Current Report — Form 8-K Filing Table of Contents
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1: 8-K Dor - Steve Kanzer Resignation From Board of HTML 14K
Directors
2: EX-99.1 Steve Kanzer Letter of Resignation HTML 130K
As
you
know, I have voiced my opinion that at the May 9, 2007 meeting of the Oncology
Drug Advisory Committee convened by the FDA to consider the efficacy of orBec®,
six (6) of the ten (10) committee members participating, including five (5)
of
the seven (7) committee members voting against orBec®, had in my opinion
financial conflicts of interest as defined under the Federal Advisory Committee
Act and the regulations thereunder relating to their imputed financial interest
in the four investigational products and programs that represent the closest
directly competitive products for the unmet medical need that, if approved,
orBec® would be intended to treat. Attachments (1)(2)(3). Had all of the
committee members having such financial conflicts of interest been appropriately
excluded from participating in the meeting, as I believe they should have been,
the outcome of the meeting would have been a 2-2 vote, a very different
outcome.
As
you
are also aware, my interest as well as that of the American public in the topic
of reducing financial conflicts of interest in FDA advisory committee meetings
transgresses that of DOR. This topic was the subject of proposed legislation
in
the form of Senate Amendment 1034: To reduce financial conflict of interest
in
FDA Advisory Panels, that was debated and voted upon by the full Senate
resulting in 47 Senators voting in favor and 47 Senators voting against on
May9, 2007.
In
order
that my opinion and interest in this subject not distract from the FDA’s
decision as to whether to grant approval to orBec®, I hereby resign from the
board of directors effective immediately and request that you file this letter
with the Form 8-K disclosing my resignation as soon as practicable together
with
the attachments hereto as you are so required under Item 5.02(a)(2) of Form
8-K.
It
has
been a pleasure to serve on this board for these last 11 years. I wish you
all
the success in gaining approval for this life saving drug so that it may be
made
available to patients as well as for the future success of the
company.
Sincerely,
/s/
Steve
H. Kanzer
Steve
H.
Kanzer, CPA, Esq.
Attachment
1
Treatment
for Acute Graft-Versus-Host Disease
This
study is currently recruiting patients.
Verified
by National Heart, Lung, and Blood Institute (NHLBI) May
2007
Sponsors
and Collaborators:
National
Heart, Lung, and Blood Institute (NHLBI)
National
Cancer Institute (NCI)
Blood
and Marrow Transplant Clinical Trials Network
Information
provided by:
National
Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov
Identifier:
NCT00224874
Purpose
The
study
is a randomized Phase II, four arm treatment trial. The primary purpose of
the
study is to define new agents with promising activity against acute
graft-versus-host disease (GVHD) suitable for testing against corticosteroids
alone in a subsequent Phase III trial.
Condition
Intervention
Phase
Graft
vs Host Disease
Immune
System Disorders
Drug: Etanercept
Drug: Mycophenolate
Mofeil
Drug: Denileukin
Diftitok
Drug: Pentostatin
Phase
II
MedlinePlus related
topics: Immune System and Disorders
Genetics
Home Reference related
topics: Immune System and Disorders
Study
Type: Interventional
Study
Design: Treatment, Randomized, Open Label, Active Control,
Parallel Assignment, Efficacy Study
Official
Title: Initial Systemic Treatment of Acute GVHD: A Phase II Randomized
Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox
(ONTAK), and Pentostatin in Combination With Corticosteroids (BMT CTN #0302)
Further
study details as provided by National Heart, Lung, and Blood Institute
(NHLBI):
Primary
Outcome Measures:
·
Proportion
of CR at Day 28 of therapy
Secondary
Outcome Measures:
·
Proportion
of partial response, mixed response, and progression (measured at Day
28)
·
Proportion
of treatment failure (measured at Day 14)
·
Incidence
of GVHD flares requiring increasing therapy before Day 90
·
Incidence
of discontinuation of immune suppression without flare (measured at
Days
90, 180, and 270 post-treatment)
·
Incidence
of chronic GVHD (measured at 9 months)
·
Overall
survival at 6 and 9 months post initiation of therapy
·
Incidence
of systemic infections within 3 months of initiation of therapy
·
Incidence
of EBV-associated lymphoma
Total
Enrollment: 180
Study
start: September 2005
BACKGROUND:
Acute
graft-versus-host disease (GVHD) is the major complication of allogeneic
hematopoietic stem cell (HSC) transplantation. Acute GVHD produces significant
morbidity and complicates patient management resulting in organ toxicity,
frequent infections, malnutrition, and substantial delay in recovery from
transplantation. Corticosteroids have been the primary therapy for acute GVHD
for over three decades. Various additional immunosuppressive strategies have
been tested as GVHD therapy but neither anti-thymocyte globulin (ATG),
CD5-immunotoxins, IL-1 antagonists nor other agents have been demonstrably
helpful in either control of GVHD symptoms or improvement in survival. Published
response rates of complete response (CR) to acute GVHD therapy with
corticosteroids range from 25-41%. These rates will be used as benchmarks for
assessing efficacy of promising new agents. New immunosuppressive agents and
strategies are required to improve the management of GVHD and decrease the
toxicities of the immunosuppressive regimens.
DESIGN
NARRATIVE:
In
this
trial, patients with newly diagnosed acute GVHD will be randomly assigned to
receive corticosteroids plus one of four new agents (etanercept, MMF, denileukin
diftitox [Ontak], and pentostatin). A control arm of only corticosteroids will
not be employed. Each agent will be assessed for safety and efficacy (at least
35% complete remission [CR] rate at Day 28 of therapy can be expected from
previously untreated patients).
Eligibility
Ages
Eligible for Study: 2 Years and above, Genders Eligible for
Study: Both
Criteria
Inclusion
Criteria:
·
Prior
allogeneic hematopoietic stem cell transplant using either bone marrow,
peripheral blood stem cells, or cord blood
·
De
novo acute GVHD diagnosed within 48 hours prior to enrollment; biopsy
confirmation of GVHD is strongly recommended but not required; enrollment
should not be delayed awaiting biopsy or pathology results; the patient
must have had no previous systemic immune suppressive therapy given
for
treatment of acute GVHD except for a maximum 48 hours of prior
corticosteroid therapy (at least 1 mg/kg/day methylprednisolone)
·
Patients
that have undergone a scheduled donor lymphocyte infusion (DLI) as
part of
their original transplant therapy plan
·
ANC
greater than 500/µL
·
Clinical
status at enrollment to allow tapering of steroids to not less than
1
mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of
therapy (e.g., persisting malignant disease suggesting the need for
accelerated taper of immunosuppression)
·
Estimated
creatinine clearance greater than 30 mL/minute
·
Assent
and educational materials provided to, and reviewed with, patients
under
the age of 18
Exclusion
Criteria:
·
ONTAK,
pentostatin, or etanercept given within 7 days of enrollment
·
Active
uncontrolled infection
·
Patients
that have undergone an unscheduled DLI, or DLI that was not part of
their
original transplant therapy plan
·
If
any prior steroid therapy (for indication other than GVHD), treatment
at
doses of at least 0.5 mg/kg/day methylprednisolone within 7 days prior
to
onset of GVHD
·
Patients
unlikely to be available at the transplant center on Day 28 and 56
of
therapy
·
A
clinical syndrome resembling de novo chronic GVHD developing at any
time
after allotransplantation (see Chapter 2 of the BMT CTN Manual of
Procedures for details of de novo chronic GVHD)
·
Other
investigational therapeutics for GVHD within 30 days, including agents
used for GVHD prophylaxis
·
Patients
who are pregnant, breast feeding, or if sexually active, unwilling
to use
effective birth control for the duration of the study
·
Adults
unable to provide informed consent
·
Patients
with a history of intolerance to any of the study drugs
Location
and Contact Information
Please
refer to this study by ClinicalTrials.gov identifier NCT00224874
Health
Authority: United States: Food and Drug Administration
ClinicalTrials.gov
processed this record on May 25, 2007
Attachment
2
Combination
of Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox (Ontak), and
Pentostatin With Steroids
This
study is currently recruiting patients.
Verified
by M.D. Anderson Cancer Center May 2007
Sponsors
and Collaborators:
M.D.
Anderson Cancer Center
National
Heart, Lung, and Blood Institute (NHLBI)
National
Cancer Institute (NCI)
National
Institutes of Health (NIH)
Information
provided by:
M.D.
Anderson Cancer Center
ClinicalTrials.gov
Identifier:
NCT00474149
Purpose
Primary
Objective:
1.
To
estimate the proportion of CR at Day 28 of therapy for newly diagnosed acute
GVHD for each of these agents given in combination with corticosteroids.
Secondary
Objectives:
1.
To
determine:
1.
proportion
of partial response (PR), mixed response and progression at Day 28
2.
proportion
of treatment failure (no response, progression, or mortality) by Day
14
3.
the
incidence of GVHD flares requiring increasing therapy before Day 90.
Condition
Intervention
Phase
Graft-Versus-Host
Disease
Drug: Etanercept
Drug: Mycophenolate
Mofetil (MMF)
Drug: Denileukin
Diftitox (Ontak)
Drug: Pentostatin
Phase
II
MedlinePlus related
topics: Immune System and Disorders
Genetics
Home Reference related
topics: Immune System and Disorders
Study
Type: Interventional
Study
Design: Treatment, Randomized, Open Label, Uncontrolled,
Parallel Assignment, Safety/Efficacy Study
Official
Title: Initial Systemic Treatment of Acute GVHD: A Phase II Randomized
Trial Evaluating Etanercept, Mycophenolate Mofetil (MMF), Denileukin Diftitox
(Ontak), and Pentostatin in Combination With Corticosteroids
Further
study details as provided by M.D. Anderson Cancer Center:
Total
Enrollment: 180
Study
start: August 2005
GVHD
is a
medical condition where transplanted donor cells attack and damage your tissues
after you have a transplant. In about 40% of cases, GVHD can be controlled
with
treatments that use corticosteroids (like prednisone). More often, patients
need
long-term drug therapy to control their GVHD symptoms and to suppress the immune
system, but this type of long-term drug therapy has risks and side effects.
Because of the risks of continued GVHD and of GVHD treatment, new drugs to
control GVHD are being tested in this study.
Etanercept
is an anti-inflammatory and immune suppressive drug. MMF is an immune
suppressive drug that blocks the growth of lymphocytes (immune cells), which
can
cause GVHD. Denileukin diftitox is an immune suppressive drug but has also
been
used to treat certain kinds of lymphocyte cancers called T-cell lymphomas.
Pentostatin is an immune suppressive drug that is sometimes used as an
anticancer chemotherapy drug as well.
Before
you can start treatment on this study, you will have what are called "screening
tests.” These tests will help the doctor decide if you are eligible to take part
in this study. You will have about 1-2 tablespoons of blood drawn for routine
blood tests. Women who are able to have children must have a negative blood
or
urine pregnancy test before receiving treatment.
If
you
are still eligible to take part in this study, you will be randomly assigned
(as
in a roll of the dice) to receive one of 4 study drugs -unless you are already
receiving MMF; then only one of the other three drugs will be assigned to you.
About the same number of participants will be assigned to each group.
If
you
are assigned to the etanercept group, the drug will be given by injection under
the skin (subcutaneously) twice a week for up to 4 weeks. The doses will be
given on the same 2 days each week, whenever possible.
If
you
are assigned to the MMF group, it will be given twice a day as either capsules
or a liquid, depending on which formulation your body tolerates and absorbs
better. It may be continued for 8-10 weeks, or as long as GVHD is active.
If
you
are assigned to the denileukin diftitox group, it will be given intravenously
(IV--through a needle in your vein) over about 60 minutes on Days 1, 3, and
5 of
the first week, and then repeated in the third week (Days 15, 17, and 19) of
your treatment.
If
you
are assigned to the pentostatin group, it will be given by IV over 15-30 minutes
on Days 1, 2, and 3 of the first week, and repeated in the third week on Days
15, 16, and 17 of your treatment.
No
matter
what group you are assigned to, you will also receive prednisone or
methylprednisolone steroid therapy. Steroids like prednisone or
methylprednisolone are the usual therapy of acute GVHD. There is no placebo
or
sugar pill treatment in this trial. Everyone in the study will receive
prednisone or methylprednisolone plus one of the four new drugs, unless you
are
already receiving MMF; then only one of the other 3 drugs will be assigned
to
you. All patients in the study will be randomly assigned (like flipping a coin)
to receive one of the four new study drugs with some statistical adjustment
to
insure that about the same number of patients will receive each of the new
study
drugs.
Throughout
the study, you will be watched closely for symptoms of GVHD, blood cell count
changes, changes in kidney and liver function, and any signs of infection.
Your
GVHD symptoms will be recorded at least once a week for the first 8 weeks.
The
blood tests at Week 4 and Week 8 must be done at the transplant center. Other
weekly exams and tests, such as routine blood tests (about 1-3 tablespoons
each
time), urine tests, and x-rays, may be done at the transplant center or at
a
local doctor’s office, if your condition improves and the office is closer to
where you live.
If
you
are assigned to the MMF treatment group, you will have extra blood samples
drawn
to study the actions of this drug in your body. You will have about 1 teaspoon
of blood drawn at 4 different times on one day between Days 3 and 7, and again
on another day between Days 10 and 14 (for a total of about 2-3 tablespoons).
This blood will be drawn from an existing central venous catheter or a temporary
peripheral venous catheter (a needle and small tube inserted into your vein,
in
order to lower the number of times you are stuck with a needle.)
Your
participation in this study will be approximately nine months. You may be taken
off study (with or without your consent) if intolerable side effects occur,
you
need a treatment not allowed on this study, you are unable to keep appointments
or take the study drugs as scheduled, you become pregnant, or the study chair,
sponsor, or FDA decides that it would be in your best interest to stop.
This
is
an investigational study. All 4 drugs being tested in this study are approved
by
the FDA for treating diseases other than GVHD. Their use in this study is
considered investigational. All study drugs and the cost of research tests
(such
as the optional blood testing and storage) will be provided by the sponsor.
Any
other testing considered standard of care will be the financial responsibility
of you and/or your insurance company. Up to 180 participants will take part
in
this study. Up to 24 will be enrolled at M. D. Anderson.
Eligibility
Ages
Eligible for Study: 10 Years and above, Genders Eligible for
Study: Both
Criteria
Inclusion
Criteria:
1.
Prior
allogeneic hematopoietic stem cell transplant using either bone marrow,
peripheral blood stem cells or cord blood. Recipients of non-myeloablative
transplants are also eligible.
2.
De
novo Grade B-D acute GVHD diagnosed within 48 hours prior to enrollment.
Biopsy confirmation of GVHD is strongly recommended but not required.
Enrollment should not be delayed awaiting biopsy or pathology results.
The
patient must have had no previous systemic immune suppressive therapy
given for treatment of acute GVHD except for a maximum of 48 hours
of
prior corticosteroid therapy (>1 mg/kg/day methylprednisolone).
3.
No
previous immune suppressive therapy given for treatment of acute GVHD
except for a maximum 48 hours of prior corticosteroid therapy >/= 1
mg/kg/day methylprednisolone.
4.
Clinical
status at enrollment to allow tapering of steroids to not less than
1
mg/kg/day methylprednisolone (1.4 mg/kg/day prednisone) at Day 28 of
therapy. This will be cleared by the Principal Investigator.
5.
Absolute
neutrophil count (ANC) greater than 500/microL
6.
Estimated
creatinine clearance greater than 30 mL/minute. At our institution
this
will be calculated with the Cockroft-Gault equation
7.
Written
informed consent from patient, parent or guardian.
8.
Documentation
that the assent document and education materials have been provided
to,
and reviewed with, patients under the age of 18.
9.
Greater
than or equal to 10 years of age at the time of enrollment.
Exclusion
Criteria:
1.
ONTAK,
pentostatin, or etanercept given within 7 days of enrollment
2.
Active
uncontrolled infection
3.
GVHD
developing after donor lymphocyte infusion
4.
Patients
receiving methylprednisolone>0.5mg/kg/day (or 0.6 mg/kg/day prednisone)
within 7 days of onset of acute GVHD. If steroid therapy has been
administered for a non-GVHD related condition and tapered to < 0.5
mg/kg/day methylprednisolone (or 0.6mg/kg/day prednisone) for seven
or
more days prior to the onset of acute GVHD, the patient is eligible.
5.
Patients
unlikely to be available at the transplantation center on Day 28 and
56 of
therapy.
6.
A
clinical syndrome resembling de novo chronic GVHD developing at any
time
after allotransplantation. See Chapter 2 of the BMT CTN Manual of
Procedures for details of de novo clinical GVHD.
7.
Other
investigational therapeutics for GVHD within 30 days, including agents
used for GVHD prophylaxis
8.
Patients
who are pregnant, breast feeding, or, if sexually active, unwilling
to use
effective birth control for the duration of the study.
9.
Adults
unable to provide informed consent
10.
Patients
with a history of intolerance to any of the study drugs.
11.
Patients
with isolated limited skin (stage I) as the sole manifestation of acute
GVHD.
Location
and Contact Information
Please
refer to this study by ClinicalTrials.gov identifier NCT00474149
Health
Authority: United States: Food and Drug Administration
Attachment
3
Pentostatin
in Treating Patients With Refractory Chronic Graft-Versus-Host
Disease
This
study is currently recruiting patients.
Verified
by National Cancer Institute (NCI) May 2007
Sponsors
and Collaborators:
Cancer
and Leukemia Group B
National
Cancer Institute (NCI)
Information
provided by:
National
Cancer Institute (NCI)
ClinicalTrials.gov
Identifier:
NCT00074035
Purpose
RATIONALE:
Pentostatin may be effective in treating chronic graft-versus-host disease
by
stopping the immune system from rejecting donor stem cells or donor white blood
cells.
PURPOSE:
This phase II trial is studying how well pentostatin works in treating patients
with chronic graft-versus-host disease that is refractory (not responsive)
to
treatment with steroids.
Condition
Intervention
Phase
Brain
and Central Nervous System Tumors
Breast
Cancer
Chronic
Myeloproliferative Disorders
Gestational
Trophoblastic Tumor
Graft
Versus Host Disease
Leukemia
Lymphoma
Multiple
Myeloma and Plasma Cell Neoplasm
Ovarian
Cancer
Testicular
Cancer
Drug: pentostatin
Procedure: biological
therapy
Procedure: complications
of therapy assessment/management
Procedure: graft
versus host disease prophylaxis/therapy
Procedure: supportive
care/therapy
Phase
II
MedlinePlus related
topics: Breast Cancer;
Cancer;
High Risk Pregnancy;
Immune System and Disorders;
Leukemia, Adult Acute;
Leukemia, Adult Chronic;
Leukemia, Childhood;
Lymphoma;
Multiple Myeloma;
Ovarian Cancer;
Testicular Cancer
Genetics
Home Reference related
topics: breast cancer
Study
Type: Interventional
Study
Design: Supportive Care, Open Label
Official
Title: A Phase II Trial Of Intravenous Pentostatin For The Treatment Of
Patients With Refractory Chronic Graft-Versus-Host Disease
Further
study details as provided by National Cancer Institute (NCI):
Total
Enrollment: 37
Study
start: December 2003
OBJECTIVES:
Primary
·
Determine
the response rate in patients with refractory chronic graft-versus-host
disease treated with pentostatin.
Secondary
·
Determine
the time to next immunosuppressive agent (i.e., the time to progression
from best response) in patients treated with this drug.
·
Determine
the toxicity of this drug in these patients.
·
Determine
the infection rate in patients treated with this drug.
·
Determine
the pharmacokinetics of this drug in these patients.
·
Determine
the changes in lymphocyte populations in patients treated with this
drug.
·
Determine
the survival of patients treated with this drug.
OUTLINE:
This is a multicenter study.
Patients
receive pentostatin IV over 20-30 minutes on day 1. Treatment repeats every
14
days for 6 courses in the absence of disease progression or unacceptable
toxicity.
Patients
who achieve a complete response after 6 courses receive 4 additional courses.
Patients who achieve a partial response, minor response, or stable disease
after
6 courses may receive up to 6 additional courses.
Patients
are followed every 4 weeks for 1 year, every 3 months for 2 years, and then
annually for 5 years.
PROJECTED
ACCRUAL: Approximately 37 patients will be accrued for this study.
Eligibility
Ages
Eligible for Study: 18 Years and above, Genders Eligible for
Study: Both
Criteria
DISEASE
CHARACTERISTICS:
·
Histologically
confirmed chronic graft-versus-host disease (GVHD) after allogeneic
hematopoietic stem cell transplantation or donor lymphocyte infusion
·
Progressive,
quiescent, or de novo onset
·
Extensive
stage disease requiring systemic immunosuppressive therapy, defined
according to Seattle criteria as 1 of the
following:
·
Generalized
skin involvement
·
Limited
skin involvement or hepatic involvement with any of the
following:
·
Liver
histology showing chronic progressive hepatitis, bridging necrosis,
or
cirrhosis
·
Eye
involvement (i.e., Schirmer's test with less than 5 mm wetting)
·
Involvement
of minor salivary glands or oral mucosa
·
Involvement
of any other organ
·
Failed
prior corticosteroid therapy, meeting 1 of the following
criteria:
·
Progressive
disease or less than a minor response in any organ system despite 2
weeks
on steroid therapy at a dose of at least 1 mg/kg of methylprednisolone
or
equivalent
·
No
response or minor response after at least 4 weeks of steroid therapy
at a
dose of least 0.5 mg/kg of methylprednisolone or equivalent
·
Less
than a partial response after 8 weeks of steroid therapy at a dose
of
least 0.5 mg/kg of methylprednisolone or equivalent
·
Required
a dose of least 0.5 mg/kg of methylprednisolone or equivalent after
completion of at least 12 weeks of corticosteroid therapy in order
to
maintain a partial response or better
·
Required
a dose of least 10 mg/kg of methylprednisolone or equivalent after
completion of at least 18 weeks of corticosteroid therapy in order
to
maintain a partial response or better
·
Progressive
extensive stage chronic GVHD after completion of at least 18 weeks
of
corticosteroid therapy and currently requiring reintroduction of
corticosteroid therapy at a dose of least 10 mg/kg of methylprednisolone
or equivalent OR an additional therapy (e.g., photopheresis or
psoralen-ultraviolet-light [PUVA] therapy)
·
Established
chronic GVHD either not improving or progressing on other
immunosuppressive agents allowed provided steroid refractoriness has
been
previously established
PATIENT
CHARACTERISTICS:
Age
·
18
and over
Performance
status
·
0-3
Life
expectancy
·
Not
specified
Hematopoietic
·
Absolute
neutrophil count greater than 1,000/mm^3
·
Platelet
count greater than 50,000/mm^3 (without transfusion)
Hepatic
·
Not
specified
Renal
·
Creatinine
clearance at least 30 mL/min
Other
·
Not
pregnant or nursing
·
Negative
pregnancy test
·
Fertile
patients must use effective contraception
·
HIV
negative
·
No
active infection
PRIOR
CONCURRENT THERAPY:
Biologic
therapy
·
See
Disease Characteristics
Chemotherapy
·
Not
specified
Endocrine
therapy
·
See
Disease Characteristics
·
No
concurrent corticosteroids as antiemetics
Radiotherapy
·
Not
specified
Surgery
·
Not
specified
Other
·
Concurrent
continuation of other immunosuppressants administered during onset
or
progression of chronic GVHD is allowed
·
No
concurrent mechanical ventilation
Location
and Contact Information
Please
refer to this study by ClinicalTrials.gov identifier NCT00074035
United
States, Delaware
Beebe
Medical Center, Lewes, Delaware, 19958, United
States; Recruiting
Clinical
Trials Office - Beebe Medical Center 302-645-3171
CCOP
- Christiana Care Health Services, Newark, Delaware,
19713, United States; Recruiting
Clinical
Trial Office - CCOP - Christiana Care Health Services 302-733-6227
United
States, Illinois
Cancer
Care and Hematology Specialists of Chicagoland - Niles, Niles,
Illinois, 60714, United States; Recruiting