Full Text CA-93-09

PHASE II TRIALS OF NEW ANTI-CANCER AGENTS

NIH GUIDE, Volume 22, Number 5, February 5, 1993

RFA:  CA-93-09

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Clinical Trial 
  Chemotherapeutic Agents 


National Cancer Institute

Letter of Intent Receipt Date:  April 1, 1993
Application Receipt Date:  June 10, 1993

PURPOSE

The Division of Cancer Treatment (DCT), National Cancer Institute
(NCI) invites applications from single institutions or consortia of
institutions wishing to perform scientifically directed Phase II
trials of promising anti-cancer agents particularly in, but not
limited to, tumors of special interest such as breast, ovarian, lung,
and urologic cancers and to conduct laboratory studies in support of
the clinical trials such that their conduct leads to a greater
understanding of the relationship between drug administration and
biological changes in patients.

The numbers of promising new agents with novel mechanisms of action
has increased in recent years, and many of these new agents can only
be accurately evaluated in patients in whom the cancer cells have
been biologically characterized (e.g., for the presence of a specific
gene, cytoplasmic protein, or cell surface receptor to which the
agent is targeted).  The increasing numbers of promising new agents
with novel mechanisms of action and the large number of institutions
both capable of and interested in conducting Phase II clinical trials
of cancer therapies in parallel with appropriate biological studies
of the cellular target of the particular agent makes it desirable to
expand NCI support in this area.  Institutions responding to this RFA
should be able to perform Phase II trials in parallel with
pharmacological, immunological, biochemical, or other appropriate
biological studies of the cancer cells from individual patients.

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,
Phase II Trials of New Anti-Cancer Agents, 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

Domestic for-profit and non-profit organizations such as
universities, colleges and hospitals and governments and their
agencies are eligible to apply.  Applications from minority
individuals and women are encouraged.  An applicant may consist of a
single institution or a consortium of institutions for the purpose of
accessing a sufficient patient population.  An applicant functions as
an integrated unit with a common goal and is under the guidance and
direction of a single Principal Investigator.  Participation by
foreign institutions in the non-clinical aspects of this project is
acceptable.  All accrued patients must be treated in the United
States.

MECHANISM OF SUPPORT

Support of this program will be through the Cooperative Agreement
(U01), an assistance mechanism in which substantial NCI programmatic
involvement with the recipient during performance of the planned
activity is anticipated.  The nature of NCI staff involvement is
described in the section SPECIAL REQUIREMENTS, Terms of Cooperation,
Nature of Participation by NCI Staff.  Applicants will be responsible
for the planning, direction, and execution of the proposed project.
There is no intent, real or implied, for NCI staff to direct awardee
activities or to limit the freedom of investigators.

Under the Cooperative Agreement, a relationship exits between the
recipient of the award and the NCI, in which the recipient is
responsive to the requirements and conditions set forth in the RFA.
Specifically, the Principal Investigator defines the details for the
project within the quidelines of the RFA, retains primary
responsibility for the performance of the activity, and agrees to
accept close coordination, cooperation and assistance of the NCI
extramural staff (through the NCI Program Director) in all aspects of
scientific and technical management of the project in accordance with
the Terms of Cooperation.

Except as otherwise stated in this RFA, awards will be administered
under PHS grants policy as stated in the Public Health Service Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised
October 1, 1990.

This RFA is a one-time solicitation.  However, if it is determined
that there is a sufficient continuing program need, the NCI will
invite recipients of awards under this RFA to submit competitive
continuation cooperative agreement applications for review according
to the procedures described in Review Considerations, Part A.

It is anticipated that the average amount of the total direct costs
per year for each award will range from $150,000 to $200,000.

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.  This funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.  It is
anticipated that six to eight awards will be made.  The total project
period for applications submitted in response to the present RFA may
not exceed four years.  The earliest feasible start date for the
initial awards will be April 1, 1994.  Although this program is
provided for in the financial plans of the NCI, the award of
cooperative agreements pursuant to this RFA is also contingent upon
the availability of funds for this purpose.

RESEARCH OBJECTIVES

A.  Background

The purpose of this RFA is to provide support for Phase II
scientifically-directed clinical trials with investigational
anti-cancer agents.  New therapeutic agents for cancer are initially
investigated in patients by means of Phase I clinical trials designed
to evaluate the pharmacology, toxicities, and biological effects of
the agents.  Agents that have favorable characteristics in the Phase
I setting are then studied in Phase II trials designed to
characterize their anti-tumor activity.  If efficacy is established
in a particular tumor site in Phase II testing, it may be necessary
to study the agent alone, or in combination in further Phase II or
even large scale randomized Phase III trials.

Specifically, the objectives of Phase II trials are:

a.  when testing new agents that have just completed Phase I trials,
to confirm that the dose and schedule chosen can be safely
administered in subsequent Phase II trials;

b.  to determine the antitumor activity of existing antitumor agents
that can be administered in significantly higher doses when used with
colony stimulating factors or other factors that modulate toxicity or
antitumor activity;

c.  to determine the antitumor activity of combinations of antitumor
agents and modalities;

d.  to determine the spectrum of antitumor activity for new agents in
selected human cancers.

e.  to gain further insight into the pharmacokinetics and metabolism
of the therapeutic agent,  its mechanisms of action and/or toxicity
and identification of the particular patient population most likely
to benefit from its effects through the performance of parallel
biological studies.

Recent advances in understanding of the pathobiology of malignancy
are leading to the development of a wide range of novel anti-cancer
therapeutic agents which require Phase II testing.  These agents
include new classes of cytotoxic agents derived from natural
products, agents acting via immune-stimulatory effects, and agents
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 classic
direct anti-RNA or DNA synthesis cytotoxic mechanisms and indirect
immunologic mechanisms, but also through growth inhibition by
interruption of specific oncogene-associated biochemical functions,
biochemical reversal of drug resistance to other anti-cancer agents,
inhibition of protein synthesis through targeted toxins, induction of
differentiation and/or programmed cell death (apoptosis), and through
anti-tumor angiogenesis.  In addition, new strategies to overcome
resistance to conventional cancer therapeutic approaches are also of
interest.

In an attempt to reduce the time period between new drug discovery
and the general introduction of an effective new therapy to patients,
the NCI offers assistance at many levels to investigators attempting
to develop active new cancer therapies.  In addition to the funding
assistance offered to the investigator(s) by this RFA, NCI may
sponsor (in the Food & Drug Administration sense) or co-sponsor the
agents under development.  An organization or individual who assumes
legal responsibilities for supervising or overseeing clinical trials
with investigational agents is termed a sponsor.  As sponsor of an
investigational drug, DCT and specifically, CTEP, is responsible for
seeing that clinical trials proceed safely and rationally from the
initial dose-finding studies through to a definitive evaluation of
the role of the new drug in the treatment of one or more specific
cancer(s).  Fulfillment of this goal obviously requires the active
participation of CTEP staff throughout the entire process.  NCI
sponsorship of investigational agents increases the likelihood that
agents will be further developed so that they will ultimately be
broadly available for use in cancer treatment and will accelerate the
time frame in which this process would occur.

B.  Research Goals and Scope

The aims of this initiative are:  (1) to provide support for Phase II
trials of promising new anti-cancer agents, particularly in, but not
limited to, tumors of special interest such as breast, ovarian, lung,
and urologic cancers; and (2) to provide support for appropriate
laboratory correlative studies in cancer patients receiving these
anti-cancer agents.  The laboratory studies should be in support of
the clinical trial, such that their conduct leads to a greater
understanding of the relationship between drug administration and
biological changes in patients.  Laboratory studies would include
pharmacokinetic studies of cytotoxic, immune-modulating,
differentiation-inducing, and/or targeted anti-cancer agents,
including monitoring of metabolites and intracellular products when
appropriate, or other relevant pharmacology correlative studies.
Measurement of particular biological responses would also be
desirable particularly when this information would be relevant to the
interpretation of the success or failure of the agent in individual
patients entered into the Phase II trial (e.g., changes in signal
transduction pathways, immune modulation, induction or suppression of
specific gene function, other indicators of differentiation
induction, or induction of apoptosis).

Specific objectives and scientific approaches will be
investigator-originated and should reflect the creativity and
capability of the investigators.  This RFA provides an opportunity
for clinical and laboratory investigators within an institution or
consortia of institutions to develop a program in drug development
which utilizes the strengths of pre-existing basic scientific
expertise and available clinical resources.  The applicant/awardee
Principal Investigator will select the specific agents to be tested
in accord with their area of scientific interest and expertise and
will develop a series of appropriate phase II trials with supporting
protocol documents.  The NCI may provide NCI-sponsored IND agents or
provide assistance to the awardee by sponsoring or co-sponsoring
other selected agents.

Each Phase II awardee/consortium will be expected to complete on
average two to three Phase II trials per year, with each trial
encompassing 20 to 40 patients.  In all categories of diseases, the
awardee must select those patients for trial with the best
performance status and with the minimum amount of prior treatment
that is consistent with ethical medical practice.  Sufficient numbers
of patients should be available in order to allow completion of the
trials in a timely manner.  These trials should also include
evaluation of laboratory parameters which reflect the biological or
biochemical effects of therapy in a relatively homogeneous group of
patients as preparations for larger studies which may show
correlations with response or toxicity.  Studies of regional drug
administration will be permitted upon documentation of expertise with
necessary techniques of drug delivery and pharmacology and evidence
that this therapeutic approach might yield meaningful therapeutic
benefit to patients.  Similarly, exploration of the upper end of the
dose-response curve, using appropriate approaches for protection of
normal tissues, may be permitted in suitably documented
circumstances.

The Principal Investigator will ensure that these Phase II trials
conform to accepted standards of patient care.  For example, patients
should:

a.  have a microscopically confirmed diagnosis of cancer;

b.  be staged by conventional methods and found to have disseminated
disease not amenable to curative intent therapy with surgery and/or
radiotherapy;

c.  have already received and failed appropriate initial systemic
treatment.  For diseases for which active systemic treatment exists
(e.g., the acute leukemias, diffuse non-Hodgkin's lymphomas,
Hodgkin's disease, testicular cancer, limited small cell lung cancer,
ovarian carcinoma), patients should have received the minimum extent
of prior treatment compatible with current ethical standards of care,
and should have a high performance status.  For other diseases in
which only partially effective non-curative therapy is available
(e.g., carcinomas of the head and neck, hormone-refractory prostatic
carcinoma, bladder and stomach cancer, sarcomas), entry of patients
with no prior therapy may be appropriate.

d.  receive appropriate initial and follow-up, hematologic,
biochemical, radiologic. and immunologic investigations; and

e.  have given a signed informed consent indicating that they are
aware of the investigational nature of the studies involved.

Each applicant institution is responsible for coordination of
protocol development and submission, study conduct, quality control
and study monitoring, collection of data, data management and
analysis, adherence to NCI requirements for investigational agents,
adherence to FDA/DHHS regulations, and performance reporting of data
from the Phase II trials.  An applicant may consist of a consortia of
institutions, each contributing scientific expertise and/or
appropriate patient populations.  Multi-institution studies must be
conducted in accordance with the "DCT GUIDELINES FOR MULTICENTER
INVESTIGATIONAL AGENT STUDIES" (available upon request from Dr. David
Parkinson at address below).  For selected Phase I and selected Phase
II studies 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
of the biweekly Phase I/II investigator data submissions, and to
produce periodic routine reports of the results and special reports
as necessary.  For selected Phase II studies, the awardee
institution's source documentation will be reviewed on-site three
times per year by the CTMS.

Each applicant institution is responsible and accountable for both
the use of the funds provided and for the performance of the
cooperative agreement supported activity.

SPECIAL REQUIREMENTS

A.  Minimal Requirements for Application

1.  Investigators should include in the APPENDIX of the cooperative
agreement application draft copies of proposed protocols that might
be undertaken in the first year and should identify the particular
areas of laboratory expertise which would be utilized in the
performance of these trials.

2.  The applicant must demonstrate in the application the ability to
meet the following requirements:

a.  documented numbers of eligible patients with a history of
adequate accrual to complete on average two to three Phase II trials
annually.

b.  laboratory support within the institution to perform
pharmacokinetic studies of cytotoxic, immune-modulating,
differentiation-inducing, and/or targeted anti-cancer agents,
including monitoring of metabolites and intracellular products when
appropriate, or other relevant pharmacology correlative studies;

c.  technical expertise and evidence of specific focus (e.g.,
pathology, immunopathology, molecular biological support) within the
institution which would allow the measurement of biological response
particularly when this information would be relevant to the
interpretation of the success or failure of the agent in individual
patients entered into the Phase II trial (e.g., changes in signal
transduction pathways, immune modulation, induction or suppression of
specific gene function, other indicators of differentiation
induction, or induction of apoptosis);

d.  adequate central data collection and processing capabilities as
well as biostatistical expertise and the capability to meet FDA
requirements for the conduct of research using investigational
agents.  These specifically include:

1)  Supplying required information via study summary reports to CTEP
and the capability to transmit patient data to the NCI's Clinical
Trials Monitoring Service (CTMS) on a biweekly basis for selected
trials.

2)  prompt reporting of ADRs to CTEP for investigational agents
supplied by NCI in accordance with the CTEP guidelines (mailed
annually to all registered investigators).

e.  adequate pathology support for tumor classification and for
banking and distribution of tumor tissues for concurrent and future
studies.

f.  adequate mechanisms in place to ensure that all patients:

1)  have histologically confirmed diagnosis of cancer;

2)  have refractory disease not amenable to therapy with curative
intent using surgery, chemotherapy, and/or radiotherapy or any other
form of known effective therapy;

3)  have acceptable performance status and acceptable renal, liver,
and hematologic function; and

4)  have given signed informed consent in accordance with 45 CFR 46,
Protection of Human Subjects, indicating that they are aware of the
investigational nature of the studies involved.

g.  adequate mechanisms for monitoring accrual performance and
criteria for continued participation by each participating
institution.

3.  The applicant institution and each participating institution
associated with an applicant consortium must demonstrate the ability
to meet the following requirements:

a.  Evidence of a level of supportive care appropriate for the
treatment of patients with advanced malignancies;

b.  Adequate patient accrual with annual monitoring to assure
continued enrollment of patients on Phase II trials.

c.  Intensive care and blood bank facilities on-site and functioning
24 hours per day.

d.  Adequate physician, nursing and data management resources to
comply with all data reporting requirements (through the PI) of
NCI-sponsored Phase II trials.

e.  Appropriate drug accountability procedures as required for
utilization of NCI-supplied investigational agents.

4.  In the case of consortium applications, the applicant must
demonstrate how it will collect, analyze and report data from Phase
II trials; and how it will coordinate protocol development and
submission, study conduct, quality control and study monitoring, data
management and analysis, adherence to requirements regarding
investigational drug management and federally mandated regulations,
and protocol and progress reporting.

5.  All costs required for these studies must be included in the
application and must be fully justified.  These costs include the
additional costs of clinical research associated with Phase II
studies including costs for patient accrual, sample handling,
laboratory studies, quality assurance, data management and data
analysis, study monitoring, travel, an on-site audit program and the
biweekly electronic data submissions to the NCI's Clinical Trials
Monitoring Service when required.  For Phase II trials with DCT IND
agents for which the awardee is responsible for providing the on-site
monitoring, the awardee shall contract with the NCI's Clinical Trials
Monitoring Service for the performance the audits.  The awardee(s)
will be expected to provide two audits per institution during the
cooperative agreement period and to request funding accordingly.
Funds requested for the audit program will be restricted for this
purpose only.  The on-site audit requirements are described in the
section entitled SPECIAL REQUIREMENTS, TERMS OF COOPERATION,
RESPONSIBILITIES OF AWARDEE.

6.  If capitation costs are requested as reimbursement for patient
accruals, the cost per patient must be broken down and justified,
e.g.:

a.  estimate of physician time spent on research (e.g., to obtain
informed consent, to fill out data forms, and others) and the
resultant cost.  Time spent delivering standard medical care is not
allowable.

b.  estimate of data manager or nurse time to meet research
requirements (e.g., compiling and mailing data, specimens) and the
resultant cost.

c.  cost of mailing or handling research-related patient specimens,
forms, materials (e.g., slides, X-ray)

d. other consultant costs (e.g., pathology, radiology).

7.  Travel funds for one meeting per year for two representatives
from an Institution should be included in the budget.  The applicant
should also request funding for the initial Phase II strategy
meeting.

B.  Terms of Cooperation

The following Terms of Cooperation are in addition to and not in lieu
of otherwise applicable OMB administrative guidelines, HHS grant
administration regulations at 45 CFR Part 74 and 92, and other HHS,
PHS and NIH grant administration policy statements.  The NCI
arbitration process for the cooperative agreement in no way affects
the rights of awardees to appeal selected post award administrative
decisions in accordance with PHS regulations at 42 CFR part 50,
subpart D and HHS regulations at 45 CFR part 16.

Nature of Participation By NCI Staff

The role of the Cancer Therapy Evaluation Program (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.

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

The NCI Program Director (see INQUIRIES) will serve as a resource
available to the Principal Investigator (PI) for specific scientific
information with respect to treatment regimens and clinical trial
design.  The NCI Program Director will assist the PI as appropriate
in developing information concerning the scientific basis for
specific trials and also will be responsible for advising the PI of
the nature and results of relevant trials being carried out
nationally or internationally.  The NCI Program Director will also
provide updated information on the efficacy and toxicity of
investigational new agents supplied to the PI under an
Investigational New Drug (IND) Application sponsored by the DCT.

The NCI Program Director will sponsor an initial Phase II strategy
meeting with the PIs to review the research plans proposed by each
individual research group to ensure that they are compatible with the
overall goals of the RFA, to ensure avoidance of duplication of
effort with other ongoing clinical trials and to ensure the most
effective use of available resources including investigational
agents.  An arbitration system, as detailed below, will be available
to resolve disagreements between the NCI and the awardee
institution(s).

The NCI Program Director will sponsor annual Phase II strategy
meetings  to review relevant scientific information, to review
progress in the clinical trials, and to review the status of newly
available investigational agents in order to plan future activities.

2.  CTEP Assistance in Protocol Development

A 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), which must review and approve every
protocol involving DCT investigational agents.  The PRC is chaired by
the Associate Director, CTEP, and is comprised 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 by the PRC chairperson.

Communication at the various stages of protocol development is
encouraged as necessary to promote protocol development and
implementation.  All protocols should be preceded by a written
declaration of interest in conducting a particular study from the PI
using the format described in the GUIDELINES FOR SUBMITTING LOIs -
Letter of Intent/INVESTIGATIONAL DRUG TRIAL (available upon request
from Dr. David Parkinson at the address below).  The LOI should be
sent to the CTEP LOI Coordinator who receives, logs in and schedules
LOIs for review by the PRC (see RESPONSIBILITIES OF AWARDEES).  The
PRC will formally review the LOI.  Following LOI review, the NCI
Program Director will provide a Program response to the PI 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 including relevant
pharmacokinetic and pharmacodynamic data concerning investigational
agents; c) availability of investigational agents, including biologic
response modifiers; d) the scientific rationale and value of the
proposed study, the design, the statistical requirements; and e) the
implementation of the study, if indicated.  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 Dr. David Parkinson at the address
below, for further discussion of these mechanisms).

3.  CTEP Review of Proposed Protocols

The awardee protocols will be reviewed by the PRC which meets weekly.
It will be chaired by the Associate Director, CTEP.  Ad hoc
reviewers, external to NCI, will be utilized when deemed appropriate
by the PRC chairperson.

An Investigational Drug Branch (IDB) Physician (Drug Monitor) is
assigned to each DCT IND agent to assist in the coordination of its
development.  Following the review of the protocol by the PRC, the
NCI Program Director will provide the PI with a consensus review
prepared by the IDB Drug Monitor.  The consensus review describes
required or recommended modifications and other suggestions, as
appropriate.  The NCI Program Director will not serve as the
consensus reviewer. (See the DCT Investigator's Handbook, for further
information regarding protocol review at CTEP).

The major considerations relevant to Protocol Review by CTEP include:
a) the strength of the scientific rationale supporting the study; b)
the medical importance of the question being posed; c) the avoidance
of unnecessary duplication with other ongoing studies; d) the
appropriateness of study design with respect to development of the
IND agent; e) a satisfactory projected accrual rate and follow-up
period; f) patient safety; g) compliance with federal regulatory
requirements; h) adequacy of data management; and i) 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 by the NCI Program Director to the
PI as a consensus review within 30 days of protocol receipt by the
NCI.  The NCI Program Director will be available to assist the PI in
developing a mutually acceptable protocol, consistent with the
research interests, abilities and strategic plans of the PI and of
the NCI.

Disagreements arising pursuant to protocol approval will be submitted
to an arbitration panel to determine the suitability of a protocol
that has been disapproved.  An arbitration panel composed of one
awardee institution nominee, one NCI nominee, and a third member with
clinical trials expertise chosen by the other two nominees will be
formed to review the CTEP decision and recommend an appropriate
course of action to the Director, DCT. These special arbitration
procedures in no way affect the awardee's right to appeal an adverse
determination in accordance with PHS regulations at 42 CFR Part 50,
Subpart D, and HHS regulations at 45 CFR Part 16.

NCI will not provide investigational agents or permit expenditure of
NCI funds for a protocol that it has not approved unless CTEP's
disapproval has been modified by the arbitration process outlined
above.

4.  CTEP Review of Quality Control and Study Monitoring

The Head, Quality Assurance and Compliance Section (QACS), RAB, CTEP
will review and provide advice, through the NCI Program Director,
regarding mechanisms established by the awardee institution for study
monitoring including the awardee's on-site monitoring program.  (See
9. CTEP Review of Federally Mandated Regulatory Requirements.)

5.  CTEP Review of Data Management and Analysis

The Chief, Biometrics Research Branch (BRB), CTEP will review awardee
institution mechanisms for data management and analysis. (See
RESPONSIBILITIES OF AWARDEES).  When deemed appropriate, the Chief,
BRB will make recommendations to the PI, through the NCI Program
Director, 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 consortia participants.

6.  Access to Data

The NCI will have access to all data generated under this cooperative
agreement and will 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.

7.  CTEP Involvement in Protocol Closure

The NCI Program Director will monitor protocol progress.  When a
study involves a DCT IND agent, the Head, QACS and the IDB Drug
Monitor as well as the NCI Program Director will monitor protocol
progress.  The NCI Program Director or the IDB Drug Monitor may
request that a protocol 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; f) emergence of new information that
diminishes the scientific importance of the study question; and g)
failure to collect data in a timely manner.  NCI will not provide
investigational agents or permit expenditures of NCI funds for a
study after requesting closure (except for patients already
on-study).  If disagreements develop over NCI-recommended study
closure for reasons other than patient safety or regulatory concerns,
NCI will establish an arbitration process identical to that described
above for protocol disapproval.

8.  CTEP involvement in Investigational New Drug Applications

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

b.  The NCI Program Director assisted by the Chief, Regulatory
Affairs Branch (RAB), CTEP, will advise investigators of specific
requirements and changes in requirements concerning IND sponsorship
that the FDA may mandate.  Investigators performing trials under
cooperative agreements will be expected, in cooperation with the NCI,
to comply with all FDA monitoring and reporting requirements for
investigational agents.

c.  Investigators performing NCI funded Phase II Clinical Trials will
be advised by the NCI Program Director of potential studies that will
be relevant to new avenues of cancer therapy.  When this involves
investigational agents, the NCI Program Director 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).

9.  CTEP Review of Federally Mandated Regulatory Requirements

The Head, QACS, through the NCI Program Director, will advise the PI
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 awardee institutions. (See RESPONSIBILITIES
OF AWARDEES).

For specific Phase I and Phase 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
specific Phase II trials, the NCI Program Director shall assign CTMS
monitoring if the PRC expresses concern with excessive toxicity.  For
these trials, source documentation will be reviewed on-site three
times per year by the CTMS.

For Phase II trials with DCT IND 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).

10.  CTEP Review of Progress

Progress will be reviewed at least annually by the NCI Program
Director on the basis of the information provided at the annual Phase
II strategy meetings, in the continuation application, in the study
summary reports submitted to the IDB Drug Monitor or by CTMS reports.
In addition, periodic accrual information may be requested from the
PI by the NCI Program Director for all active studies when deemed
appropriate.

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

Responsibilities of Awardees

It is the responsibility of the PI to develop the details of the
research design, including definition of objectives and approaches,
planning, implementation, analysis, and publication of results,
interpretations and conclusions of studies.  The PI shall, with CTEP
assistance, develop Phase II protocols for clinical cancer research
in accord with its research interests, abilities and goals and in
accord with research goals established at the Phase II strategy
meetings 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.

1.  Protocol Development

The PI shall designate a Protocol Chairperson for each proposed
study.  The PI will be responsible for communication with the
appropriate CTEP staff.  The PI, with CTEP assistance, is responsible
for coordinating protocol development, protocol submission, study
conduct, quality control and study monitoring, drug ordering, data
management and analysis, protocol amendments/status changes,
adherence to requirements regarding investigational drug management
and federally mandated regulations and protocol and performance
reporting.

2.  Protocol Submission

The PI will submit protocols to the CTEP Protocol and Information
Office in a timely fashion for review and approval by NCI.  All
protocols should be preceded by a written LOI for Investigational
Drug Trials from the PI to the CTEP LOI Coordinator declaring
interest in conducting a particular study.  The LOI shall describe
the hypothesis to be investigated, the general design of the
contemplated trial plus relevant information on accrual capabilities
to document feasibility.  Protocols from multi-institution consortia
will be developed and submitted and studies will be conducted in
accordance with the "DCT GUIDELINES FOR MULTICENTER INVESTIGATIONAL
AGENT STUDIES" (available upon request from Dr. David Parkinson at
the address below).   The PI will communicate the results of the NCI
review of protocols to the consortia institutions.

3.  Quality Control

The awardee institution will establish mechanisms for quality control
of therapeutic and diagnostic modalities employed in its trials.
Quality control at a minimum must consist of:

a.  Pathology:  Verification of pathologic diagnosis in cases where
known variability in the accuracy of histologic diagnosis is a
potentially serious problem and where pathology data may provide
important prognostic information.

b.  Radiation Therapy:  Review (either concurrent or retrospective)
of port films and compliance with protocol- specified doses for
individual patients, where relevant. Determination of adequacy of
radiation delivery with the assistance of the Radiological Physics
Center (RPC), whose functions usually include equipment dosimetry,
periodic institutional visits and other aspects of physics review.

c.  Chemotherapy:  Review of flow sheets with determination of
protocol compliance in dose administration and dosage modification.

d.  Surgery:  Assessment of adequacy of protocol-specified surgical
procedures (where relevant) through review of operative notes and
study-specific surgical forms.

4.  Study Conduct and Monitoring

The awardee institution will establish mechanisms for study
monitoring.  The awardee is responsible for ensuring accurate and
timely knowledge of the progress of each study through:

a.  registration, tracking and reporting of patient accrual and
adherence to defined accrual goals;

b.  ongoing assessment of case eligibility and evaluability;

c.  timely medical review and assessment of patient data;

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

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

f.  timely communication of results of studies;

g.  an on-site monitoring program (see 7.c) below); and

h.  establishing data management support capabilities that ensure
that data will be submitted via electronic transfer biweekly to NCI's
Clinical Trials Monitoring Service (CTMS) if appropriate. (See 7.d.
below).

5.  Data Management and Analysis

The awardee institution 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) sufficiently uniform across the consortia
institutions.

6.  Investigational Drug Management

Investigators performing trials under cooperative agreements must be
NCI registered investigators (Form FDA 1572) and will be expected to
implement CTEP requirements described in the DCT Investigators'
Handbook for storage and accounting for investigational agents, to
abide by NCI/HHS Drug Accountability Records (DAR) procedures, and to
comply with all FDA requirements for investigational agents.

7.  Compliance with Federally Mandated Regulatory Requirements

The awardee institution 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:

a.  methods for assuring that the awardee institution and each
institution where investigators are conducting Phase II 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
amendments are approved by the IRB; that each investigator is
registered with the Drug Management and Authorization Section (DMAS),
CTEP with a current form FDA 1572 on file; and that each patient (or
legal representative) gives written informed consent prior to entry
on study.

b.  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 may require
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.

c.  an on-site monitoring program which 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, protocol compliance 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 4 weeks prior to the date of the audit.

d.  For the specific Phase II trials that require monitoring by the
CTMS three times per year, information must be provided via
electronic transfer to the CTMS at two week intervals and includes:
registration of each patient entered onto a Phase 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.

8.  Progress Review

For multi-institution trials, the PI will establish a mechanism for
assessing performance of its consortia participants, with particular
attention to accrual of adequate numbers of eligible patients onto
consortium trials, timely submission of required data and
conscientious observance of protocol requirements.  This mechanism
will include a procedure for recommending an adjustment of
institutional funds within the consortium as appropriate for the
level of participation in consortium activities, including (but not
limited to) accrual.

If the Progress Review indicates poor performance by a participating
institution, the awardee may replace the institution.  Any changes in
the participating institutions should be noted in the application for
continuation grant (PHS 2590 Rev 9/91).  If during the course of the
budget period the awardee chooses to change consortium institutions,
the new consortium must have an approved Assurance of Compliance for
the Protection of Human Subjects on file with OPRR.  The awardee will
be responsible for assuring that no patients are accrued to a
protocol at a participating institution until the protocol has been
reviewed and approved by the IRB.  If a change in consortium
institution involves adding a foreign consortium, a change in key
personnel, or change of scope or research objectives, the awardee
must request the prior approval of the NCI.  The procedure for
requesting prior approval is described in the "Methods for Grantees
to Request Approvals", PHS Grants Policy Statement, p. 8-6.

9.  Attendance at Meetings

The PI or appropriate representative(s) of the awardee institution,
shall attend the initial Phase II strategy meeting. At the initial
strategy meeting, the PIs and the NCI Program Director, assisted by
other CTEP staff, will review the research plans proposed by each
individual research group to ensure that they are compatible with the
overall goals of the RFA, to ensure avoidance of duplication of
effort and to ensure the most effective use of available resources
including investigational agents.  The PI or appropriate
representative shall attend the annual Phase II strategy meetings to
review relevant scientific information, to review progress in the
clinical trials, and to review the status of newly available
investigational agents in order to plan future activities.

10.  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, study
summary reports will be requested prior to the due date of the annual
report to the FDA required of IND sponsors.  A system for providing
such information in a timely manner must be in place.

11. 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.

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

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

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

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

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

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
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 April 1, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the
names of other key personnel, the participating institutions, and the
number and title of the RFA in response to which the application may
be submitted.

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

The letter of intent is to be sent to Dr. David R. Parkinson at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

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 Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 496-7441; and from the NCI Program Director named below.

The RFA label available in the PHS 398 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 of Cooperation 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 single-sided photocopies, in one
package with the appendices 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 650
6130 Executive Boulevard
Rockville, MD  20892

Applications must be received by June 10, 1993.  If an application is
received after that date, it will be returned.  If the application
submitted in response to this RFA is substantially similar to a
research grant application already submitted to the NIH for review,
but has not yet been reviewed, the applicant will be asked to
withdraw either the pending application or the new one.  Simultaneous
submission of identical applications will not be allowed, nor will
essentially identical applications be reviewed by different review
committees. Therefore, an application cannot be submitted in response
to this RFA that is essentially identical to one that has already
been 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

A.  Review Procedure

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration. Applications
that are judged to be non-responsive will be returned by the NCI.
Applications 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 revised application would not be considered an
application for a Cooperative Agreement nor would it be considered a
response to an RFA.  Questions concerning the responsiveness of
proposed research to the RFA are to be directed to program staff (see
INQUIRIES).

Applications may be triaged by an NCI peer review group on the basis
of relative competitiveness.  The NCI will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical review by an
appropriate peer review group convened by the Division of Extramural
Activities, NCI.  The second level of review will be provided by the
National Cancer Advisory Board.

B.  Review Criteria

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

1.  scientific, technical, medical significance and originality of
proposed research as reflected in the protocols, research plans and
strategies that address the clinical and laboratory considerations
for Phase II studies using cytotoxic and biologic agents alone or in
combination; evidence that the proposed scientific studies would
contribute to a greater understanding of the nature of the
therapeutic agent which may include but are not limited to an
understanding of its mechanism of action, mechanisms of resistance,
or differences among patients with respect to pharmacology or
metabolism.

2.  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research including:

a.  adequacy of plans for the development, implementation and
analysis of Phase II clinical trials

b.  adequacy of plans for correlative laboratory studies and
evaluation of the data with respect to treatment administration or
treatment outcome

c.  adequacy of statistical approach for correlating research studies
with treatment outcomes in Phase II trials.

d.  adequacy of plans for effective collaboration among laboratory,
clinical, and statistical investigators.

e.  adequacy of mechanisms for quality control, study monitoring,
data management and reporting, data analysis, investigational drug
management, and compliance with regulatory requirements

3.  qualifications and research experience of the Principal
Investigator and staff, particularly but not exclusively, in the area
of the proposed research including:

a.  experience and competence of the Principal Investigator and
clinical investigators in the development, implementation and
analysis of Phase II trials.

b.  adequacy of proposed time commitment by the Principal
Investigator and Co-Investigators.

c.  experience in the daily management and treatment of patients with
various malignant tumors and assessment of eligibility/evaluability
of these patients in cancer clinical trials.

d.  experience of the investigators in obtaining blood and/or tissue
specimens for research purposes from patients entered onto clinical
trials and the evaluation of those data with respect to treatment
administered or treatment outcome.

e.  experience in performance of laboratory/correlative studies
relevant to the development of a class of anticancer therapeutic
agents and evaluation of the data with respect to treatment
administration or treatment outcome.

4.  availability of resources necessary to perform the research
including:

a.  adequacy of the available facilities for clinical and
laboratory/correlative studies, data management resources, and
patient population.

b.  demonstration of availability of and access to appropriate
numbers of patients eligible to receive defined treatments on phase
II clinical trials and to appropriate human tissue with the
associated pathological data and clinical follow-up.

c.  For multi-institutional applications:

1)  adequacy of mechanisms for coordination of patient entry and
review of trial results as the study progresses;

2)  adequacy of methods for collection of data collection and
reporting  from each institution ; and

3)  for studies in which blood or tissue samples will be obtained
from patients, adequacy of methods for shipment of specimens from the
institution to the appropriate laboratory.

5.  adequacy of provisions for the protection of human subjects and
the humane treatment of animals (if laboratory studies involving
animals are proposed).

6.  Adequacy of the plans for inclusion of women and minorities.

7.  Commitment to accept provisions outlined under Terms of
Cooperation.

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

AWARD CRITERIA

The anticipated date of award is April 1, 1994.  In addition to the
technical merit of the application, NCI will consider how well the
Applicant Institution met the goals and objectives of the program as
described in the RFA, availability of resources, and balance of study
populations.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be responsive are strongly encouraged and may be
directed to the program staff listed below.  The program staff
welcomes the opportunity to clarify any issues or questions from
potential applicants.

Direct inquiries regarding programmatic issues to:

Dr. David Parkinson
Chief, Investigational Drug Branch
Cancer Therapy Evaluation Program
National Cancer Institute
Executive Plaza North, Room 734
Bethesda, MD  20892
Telephone:  (301) 496-5223
FAX:  (301) 480-4663

Direct inquiries regarding fiscal matters to:

Joan Metcalfe
Grants Management Specialist
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 28
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
Sections 301, 410, and 411, Part A (Public Law 78-410, 42 USC 241 as
amended, Public Law 99-158, 42 USC 285a) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 52 and 45 CFR
Part 74 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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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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