ABOUT FAST-TRACK:
"The FDA grants fast track status to drugs that treat a serious or
life-threatening disease for which there is an unmet medical need. Under the program, drug
sponsors are entitled to early consultation with agency medical reviewers, can rely on
surrogate endpoints in clinical trials and have the option to file certain portions of the
new drug application in advance of the entire application."
RATIONALE:
We submit that new agents that can help to manage low grade NHL without compromising
important bone marrow function satisfies an "unmet medical need" for
the following reasons:
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Currently, both the disease and most standard treatments compromise bone marrow
function, which can contributes to the incidence of mortality. A2
A3 A4
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Risks of infections (fungal, viral, bacterial) increase with compromised immunity and is
often the cause of death for lymphoma and other blood-cancer patients. A2
A3 A4
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Standard treatments have not improved survival benefit, and do not
cure indolent lymphomas. It is generally
acknowledged that survival benefit for indolent lymphomas has reached a
plateau. abstract
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Emerging immunotherapies (vaccines, antibodies) may require immune competence to work
optimally. Therefore, it is in the best interest of the patient to retain immune competency as we
treat the disease. (Early studies show that Rituxan as frontline treatment of patients
without bulky disease is more effective. A1) Enhancing
the effects of Rituxan may provide a foundation for making
this strategy possible.
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Standard chemotherapy and radiation are effective, but may select for more refractory
and aggressive surviving cells. As Boik writes: "it is reasonable to
suppose from the above discussions that the surviving cells may be highly primed for
mutations and that these therapies could therefore eventually produce more adaptable, more
aggressive cancers that are not easily treated." B1
Chemotherapy and radiation are
the classic double-edged swords. We may not improve survival and quality of life unless we
move away from, or postpone, this treatment paradigm.
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In some patients "watch and wait" can lead to bulky disease, which can
increases the risk of transformation.
(It is thought that bulky disease leads to hypoxic (low oxygen) conditions, which can
select for malignant cells that are capable of recruiting a blood supply and thus become
more aggressive.
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POTENTIAL BENEFITS:
Having an array of low- or non-toxic therapies available will have the following
benefits:
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Physicians can combine, sequence and alternate safer therapies based on individual
clinical responses. We already see investigators designing
creative combinations with Rituxan. Each approval of a low toxic
agent provides opportunities for identifying synergistic combinations
and sequences of low toxic treatments.
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Treating patients with low toxic combinations might very well avoid problems associated with
watchful waiting: depressed immunity, developing bulky disease, pleural effusions,
progressive bone marrow involvement, and transformation. Since the
current standard treatments have not significantly impacted survival,
it's likely that many patients with indolent NHL will be willing to
participate in studies of this kind.
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Using low toxic combinations may allow patients to avoid chemotherapy until safer combinations
of treatments fail to benefit. These interventions are less likely
to preclude the use of cytotoxic therapies.
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Chemotherapy, when needed, can be used in lower doses, combined with safer agents for
likely synergistic results. (We already see this for Rituxan, and combining Rituxan with
chemotherapy, and possibly radiation, has benefited patients with aggressive NHL,
significantly.)
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Applying the FDA Fast Track provision can reduce the cost of developing
safer
agents and ultimately reduce costs for patients, and insurance providers.
We need to identifying and apply surrogate endpoints to the evaluation
process to speed approval of new agents in this category until survival
benefits are seen.
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It will encourage pharmaceutical companies to develop other useful therapies that meet this criteria.
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Currently, many therapeutic ideas are not pursued because of the anticipated time and
costs, and uncertainty of the FDA approval process.
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No one can say for sure that the combining and sequencing safe therapies early will
benefit survival, but we do know that approaches used today do not. The risks of applying
safer remedies early appears to be low. We may discover that some therapeutics will work
optimally only when given prior to treatments that compromise immune function. We cannot
know this without trying. Therefore, we are obligated to try it.
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"Watch-wait-treat with Standard therapies" is not better or worse than
"treat early with Standard" in terms of survival benefit.
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ISSUES AND CONSIDERATIONS:
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Many scientists believe that it's not likely that the search for the single-agent cure
for cancer will ever be successful. Cancer cells are characterized by multiple mutations
and the ability to adapt.
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The quest to quantify the value of a single agent compared to other single agents is
seen by many patients and some scientists (including scientists with cancer) to be a waste
of time. Unique characteristics of the patients, the patient's disease, the patient's treatment
history, and numerous other variables makes this so.
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History shows that only after investigators combined chemotherapy agents in smaller doses
that progress was made with cytotoxic approaches.
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Phase III tests that compare the efficacy of standard toxic therapies to the efficacy of
a new safe therapy does not make sense. We cannot continue to undervalue the significance
of a therapy that does not undermine immune function. (Apples and oranges.)
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If Phase II results demonstrate benefit, and the drug does not compromise immunity, then
it should be made available through expanded access programs and give
Accelerated Approval status.
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| Will faster approval of low toxic therapies sometimes backfire and cause problems? Yes,
probably. It appears more likely, however, that the limitations of
cytotoxic approaches has been firmly established and progress might
require letting go of this strategy when possible.
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Patients may have to be prepared to free the drug sponsors from liability, at least in
the short term.
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There is a need to identify biologic surrogate end points
-- alternate ways to determine the clinical benefit of a compound.
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CANDIDATES FOR FAST TRACK STATUS:
This list is by no means conclusive. Experts can better determine which agents meet the
criteria: efficacy, even limited efficacy, without damaging bone marrow function. We can
expect that the key to the successful use of these compounds will be found in combing them
creatively based on the needs and responses of individual patients. For example, at
ASCO,
it was reported that the response rate for interferon plus rituximab was 94% (48% CR),
whereas that for continued rituximab alone was 77% (22% CR).
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LL-2 (anti-cd22, epratuzumab (LymphoCide(TM)) "At the optimal weekly infusion of
360-480 mg per square meter, repeated four times, 60 percent of patients with low-grade,
follicular NHL had an objective response, half of whom were complete responses,"
commented Dr. John Leonard, principal investigator of the study and Clinical Director of
the Center for Lymphoma and Myeloma at New York Presbyterian Hospital.
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Arsenic Trioxide: This treatment, if it proves effective in a current pilot study, is
not myelosuppressive, according to Dr. Waxman of Mount Sinai MC, and is very well
tolerated in the low doses that are used.
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Antisense (anti-bcl-2): This agent has had some success. It's key potential may be it's
ability to sensitize malignant cells that over-express bcl-2 to other treatments.
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Anti-PKC (anti-Protein Kinase C) ISIS 3521: Results from the Phase I studies of ISIS
3521 demonstrated that the drug was well tolerated and demonstrated encouraging antitumor
activity. Responses were seen at several dosing levels of ISIS 3521 in each of the trials.
Two patients with lymphoma experienced complete responses after receiving 18 and 9 months
of treatment with no recurrence of disease in either patient after 21 and 14 months,
respectively.
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idiotype vaccines (many variations, including dendritic-pulsed): There appears to be
enough data safety and efficacy data to approve some forms of idiotype vaccines and to
fast track the approval of many others.
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HSP vaccines (see idiotype vaccines)
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Antiangiogenic agents (such as endo/angiostatins): Promise to
complement other therapies
and many, especially endogenous (from self) compounds appear to be extremely safe. VEGF
rises in aggressive lymphomas and it's thought that mutations that make lymphoma cells
more capable of angiogenesis contributes to their aggressive character.
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Flavopiridol: broad spectrum inhibitor of cyclin-dependent kinases
(CDKs), flavopiridol,
now undergoing Phase II single-agent trials and Phase I combination trials (with
paclitaxel and cisplatin).
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REFERENCES
A1 Semin Oncol 2000 Dec;27(6 Suppl 12):25-9 Rituximab as first-line systemic therapy
for patients with low-grade lymphoma. Hainsworth JD. Sarah Cannon Cancer Center,
Nashville, TN 37203, USA.
A2) Am J Hematol 2001 May;67(1):1-5 Clinical and pathologic findings in 52
consecutively autopsied cases with multiple myeloma. Department of Hematology,
International Medical Center of Japan, Tokyo, Japan.
A3) Ann Oncol 2000 Jan;11(1):59-64 Hodgkin's disease: correlation between causes of
death at autopsy and clinical diagnosis. Provencio M, Espana P, Salas C, Navarro F,
Bonilla F.
CONCLUSIONS: Autopsy study in Hodgkin's disease confirms a high rate of discrepancy
between final clinical diagnosis and postmortem lesions despite advances in diagnostic
methods. Autopsy revealed causes of death directly related to the treatment, as well as
some lesions directly related to patient death and secondary to treatment. Infectious
processes are likely to remain undetected and their symptoms can mimic tumor progression.
A4) Haematologica 1991 Mar-Apr;76(2):135-40 Infections in haematologic
neoplasms:
autopsy findings. Nosari A, Barberis M, Landonio G, Magnani P, Majno M, Oreste P, Sozzi P.
Divisioni di Ematologia, Patologia e Oncologia, Ospedale Niguarda Ca Granda,
Milano,
Italy.
CONCLUSIONS. Infections were the cause of death in 63% of patients. In this group of
patients bacterial infections accounted for 43% of deaths; fungal infections were frequent
too (28%), mainly among leukemic patients; viral (9%), mycobacterial (7%) and polymicrobic
infections (11%) were also documented. Haemorrhages were less frequently fatal (12%) due
to the availability of haemocomponents. A high number of fatal haemorrhages were
associated with fungal infections. Neoplastic progression was the real cause of death in
only a few cases, and cardiovascular and pulmonary complications were fatal in the great
majority of the other patients.
A5) Med Klin 1994 Jun 15;89(6):299-304 Systemic fungal infections in hematologic
neoplasms. An autopsy study of 1,053 patients Pfaffenbach B, Donhuijsen K, Pahnke J, Bug
R, Adamek RJ, Wegener M, Ricken D.
ADD ASCO abstract here ??
B1 Natural Compounds in Cancer Therapy, John Boik
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