The New Approaches to Brain Tumor
Therapy (NABTT) CNS Consortium:
Organization, Objectives, and Activities
Stuart A. Grossman, MD, Joy D. Fisher, MA,
Steven Piantadosi, MD, PhD, and Henry Brem, MD
The primary goals of the NABTT CNS Consortium are to develop scientific
advances
and improve clinical outcomes for patients with primary brain tumors.
Background: Despite advances in neuro-imaging, neurosurgery, radiation
therapy, and chemotherapy, limited progress has been made in the treatment of patients
with high-grade astrocytomas. The National Cancer Institute has attempted to speed
advances in this field by funding CNS consortia to conduct innovative clinical trials in
this patient population since 1994.
Methods: The NABTT CNS Consortium is composed of a consortium headquarters
and nine member institutions with outstanding multidisciplinary expertise, clinical and
laboratory research capabilities, and access to large numbers of patients with brain
tumors.
Results: The objectives of the NABTT Consortium are to improve the
therapeutic outcome for adults with primary brain tumors, to conduct basic science and
clinical research, and to improve the care and quality of life of adults with primary
brain tumors. NABTT's clinical studies have discovered important drug
interactions between anticonvulsant and antineoplastic agents, defined the activity of
paclitaxel and 9-aminocamptothecin in glioblastoma multiforme, tested a novel dose
escalation strategy for brain tumor trials, and established new protocol
"classes" to expedite and standardize clinical research in this field.
Conclusions: Significant progress in the care of patients with primary
brain tumors is likely to result from the highly focused and multidisciplinary efforts of
the NIH-funded CNS consortia.
Introduction
Primary brain tumors affect approximately 17,000 patients each year
in the United States.1 Sixty percent of all primary brain tumors are gliomas,
and the majority of these are high-grade astrocytomas.2 Despite the significant
advances in surgery, radiation therapy, and chemotherapy during the past three decades,
adults with newly diagnosed high-grade astrocytomas have a median survival of less than
one year, and virtually none are cured of their illness.3 Chemotherapy, in
particular, has had limited impact on the survival of these patients.4-6
The treatment of primary brain tumors is complicated by many
factors. These include the apparent resistance of these tumors to conventional treatments,
the susceptibility of adjacent normal brain to adverse effects of therapy, the limited
capacity of brain tissue for repair, the dissemination of malignant cells through brain
parenchyma, the presence of a variably disrupted blood-brain barrier that complicates drug
delivery to the tumor, and leaky capillaries that result in peritumoral edema and
increased intracranial pressure. In addition, clinical trials are hampered by the
inability to differentiate between progressive tumor, sequelae of therapy (ie, necrosis),
or changes in blood-brain-barrier integrity due to radiation therapy or adjustments in
glucocorticoid doses using clinical criteria or neuroimaging studies.7
Many basic principles regarding the treatment of these malignancies
stemmed from protocols conducted by several large National Institutes of Health
(NIH)-funded cooperative groups. Large, randomized, comparative (phase III) studies of the
Brain Tumor Study Group (BTSG) and the Radiation Therapy Oncology Group (RTOG) identified
critical prognostic factors, defined optimal radiation doses and fields, and demonstrated
the limited value of adjuvant chemotherapy and radiosensitizers in these diseases.
However, by the mid 1980s, it was clear that little further progress was likely from
large, costly, time-consuming phase III studies comparing modifications or combinations of
available therapies. As a result, in 1993, the NIH solicited applications for small,
innovative consortia to work with the National Cancer Institute (NCI) under the auspices
of a research project cooperative agreement (UO1). This Request for Application (RFA) was
designed to stimulate advances in the treatment of patients with high-grade astrocytomas
by joining into one consortium those institutions with large numbers of brain tumor
patients, multidisciplinary expertise in the care of these patients, a record of
excellence in clinical research, and access to exciting new therapeutic approaches for
these patients. It was hoped that these CNS consortia would conduct studies of toxicity,
dose finding, and safety (phase I and phase II) of novel therapeutic approaches for adults
with high-grade astrocytomas.
The application process for this grant required the Consortium
headquarters and each institution that wished to participate in the Consortium to submit
separate applications to the NCI. Each of these applications underwent peer review and was
assigned a priority score. The NCI used these priority scores to determine which consortia
would be funded and which institutions had priority scores that were high enough to
qualify for funding.
In 1994, three CNS Consortia were funded for four years. They were
headquartered at the University of California at San Francisco, the M.D. Anderson Cancer
Center in Houston, and The Johns Hopkins Oncology Center in Baltimore. In 1998, following
a similar application and peer review process, two CNS Consortia were awarded funding for
an additional five years. This manuscript describes the objectives, organization, and
activities of the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium.
The NABTT CNS Consortium
The primary long-term objective of the NABTT CNS Consortium is to
improve the therapeutic outcome for adults with primary brain tumors by fostering phase I
and phase II clinical evaluations of promising new agents, biologic approaches, routes of
administration, and trial design. The secondary objective of the Consortium is to share
clinical and laboratory data and human brain tumor specimens in order to conduct research
pertaining to the basic biology of primary brain tumors and the neuro-pharmacology of new
therapies for primary brain tumors, as well as to improve the care and quality of life of
adults with primary brain tumors.
The NABTT CNS Consortium was originally funded in 1994 with six
participating institutions: Brown University (Providence, RI), Columbia University (New
York, NY), Henry Ford Hospital (Detroit, Mich), The Johns Hopkins University (Baltimore,
Md), Massachusetts General Hospital (Boston, Mass), and Northwestern University (Chicago,
Ill). Each of these institutions had an experienced multidisciplinary neuro-oncology team,
a large number of adults with primary brain tumors, exceptional institutional resources,
and an eagerness to try new therapeutic approaches. In addition, these centers had an
abundance of high-quality, peer-reviewed, clinically relevant neuro-oncology research
underway as evidenced by numerous NIH funded grants (P-20 Brain Tumor Center Feasibility
Grants, National Cooperative Drug Discovery Groups, Neuro-Oncology Training Grants, R01s)
and extensive publications in this field. In the 1998 grant renewal, the following
institutions were awarded grants by the peer review process: Emory University (Atlanta,
Ga), Henry Ford Hospital (Detroit, Mich), The Johns Hopkins University (Baltimore, Md),
Massachusetts General Hospital (Boston, Mass), Moffitt Cancer Center (Tampa, Fla), the
University of Alabama (Birmingham, Ala), the University of Pennsylvania (Philadelphia,
Pa), the University of Texas Health Science Center (San Antonio, Tex), and Wake Forest
University (Winston-Salem, NC) (Fig 1).
As the basic organizational structure of NABTT served the Consortium
well during its first four years, it has been preserved with few changes. NABTT's
organizational structure is shown in Figs 2 and 3. The major additions to the Consortium's
structure since 1993 are (1) the Correlative Biology Center, which has been added to the
Consortium headquarters to meet the specifications of the new RFA, (2) the Designated
Pharmacology Laboratories, which take advantage of the wide range of pharmacologic
expertise within NABTT rather than designating only one location for pharmacologic
studies, (3) the formal relationships with pharmaceutical companies, which did not exist
when the grant was initially funded, and (4) the Conflict of Interest Committee, which has
been added to the Consortium headquarters to cope with issues relating to NABTT
investigators and the Consortium studies of products coming from pharmaceutical companies.
The carefully considered and well-defined organizational structure
of NABTT has been instrumental in its success. NABTT has a formal constitution signed by
each institution's principal investigator that specifies the rules by which these
institutions will collaborate. The NABTT CNS Consortium is comprised of the Consortium
headquarters and the nine participating institutions. The Consortium headquarters contains
a Central Operations Office, a Scientific Research Center, a Pharmacology Center, a
Correlative Biology Center, and a Biostatistics Center. Seven outstanding clinician
investigators and scientists serve on NABTT's Advisory/External Review Board to help shape
and steer the Consortium. In addition, there is a formal affiliation with the Eastern
Cooperative Oncology Group (ECOG), with the chairman of ECOG's Brain Tumor Committee
sitting as a nonvoting member of NABTT's Executive Committee to facilitate transfer of
promising NABTT phase II studies to the phase III setting.
The Operations Office and Biostatistical Center work closely to
ensure that the Consortium functions smoothly and efficiently. Their major efforts are to
foster (1) Consortium interactions (meetings, telephone conferences, internet
communications), (2) clinical research within NABTT (translate concepts into protocols and
ensure that these produce accurate and complete data that is published in a timely
fashion), (3) Interactions with NABTT's 11 standing Scientific Committees,
Advisory/External Review Board, the NCI, ECOG, and pharmaceutical companies, (3) protocol
development and submission, (4) prioritization of studies, (5) patient registration, (6)
data collection and management, (7) study monitoring and analysis, (8) publication, (9)
correlative studies between laboratory and clinical investigations, (10) central review
and quality control, (11) audits, and (12) investigational drug management and reporting.
The Scientific Research Center is responsible for the generation of new clinical research
studies to be undertaken from the Consortium. As such, it draws on and consolidates the
resources available throughout the Consortium. The Pharmacology Center is responsible for
the design, conduct, and analysis of all pharmacologic measurements relating to research
conducted by this Consortium. The Correlative Biology Center has funding to disperse each
year to worthy projects that utilize the Consortium's data and expertise to learn more
about the basic biology of these malignancies.
Since 1993, a total of 31 clinical protocols have been written for
the Consortium: 7 for patients with newly diagnosed high-grade astrocytomas, 19 for
patients with recurrent high-grade astrocytomas, 3 for patients with non-astrocytomas, and
2 nontherapeutic protocols. A total of 178 patients have been entered on NABTT therapeutic
protocols, and 669 have been registered for NABTT nontherapeutic protocols.
Considerable attention has been focused on issues of quality
assurance within the Consortium. All fully participating NABTT institutions have undergone
an external review of their NABTT studies. The quality of NABTT's research data is
excellent. For example, recent audits of NABTT studies of 9-aminocamptothecin have
demonstrated that over 94% of the 61 patients accrued were eligible for the studies and
97% were evaluable. Furthermore, 87% of all data was available to the Central Operations
Office in one month or less. Central reviews of pathology and radiologic studies have been
performed for all patients who were believed to be responders to protocol therapy. Central
biostatistical input has been included in all protocols, and reports and the pharmacologic
studies have been successful and informative.
Accrual to therapeutic protocols has also been impressive. Although
it was originally anticipated that most of NABTT's protocols would be phase II studies,
the pharmacologic observations described below have transformed most of these into phase I
studies. These are slower and more labor intensive. A small cohort of patients is accrued,
and then a pause of at least one month follows to accumulate toxicity information before
reopening the protocol at a higher dose. As a result, the protocol becomes unavailable for
long stretches of time. However, accrual has been rapid when these protocols are open. For
example, in the dose-escalation carmustine (BCNU) wafer protocol that NABTT is conducting,
available patient slots are routinely filled or reserved within days of opening, and
patients are often waiting in anticipation of the protocol's reopening. NABTT is now
running several protocols at the same time to ensure that protocols are usually available
to eligible patients who wish to participate in clinical trials. The NABTT CNS Consortium
has impressive potential to accrue patients with primary brain tumors. In 1996, our member
institutions saw a total of 2,116 patients with primary brain tumors, which is a sizable
percentage of the national total. Over 1,000 of these were patients with high-grade
gliomas, and 472 were placed on an NABTT, cooperative group, pharmaceutical, or
institutional trial.
NABTT Accomplishments
Although the NABTT CNS Consortium is a relatively young cooperative
group, its early years have been productive. Its primary strengths lie in its outstanding
institutions, investigators, and organizational structure, its access to large numbers of
patients with primary brain tumors, and its firm commitment to multidisciplinary research.
Furthermore, it is committed to novel systemic and local treatment approaches, unique
trial designs, thoughtful pharmacologic correlations, and meticulous clinical research.
These features of the Consortium have made NABTT an ideal setting to test new agents and
to make important observations regarding the therapy of patients with primary brain
tumors. Some of NABTT's early findings and novel approaches are outlined below.
1. Important Drug Interactions Between Anticonvulsant and
Antineoplastic Agents
NABTT investigators were the first to note that anticonvulsants have
a major effect on the pharmacology of several chemotherapeutic drugs. NABTT's initial
clinical trial used paclitaxel at a dose of 140 mg/m2 as a 96-hour continuous
intravenous infusion. This was the maximum tolerated dose (MTD) in phase I studies and
resulted in considerable myelosuppression and alopecia in patients with breast cancer and
lymphomas. However, in the NABTT study that treated patients with newly diagnosed
glioblastoma multiforme, this dose was not associated with significant toxicity, and
plasma paclitaxel levels were approximately one fifth of those seen in patients with other
solid tumors. As all of the early patients on this study were also taking phenytoin, a
P450 activator, it was hypothesized that this increased the degradation of paclitaxel. For
this reason, NABTT's phase II trial was converted to a dose-escalation study, and the MTD
was noted to be 200 mg/m2 in patients receiving enzyme inducing anticonvulsant
drugs.8
The second agent studied by the NABTT was of 9-aminocamptothecin. As
there are no known hepatic metabolites of this drug, the concomitant use of hepatic
enzyme-inducing anticonvulsants was not expected to affect the pharmacology of this agent.
However, once again at the MTD, which was determined in patients with systemic neoplasms,
no toxicities were observed at a dose of 850 µg/m2 per day for three days.
This trial was also converted to a dose-escalation study The dose-escalation portion of
these trials has recently been completed, and the MTD for newly diagnosed patients on
enzyme-inducing anticonvulsants is 1776 µg/m2 per day.9 These
studies suggest that using an
MTD obtained in patients not on anticonvulsants could result in significant underdosing in
patients with brain tumors, and that careful pharmacologic studies are required in new
drug development in this patient population.
2. Paclitaxel and 9-Aminocamptothecin in Patients With Glioblastoma
Several unique trial designs are being tested within the NABTT CNS
Consortium. One of these utilizes pre-irradiation chemotherapy to screen new agents
(paclitaxel, 9-aminocamptothecin, and CI-980) for activity in patients with newly
diagnosed glioblastoma multiforme who have measurable residual disease after surgery.
These previously untreated tumors are the most likely to respond, and their responses are
the easiest to assess radiologically. Thus, new agents can be screened for efficacy with
relatively few patients using a two-stage design. This approach was used to determine
that, even at the proper MTD, systemically administered paclitaxel and 9-aminocamptothecin
have minimal efficacy in patients with glioblastoma multiforme.7,10 Studies
with CI-980 are currently underway. NABTT is also studying the potential risks and
benefits of this trial design. To date, the use of preirradiation paclitaxel does not
appear to have adversely affected survival.
3. Novel Dose Escalation Strategy for Brain Tumor Trials
A second novel trial design being used by NABTT involves a modified
continuous reassessment method for phase I dose escalation. This was implemented when it
became clear that many NABTT trials would require dose escalation because of drug
interactions associated with anticonvulsant medications. In NABTT studies of
9-aminocamptothecin, the MTD was reached using far fewer patients using the continual
reassessment method than if conventional phase I dose-escalation techniques had been
employed.11,12 To our knowledge, this is the first time this dose-escalation
method has been employed in a cooperative group setting.
4. Multisite Phase I Trials in Brain Tumors
Phase I studies are typically restricted to one institution because
of the need for real time reporting of patient toxicities. Furthermore, patients with
central nervous system involvement are usually excluded from these trials. For these
reasons, it was expected that NABTT would conduct primarily phase II studies. However, as
a result of the unexpected drug interactions noted with paclitaxel and 9-aminocamptothecin
and the availability of novel agents from pharmaceutical companies, as many as two thirds
of NABTT studies have been multisite phase I studies. Furthermore, additional data
collection to meet pharmaceutical company and FDA requirements are required for two of
these dose-escalation studies (RSR-13 and BCNU polymers). NABTT's Central Operations
Office has demonstrated its ability to conduct these studies and collect and process the
appropriate data simultaneously at all member institutions.13,14 The success of
these undertakings is
evident as an increasing number of pharmaceutical companies are requesting NABTT to
evaluate their novel approaches to the treatment of primary brain tumors.
5. New Protocol "Classes" for Brain Tumor Trials
NABTT is also experimenting with a new classification of protocols
for patients with primary brain tumors to speed protocol development and to standardize
eligibility and response criteria. This should allow them to crudely compare treatments.
Each protocol class has a different objective, set of eligibility criteria, and protocol
design (Table). Class A protocols are designed to screen new agents for efficacy in the
preirradiation setting with response as the endpoint. Noncytotoxic therapies, where
typical partial and complete response are not anticipated, are best studied in class B
protocols where time to progression or survival is the endpoint. Class C are conventional
protocols that assess response in patients with recurrent disease. Class D protocols are
designed for patients with local recurrences who are eligible for regional therapies, such
as direct local injections of chemotherapy or radiation or gene therapy trials. Class E
protocols are for patients with histologies other than high-grade astrocytomas, and Class
F protocols are for nontherapeutic protocols.
Clinical Protocol Classifications of
NABTT CNS Consortium |
| Class A |
Newly diagnosed glioblastoma multiforme with measurable disease
(primary endpoint is response) |
| Class B |
Newly diagnosed glioblastoma multiforme with or without measurable
disease (primary endpoint is survival) |
| Class C |
Recurrent high-grade astrocytoma with measurable disease (primary
endpoint is response) |
| Class D |
Locally recurrent high-grade astrocytoma (suitable for local therapies
such as polymeric chemotherapy implants) |
| Class E |
Histology other than high-grade astrocytoma (CNS lymphoma, meningioma,
etc.) |
| Class F |
Nontherapeutic protocols (brain bank, correlative biology, quality of
life, etc.) |
The standardization of entry criteria is already paying dividends
with the creation of the NABTT Glioblastoma Database.15 This database currently
contains over 104 adults with newly diagnosed glioblastoma multiforme who were treated
with preirradiation paclitaxel, 9-aminocamptothecin, or CI-980 chemotherapy or RSR-13 with
radiation. This cohort provides 75 patient years of survival experience and yields a
reasonably precise historical estimate of the failure (death) rate in this NABTT
population. This can be used to estimate the efficacy of novel cytotoxic and noncytotoxic
approaches to GBM in relatively small phase II studies. Although decision rules will
depend on therapy-related toxicities, in general, a > or = 25% reduction in the failure
rate compared to this historical series would be considered strong evidence in favor of
proceeding to a formal comparative trial, while a <25% reduction would not be considered
reliable or promising enough to initiate a phase III trial.
6. New Sources of Therapeutic Agents
Patient accrual during the early months of
the NABTT CNS Consortium was slow for several reasons. First, the planned phase II studies
became phase I studies. This required that accrual be limited to cohorts at each dose
level, followed by a mandatory pause while toxicity data at that dose matured. Thus, a
larger number of active protocols were needed to ensure steady and higher accrual.
Furthermore, NABTT was relying entirely on the NCI to provide new agents, and sometimes
this process took longer than anticipated. With the support of Cancer Therapy Evaluation
Program (CTEP)/NCI, we sponsored the first NABTT Industrial Meeting in the spring of 1996
in conjunction with our biannual NABTT Meeting. We had senior management and scientists
from six pharmaceutical companies making presentations to our investigators. Two of those
companies (Guilford Pharmaceuticals and Allos Therapeutics) have subsequently entered into
formal agreements with NABTT, and their products are currently in trials within the NABTT
CNS Consortium. These protocols were written by NABTT investigators in cooperation with
the pharmaceutical company. They underwent review within NABTT and were then sent to the
NCI/CTEP for formal review and approval before they were activated.
Guilford Pharmaceuticals, Inc, is providing escalating doses of BCNU
in their controlled-release polymeric implants. Laboratory data suggest that wafers
containing higher doses of BCNU than in the currently FDA-approved Gliadel polymer
implants (3.9% BCNU) might be more effective. NABTT has conducted dose escalations in
patients eligible for the commercially available 3.9% polymer in conjunction with an
independent Safety Monitoring Committee. To date, the BCNU loading in the wafers has been
studied at 6.5%, 10%, and 14.5%. Patients have recently been accrued to 20% BCNU wafers.
The total amount of BCNU delivered regionally to the brain is 73 mg in the 3.9% polymer
and 320 mg in the 20% formulation.14
Allos Therapeutics, Inc, is providing RSR-13, an allosteric modifier
of hemoglobin that shifts the oxygen dissociation curve promoting oxygen release to
tissues. This is currently being evaluated using short-term infusions to relieve tissue
hypoxia in myocardial infarction and strokes. However, it may be possible to dramatically
improve oxygenation within glioblastomas and thereby improve the results of radiotherapy
and chemotherapy. Preclinical work in this regard is encouraging. NABTT is now conducting
the first and only study of this compound in patients with newly diagnosed glioblastoma
multiforme in conjunction with radiation therapy. Dosing was initially begun every other
day during radiation therapy and then escalated to every day. The toxicity of these
therapies is still under evaluation.13
A second NABTT Industrial Meeting occurred in June of 1997 in
conjunction with the regularly scheduled biannual NABTT Meeting in Detroit. Five
pharmaceutical companies participated sharing a wide range of therapeutic compounds
suitable for clinical trials in primary brain tumors. Negotiations are well along, with
several of these companies to begin trials of their products within NABTT. Isis
Pharmaceuticals, Inc, has asked NABTT to test an antisense oligonucleotide against protein
kinase C alpha in patients with recurrent high-grade astrocytoma, and Schering-Plough Corp
is working with the Consortium to develop an ad-P53 gene therapy trial. These efforts to
involve pharmaceutical companies have provided new opportunities for NABTT to test a wide
variety of novel compounds. They have also provided innovative surgery- and
radiotherapy-based protocols that have helped to solidify support for NABTT within our
member institutions. However, it is important to note that the primary source of new
agents for NABTT clinical trials remains the NCI.
The NABTT CNS Consortium is funded by the NIH to conduct innovative
clinical trials. Thus, for these trials, the pharmaceutical companies are only assessed
costs to NABTT headquarters and member institutions that are above and beyond typical
NABTT protocols. These funds are paid to the NABTT Operations Office and are channeled
into program income to this NIH grant through arrangements that have been made with the
NCI. These funds are allocated by the Executive Committee based on each institution's
accrual to NABTT's therapeutic protocols and the need for additional funding. Thus, there
is no preferential reimbursement to a participating institution for placing patients on a
trial that tests an agent from a pharmaceutical company over one that originated from the
NCI. Funding also goes to the NABTT headquarters to cover additional costs at the central
offices.
Conclusions
When NABTT investigators responded to the original RFA in 1993, they
believed that this Consortium could provide an exciting framework to advance clinical
brain tumor research. Our growth and experience over the past four years make us even more
optimistic about NABTT's potential to contribute. Currently, NABTT has clinical protocols
chaired by medical oncologists, neurologists, radiation oncologists, and neurosurgeons.
These are evaluating the toxicity and efficacy of local and systemic therapies including
cytotoxic and noncytotoxic drugs, an antisense oligonucleotide, a radiation enhancer, and
gene therapies. In addition, the Consortium has large numbers of patients with brain
tumors, an increasing number of novel therapeutic approaches from the NCI and from the
pharmaceutical industry, and a basic science effort to learn more about the biology of
these tumors. All of these focused multidisciplinary efforts are directed toward NABTT's
primary goal, which is to provide significant scientific advances in the treatment of
patients with primary brain tumors in the near future.
Drs Brem and Piantadosi are consultants to Guilford Pharmaceuticals, Inc. Dr Brem is
also a consultant to Rhone-Poulenc Rorer, and Guilford Pharmaceuticals, Inc., has provided
a gift for research in Dr Brem's laboratory. The Johns Hopkins University and Dr Brem own
Guilford stock, the sale of which is subject to certain restrictions under University
policy. The terms of this arrangement are being managed by the University in accordance
with its conflict of interest policies.
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From the New Approaches to Brain Tumor Therapy CNS Consortium, Baltimore, Md.
Address reprint requests to Stuart A. Grossman, MD, at the NABTT CNS
Consortium, Room 132, The Johns Hopkins Oncology Center, 600 North Wolfe St, Baltimore, MD
21287.
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