DFCI ALL Consortium Protocol 11-001
Site Initiation Visit Part I:
Protocol Overview
Lewis Silverman, MD
September 27, 2012
Protocol 11-001: Study Design
• Randomized study to determine Safety and
Feasibility of IV Calaspargase Pegol (SCPEG) compared with IV Oncaspar in
children and adolescents with newly
diagnosed ALL and lymphoblastic
lymphoma
Background
• Calaspargase Pegol
– EZN-2285
– SC-PEG
• Similar to Oncaspar, but more stable linker
(SC-linker)
• Soon to replace Oncaspar as only
commercially available form of PEG-ASP
in North America
COG AALL07P4
• Randomized comparison of SC-PEG vs Oncaspar
• HR ALL
• COG Augmented BFM backbone
– Induction: 1 dose
– IM#1: 2 doses (Days 2 + 22)
– DI#1:
2 doses (Days 4 + 43)
– IM #2: 2 doses (Days 2 + 22)
Only SER
– DI #2: 2 doses (Days 4 + 43)
COG AALL07P4
• Induction dose: Day 4
• Initial Comparison: Each dosed at 2500 IU/m2
• Toxicity data similar to IV Oncaspar
• SC-PEG appears to have longer half-life
Percentage of patients with serum asparaginase activity level >
0.1 IU/mL on COG Protocol AALL07P4
Day after dose
Oncaspar
SC-PEG
15
100%
100%
22
85%
100%
29
22%
100%
SC-PEG on DFCI Backbone
•
Can SC-PEG be given every 3-weeks
during post-induction treatment phases?
–
•
Goal: Achieve 30 weeks of asparagine
depletion
How will this dosing compare with every
2-week IV Oncaspar?
–
–
NSAA
Toxicity
11-001: Primary Objective
Primary Objective
• To assess the safety and feasibility
associated with the administration of IV
SC-PEG given as a single dose during
Remission Induction and every 3-weeks for
30 weeks during post-induction therapy
•
•
Toxicity
NSAA
Protocol 11-001: Study design
• Randomized comparison of IV SC-PEG vs IV
Oncospar
–
–
Induction: 1 dose (by randomization) at 2500 IU/m2
Post-Induction
•
•
SC-PEG 2500 IU/m2 every 3-weeks
Oncospar 2500 IU/m2 every 2-weeks
• Total planned accrual: 240 patients
Primary Objective: Safety
• Safety: Determining that SC-PEG is not more toxic
than IV Oncaspar
• Primary endpoint is not comparison of randomized
arms
• Each arm will be compared to baseline IV Oncaspar
toxicity rate on 05001
–
–
Study is powered to determine whether SC-PEG arm is
more toxic than baseline IV Oncaspar (05-001)
IV Oncaspar arm on 11-001 is to ensure that baseline
toxicity on 11-001 is not significantly different than
05001
Primary Objective: Feasibility
• Pharmacokinetics of every 3-week SC-PEG
– “Feasible”: Proportion of pts with at least one
NSAA > 0.1 IU/mL during consolidation phase
with SC-PEG is not significantly lower than
with IV Oncaspar
– Of first 114 pts treated on 05-001, 100% had at
least one NSAA > 0.1 IU/mL
Primary Objective: Feasibility
• Pharmacokinetics of every 3-week SC-PEG
– Direct comparison of 2 arms
– Assume 99% of pts on IV Oncaspar arm have
at least one NSAA > 0.1 IU/mL
– With 112 evaluable pts on each arm, there is
89% power to detect a 10% reduction in
proportion of pts with at least one NSAA > 0.1
IU/mL
SC-PEG: Secondary Objectives
• To determine the proportion of samples with
NSAA > 0.025, ≥ 0.10, ≥ 0.20, and ≥ 0.40 IU/mL
prior to each dose for both arms
• To directly compare NSAA levels between
the
two arms at weeks 7, 13, 19, and 25 for every 2week IV Oncaspar and compare them to every 3week IV SC-PEG.
Early Stopping Rules
• Safety (Toxicity)
• MRD
• ASP PK
Early Stopping Rules
• Safety Monitoring
– Safety data reviewed every 6 months by DMC
– Monitor proportion of pts with ASP-related
toxicity to ensure rate does not significantly
differ from 27%
– Early stopping rules: Trial to stop if toxicity on
either arm appears to exceed 27%:
•
eg, 30 pts/arm: 12 or more (40%) with toxicity (80%
CI: 28-53%)
Early Stopping Rules
• MRD Monitoring
– Of first 432 B-ALL pts on 05001,12.5% with
high MRD ( > 0.001 by PCR)
– 11-001: Early stopping if proportion of pts with
high end-induction MRD exceeds 12.5%
•
eg, 30 pts/arm, assuming 28 evaluable, study
stopped if > 7/28 (25%, 80% CI: 14-38%) with high
MRD
Early Stopping Rules
• Induction Asp PK
– Ensure that most pts treated with SC-PEG have
level > 0.1 IU/mL 18 days after induction dose
– On Protocol 05-001: 88% of pts had this level
18 days after IV Oncaspar
– Will monitor level, and stop if proportion of pts
with this level on either arm is lower than 88%
•
eg, 30 pts/arm, it would be unacceptable if < 23
(77%, 80% CI: 64-87%) have level >0.1 IU/mL
Protocol 11-001: Secondary Objectives
• To determine the feasibility of administering antibiotic
prophylaxis during the remission induction phase.
• To describe the outcome of children and adolescents with
lymphoblastic lymphoma treated with a DFCI ALL
Consortium treatment regimen.
• To explore the impact on outcome of changing therapy for
patients with B-ALL based on end-induction minimal
residual disease (MRD) and/or high-risk cytogenetics
(MLL-gene rearrangements or low hypodiploidy).
Protocol 11-001: Secondary Objectives
•
To assess the feasibility of vitamin D screening and
supplementation.
–
To determine the prevalence of vitamin D deficiency at the
following time-points: diagnosis, end of remission induction,
start of continuation, conclusion of therapy, and one year after
the conclusion of therapy.
–
To assess the feasibility of correcting vitamin D deficiency with
supplementation of vitamin D and calcium in patients found to
have vitamin D deficiency.
–
To explore the relationship between vitamin D status and
skeletal toxicity (fracture and osteonecrosis) in children and
adolescents undergoing therapy for ALL.
–
To explore risk factors for vitamin D deficiency, including
demographic variables such as age, sex, and ethnicity, as well as
geographic location (geographic latitude) and season of
measurement.
Protocol 11-001: Biology Objectives
•
To determine the feasibility of prospective screening for absence of
biallelic TCRg deletions (ABGD) via qPCR in patients with T-ALL
–
–
•
To determine the feasibility of prospective screening for abnormalities
(eg, mutations, deletions, rearrangements) of IKZF1, CRLF2 and
JAK1/2 in patients with newly diagnosed B-ALL.
–
–
•
•
To determine the frequency of ABGD in patients with T-cell ALL at diagnosis
To explore the correlation between early T-cell precursor (ETP) phenotype and
ABGD
To determine the frequency of these abnormalities in standard-risk and high-risk
patients
To explore the correlation between the presence of these abnormalities and endinduction MRD levels.
To explore the relationship between mitochondrial BCL-2 family
preconditions and response to chemotherapy as measured by induction
response, end-induction MRD level and event-free survival (EFS).
To obtain patient samples for the development of primary xenograft
mouse models with the goal of identifying novel therapies for high-risk
(including those with high end-induction MRD, T-ALL with ABGD)
and relapsed patients.
11-001: Antibiotic Prophylaxis
• Documented infections (primarily bacteremias) in
> 25% of patients during Induction
• 2% of patients die during induction of infection
(~4% of HR patients)
• Episodes of bacteremia during induction are
significant source of morbidity
–
–
–
prolonged hospitalization
ICU/significant complications
dose reductions and delays in chemotherapy
11-001: Antibiotic Prophylaxis
• In 2005, two large double-blind, placebo
controlled trials using levofloxacin in adult cancer
patients with neutropenia were published.
–
Both demonstrated benefit of levofloxacin (fewer
episodes of fever, fewer infections) in cancer patients,
especially those with acute leukemia
• In 2008, the National Comprehensive Cancer
Network (NCCN) recommended the use of
fluoroquinolone prophylaxis in high risk cancer
patients, including leukemia patients receiving
induction chemotherapy.
11-001: Antibiotic Prophylaxis
• Non-randomized testing of fluoroquinolone
prophylaxis during induction phase.
• All afebrile patients will begin either levofloxacin
or moxifloxacin during steroid prophase
–
Continue until count recovery of (ANC > 200/mm3 or
APC > 500/mm3) or initiation of broad-spectrum
antibiotics for fever.
• Patients unable to tolerate fluoroquinolone should
receive cefipime instead
• Prophylaxis is mandatory
11-001: Antibiotic Prophylaxis
Statistical Plan:
• Rates of bacteremia will be compared to historic
controls (25% rate of bacteremia on 05-001)
• Only infections in ALL patients will be considered
• Will consider infection rate in each randomized
arm separately
• With 103 evaluable ALL patients per arm, we
would have 82% power to detect a 12% reduction
in the rate of bacteremia
Eligibility (Section 3)
• Confirmed Diagnosis of ALL or Lymphoblastic
Lymphoma
–
ALL
•
•
•
–
>30% marrow involvement
If circulating blasts: flow cytometry confirmation of ALL sufficient
for registration; marrow should be performed “as soon as feasible,
preferably prior to initiation of any therapy”
Excluded: Mature B-cell ALL, Leukemia of Ambiguous Lineage
Lymphoblastic Lymphoma: Radiographic evidence of lymphoma
with:
•
•
•
Biopsy of involved site
Cytology from pleural or other fluid
Marrow aspirate with < 30% lymphoblasts
Eligibility
• Prior Therapy: None allowed, except
– Corticosteroids: < 7 days within 4-weeks preceding
registration (should treate without prophase)
•
–
–
Not Eligible if > 7 days steroid within previous 4-weeks, or
more than 28 days of steroids within previous 6 months
IT Cytarabine (single dose)
Emergent Radiation Therapy: Mediastinum, other lifethreatening masses
Eligibility
• Age 365 days to < 18 years
• Direct bilirubin < 1.4 mg/dL
• Signed, informed consent
Exclusion Criteria
• Chronic steroid pre-treatment, as defined above
• Any other prior cancer and/or any prior
chemotherapy or radiation (at any time in the past)
–
Exception: Pts treated for cancer with surgey only > 5
years preceding registration
• Currently on an investigational agent
• Known HIV-positivity (HIV testing not required
for enrollment)
Exclusion Criteria
• Uncontrolled intercurrent illness
– Infection with sepsis
– Life-threatening tumor lysis syndrome (eg, renal
failure)
– Congestive hear failure
– Uncontrolled bleeding (intracranial hemorrhage)
• Psychiatric or Social situation that would limit
compliance
• Pregnancy
–
Pregnancy test required of females of childbearing
potential prior to start of therapy
Informed Consent
• Copy of signed, dated informed consent document must
be sent to DFCI for patient to be registered.
• ONLY physicians who are listed on the 1572 form may
consent participants to 11-001
• ONLY attending physicians may consent participants to
11-001
• Per DFCI Consenting Policy: fellows, nurses, pharmacists
may not consent to 11-001 without attending co-sign
Informed Consent
• Informed Consent Document is necessary but not
sufficient to document informed consent process
• Review of Consent Discussion must be in medical record
• Essential elements of note:
–
–
–
–
–
Research study was fully explained to the participant and/or
parents
Risks and alternative treatment options were discussed
The participant and/or parents had all of his/her questions
regarding the study answered.
They understand they can withdraw consent at any time
The participant and/or parents signed the research consent form
and was/were given a copy of the signed consent form
Registration
• Note: Only patients who consent to Asparaginase
randomization will be enrolled on study
–
No “direct assignments” for patients who refuse
randomization
• Weekdays: Randomization performed at time of
registration
• Off-hours: Registration allows start of therapy;
Randomized assignment made and communicated
to site on next business day
Risk Classification: Differences from 05-01
–
–
Essentially same criteria for SR, HR, VHR
Slight modification in definition of
“Hypodiploidy”
•
–
Now < 44 chromosomes (formerly < 45
chromosomes
Lymphoblastic lymphoma risk-stratified like
ALL, but no MRD
Risk Group Classification (Section 5)
• Initial Risk Group: Age, WBC,
Immunophenotype, CNS status (if known)
• Final Risk Group: Cytogenetics, MRD (BALL only)
Standard Risk
All of the criteria must be met:
•
Age: 365 days to < 10 years.
•
WBC count: Highest pre-treatment WBC <50,000/mm3 (prior to
registration).
•
CNS leukemia: No evidence of CNS leukemia, defined by meeting
all of the following criteria:
–
–
Diagnostic lumbar puncture (Day 1) without any CSF blast cells on
cytospin (CNS-1) or fewer than 5 WBC/hpf in CSF with blast cells
noted on cytospin (CNS-2). If traumatic tap (>10 RBC's on CSF cell
count) with > 5 WBC cells are seen, use Steinherz/Bleyer algorithm
(see 5.1.6) to determine if patients should be considered CNS-2 or
CNS-3 for purposes of risk group assignment.
CNS-1 CSF on Days 18 and 32. Absence of a cranial nerve palsy at
diagnosis.
Risk Group Classification: Standard Risk
• Immunophenotype: Predominance of B-precursor cell
surface antigens on lymphoblasts.
• Chromosomal abnormalities: Absence of t(9;22), MLL
gene translocations and hypodiploidy < 44 chromosomes
as determined by karyotype, PCR or FISH analysis. If
chromosomal data unavailable, may continue to be treated
as SR if all other risk group criteria are met.
• MRD (leukemia patients only): MRD level < 0.001 on a
marrow sample obtained at end of remission induction
therapy (Day 32). SR patients whose end-of-induction
MRD status cannot be determined will remain SR.
Risk Group Classification: High Risk
Any of the following
•
•
•
Age: 10 to < 18 years
WBC count: Highest pre-treatment WBC >50,000/mm3 (prior to
registration).
CNS leukemia: Evidence of CNS leukemia, defined by meeting any of
the following criteria:
–
–
–
–
Diagnostic lumbar puncture (Day 1) with 5 or greater WBC/hpf and blast
cells on cytospin (CNS-3). If traumatic tap (>10 RBC's on CSF cell count)
with > 5 WBC cells are seen, use Steinherz/Bleyer algorithm (see 5.1.6) to
determine if patients should be considered CNS-2 or CNS-3 for purposes
of risk group assignment.
CNS-2 on Day 18 or 32.
CNS-3 on Day 18.
Presence of a cranial nerve palsy at diagnosis.
High Risk
• Immunophenotype: Predominance of T-cell
markers on lymphoblasts.
• MRD (B-ALL only):
–
–
–
B-precursor HR patients with MRD level < 0.001 on a
marrow sample obtained at Day 32 will continue to be
treated as HR.
B-precursor HR patients with MRD levels > 0.001 at
Day 32 will be re-classified and re-consented as very
high risk
B-precusor HR patients whose end-of-induction MRD
status cannot be determined will remain HR.
Very High Risk
Any of the following
• Chromosomal abnormalities:
–
–
MLL gene translocations [such as t(4;11)]
Hypodiploidy < 44 chromosomes by karyotype
or FISH analysis.
• MRD status (leukemia patients only): B-
ALL patients with MRD >0.001 at Day 32.
Ph+ ALL
• Patients with t(9;22) will be removed from study
prior to Day 15.
• These patients will be eligible to enroll on the
open COG Protocol for Philadelphia chromosomepositive ALL.
–
–
Diagnostic sample from DFCI MRD lab to be sent to
COG lab to allow MRD determination on COG study
Site responsible for sending flow histograms from
diagnosis to MRD Flow Cytometry Lab
Lymphoblastic Lymphoma:
Risk Group Classification
•
Patients will be classified as Standard
Risk, High Risk or Very High Risk based
on
–
–
Age, immunophenotype, CNS status and
cytogenetics (same as for ALL patients)
MRD will not be used for risk-group
classification.
Steinherz/Bleyer Algorithm to Interpret
Traumatic LP’s
• Traumatic LP: >10 RBC per high power
field with > 5 WBC/hpf:
• Traumatic CSF specimens should be treaetd as
CNS-3 if:
CSF WBC/CSF RBC > 2x (Blood WBC/Blood RBC)
• All other traumatic CSF specimens with blasts
should be treated as CNS2.
Cytogenetics/FISH/PCR
• Required Studies:
– Karyotype
– FISH (PCR insufficient screening test):
•
•
–
TEL/AML1 (also screens for iAMP21)
MLL (screens for all fusion partners)
FISH or PCR:
•
BCR-ABL
Cytogenetics/FISH/PCR
• Suggested Studies (esp if normal or
uninterpretable karyotype)
–
–
–
FISH for trisomies 4,10,17
FISH for 9p deletions
FISH or PCR for t(1;19)
Cytogenetics/FISH/PCR
• Reports must be sent to DFCI for central
review prior to Day 15
• Please ensure that all tests that were
performed are clearly listed on report(s)
Final Risk Group Assignment
•
Final Risk Group Assignment will be made no later than 21 days after
start of Consolidation I phase, and only after receipt of following
source documents:
–
–
–
–
–
–
•
Path reports confirming diagnosis (and scan reports of involved sites for
LL)
Path and scan reports confirming complete remission
Diagnostic flow cytometry reports (ALL only)
Diagnostic cytogenetics, FISH, PCR (ALL only)
CBC with differential from diagnosis and from end of induction
CSF cell count/cytospin (and/or cytopath) from diagnosis and end of
induction
DFCI Study Team will call/email verification of MRD results (if
applicable) and final risk group assignment to participating site
Protocol 11-001: Treatment (Section 6)
–
–
–
–
–
–
Steroid Prophase
Induction
Consolidation I
CNS Phase
Consolidation II
Continuation
11-001: Treatment
• Section 7.2.1: Allowable variations in dose/timing
– Dose: variations within 10% of calculated dose
(rounding)
– Timing (treatment/procedures):
•
•
–
Induction, Consol I, CNS, Consol II: +/- 3 days
Continuation: +/- 7 days
Schedule (drugs given multiple times/day)
•
+/- 3 hours from specified intervals
• Any variation in dosing outside of these
parameters are considered protocol violations
–
Anything can be delayed/modified for significant
illness (must be discussed in advance)
11-001 Induction: Differences from 05-01
• Induction Phase
– Essentially the same as 05-01 (including prophase)
– Randomized: SC-PEG vs IV-PEG (Day 7)
•
–
–
PK samples required pre-dose, weekly after dose x 4
Antibiotic Prophylaxis (begin during prophase)
Steroid taper at end of induction to begin at Day 32
•
•
Adrenal suppression after 1 month of steroids
?reduce fever/illness during Consol I phase
11-001: Prophase
• Methylpred Day 1-3
• IT cytarabine Day 1
– Twice-weekly until 3 consecutive clear if
•
•
•
•
–
CNS-2
CNS-3
Traumatic LP with blasts
Cranial nerve palsy (continue until Day 18)
CSF sample to Peter Cole (optional)
• Begin antibiotic prophylaxis (if afebrile)
– Continue until ANC > 200 or APC > 500, or fever
develops
11-001 Induction
• Days 4-32: Methylpred 3x/day or pred 2-3x/day
– Day 32: Begin taper (should be off steroids by Day 39)
– Taper should be administered even if Consol I delayed
• Days 4,11,18,25: Vincristine
• Days 4,5: Doxorubicin +/- Dexrazoxane (HR)
• Day 6: methotrexate (low dose)
• Day 18: IT MAH
11-001: Induction
• Day 7: Asparaginase by Randomization
• SC-PEG vs Oncaspar
– Each dosed at 2500 IU/m2
– Each given over 1 hour
• Labs (Required): ASP PK/Antibody
– Pre-dose
– End of infusion
– Days 11, 18, 25 and 32
11-001: End of Induction
• ALL patients:
– Marrow must be done at Day 32 (send sample for MRD)
– CXR/Chest CT if AMM at diagnosis
– LP with IT MTX if counts recovered
•
CSF sample to Peter Cole (optional)
• Lymphoma patients:
– Repeat scans of involved sites
– Marrow only if involved at diagnosis
– LP with IT MTX if counts recovered
•
CSF sample to Peter Cole (optional)
Definition of Complete Remission
• ALL
–
–
–
–
–
Count recovery: APC > 1000, platelets > 100K
Interpretable marrow with < 1% blasts
No peripheral blood lymphoblasts
No blasts in CSF
> 70% reduction in size of any mass present at diagnosis (scan)
• Lymphoblastic Lymphoma
–
–
–
–
> 70% reduction in size of largest nodes/masses at diagnosis
No evidence disease on exam
Interpretable marrow with < 1% blasts (if involved at diagnosis)
No blasts in CSF
Induction Failure
• > 1% blasts in marrow (confirmed by flow, FISH,
other studies)
• CNS-3
• < 70% reduction in size of any mass noted at
diagnosis, or any new, biopsy-proven mass
• All patients with induction failure are removed
from protocol treatment
Delayed Recovery
• If no peripheral blood criteria at Day 32
– Marrow at Day 32, send for MRD (ALL only)
– No LP
– Give vincristine 1.5 mg/m2/dose (max 2 mg)
weekly until count recovery
– Repeat marrow must be done when counts
recover
– CR must be documented by Day 53 for patients
to remain on study
11-001 Consolidation I:
Differences from 05-01
• Consolidation I: No change
– End-induction steroid taper during 1st week if
Consol I begins at Day 32
• VHR Consol IB and IC: No change
– ASP randomization begins during Consol IC
11-001: Consolidation I
• Starting Criteria
– Documented CR
– APC > 1000, platelets > 100K
– SGOT < 8x normal
– Direct bili < 1.4 mg/dL (23.9 micromoles/L)
– Normal creatinine for age
– No mucositis
– No ascites/effusions/significant edema
• May be delayed for significant illness
11-001: Consolidation I
•
•
•
•
VCR (Day 1)
6MP (Days 1-14)
Dox/Dexrazoxane (Day 1): HR only
HD MTX over 24 hours
–
–
SR: Day 1
HR: 8-24 hours after doxorubicin
• IT MTX (if > 72 hours since Day 32 IT MTX)
• Steroid Taper
– Should be completed by Day 39
Consolidation I
• Final Risk group classification should be
made no later than 21-days after start of
Consolidation I
11-001: Consolidation IB (VHR only)
• To begin approx 21 days after start of
Consol IA
• Starting Criteria
–
–
–
–
–
APC > 750, platelets > 75K
SGOT < 8x normal
Direct bili < 1.4 mg/dL (23.9 micromoles/L)
Normal creatinine for age
No or nearly fully resolved mucositis
11-001: Consolidation IB (VHR only)
• Cyclophosphamide (Day 1)
• 6MP (Days 1-14)
• Low dose cytarabine:Days 2-5, 9-12
–
–
–
Once 4-day course commences, give all 4-doses
regardless of counts
Delay Day 9 if APC < 500 or platelets < 50K
If Day 9 cannot be given by Day 23, omit the second 4day course
11-001: Consolidation IC (VHR)
• To begin approx 21 days after start of
Consol IB
• Starting Criteria
–
–
–
–
APC > 750, platelets > 75K
SGOT < 8x normal
No or nearly fully resolved mucositis
Suggestion: check amylase prior to ASP
11-001: Consolidation IC (VHR)
• HD araC 2 gm/m2 q12 hours x 4 doses
(Days 1-2)
• Etoposide daily Days 3-5
• Dexamethasone 18 mg/m2/day oral or IV
divided twice daily: Days 1-5
• ASP by randomization Day 8
11-001: Consolidation IC (VHR)
• ASP by randomization (Day 8)
– SC PEG 2500 IU/m2 IV over 1 hour
•
–
Continue every 3 weeks for 10 doses (30 weeks)
Oncaspar 2500 IU/m2 IV over 1 hour
•
Continue every 2 weeks for 15 doses (30 weeks)
• Required samples: ASP PK/Antibody
– Prior to every dose, including 1st dose
11-001 CNS phase: Differences from 05-01
• CNS Phase
– Marrow on Day 1 for VHR patients (MRD)
– CSF samples to Peter Cole (4th LP)
•
–
Optional
New criteria for cranial radiation
•
Criteria for XRT
•
•
•
•
VHR
T-ALL
CNS-3
HR B-ALL with WBC > 100K no longer a criterion
11-001: CNS Phase
• 21 days from start of Consolidation I
• Starting Criteria:
– APC > 1000, platelets > 100K
– Direct bilirubin < 1.4 mg/dL (23. 9 micromoles/L)
– SGOT < 8x normal
– No mucositis
– Amylase prior to ASP (Suggested)
11-001: CNS Phase-SR
• VCR: Day 1
• 6MP: Days 1-14
• Dexamethasone 6 mg/m2/day (Days 1-5)
• Twice weekly Triple IT x 4 doses
– Dose by age
• ASP by randomization (Day 1)
11-001: CNS Phase-HR
• VCR: Day 1
• Doxorubicin/Dexrazoxane: Day 1
• 6MP: Days 1-14
• Dexamethasone 18 mg/m2/day (Days 1-5)
• Twice weekly Triple IT x 4 doses
– Dose by age
• ASP by randomization (Day 1)
11-001: CNS Phase (SR, HR)
• ASP by randomization (Day 1)
– SC PEG 2500 IU/m2 IV over 1 hour
•
–
Continue every 3 weeks for 10 doses (30 weeks)
Oncaspar 2500 IU/m2 IV over 1 hour
•
Continue every 2 weeks for 15 doses (30 weeks)
• Required samples: ASP PK/Antibody
– Prior to every dose, including 1st dose
CNS Phase: Radiation
• No XRT
–
–
–
SR ALL/LL
HR B-precursor ALL/LL: CNS1, CNS2
T-cell LL: CNS1, CNS2
• 12 Gy XRT
–
–
T-cell ALL: CNS1, CNS2
VHR ALL/LL: CNS1, CNS2
• 18 Gy XRT
–
–
–
CNS3 at diagnosis
Cranial nerve palsy at diagnosis
CNS2 at Day 18
11-001 Consolidation II/ Continuation:
Differences from 05-01
• Consolidation II/Continuation
– New criteria to start cycles
•
•
–
IV/IM Methotrexate to be given on same day as ASP
•
–
APC > 750/mm3 (instead of 1000)
Platelets > 75,000/mm3 (instead of 100K)
PO MTX allowed up to 3x during protocol (for vacation, etc)
HR/VHR: Only 10 cycles of high-dose dexamethasone
11-001: Consolidation II
• Starting Time: 21 days for start of CNS
phase
• Criteria to start each 3-week cycle
– APC > 750, platelets > 75K
– Mucositis: None or mild
– SGOT < 8 x normal
– Direct bili < 1.4 mg/dL (23.9 micromoles/L)
11-001: Consolidation II
• Criteria to continue each 3-week cycle
(Days 2-21)
–
–
–
–
APC > 500, platelets > 50K
Mucositis: None or mild
SGOT < 8 x normal
Direct bili < 1.4 mg/dL (23.9 micromoles/L)
11-001: Consolidation II
• Criteria to administer asparaginase
– No clinical pancreatitis
– No new, untreated DVT
– Direct bili < 1.4 mg/dL (23.9 micromoles/L)
•
–
Triglycerides < 2000 (<22.8 mmol/L)
•
–
Must be checked prior to each dose
Does not need to be checked, but if value known,
must hold if > 2000
May administer regardless of blood counts,
mucositis or SGOT
Consolidation II
• SR: Every 3-week cycle
– VCR: Day 1
– Dex: 6 mg/m2/day divided twice-daily: Days 1-5
•
–
6MP: Days 1-14
•
–
–
If taper used, total dose given each cycle should not exceed 30
mg/m2
Daily dose may be adjusted to accommodate available tablets
to achieve 14-day total
MTX: Days 1, 8, 15
ASP by randomization to complete 30 total weeks
(including CNS Phase)
Consolidation II
• HR: Every 3-week cycle
–
–
VCR: Day 1
Doxorubicin/Dexrazoxane: Day 1
•
•
–
Dex: 18 mg/m2/day divided twice-daily: Days 1-5
•
•
–
If taper used, total dose given each cycle should not exceed 90 mg/m2
10 cycles only, then give 6 mg/m2/day twice-daily
6MP: Days 1-14
•
–
Until total cumulative dose 300 mg/m2 +/- 15 mg/m2
After total dose achieved, begin weekly MTX
Daily dose may be adjusted to accommodate available tablets to
achieve 14-day total
ASP by randomization to complete 30 total weeks (including CNS
Phase)
Consolidation II, SR and HR
• Triple IT chemotherapy
– No XRT: Every 9 weeks x 6 doses, then every 18
weeks
•
•
•
–
XRT: Every 18 weeks
•
•
•
–
1st dose 9 weeks after CNS LP #1
Always administer at start of 3-week cycle
No IV MTX on same day as Triple IT chemo
1st dose 18 weeks after CNS LP#1
Always administer at start of 3-week cycle
No IV MTX on same day as Triple IT chemo
CSF to Peter Cole (LP#1 of Consol II phase)--optional
11-001: Consolidation II (SR, HR)
• ASP by randomization (Day 1)
– SC PEG 2500 IU/m2 IV over 1 hour
•
–
Continue every 3 weeks for 10 doses (30 weeks)
Oncaspar 2500 IU/m2 IV over 1 hour
•
Continue every 2 weeks for 15 doses (30 weeks)
• Required samples: ASP PK/Antibody
– Prior to every dose
11-001: Continuation
• Starting Time: Completion of all
components of Consolidation II
–
–
SR: All doses of ASP
HR/VHR: All doses of ASP, cumulative dox
300 +/- 15 mg/m2, 10 cycles with high-dose
dex (including CNS phase)
11-001: Continuation
• Criteria to start each 3-week cycle
–
–
–
–
APC > 750, platelets > 75K
Mucositis: None or mild
SGOT < 8 x normal
Direct bili < 1.4 mg/dL (23.9 micromoles/L)
• Criteria to continue each 3-week cycle (Days 2-21)
–
–
–
–
APC > 500, platelets > 50K
Mucositis: None or mild
SGOT < 8 x normal
Direct bili < 1.4 mg/dL (23.9 micromoles/L)
Continuation (All risk groups)
• Every 3-week cycle
– VCR: Day 1
– Dex: 6 mg/m2/day divided twice-daily: Days 1-5
•
–
6MP: Days 1-14
•
–
If taper used, total dose given each cycle should not exceed 30
mg/m2
Daily dose may be adjusted to accommodate available tablets
to achieve 14-day total
MTX: Days 1, 8, 15
Continuation (All risk groups)
• Triple IT chemotherapy
– No XRT: Every 9 weeks x 6 doses, then every 18
weeks
•
•
•
–
1st dose 9 weeks after CNS LP #1
Always administer at start of 3-week cycle
No IV MTX on same day as Triple IT chemo
XRT: Every 18 weeks
•
•
•
1st dose 18 weeks after CNS LP#1
Always administer at start of 3-week cycle
No IV MTX on same day as Triple IT chemo
Duration of Therapy (Section 6.17)
• 104 weeks (+/- 2 weeks) after CR
documented
–
–
Even if significant delays or dose modifications
during therapy
Therapy should not be stopped in midst of a 3week continuation cycle
Duration of Therapy
• Removed from Protocol Therapy if:
– Ph+ ALL
– Induction Failure
– Relapse
– SMN
– Withdrawal by participant
– Investigator feels that further treatment is unacceptable
(change in condition, compliance)
• Duration of follow-up (Section 6.18): Indefinite
– Including those who stop treatment early, unless
withdrawal of consent
Supportive Care (Section 6.16)
• Mandatory infection prophylaxis during
prophase/induction
–
–
Levofloxacin/Moxifloxacin
Cefipime if allergic
• Bactrim prophylaxis after achieving CR
• GCSF, GMCSF allowed at discretion of treating physician
• Use of corticosteroids for other conditions
–
–
–
Allowed: Blood pre-med, allergic rxn, RAD
Must be discussed: Prolonged use (more than a few days at a time)
Prohibited: Steroids as antiemetics
Supportive Care (Section 6.16)
• Leucovorin after IT chemotherapy: Allowed
at discretion of treating clinician for:
–
–
Down Syndrome
History of excessive toxicity with prior IT
MTX
Dose Modifications:
Consolidation II/Continuation (Section 7.2.8)
• APC < 750 or platelets < 75K when cycle is due:
– Hold cycle (including vcr, dexamethasone, IT chemo)
– Proceed with ASP if ASP-criteria met
– Consider dose reduction of MTX/6MP by 20% when
counts recover
– HR/VHR: Reduce 6MP first, then doxorubicin
•
–
May only reduce Doxorubicin once (to 80% dose)
Consider TPMT testing for persistent or excessive
myelosuppression
Dose Modifications:
Consolidation II/Continuation (Section 7.2.8)
• APC < 500 or platelets < 50K during cycle:
– Hold MTX and 6MP for remainder of cycle (do
not restart)
– Consider dose reduction of both agents at start
of cycle by 20%
– HR/VHR: Reduce 6MP first, then doxorubicin
•
–
May only reduce Doxorubicin once (to 80% dose)
Consider TPMT testing for persistent or
excessive myelosuppression
Dose Modifications:
Consolidation II/Continuation (Section 7.2.8)
• SGOT > 8 x normal, direct bili > 1.4 mg/dL or
Mucositis:
–
–
–
–
Hold start of cycle (Hold ASP for direct bili, not SGOT
or mucositis)
If during cycle, hold MTX and 6MP until within
acceptable range; may restart during same cycle
Consider dose reduction of both agents at start of next
cycle or when resumed by 20%
HR/VHR: Reduce 6MP first, then doxorubicin
•
May only reduce Doxorubicin once (to 80% dose)
Dose Modifications:
Asparaginase (Section 7.2.8.5)
• Clinical Allergy
– Switch to Erwinia 25000 IU/m2 IM twiceweekly to complete 30 weeks of asparaginase.
•
If Erwinia allergy, stop all ASP
• Silent Allergy
– If 2 consecutive NSAA are non-detectable
(<0.025 IU/mL), switch to twice-weekly
Erwinia as above
Dose Modifications:
Asparaginase (Section 7.2.8.5)
• Thrombosis (Appendix II)
– Hold ASP
– Begin anticoagulation
– Resume ASP after coagulation status stabilized
and clinical symptoms resolved
•
–
May permanently discontinue after severe CNS
event (no restart)
If recurrence after restart, permanently stop
Dose Modifications:
Asparaginase (Section 7.2.8.5)
• Lipemic Blood
– Triglyceride levels not required (discouraged)
– Hold if found to be high (>2000 or 22.8
mmol/L)
– Resume when levels are within acceptable
range
– Lipid lowering agents may be used at discretion
of treating clinician
Dose Modifications:
Asparaginase (Section 7.2.8.5)
• Pancreatitis
–
Asymptomatic enzyme elevation: Hold ASP if > 3 x normal,
resume when below this level
•
–
Mild/Moderate: symptoms < 72 hours duration with amylase
and/or lipase elevation
•
•
•
–
If receiving cranial radiation, check lipase
Hold ASP
Resume when signs, symptoms, enzymes return to baseline
May permanently discontinue after recurrent episodes of
mild/moderate pancreatitis
Severe: symptoms > 72 hours with amylase/lipase elevation, or
pseudocyst, or life-threatening complications
•
Permanetly discontinue
Dose Modifications:
Asparaginase (Section 7.2.8.5)
• Asparaginase Intolerance: Pt permanently
stops ASP having received 10 or fewer
weeks
–
–
SR: Add 3 cycles of HR Consol II
(Doxorubicin + dexrazoxane, high-dose dex)
HR: No changes; Continue rest of doxorubicin.
Need to give 10 cycles with high-dose
dexamethasone
Dose Modifications:
Dexamethasone (Section 7.2.8.7)
• Taper allowed for withdrawal pain: do not exceed total
•
•
•
•
intended dose for the cycle
Permanently discontinue for symptomatic osteonecrosis
(symptoms + scan)
Hold for fracture; resume when healed (scan, symptoms,
clearance by orthopedist); do not make up missed doses
May be held for pancreatitis
Severe, intolerable behavioral changes
–
–
–
HR/VHR: may be reduced to lower dose during Consol II
SR: may be stopped or given less frequently (need to discuss first)
May switch to prednisone
Required Studies: Section 10.1 (Induction)
Study
Entry
Day
1
Day4
Day
11
Day
18
Day
25
Day
32
Physical Exam
X
X
CBC w/differential and platelets
X
Serum chemistry a
X
X
Bone Marrow aspirate/biopsy
for morphology
X
Xb
Bone Marrow
Immunophenotype, cytogenetics,
FISH and/or PCR
Xc
MRD (Marrow/Blood)
X
Biology Research Studies
(Marrow/Blood)
Xe
Asparaginase PK samples
(blood)
X
X
X
X
Xd
X
X
Xb
X
X
Required Studies: Section 10.1 (Induction), cont’d
Study
Entry
Day
1
Vitamin D 25 OH level (blood)
Xf
CSF for cell count, cytospin
Xk
Day
4
Day
11
Day
18
Day
25
Day
32
Xf
Xk
X
Chest x-ray
X
Xg
CT scans (Neck, chest, abdomen, pelvis)
Xh
Xi
Echocardiogram (recommended, not
required)
X
B-HCG (urine or serum)
Xj
AE/Toxicity Assessment L
X
X
X
X
X
X
X
Required Studies: Post-Induction
CNS
Phase
Physical Exam
X
CBC w/differential and platelets
X
Serum chemistryb
X
Bone Marrow aspirate for
morphology
Xc
MRD (Marrow/Blood)
Xc
Asparaginase PK samples (blood)
Xd
Consolidation
II
Continuation
End of
Therapy
X
Xa
Xa
Xa
Xa
Xd
Xe
Vitamin D level (blood)
Xe
Xf
Echocardiogram
CSF
Xg
Xg
AE/Toxicity Assessmenth
X
X
X
X
Outside Affiliate Sites (Section 15)
• Some standard-of-care lab studies and treatments may be
performed at satellite sites affiliated with a Participating
Site
• It is the responsibility of the Participating Institution to
which the satellite is affiliated to monitor all care that is
performed at the satellite in order to ensure protocol
compliance and screen for AEs.
• Only those Labs and Treatments Listed in Protocol
(Section 15) can be performed at Affiliate Site
Affiliate Sites:
Allowed Labs and Treatment
• Laboratory Studies
–
Standard-of-care labs used to determine whether starting criteria
for chemotherapy are met and/or to monitor for side effects
•
CBC, LFTs, amylase, lipase, triglyceride levels
• Therapy
–
–
–
–
–
Standard-of-care chemotherapy agents (eg, vincristine,
doxorubicin/dexrazoxane) administered during Consolidation II or
Continuation phases
IM Erwinia asparaginase (for patients who develop allergy to PEG
asparaginase)
Oral agents (eg, prednisone, dexamethasone, 6-mercaptopurine)
may be administered in the home or at a satellite site.
IV/IM methotrexate (Consolidation II or Continuation phase only)
Low-dose IV cytarabine during the Consolidation IB phase
Procedures
• Diagnostic Procedures and Radiographic Studies
– Diagnostic marrow, nodal and/or mass biopsies and
scans that have already been performed at an outside
institution do not have to be repeated prior to study
entry
– Pathologic/radiographic interpretation of these studies
confirming protocol eligibility must be performed at
Lead Institution or Participating Institution
• All subsequent marrows, restaging studies and
LP’s with IT chemo may only be done at
Participating Site (not at Affiliate)
Labs/Therapies that Cannot be Performed
at Affiliate Site
The following can only be performed at Participating
Site (not allowed at Affiliate Site)
• Lab Studies
–
–
All Research Labs
MTX levels (Consolidation I)
• Treatment
– All doses of Oncaspar or SC-PEG
– All IV chemo during Prophase, Induction,
Consolidation I and CNS phase (except low-dose araC
during Consol IB)
– All IT chemotherapy (any phase)
DFCI ALL Consortium Protocol 11-001
Site Initiation Visit Part II:
Regulatory Overview
Lewis Silverman, MD
October 11, 2012
Process to Open 11-001 at Outside Sites
• DFCI IRB approved protocol is provided to outside sites
•
•
•
•
•
and submitted to local IRB
Consortium site IRB approval is submitted to DFCI IRB
adding consortium site onto the study
DFCI IRB approval of the addition of the consortium site
is submitted to FDA with consortium site FDA Form 1572
SIV (teleconference)
Sigma-Tau approves all required regulatory documents and
ships drug to consortium site
11-001 may be open to enrollment
Timeline to Open at Outside Sites
US Sites
• In process
• Contract
• LOI with Sigma-Tau
• IRB Approvals at Consortium Sites
Canadian Sites
• End of October 2012
– Sigma Tau to submit final Drug Master File (DMF) to Health Canada for
SC-PEG
– Beginning of November: CTA to be submitted to Health Canada
(immediately after DMF submission)
• 60 day review period for the CTA
• 11-001 can open at Canadian sites upon CTA approval
Required Regulatory Documents
• Must be submitted to DFCI prior to activation of
study at each site:
–
–
–
1572 (DFCI will provide Template)
Site PI and Co-Investigators CV, FDFs, Licenses
Lab Documents
•
–
–
–
–
–
CLIA/CAP/Lab Normal Ranges/Lab Directors CV and License
Initial IRB Approval
IRB Membership List
Delegation of Authority Log
Protocol Signature Page
IRB Letter of Assurance (FWA)
Site Regulatory Binder
•
•
•
•
•
•
•
•
•
•
Protocol
Investigator Brochure
Consent Form
FDA 1572
CV/Licenses/Financial
Disclosure
Laboratory Documents
Delegation of Authority
Log
Protocol Training
Monitoring Log/Reports
Screening/Enrollment Log
•
•
•
•
•
•
•
•
•
•
•
Drug Accountability Records
Initial IRB Application
Initial IRB/SRC Review
Amendments
Protocol Deviations/Violations
Continuing Review
Study Close Out
SAEs
IND Safety Reports
DMC Reports
General Correspondence
Site Initiation Visit
• DFCI leads SIV via teleconference
• Expected attendees (must be documented)
–
–
Site PI
All site co-investigators (other MD’s who will consent patients)
•
–
Only co-investigators can sign informed consent, so any MD who will
consent participants must be listed as co-investigator
Site study staff (eg, research nurse, CRA, pharmacists, etc)
• Topics to be covered
–
Objectives, rationale, study design, eligibility, registration,
required data, treatment schedule, side effects, SAE reporting, dose
modification
• SIV must be completed before site is activated
On-going Training
• On-going training (Documented in Training
Log at each site)
–
Must be performed and documented for
•
•
–
Individuals unable to join the SIV
Anyone joining the study team in the future
Training Log documents
•
•
What study information was reviewed
Training was conducted by a person with
appropriate level of knowledge
Monthly Teleconferences
•
Study Updates
•
Expected Attendees:
– Site PI, study staff
•
Agenda: Discuss study-related issues, including
– Study Accrual
– SAE’s/AE’s
– Deviations/Violations
– Protocol Amendments
– Clinical issues
•
Review Minor Deviation/Violation Logs
•
Teleconference minutes will be posted on the ALL Consortium
Website
Ordering Study Drug
• Initial order
– DFCI receives initial required regulatory documents
– Regulatory documents are provided to Sigma-Tau
– Initial shipment of drug will be sent directly to site
from Sigma-Tau
• Future orders
– Re-order directly through Sigma-Tau
Protocol Review and Amendments (Section 14.1)
• DFCI will initiate all protocol changes and
distribute updated IRB approved protocols to
outside sites
• Current version of the Protocol will be posted on
the ALL Consortium Website
• Amendments must be submitted to local IRB
within 30 days of receipt (DFCI Policy)
Consent Form Changes (Section 14.2)
• DFCI will initiate consent form changes and distribute
finalized updated Model Consent Form to all sites
• Reference DFCI SOP regarding what language can/can not
be changed
• All revised consent forms must be approved by DFCI prior
to IRB submission
• Current DFCI Model Consent Form will be posted on
DFCI ALL Consortium Website
Adverse Event Reporting Requirements
(Section 12)
• All AE’s and SAE’s must be documented in
medical record and in case-report form
• Grading using CTCAE version 4.0
Adverse Event
• An adverse event (AE) is any undesirable
sign, symptom or medical condition or
experience that develops or worsens in
severity after starting the first dose of study
treatment or any procedure specified in the
protocol, even if the event is not considered
to be related to the study.
Adverse Event: Exceptions (Section 12.1.1)
The following expected toxicities related to the diagnosis and treatment of ALL but thought
to be unrelated to asparaginase do not need to be recorded as AEs, unless they meet
definition of an SAE:
– Blood count abnormalities (any grade)
– Electrolyte abnormalities (any grade)
– Uric Acid (any grade)
– Transaminitis without clinical symptoms
– Mucositis (grade 2 or below)
– Nausea (any grade)
– Vomiting (any grade)
– Fatigue (any grade)
– Anorexia (any grade)
– Fever (any grade)
– Constipation (any grade)
– Diarrhea (any grade)
– Hypertension thought to be related to steroids (grade 2 or below)
– Hyperglycemia related to steroids that does not require the use of insulin
– Neuropathy – sensory, motor, or cranial (grade 3 or below and thought to be related
to Vincristine)
Serious Adverse Event (Section 12.1.2)
Any adverse event, regardless of causality that:
• Results in death
• Is life-threatening.
• Requires intensive inpatient medical interventions,
including mechanical ventilation, pressor support, and/or
fluid resuscitation, or emergent surgical operations.
–
Unplanned hospital admissions for febrile neutropenia, bacteremia
or other documented infections, seizure, pancreatitis, thrombosis,
nausea/vomiting, diarrhea, and other expected toxicities from the
study treatment will not be considered a SAE unless the severity of
the condition is considered life-threatening and/or lead to intensive
medical interventions or surgical procedures.
Serious Adverse Event
• Results in persistent or significant disability/incapacity.
Disability is defined as a substantial disruption of a
person’s ability to conduct normal life functions.
• Is a congenital anomaly or birth defect; or
• Is an important medical event that may jeopardize the
participant and require medical or surgical intervention to
prevent one of the outcomes listed above.
–
An example of such a medical events is allergic bronchospasm
requiring intensive treatment in an emergency room or in the
hospital.
SAE: Exceptions
•
Events not considered to be serious adverse events are
hospitalizations for:
– Routine treatment or monitoring of the studied indication, not
associated with any deterioration in condition, or for elective
procedures
– Elective or pre-planned treatment for a pre-existing condition that
did not worsen (including pre-planned hospital admissions and/or
surgeries), provided condition did not deteriorate in an unexpected
manner during trial
– Toxicities that are expected from the study treatment and are not
considered life-threatening (ie, do not require intensive medical or
surgical management, as defined above).
– Emergency outpatient treatment for an event not fulfilling the
serious criteria outlined above and not resulting in inpatient
admission
– Respite care
SAE Reporting
• Must report all SAE’s that occur after initial dose of study
treatment, during treatment or within 30 days of last dose
of treatment
• Report to Overall PI (Dr. Silverman) must be made within
24 business hours of learning of the event
• Events required to be reported are outlined in protocol
section 12.1.2 and also include the following:
–
–
–
All Grade 2 and 3 events that are unexpected and at least possibly
related to study treatment
All Grade 4 events that are unexpected or not specifically
exempted in protocol
All Grade 5 (fatal) events
SAE Reporting
•
•
SAE report must be completed on the MedWatch 3500 or MedWatch 3500A form.
Report must be emailed or faxed to the Overall PI and DFCI Research Nurse WITHIN
24 BUSINESS HOURS OF INITIAL STUDY TEAM NOTIFICATION (this
includes Investigator notification).
–
–
–
–
•
SAE reports MUST include the following information within the narrative (which can
be attached if it does not fit on the Medwatch form):
–
–
–
–
–
–
–
–
•
•
Lewis Silverman, MD: 617-632-6191, lewis_silverman@dfci.harvard.edu
Cailin Toomey: 617-632-3960, cailin_toomey@dfci.harvard.edu
Email: dfcipediallstudyteam@dfci.harvard.edu
FAX: 617-632-3977
CTCAE V4 Event Name (for every serious event reported)
Grade of Event
Relationship (not related, unlikely, possibly, probably, definitely)
Expectedness (is the event listed in the consent or IB as risk?)
Date of study team notification of event
Participant study ID and Initials
Date of study Enrollment
Current phase of treatment
DFCI is responsible for submitting all SAEs to FDA, Sigma Tau, and Health Canada
If Sigma-Tau requires additional information, they will follow up directly with sites
SAE Reporting to DFCI IRB
•
The following SAE’s must be submitted to DFCI IRB within 10 business days:
Grade 2 and 3 events that are unexpected and possibly, probably, or definitely
related/associated with the intervention
– All grade 4 events – unless expected AND specifically listed in the protocol as not
requiring reporting
– All grade 5 events, regardless of relationship
** Note: Grade 2 and 3 laboratory abnormalities that are considered by the
investigator to be clinically insignificant and do not require therapy, or adjustment
in prior therapy, do not need to be reported to DFCI IRB as an SAE.
–
•
Each site is responsible for completing the DFCI IRB SAE Reporting Form
and submitting to DFCI Study Team for IRB submission
•
Sites must use current form available on the DFCI ALL Consortium Website
•
SAE’s submitted to DFCI IRB will be posted on website
•
Sites responsible for reporting any SAE’s to their own IRB as per their
institutional policies
Investigator’s Brochure:
Calaspargase pegol
(EZN-2285, SC-PEG E. coli L-asparaginase)
• Current version:
Edition number: 6.0
– Release date: October 17, 2011
Updated version will be released annually by Sigma-Tau
If new risks are identified, consent form changes will be
initiated by DFCI
Site PIs must review and sign/date updated versions of IB
Sites should submit updated Ibs to their IRBs as required
by their local IRB
–
•
•
•
•
IND Safety Reports
•
All study staff will be added to Sigma Tau’s email distribution list to
receive SC-PEG IND Safety Reports
•
All IND Safety Reports will be posted on the DFCI ALL Consortium
Website
•
Each site will submit IND Safety Reports to their IRB per their local
IRB policy
•
DFCI will distribute information about all SAEs that occur on 11-001
to all outside sites
–
•
Posted on DFCI ALL Consortium Website
If new risks are identified, consent form changes will be initiated by
DFCI
Safety Monitoring by DMC
• Independent committee
• Meets twice-yearly
• Reviews safety and efficacy data from
participating sites to assess treatment benefit or
harm to study participants
–
–
Review study conduct to date (summary report)
Review all SAE reports
• Determines if study may proceed as planned (no
safety concerns)
• Report posted on ALL Website
Data Submission Requirements
• Missing forms reports will be posted for
each site on the DFCI ALL Consortium
Website
• Timely data submission is required
Data Submission: New DMC Requirements
•
•
•
•
Overall Missing Forms for the trial must be <20%
Overall Missing Toxicity Forms for the trial must be <20%
Each individual site must have < 35% of forms missing
Each individual site must have < 35% of toxicity forms
missing.
• More stringent protocol specific reporting rules may be
added as necessary to a protocol.
• If any of the above are not met, they MUST be met at the
next running of the report or they will be reported to the
DMC. The DMC may suspend registration to either the
protocol/site with the issue OR to all ALL Consortium
Trials in which the site participates.
Violations and Deviations (Section 20.7)
• Protocol Deviation: Any departure from
the defined procedures set forth in the IRBapproved protocol which is prospectively
approved prior to its implementation.
• Protocol Violation: Any protocol deviation
that was not prospectively approved by the
IRB prior to its occurrence.
Minor Deviations/Violations
• Minor Deviations/Violations
•
•
Each site will maintain Minor Deviation/Violation Log
Minor deviation log submitted to DFCI Study Team Monthly
•
•
Must include detail of deviation and corrective action plan
Submitted to DFCI IRB at time of Continuing Review
• Examples:
•
•
Timing of treatment exceeds allowable deviation (eg, medication
was > 3 hours late)
Cycle started although not all specified criteria were met
•
Note: if you get permission in advance to start cycle, this is not a
violation (allowed in protocol)
Minor Deviations/Violations
 Minor Deviation/Violations submitted to
DFCI IRB as a Major Deviation/violation
if:



3 for more minor deviations for the same
subject (or of the same type)
Impact the safety of participants
Compromise the integrity of the study data
and/or affect subject’s willingness to participate
in the study
Major Deviations/Violations
• Must be reported to DFCI and local IRB in a timely
manner
–
–
Site reports to DFCI study team and to their local IRB
DFCI study team submits to DFCI IRB
• Outside sites to complete DFCI Major Deviation/Violation
Form and submit to DFCI study team
–
Must include corrective action plan!
• Examples:
–
–
Enrollment of participant who did not meet all inclusion/exclusion
criteria
Study visit or procedure conducted outside of required timeframe
that, in the opinion of the PI, may affect participant safety or data
integrity
Study Monitoring (Section 20.8)
• Virtual Monitoring of each site
• On-Site Monitoring
Virtual Monitoring
• Participating institutions will be required to submit source
documents to the Lead Institution for virtual monitoring:
– All eligibility source documentation
– Registration Documents – Consent form, eligibility
checklist
– Pathology reports confirming diagnosis
– All screening laboratory reports and scans
– All results of the “Required Assessments”
– Any extra source documentation (i.e., admission notes,
scans, culture results) pertaining to a serious adverse
event (SAE).All results of the “Required Assessments”
at study entry and at the date of remission
assessments
On-Site Monitoring
• Annually, after 3 participants have been enrolled
• Review of all
– Regulatory documentation
– Source documentation (Diagnosis, Informed consent,
CR, AE/SAE, required labs)
– Drug accountability
• Note: All eligibility requirements must be found
either in source documentation (eg, lab reports) or
must be included in MD note (eg, “no known
history of HIV”).
–
Eligibility checklist is not source documentation
On-Site Monitoring
• More frequent on-site monitoring visits will
be made if sub-standard performance is
discovered. For example:
–
–
–
Data not entered on time
Unreported adverse events
Enrolling ineligible participants
Audits (Section 20.9.1)
•
Auditing: Systematic and independent examination of all trial-related
activities and documents
–
To determine if evaluated activities were appropriately conducted
•
DFCI QACT will conduct on-site auditing
•
Scheduled at each site after the first 10 subjects are accrued and then
annually if 10 subjects accrue since the time of the last audit.
–
•
If a site enrolls less than 10 participants, they will undergo one audit over
the course of the study.
Approximately 3-4 subjects would be audited at the site over a 2 day
period
Audits
• QACT Audit Team submits reports to
DF/HCC Audit Committee with audit rating
and recommendations
• PI/Site will receive final copy of report
–
May require implementation of corrective
action plans, further follow-up
Sub-Standard Performance (Section 20.9.4.1)
“Participating Institutions that fail to meet the performance
goals of accrual, submission of timely accurate data,
adherence to protocol requirements, and compliance with
state, federal, and Good Clinical Practice guidelines, will
be recommended for a six- month probation period. Such
institutions must respond with a corrective action plan and
must demonstrate during the probation period that
deficiencies have been corrected, as evidenced by the
improved performance measures. Participating Institutions
that fail to demonstrate significant improvement will be
considered by the Protocol Chair for revocation of
participation.”
Electronic Data Capture System
• Inform Version 5.5
• Training:
– Must complete training for Inform version 5.5
and provide training completion certificate to
DFCI study team
– Contact Annette Dalton for access to training:
annette_dalton@dfci.harvard.edu
• Queries are expected to be resolved in real
time
STUDY SAMPLES
Asparaginase PK Samples- Mandatory
• Obtain 3ml of peripheral blood in one red top tube
Samples should be processed as soon as possible
Schedule
– Induction Phase:
–
•
•
•
–
–
Day 7 (1 sample collected just prior to first dose of Asparaginase; 2 nd sample
collected 5-10 min after completion of Asparaginase infusion)
Day 11, Day 18, Day 25 and Day 32
Post Induction: Just PRIOR to each dose of asparaginase
administered during post induction treatment phases
If patient is switched to twice-weekly Erwinia, samples should be
obtained every 3-weeks (or at the start of the chemotherapy cycle
if cycle is delayed) just prior to the Erwinia dose
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Asparaginase PK Samples- Mandatory
Processing (Protocol Section 9.1):
• Allow the tube to stand at room temperature for 30 min to clot (do not
place the tube in ice).
• Centrifuge the clotted blood sample at 1,100-1,300 x g for 10 minutes
at 25º C. Record the time that the sample was centrifuged.
• Using a disposable pipette, carefully remove the serum (uppermost
clear layer) without disturbing the pelleted blood cells and buffy coat,
and transfer it into a 2 mL self-standing polypropylene cryogenic tube
with external threads.
• Immediately place the labeled cryotube in a freezer maintained at 70ºC or lower until packaged for shipment. Record the time that the
sample was placed in the freezer.
• Ship on dry ice to Dr. Jeff Supko at MGH Monday through
Wednesday (can be batched weekly)
142
MRD Samples-Leukemia patients Only
•
•
•
•
Marrow- One purple top (EDTA) tube, with 2-3mL of bone marrow aspirate
Blood-One purple top (EDTA) tube , with 2-3mL of peripheral blood
Schedule:
– At time of study entry (pre-treatment): Required of all leukemia
patients
– Induction Phase, Day 18 (if consent obtained for Day 18 bone marrow
study)
– Induction Phase, Day 32: Required of all leukemia patients
– VHR patients only:
• Consolidation IB, Day 1: Peripheral blood
• Consolidation IC, Day 1: Peripheral blood
• CNS Phase, Day 1: Bone Marrow and Peripheral blood
– At time of suspected relapse
Shipping: Send at room temperature, same day overnight to DFCI
143
Biology Samples- optional
• Marrow: 1-2 purple top (EDTA) tubes each with 2-3 mL of
bone marrow aspirate in purple top (EDTA) tube
• Peripheral Blood: 1-2 purple top (EDTA) tubes, each with
2-3 mL of blood
• Schedule:
• At time of study entry (pre-treatment)
• At time of suspected relapse
• Shipping: Send at room temperature, same day overnight
to DFCI
144
CSF Samples-Optional
•
•
•
•
•
Obtain 1-3 mL of leftover CSF (collected at the time of a therapeutic
lumbar puncture, just prior to the administration of intrathecal
chemotherapy)
Place on ice immediately after sample acquisition
Within 1 hour of collection, centrifuge specimen for 5 minutes then
aliquot into cryovials and immediately freeze at -80 degrees
Schedule:
– Day 1 Lumbar Puncture (will be changed to Day 18 in future
amendment)
– Day 32 (end-induction) Lumbar puncture
– 4th Lumbar puncture during the CNS phase
– 1st Lumbar puncture performed during the Consolidation II phase
Shipping:
– Supernatant should be shipped on dry ice
– Ship to Dr. Peter Cole at Albert Einstein College of Medicine
145
Vitamin D Samples-Optional
• Schedule:
– Prior to starting treatment
– End of induction
– At the start of the 1st or 2nd cycle of
Continuation
– End of treatment
– Recheck according to guidelines in protocol for
those with low Vitamin D levels
– To be sent to local institutional lab
146
QUESTIONS?