS section,
Terms and Conditions of Award.  The earliest anticipated date of award is August
1, 1999.

Schedule

Letter of Intent Receipt Date:    October 21, 1998
Application Receipt Date:         November 18, 1998
Review by NCI Advisory Council:   May 1999
Earliest Anticipated Award Date:  August 1, 1999

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.

Direct inquiries regarding scientific issues to:

Ellen Feigal, M.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
31 Center Drive, Room 3A44, MSC 2440
Bethesda, MD  20892-2440
Telephone:  (301) 496-6711
FAX:  (301) 496-0826
Email:  FEIGALE@DCTOD.NCI.NIH.GOV

For programmatic information and address the letter of intent to:

Roy S. Wu, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-8866
FAX:  (301) 480-4663
Email:  WUR@CTEP.NCI.NIH.GOV

Direct inquiries regarding fiscal information to:

Ms. Crystal Wolfrey
Grants Management Branch
National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 282
FAX:  (301) 496-8601
Email:  Crystal.Wolfrey@NIH.GOV

Direct inquiries regarding review procedures to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  friedbet@dea.nci.nih.gov

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
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR parts 52 and 45 CFR Part 74 [and Part 92
when applicable for State and Local governments].  This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or Health
Systems agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition, Public
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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