Conditions: Acute Lymphoblastic Leukemia
Keywords: Acute Lymphoblastic Leukemia ALL B-lineage Acute Lymphoblastic Leukemia Malignant neoplasms stated as primary lymphoid haematopoietic Blinatumomab Blincyto Post allogeneic stem cell transplant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 23
Healthy volunteers: no

Brief summary:
You are being asked to take part in this study because you either had Ph positive B-lineage acute lymphoblastic leukemia (ALL) or still have a small amount of the disease and recently received an allogeneic stem cell transplant (cells from someone else).

The goal of this clinical research study is to learn if blinatumomab in patients who have had an allogeneic stem cell transplant can help to control ALL or prevent ALL from coming back in patients who either have a small amount of ALL or have had ALL in the past. The safety of this drug will also be studied.

Detailed description:
Study Drug Administration:

Every study cycle will be 6 weeks. You may receive up to 4 cycles of blinatumomab. Each cycle will start around 3, 6, 9, and 12 months after your stem cell transplant.

In each cycle, you will receive blinatumomab as a continuous infusion by vein for 4 weeks, followed by a 2 week "rest period" during which you will not receive blinatumomab.

You will need to remain in the hospital for the first 2 cycles so that you can be checked on for side effects.

Length of Study:

You may receive blinatumomab for up to 1 year. You will no longer be able to receive the study drug if the disease comes back (if you do not have ALL), if the disease gets worse (if you have a small amount of ALL), if intolerable side effects occur, or if you are unable to follow study directions.

Study Visits:

Before each cycle:

* You will have a physical exam. As part of the physical exam, you will be checked for graft versus host disease (GVHD, when transplanted donor tissue attacks the tissues of the recipient's body).
* Blood (about 4 tablespoons) will be drawn to learn the effectiveness of the stem cell transplant.
* You will have a bone marrow biopsy and aspiration to check the status of the disease and for cytogenetic testing.

Once a week during each cycle, blood (about 4 tablespoons) will be drawn for routine tests.

End of Study Visit:

About 2 weeks after your last dose of blinatumomab:

* You will have a physical exam.
* Blood (about 4 tablespoons) will be drawn to learn the effectiveness of the stem cell transplant.
* You will have a bone marrow biopsy and aspiration to check the status of the disease and for cytogenetic testing.

This is an investigational study. Blinatumomab is FDA approved and commercially available for the treatment of Philadelphia chromosome (Ph) negative B-ALL that has returned after treatment. Its use in patients with Ph positive B-lineage ALL is investigational.

Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.

Arms:
arm 1: Blinatumomab as continuous intravenous infusion at dose of 28 µg/24 hours over 4 weeks followed by 2 week treatment-free period for 6-week treatment cycle; 4 cycles of blinatumomab at 3, 6, 9, and 12 months following hematopoietic cell transplantation (HCT).

Interventions: intervention 1: Blinatumomab intervention 2: Hematopoietic Cell Transplantation
Intervention descriptions: intervention 1: Participants receive Blinatumomab as continuous intravenous infusion at a dose of 28 µg/24 hours over 4 weeks followed by a treatment-free period of 2 weeks, defined as one 6-week treatment cycle. In the first induction cycle, the initial dose of Blinatumomab is 9 µg/day for the first 7 days of treatment which then will be escalated (dose step) to 28 µg/day starting on day 8 (week 2) through day 29 (week 4). For all subsequent cycles, 28 µg/day is the dose for all 4 weeks of continuous treatment. Participants receive 4 cycles of blinatumomab at 3, 6, 9, and 12 months following hematopoietic cell transplantation (HCT). intervention 2: Hematopoietic progenitor cell infusion

Protocol document:
Prot_SAP_000.pdf: 
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The Use of Blinatumomab Post Allogeneic Hematopoietic Cell 
Transplantation to Reduce the Risk for Disease Recurrence for 
Patients with B-lineage Acute Lymphoblastic Leukemia 
 
 
 
Principal Investigator: 
Partow Kebriaei, MD 
 
 
 
 
The University of Texas MDACC   
 
 
 
 
 
 
Stem Cell Transplantation and Cellular Department 
 
 
 
 
1515 Holcombe Blvd, Unit 0432 
 
 
 
 
Houston, TX 77030 
 
 
 
 
Telephone: 713-745-0663 
 
 
 
 
Fax: 713-794-4902 
 
 
 
 
pkebriaei@mdanderson.org 
 
 
 
Collaborators: 
 
Amin Alousi, MD1 
 
Kris M. Mahadeo, MD2 
Richard Champlin, MD1 
 
 
David Marin, MD1 
 
Chitra M. Hosing, MD1 
 
Denai R. Milton, MS
4 
Elias Jabbour, MD
3  
 
Yago Nieto, MD
1 
Hagop Kantarjian, MD3 
 
 
Betul Oran, MD
1 
Kris M. Khazal, MD2 
 
Katy Rezvani, MD, PhD
1 
Issa F. Khouri, MD
1  
 
Elizabeth Shpall, MD1 
 
 
 
 
 
 
1The University of Texas M D Anderson Cancer Center, Stem Cell Transplantation and Cellular    
Therapy Department 
2The University of Texas M D Anderson Cancer Center, Division of Pediatrics 
3The University of Texas MD Anderson Cancer Center, Leukemia Department 
4The University of Texas M D Anderson Cancer Center, Biostatistics Department 
 
 
 
      
 
 


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 Table of Contents 
 
1 
Objectives.............................................................................................. 4 
 
1.1 
Primary....................................................................................................4 
 
1.2 
Secondary...............................................................................................4 
 
2 
Background............................................................................................4 
 
2.1 
Background Disease Information ............................................................4 
 
2.2 
Background Blinatumomab Information..................................................6 
 
2.3 
Blinatumomab and MRD ........................................................................7 
 
2.4 
Blinatumomab in Relapsed ALL .............................................................7 
 
2.5 
Blinatumomab Toxicity Profile ................................................................8 
 
 
3 
Drug Information...................................................................................8 
 
3.1 
Blinatumomab .........................................................................................8 
 
3.2 
Dexamethasone Premedication............................................................10 
 
3.3 
Dose Modifications ...............................................................................10 
 
4 
Patient Eligibility................................................................................. 15 
 
4.1 
Inclusion Criteria................................................................................... 15 
 
4.2 
Exclusion Criteria ................................................................................. 15 
 
5            Treatment Plan..................................................................................... 16 
 
5.1 
Overview ...............................................................................................16 
 
5.2 
Patient Registration ............................................................................. 16 
 
5.3 
Blinatumomab Administration .........................................................,.....16 
 
5.4 
GVHD Prophylaxis .................................................................................16 
 
5.5 
CNS Prophylaxis ...................................................................................16 
 
5.6 
TKI Maintenance ...................................................................................16 
 
 
 


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6 
Study Evaluations .............................................................................. 17 
 
6.1 
Pretreatment Evaluations......................................................................17 
 
6.2 
Evaluation During Study ...................................................................... 18 
 
6.3 
Evaluation of Toxicity............................................................................18 
 
7 
Criteria for Removal from Study ....................................................... 18 
 
8 
Statistical Considerations ................................................................. 19 
 
9 
Reporting Requirements ....................................................................21 
 
9.1 
Treatment Periods.................................................................................21 
 
9.2 
Adverse Events Produced by Transplant .............................................21 
 
9.3 
Adverse Events Produced by Other Treatment....................................21 
 
9.4 
Serious Adverse Events........................................................................22 
 
9.5 
Additional Reporting Requirements per Study Sponsor.......................22 
 
10 
References .......................................................................................... 24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 Objectives 
 
1.1 Primary:  To assess the feasibility of blinatumomab post allogeneic 
hematopoietic cell transplantation (HCT) as consolidation therapy in patients with 
B-lineage acute lymphoblastic leukemia (ALL). Toxicities attributable to 
blinatumomab, acute GVHD, and secondary graft failure will be the parameters to 
define feasibility.   
 
1.2 
Secondary:   
1.2.1 To evaluate the progression-free survival (PFS) rate at 1-year for patients 
with ALL compared to contemporary patient cohort. 
 
1.2.2 To evaluate other efficacy endpoints such as overall survival (OS) and 
minimal residual disease (MRD) negativity rate in patients treated with 
blinatumomab for consolidation therapy.  
 
1.2.3 To evaluate, non-relapse mortality (NRM) and chronic GVHD.   
 
 
2.0 Background 
 
2.1 
 
Risk 
for 
relapse 
following 
HCT  
Allogeneic HCT is 
a 
curative 
approach 
for 
a 
select 
group 
of 
patients with ALL.  
Overall 
survival 
(OS) ranges from 
30%-60% 
depending on the 
patients 
disease 
stage 
and 
risk 
profile at time of 
transplant 
(1,2).  
Increasingly, 
minimal 
residual 
disease (MRD), both before and after HCT, is becoming an important predictor for 
relapse (3).  In a series of 149 ALL patients transplanted in remission at MD 
Anderson Cancer Center, patients with MRD, measured by multiparameter flow 
cytometric immunophenotyping (FCI) with a sensitivity of 0.01%, present at time 
of HCT had a shorter PFS compared to patients who were MRD negative, 28% vs. 
47%, p=.08 (4).  Furthermore, among 135 patients who had MRD measured 
following HCT, 20 became positive for MRD, and 18 of these patients developed 


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overt hematologic relapse within a median of 3.8 months (4). Of note, among 32 
patients with overt relapse following HCT, 41% did NOT have preceding MRD, 
suggesting that positive MRD post HCT essentially confirms eventual relapse, but 
negative MRD post HCT in a high-risk patient does not preclude relapse. Our 
findings corroborate similar published studies (5,6).  Patients transplanted beyond 
second remission routinely have a significantly lower PFS and OS rates. In our 
study of 97 patients (CR1 51, CR2 29, others 17) treated with busulfan and 
clofarabine chemotherapy conditioning following a matched sibling (MSD) or 
matched unrelated donor (MUD) transplant, patients in CR1 had a significantly 
better disease free survival (DFS) compared with others (Figure 1).  For patients 
in CR1, the 2-yr DFS rate was 61% with 9/51 patients relapsing at median 9 
months, the 2-yr DFS rate was 40% for CR2, with 10/29 relapsing at median 3 
months, and for patients with more advanced disease, the 2-yr DFS rate was 33% 
with 3/17 progressing at a median of 3 months.  Our preliminary results with this 
regimen were similar (7). Data from the Center for International Blood and Marrow 
Transplant Research (CIBMTR) corroborate our findings. Between 1996 and 2001, 
in patients less than 20 years-old, OS ranges from 25% for patients transplanted 
beyond first remission to 50% for sibling transplants in first remission.  Similarly, in 
adult patients, greater than 20 years-old, the best outcome is noted in sibling 
transplants done in first remission with OS of 60%, as compared to 35% if 
transplants are performed beyond CR1 (CIBMTR Registry).   
 
In pediatric patients with B cell precursor acute lymphoblastic leukemia, cure rates 
with chemotherapy (in combination with radiotherapy in certain situations) can be 
as high as 80-85%. Children with second or greater relapse or refractory disease 
have dismal prognosis even when treated with allogeneic stem cell transplantation 
which is usually reserved for patients with high-risk features (i.e. poor-risk 
cytogenetic markers), those who fail to achieve remission or relapse after standard 
or intensive chemotherapy. From the CIBMTR data base, among the 1,569 
patients younger than 18 years receiving an HLA-matched sibling transplant for 
ALL between 2005 and 2015, the 3-year probabilities of survival were 73% ± 2%, 
58% ± 2%, and 40% ± 5% for patients with early (CR1), intermediate (second or 
subsequent CR), and advanced disease (primary induction failure and advanced 
disease), respectively. The corresponding probabilities of survival among the 
2,845 recipients of an unrelated donor transplant were 68% ± 2%, 56% ± 1%, and 


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43% 
± 
4%. 
Disease 
relapse 
represent 
the 
most common cause of 
death post-transplant.  
 
No 
effective 
treatment 
options exist for patients 
who 
relapse 
following 
HCT. Multiple published 
series report less than 
10% survival for these 
patients, regardless of the 
treatment modality used, 
with a median survival of 
2-3 months (2,8). To date, 
the 
most 
common 
strategy employed to reduce relapse rates after HCT has usually involved some 
form of immune manipulation, ranging from donor lymphocyte infusion (DLI) to 
second transplant (9-12).  However, although it has been consistently shown that 
patients with B-ALL who develop graft-versus-host-disease (GVHD) have less risk 
for relapse (13), DLI has not shown appreciable efficacy in this patient population; 
remission rates have been less than 10%, and have been associated with a high 
incidence of GVHD (14).  Of note, the best responses to DLI in ALL occur when 
the DLI is administered prophylactically to prevent relapse (10); this approach has 
been demonstrated in pediatric patients but no data for prophylactic DLI has been 
reported in adults. 
 
Thus, there is an unmet need for effective therapy for ALL patients at high risk for 
relapse following allogeneic HCT, with high risk defined as positive MRD and/or 
disease beyond first complete remission.  Blinatumomab has demonstrated 
efficacy in both the MRD setting (15, 16) and for patients with active disease (17). 
Importantly, since its mechanism of action is through immune modulation rather 
than cytotoxicity, it has a favorable risk profile with minimal cytopenias noted in 
patients (18). Furthermore, a recent series of 9 pediatric patients (19) and our 
personal experience in patients treated with blinatumomab after relapse following 
HCT indicate a low risk for GVHD. 
 
2.2 Blinatumomab 
 
The Bispecific T-cell Engaging (BiTE) antibody blinatumomab represents the first 
agent in a class that redirects host T-cells to cell surface antigen-expressing 
cancer cells. Blinatumomab contains the variable domains of a CD19 antibody and 
a CD3 antibody which are joined by a non-immunogenic linker (20). Upon binding 
to CD19, the cytotoxic T cells become activated and induce cell death via the pore-
forming perforin system. The drug was initially administered as an intermittent 
infusion two to three times weekly, but lack of activity and serious neurologic 


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toxicity caused the schedule of administration to be abandoned (20). Based on the 
short half-life of the drug and the mechanism of action, continuous infusion over 
several weeks were investigated. This drastically improved the activity of the drug, 
particularly in ALL, and helped reduce adverse effects. 
 
2.3 Blinatumomab and MRD 
 
The first study with blinatumomab used as continuous infusion evaluated its 
potential role in eradicating MRD (15). MRD-positivity in ALL almost universally 
heralds systemic relapse and confers poor prognosis. Patients treated in this study 
were in hematologic and morphologic CR, but had persistent or reappearing MRD 
during consolidation chemotherapy. Blinatumomab was given at a dose of 15 
µg/m2/day as a continuous infusion for 28 days every 6 weeks (14 days off) (15).  
After completing one cycle, responding patients could receive up to three 
additional consolidation cycles or proceed to ASCT if a donor is available. MRD 
conversion after one cycle was observed in 16 of 20 evaluable patients (80%). In 
a long-term follow up update (median observation time 33 months), 12 of the 20 
patients remained in CR. The estimated 3-year relapse-free survival was 60% (16). 
Nine patients underwent ASCT, but interestingly, non-transplanted patients had 
similar favorable outcome compared to the transplant group. Most relapses after 
blinatumomab treatment occurred early, within seven months of the start of therapy. 
In a confirmatory open-label multicenter phase II trial in 116 patients in 
morphologic CR with positive MRD positive, the overall rate of conversion to the 
MRD negativity was 80% (78% occurring after one cycle of treatment) (21).   
 
2.4 Blinatumomab in relapsed and refractory ALL 
 
Blinatumomab was subsequently studied in patients with active systemic ALL 
relapse. In a confirmatory open-label, single-arm, multicenter phase II study in 189 
patients with relapsed-refractory disease, blinatumomab was administered as the 
overall response rate was 43% with 80% of the responses occurring within cycle 
1. The median response duration and overall survival were 9 and 6 months, 
respectively (Table 1) (17).  
 
In a pediatric phase I/phase II study of blinatumomab in relapsed/refractory ALL 
(defined as second or later bone marrow relapse, any marrow relapse after 
ASCT, or refractory to other treatments, and had > 25% blasts in bone marrow), 
among the 70 patients (median age 8 years, range 7 months to 17 years) who 
received the recommended dosage (15 µg/m2/day for 28 days and 2 weeks 
treatment free per cycle), 27 (39%) achieved CR within the first two cycles, 14 
(52%) of whom achieved complete minimal residual disease response. 40 out of 
70 (57.1%) had undergone allogeneic HSCT prior to receiving blinatumomab, 
and 39 out of 70 (55.7%) had refractory disease. The median number of 
treatment cycles was 1 (range 1 to 5) (23). 
 
 


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2.5 Blinatumomab toxicity profile 
 
The toxicity profile of blinatumomab has been largely consistent with historical 
studies, with fever, chills, and hypogammaglobulinemia occurring frequently. 
Tremor, headache, and other mental status changes (e.g., confusion) have been 
reported. Fever, chills, and other constitutional symptoms are thought to be due to 
a cytokine release syndrome that occurs shortly after the start of therapy and are 
reduced with the use of steroids (e.g. dexamethasone 8-24 mg daily x 2-3 days). 
The adverse effects coincided with a rapid rise in activated T-cells after 
blinatumomab initiation, essentially confirming the hypothesis (22).  Life-
threatening neurologic adverse events were uncommon and generally reversible, 
but seizures have been observed in both the MRD and the active disease studies. 
Corticosteroids before the first dose and prior to dose escalation ameliorate some 
of the toxicities. 
 
The adverse reactions in pediatric patients treated with blinatumomab were similar 
to those seen in adult patients with relapsed or refractory B-cell precursor ALL. 
Adverse reactions that were observed more frequently in the pediatric population 
compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% 
vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), 
thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight gain 
(17% vs. 6%). In infants and children < 2 years of age, the incidence of neurologic 
toxicities was not significantly different than for the other age groups, but its 
manifestations were different (agitation, headache, insomnia, somnolence, and 
irritability). In the phase I/II open label blinatumomab study in pediatric patients 
with relapsed / refractory ALL, among the 70 pediatric patients treated on the trial, 
the most frequent grade 3 adverse events were anemia (36%), thrombocytopenia 
(21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had 
cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) 
interrupted treatment after grade 2 seizures. Reports of compassionate use of 
blinatumomab in pediatric patients with relapsed / refractory ALL and prior ASCT 
have shown that blinatumomab did not induce nor exacerbate acute graft versus 
host disease (24, 25). 
  
3.0 Drug Information 
 
3.1 Blinatumomab 
 
Each BLINCYTO (blinatumomab) package contains 1 vial BLINCYTO and 1 vial 
IV Solution Stabilizer.  
BLINCYTO is supplied in a single-use vial as a sterile, preservative-free, white to 
off-white lyophilized powder for intravenous administration. Each single-use vial 
of BLINCYTO contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), 
lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate 
(95.5 mg), and sodium hydroxide to adjust pH to 7.0. After reconstitution with 3 


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mL of preservative-free Sterile Water for Injection, USP, the resulting 
concentration is 12.5 mcg/mL blinatumomab.  
IV Solution Stabilizer is supplied in a single-use vial as a sterile, preservative-
free, colorless to slightly yellow, clear solution. Each single-use vial of IV Solution 
Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride 
(2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and 
water for injection. 
Since blinatumomab will be administered via continuous intravenous route, it 
needs to be stabilized at low concentrations to prevent absorption to surfaces. 
Therefore, the IV bag must be conditioned by prior addition of a product-specific 
diluent (IV solution stabilizer), resulting in a final diluent concentration of 0.5 mM 
citrate, 25 mM lysine hydrochloride and 0.002% (w/v) polysorbate 80. Sterile 
water for injection and supplies required for reconstitution and injection of 
blinatumomab will not be provided to clinical sites. 
 
Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol 
Preservative: 
Gasping syndrome (central nervous system depression, metabolic acidosis and 
irregular respiration) is a serious and potentially fatal adverse reaction in infants 
treated with benzyl alcohol-preserved drugs. The 7 days bag of BLINCYTO 
solution for infusion with benzyl alcohol is not recommended for use in pediatric 
patients weighing < 22 kg. Consider the combined daily load of benzyl alcohol 
from all sources (including BLINCYTO) when prescribing BLINCYTO to pediatric 
patients.  
 
3.1.2 Blinatumomab dosage, administration, and schedule 
 
Blinatumomab is administered as a continuous intravenous infusion (CIV). 
A single cycle of blinatumomab treatment is 4 weeks of CIV.   Since patients are 
either in remission, or have minimal residual disease at time of treatment, the 
dosing schedule for minimal residual disease will be followed.  Additionally, since 
both children and adults will be treated on this study, dosing will be weight- and 
BSA-based as per FDA guidelines for this drug. Please see section 5.3 for details 
of dosing administration.  
 
The drug administration should not be interrupted, if possible. In case of infusion 
interruption, due to any technical or logistic reason, the interruption should be as 
short as possible and the infusion continued at the earliest time possible. Every 
interruption longer than 1 hour should be documented. If the interruption is longer 
than 4 hours, re-start of the infusion should be performed under healthcare 
supervision. The patient should be observed overnight for possible side effects 
after the restart in the hospital. Administration of dexamethasone premedication 
as described in Table 3 is recommended. If possible, the infusion duration before 
and after an interruption should total 28 days per treatment cycle. 


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3.1.3 Blinatumomab inpatient dosing 
 
It is recommended that subjects are hospitalized at least during the first 3 days of 
the first induction cycle and the first 2 days of the following cycles.  
 
The infusion bags will be changed by site nursing personnel trained on the protocol 
and on the proper administration of blinatumomab. Close monitoring during the 
first 48 hours of treatment in the first 2 cycles will be indicated because of the 
potential adverse events associated with T-cell redistribution and potential 
cytokine release effects triggered by the administration of blinatumomab.  
 
3.1.4 Blinatumomab outpatient dosing 
 
After a patient meets the minimum criteria for inpatient administration and 
monitoring as described in the above section, and if a subject is deemed stable by 
the Principal Investigator or designee, continuation of blinatumomab infusion may 
continue as an outpatient. 
 
In the outpatient setting, either the subject will return to the study site for changes 
of infusion bags or the subject will be visited by a well-trained ambulant/home care 
service provider at specific intervals to change the infusion bag. The subject and 
the ambulant/home care provider will be trained and will receive written instructions 
for storage of the IV bags. 
 
In the event of drug interruptions of >4 hours, the restart of the infusion should be 
performed in the clinic/hospital under the supervision of their healthcare provider. 
 
In case of any adverse event in the outpatient setting, the ambulant/home care 
provider should directly contact their healthcare provider at the study center for 
further management.  
 
3.2 Dexamethasone premedication 
 
Premedication with dexamethasone is intended to prevent CRS events associated 
with blinatumomab treatment. Within 1 hour before the start of treatment in each 
treatment cycle, mandatory premedication with dexamethasone at 20 mg IV if ≥ 45 
Kg (or 5 mg/m2 to a maximum of 20 mg if < 45 Kg) IV is required for the prevention 
of CRS resulting from blinatumomab (Table 1). 
 
3.3. Dose modifications (interruptions, withholdings, and criteria for restarting 
treatment) (Tables 1 and 2). 
 
3.3.1 Infusion interruption/dose modification due to adverse events 
Common Terminology Criteria for Adverse Events (CTCAE) grade 4 adverse 
events at least possibly related to blinatumomab will require permanent 


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discontinuation of blinatumomab. For CTCAE grade 4 adverse events that are 
numerically defined laboratory parameters, independent investigator assessment 
should be used to determine the risk: benefit for each individual patient to continue 
or discontinue blinatumomab treatment. 
 
For CTCAE grade 3, cytokine release syndrome, and CTCAE grade 3 
DIC/coagulopathy, treatment with blinatumomab will be interrupted until the event 
resolves to at least grade 1. Blinatumomab can then be restarted at the lowest 
starting dose (9 μg/day if ≥ 45 Kg or 5 µg/m2/day if < 45 Kg). If the AE lasts for ≥ 2 
weeks, then blinatumomab will be permanently discontinued. 
 
For all other CTCAE grade 3 events and clinically significant laboratory value 
changes, investigator assessment should be used to determine the risk: benefit to 
continue blinatumomab therapy with or without dose reduction or discontinue 
therapy. 
 
Patients who have been dose reduced will have an option to receive the higher 
dose level once the AE has resolved to grade 1 or less for at least 7 days. Re-start 
of the infusion should be performed in the hospital. Before blinatumomab is re-
started, premedication with dexamethasone 20 mg if ≥ 45 Kg (or 5 mg/m2 if < 45 
Kg) IV is required. The patient should be observed overnight for possible side 
effects after the restart in the hospital. 
 
In addition to the events described above, the dose may be temporarily or 
permanently reduced to 9 μg/day if ≥ 45 Kg (or 5 μg/m2/day if < 45 Kg) if, by 
investigator´s judgment, it is necessary for safety reasons. After at least 7 days of 
dosing at 9 μg/day if ≥45 Kg (or 5 μg/m2/day if < 45 Kg), the dose may be increased 
to 28 μg/day if ≥ 45 Kg (or 15 μg/m2/day if < 45 Kg) or treatment may be continued 
at the dose of 9 μg/day after consultation with the investigator.  
 
If the interruption after an adverse event is no longer than 7 days, the same cycle 
will be continued. The infusion duration, before and after an interruption, should 
total 28 days per treatment cycle. If an interruption due to an adverse event is 
longer than 7 days, a new cycle will start. In addition, an incomplete treatment 
cycle with a treatment duration of less than 2 weeks will have to be repeated (eg, 
if cycle 1 was interrupted on day 8 for more than 7 days, the next cycle will be 
denoted as cycle 1.1 and the same assessments will be performed as in cycle 1). 
For cycle 1.1, subjects will be started at 9 μg/day if ≥ 45 Kg (or 5 μg/m2/day if < 45 
Kg) for the first 7 days of dosing followed by a dose step to 28 μg/day if ≥ 45 Kg 
(or 15 μg/m2/day if < 45 Kg) beginning at day 8 and continuing for the remainder 
of cycle 1. 
 
An infusion interruption of more than 2 weeks due to an adverse event related to 
blinatumomab will lead to permanent discontinuation of treatment. In case of 
logistical difficulties, restart of treatment can be postponed for up to 5 additional 
days without resulting in permanent treatment discontinuation. 


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Treatment may be also interrupted or permanently discontinued at the discretion 
of the investigator if any clinical/laboratory adverse event is considered to be 
medically relevant. 
 
In case of signs of cytokine release, dexamethasone should be administered orally 
or IV at a dose of at maximum 3 x 8 mg/day for subjects ≥ 45 Kg (or 0.2-0.4 
mg/kg/day divided 3-4 times per day not to exceed 24 mg/day for subjects < 45 
Kg) for up to 3 days. The dose can then be reduced step-wise over 4 days.  
 
3.3.2 Infusion interruption/dose modification due to CNS events 
In case of CNS-related adverse events, dexamethasone should be administered 
at a dose of at least 24 mg/day for subjects ≥ 45 Kg (or 0.2-0.4 mg/kg/day divided 
3-4 times per day not to exceed 24 mg/day for subjects < 45 Kg). The 
dexamethasone dose will then be reduced step-wise over 4 days. 
 
In case of CTCAE grade 3 or higher CNS-related adverse events, blinatumomab 
will be stopped immediately and a physical exam, vital signs and safety laboratory 
tests will be performed. Additional measures can be taken upon discretion of the 
investigator, depending on the nature of the adverse event. Diagnostic measures 
to exclude potential infectious causes should be conducted after CNS events ≥ 
CTCAE grade 3; an assessment of cerebrospinal fluid should be performed for 
cytology, cell count, B- and T-cell measurement (flow cytometry at local lab), and 
viral studies (HSV 1/2, HSV6, JC virus and adenovirus), and magnetic resonance 
imaging (MRI).  
 
Patients, who had experienced a Grade 3 CNS AE or SAE leading to treatment 
interruption, should have a treatment free interval of two weeks, even if the event 
has resolved to Grade 1 earlier. These patients will have to undergo MRI before 
treatment is resumed. Infusion should be re-started in the hospital, under 
supervision of the investigator and the patient should remain hospitalized for at 
least two days. 
 
Following dexamethasone premedication, a new treatment cycle will start with a 
dose of 9 μg/day if ≥ 45 Kg (or 5 µg/m2/day if < 45 Kg). Blinatumomab will be 
escalated to 28 mcg/day if ≥ 45 Kg (or 15 µg/m2/day if < 45 Kg) after 7 days if the 
toxicity does not recur. If the toxicity occurs at 9 mcg/day if ≥ 45 Kg (or 5 µg/m2/day 
if < 45 Kg)., or if the toxicity takes more than 7 days to resolve, blinatumomab 
therapy will be stopped permanently.  
 
If the CNS event was a seizure (CTCAE grade 2 or above), appropriate 
prophylactic anticonvulsant treatment will be administered during the next 
treatment cycle. 
 


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A grade 3 CNS event leading to treatment interruption at the dose of 9 μg/day if ≥ 
45 Kg (or 5 µg/m2/day if < 45 Kg) or a CNS event needing more than 1 week to 
resolve to grade ≤ 1 will result in permanent treatment discontinuation. 
 
In case of CNS-related events CTCAE Grade 4 or in case of occurrence of more 
than one seizure the infusion of blinatumomab will have to be stopped 
immediately and treatment will be permanently discontinued. For patients who 
discontinue treatment because of a CNS event ≥ Grade 3 an MRI is 
recommended. For patients in the additional evaluation cohort, an MRI is 
required after CNS event grade 3 or higher, regardless of continuation of 
treatment with blinatumomab.  
 
Table 1. Dexamethasone premedication 
 
Treatment phase 
Target 
patient 
Dexamethasone dose 
Patient Weight 
≥ 45 Kg 
< 45 Kg 
Pre-dose 
dexamethasone 
before each 
blinatumomab 
treatment 
All patients 
(before each 
cycle and 
dose 
increase) 
20 mg IV within 1 hour 
before start of treatment 
in each treatment cycle, 
and within 1 hour before 
dose increase 
5 mg/m2 IV within 1 hour 
before start of treatment 
in each treatment cycle, 
and within 1 hour before 
dose increase 
Infusion 
interruption/dose 
modification due to 
adverse event 
Patients who 
interrupt 
treatment > 
4 hours 
Dexamethasone 20 mg IV 
within 1 hour before re-
start of treatment 
5 mg/m2  IV within 1 hour 
before re-start 
of treatment 
In case of signs of 
cytokine release 
(CRS) 
Patients with 
signs of CRS 
Dexamethasone orally or 
IV at a dose maximum 3 x 
8 mg/day for up to 3 days. 
The dose should then be 
reduced step-wise over 4 
days 
Dexamethasone orally or 
IV at a dose 0.2-0.4 
mg/kg/day divided 3-4 
times per day not to 
exceed 24 mg/day  for up 
to 3 days. The dose 
should then be reduced 
step-wise over 4 days 
Infusion 
interruption/dose 
modification due to 
CNS events 
Patients with 
CNS-related 
AE 
Dexamethasone should 
be administered at a dose 
of at least 24 mg/day. 
Dexamethasone will then 
be reduced step-wise 
over 4 days. 
Dexamethasone should 
be administered at a 
dose of 0.2-0.4 
mg/kg/day divided 3-4 
times per day not to 
exceed 24 mg/day. 
Dexamethasone will then 
be reduced step-wise 
over 4 days. 
 
 
Table 2. Management of Toxicity and Blinatumomab Dosage Adjustments 


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Toxicity 
Grade 
Action 
Patient Weight 
≥ 45 Kg 
< 45 Kg 
Cytokine Release 
Syndrome (CRS) 
Grade 3 
Withhold blinatumomab 
until resolved, then restart 
blinatumomab at 9 mcg/day 
Escalate to 28 mcg/day 
after 7 days if the toxicity 
does not recur. 
Withhold blinatumomab until 
resolved, then restart 
blinatumomab at 5 
µg/m2/day. Escalate to 15 
µg/m2/day after 7 days if the 
toxicity does not recur. 
 
Grade 4 
Discontinue blinatumomab permanently 
Neurological 
Toxicity 
Seizure 
Discontinue blinatumomab permanently if more than one 
seizure occurs 
 
Grade 3 
Withhold blinatumomab 
until no more than Grade 1 
(mild) and for at least 3 
days, then restart 
blinatumomab at 9 
mcg/day. Escalate to 28 
mcg/day after 7 days if the 
toxicity does not recur. If 
the toxicity occurred at 9 
mcg/day, or if the toxicity 
takes more than 7 days to 
resolve, discontinue 
blinatumomab permanently. 
Withhold blinatumomab until 
no more than Grade 1 (mild) 
and for at least 3 days, then 
restart blinatumomab at 5 
μg/m2/day. Escalate to 15 
μg/m2/day after 7 days if the 
toxicity does not recur. If the 
toxicity occurred at 5 
μg/m2/day, or if the toxicity 
takes more than 7 days to 
resolve, discontinue 
blinatumomab permanently. 
 
Grade 4 
Discontinue blinatumomab permanently 
Other 
Clinically 
Relevant Adverse 
Reactions 
Grade 3 
Withhold blinatumomab 
until no more than Grade 1 
(mild), then restart 
blinatumomab at 9 
mcg/day. Escalate to 28 
mcg/day after 7 days if the 
toxicity does not recur. If 
the toxicity takes more than 
14 days to resolve, 
discontinue blinatumomab 
permanently. 
Withhold blinatumomab until 
no more than Grade 1 (mild), 
then restart blinatumomab at 
5 μg/m2/day. Escalate to 15 
μg/m2/day after 7 days if the 
toxicity does not recur. If the 
toxicity takes more than 14 
days to resolve, discontinue 
blinatumomab permanently 
 
Grade 4 
Discontinue blinatumomab permanently 
 
 
 


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4.0 Patient Eligibility 
 
4.1 
Inclusion Criteria: 
1.  
Patients 1-70 years of age. 
 
2. 
Patients with B-lineage ALL in a) hematologic complete remission (CR) 
beyond CR1 at time of transplant; b) primary induction failure defined as 
requiring more than one line of induction therapy; c) positive minimal 
residual disease defined by positive flow >0.01% before or after 
transplant; or d) high risk cytogenetic or molecular features consisting of 
Ph-like phenotype, detection of BCR-ABL transcript by PCR with a 
sensitivity of 1/10,000, or detection of the t(9;22) translocation in any 
metaphases by cytogenetics at time of transplant, or presence of the MLL 
gene before or after transplant.  
 
3. 
Received an allogeneic HCT within the last 100 days.  Enrollment within 
30-100 days after transplant, and after adequate recovery of counts 
defined as ANC >/= 0.5 x 109/L without daily use of myeloid growth factor 
and platelet > 20 x 109/L without platelet transfusion within 1 week, and 
adequate organ function to receive blinatumomab defined as creatinine 
clearance greater than 30 ml/min (or greater than 60 ml/min/1.73), 
ALT/AST < 5 x ULN and serum bilirubin < 3 x ULN. 
 
 4.  
Performance status of 0, 1, or 2. Karnofsky (or Lansky for subjects < 16 
years old) performance status ≥ 50. 
 
  
4.2 
Exclusion criteria: 
1. 
Relapsed ALL defined as >5% malignant blasts in bone marrow or 
peripheral blood. 
 
2. 
Active GVHD requiring systemic steroid therapy. Medications for GVHD 
prophylaxis are acceptable. 
 
3. 
Systemic steroid therapy unless for physiologic replacement 
 
4. 
Uncontrolled disease/infection as judged by the treating physician 
 
5. 
Active ALL in the central nervous system (CNS), as defined by ≥5 
leukocytes per μL with identifiable blast cells in the CSF (CNS 3 disease), 
and/or the presence of cranial-nerve palsies. 
 
6. 
Pregnant or nursing women  
 
 
 
 


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5.0 Treatment Plan 
 
5.1 This is an open-label, single-arm, phase II clinical study.  
 
5.2 All patients will be registered through Core. All of the enrolled subjects’ 
concomitant medications will be collected and readily available in the MDACC 
electronic medical record and will not be entered into the CRF. 
 
5.3 Patients will receive blinatumomab as continuous intravenous infusion over 4 
weeks. 
 
Since this study includes children and adults, dosing will be weight and BSA-
based as per FDA approved dosing guidelines:  
 
For patients >/= 45 kg, the dose is 28 mcg/day administered as a continuous 
infusion on days 1-28 of each cycle.  
 
For patients < 45 kg the dose is 15 mcg/m2/day (maximum 28 mcg/day) 
administered as a continuous infusion on days 1-28 of each cycle  
 
All patients will receive 4 cycles of blinatumomab, with first cycle administered 
within the first 3 months following HCT, and then at 6 (+/- 2 weeks), 9 (+/- 2 
weeks), and 12 (+/- 2 weeks) months following HCT (day of hematopoietic 
progenitor cell infusion).  This schedule was selected to allow for treatment with 
blinatumomab during the one year following transplant when patients are at risk 
for relapse while the GVL effect is maturing and becoming robust. 
 
5.4 GVHD prophylaxis will be as institutional standard.  
 
5.5 CNS prophylaxis will be as institutional standard. However, craniospinal 
radiotherapy for prophylaxis post HCT is not permitted.  
 
5.6 Tyrosine kinase inhibitor (TKI) use for patients with Ph+ ALL will be left to the 
investigator’s discretion. 
 
 
 
 


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6.0 
Study Evaluations  
 
6.1 
Pretreatment Evaluation 
 
 
Table 3. Pre-treatment evaluation schedule 
 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed 
consent approved by IRB 
Within 14 days before 
therapy 
Medical History 
History of present illness, known 
allergies, prior cancer history as 
far as traceable including ALL 
regimens and drugs uses, and 
past medical/ surgical history as 
far as relevant. 
Within 14 days of therapy 
Physical Examination 
Vital signs (temperature, heart 
rate, respiratory rate, blood 
pressure) and performance 
status. 
Within 14 days of therapy 
Concomitant Medications 
Document concomitant 
medications, excluding prn and 
supportive care medications 
Within 14 days of therapy 
Hematology 
CBC with differential and platelet 
count 
Within 14 days of therapy 
Biochemistry 
at least creatinine, total bilirubin, 
uric acid, LDH, SGPT or SGOT, 
tacrolimus.  
Within 14 days of therapy 
Pregnancy test 
Serum or urine, if female and/of 
child-bearing potential only 
Within 14 days of therapy 
Bone marrow 
Aspirate and/or biopsy with flow 
cytometry for confirmation of 
diagnosis; cytogenetics 
Within  30 days of therapy 
Peripheral blood 
Chimerism assessment 
Within  30 days of therapy 
Lumbar puncture 
To assess for CNS disease, as 
clinically indicated 
Within  30 days of therapy 
Imaging studies 
Chest X-ray and/or PET/CT as 
clinically indicated 
Within 30 days of therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2 Evaluation during study 
 
Table 4. Evaluation During Study 
Procedure 
Comments 
Schedule 
Hematology 
CBC with differential and platelet 
count 
Weekly during each cycle 
Biochemistry 
at least creatinine, total bilirubin, 
SGPT or SGOT, tacrolimus 
Weekly during each cycle 
Physical 
Examination 
Focused physical examination, 
including assessment for GVHD 
Prior to each treatment cycle, and at 
study completion 
Bone marrow 
Aspirate and/or biopsy, MRD  by 
multicolor flow cytometry, 
cytogenetics 
Prior to each treatment cycle, and at 
study completion will be per the PI or 
treating physician discretion  
Peripheral blood 
Multiparameter FCI for immune 
reconstitution and PB chimerism 
Prior to each treatment cycle, and at 
study completion will be per the PI or 
treating physician discretion  
Optional 
Procedure: 
Peripheral blood 
For banking in Dr. Rezvani’s 
laboratory at MDACC 
Prior to each treatment cycle, at day 7 
(+/-2 days), day 14 (+/- 2 days) and at 
completion of each treatment cycle. 
 
 
6.3 Evaluation of Toxicity 
Toxicities will be graded according to the NCI Expanded Common Toxicity 
Criteria, version 4.  
 
 
7.0 Criteria for Removal from the Study 
 
7.1 Completion of study at 1 year. 
 
7.2 Non-compliance by the patient with protocol requirements. 
 
7.3 Occurrence of CTCAE grade 4 adverse event probably or definitely related to 
blinatumomab. 
 
7.4 An infusion interruption of more than 2 weeks due to an adverse event 
related to blinatumomab. 
 
7.5 Occurrence of a CNS-related adverse event probably or definitely related to 
blinatumomab, and meeting one or more of the following criteria: 
• More than 1 seizure 
• A CNS-related CTCAE Grade 4 adverse event 
• A CNS-related adverse event leading to treatment interruption that 
requires more than one week to resolve to CTCAE Grade ≤ 1 
• A CTCAE Grade 3 CNS-related adverse event leading to treatment 
interruption that occurred at a dose of 9μg/day 
 
 
 


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8.0  Statistical Considerations  
 
8.1  Patient Characteristics 
 
Demographic and baseline characteristics will be summarized for all patients.  
Categorical measures will be summarized using frequencies and percentages, 
while continuous variables will be summarized using mean, standard deviation, 
median, minimum, and maximum. 
 
8.2  Primary Objectives 
 
The primary objective in this trial is feasibility. Treatment-related toxicities 
attributable to blinatumomab, an excess rate of acute GVHD, and an excess rate 
of secondary graft failures will be the parameters to determine feasibility. The 
successful completion of the trial without reaching stopping rules will indicate that 
the primary objective of the trial was met. Cumulative incidence time to GVHD will 
be computed from the date of allogeneic HCT to the date of event.  The cumulative 
incidence (CI) of GVHD will be determined using the competing risks method.  The 
competing risks included will be relapse and death, and patients who do not 
experience GVHD or relapse and are still alive at the last follow-up date will be 
censored at that date.   
 
8.3  Secondary Objectives 
 
8.3.1  Progression-free and Overall Survival 
 
Progression-free Survival (PFS) will be defined from date of allogeneic HCT to the 
date of disease progression or death.  Patients who are still alive at last follow-up 
date without disease progression will be censored at that date.  OS will be defined 
from date of allogeneic HCT to date of last known vital sign.  Patients who are still 
alive at the last follow-up visit will be censored.  A contemporary cohort of patients 
with ALL being transplanted in first complete remission will be identified 
prospectively. PFS and OS will be estimated using the Kaplan-Meier method and 
differences between the patients receiving blinatumomab and the contemporary 
cohort will be determined using the log-rank test. Patient outcomes in the 
contemporary cohort will be stratified by MRD status. 
 
8.3.2  Minimal Residual Disease 
 
Patients who are MRD negative at the end of the study will be summarized using 
frequency and percentage. 
 
8.3.3  Non-relapse Mortality  
 
Non-relapse mortality (NRM) will be computed from date of allogeneic HCT to last 
known vital sign.  The CI of NRM will be determined using the competing risks 


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method.  The competing risk included will be relapse and patients who are still 
alive at the last follow-up date will be censored. 
 
8.3.4  Safety Measures 
 
Safety will be assessed by vital signs, laboratory assessments, adverse events, 
and serious adverse events for all treated patients.  Categorical measures will be 
summarized using frequencies and percentages while continuous variables will 
be summarized using mean, standard deviation, median, minimum, and 
maximum. 
 
8.3.5  Continuous Toxicity Monitoring 
 
Continuous monitoring of toxicity will be assessed for all treated patients, 
beginning with the first cohort of five patients.  Assuming a prior beta distribution 
of (0.6, 1.4), the study will terminate if the Pr (δt > 0.30 | data) > 0.85, where δt is 
the toxicity rate attributable to the treatment.  Toxicities are defined as any 1) grade 
3-4 acute GVHD greater than 30%, 2) secondary graft failure >30%, or 3) NRM 
within one cycle of blinatumomab (i.e., 30 days).  The decision rule for terminating 
for toxicity is presented in Table 5 and the operating characteristics for this rule are 
presented in Table 6.  The method used to produce the decision rule and operating 
characteristics was designed by Thall, Simon, and Estey (1995). 
8.3.6 
Infection rate will be summarized by frequencies and percentages.   
 
Table 5.  Stopping Boundaries 
 
Total number of 
patients  
 
Stop if this many patients have 
toxicity: 
1-4 
Never stop with this many patients 
5 
3-5 
6-7 
4-7 
8-10 
5-10 
11-13 
6-13 
14-16 
7-16 
17-18 
8-18 
19-21 
9-21 
22-24 
10-24 
25-27 
11-27 
28-29 
12-29 
30 
Always stop with this many patients 
 
 
 
 


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Table 6.  Operating Characteristics 
 
True % of 
DLTs 
 
Pr (stopping early) 
Median Sample 
Size (interquartile) 
0.10 
0.01 
30 (30, 30) 
0.20 
0.10 
30 (30, 30) 
0.30 
0.36 
30 (13, 30) 
0.40 
0.72 
13 (5, 30) 
0.50 
0.94 
5 (5, 13) 
 
 
9.0  Reporting Requirements 
 
9.1 Treatment periods 
Active treatment period is defined from the first day of treatment administration 
through 30 days after last dose given.  The intensity of adverse events (AE) will 
be assessed according to the Common Terminology Criteria v4.0 (CTCAE).  
Adverse events and protocol deviations will be reported accordingly to MDACC 
policy and procedures. Collection of adverse events will reflect the onset and 
resolution date and maximum grade.  Intermittent events should be labeled as 
such and followed until resolution. If a patient is taken off study while an event is 
still ongoing, this will be followed until resolution unless another therapy is 
initiated.  Pre-existing medical conditions will be recorded only if an exacerbation 
occurs during the active treatment period. Co-morbid events will not be scored 
separately. 
 
9.2 Adverse events (toxicities) known to be produced by the transplant 
chemotherapy regimen: 
 
Gastrointestinal: nausea and vomiting, diarrhea, oral mucositis  
Hepatic: self-limited elevations of liver function enzymes; veno-occlusive disease 
Pulmonary: acute dyspnea, pulmonary fibrosis and interstitial pneumonitis.  
Skin:  rash. 
 
9.3 Adverse events (toxicities) known to be produced by other treatment 
components: 
The following events are not considered to be significant in relationship with the 
study treatment, would not be considered adverse events, and will not be 
collected in the study database. 
Myelosuppression-related: neutropenia, anemia thrombocytopenia, platelets and 
RBCs transfusions. 
Flu-like symptoms: low grade fever, headache, chills, cough, rhinitis, myalgia, 
fatigue, sweating and insomnia. 
Mood alteration: depression, anxiety, and agitation 
Readmissions (lasting <10 days) 
Low blood pressure due to dehydration requiring fluid replacement 
Fluid overload.  


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Fatigue. 
Laboratory serum metabolic values not reflecting end-organ (hepatic, renal) 
function and or those considered associated to the original disease  
Events that are identified to be related to the supportive treatment, e.g., steroids, 
palifermin, antibiotics. 
 
9.4  Adverse Events Considered Serious (SAEs): 
1.   Graft failure/rejection 
2.   Prolonged hospitalization due to infections and/or organ failure requiring 
extensive supportive care (i.e. dialysis, mechanical ventilation) 
3.   Readmissions from any cause resulting in a prolonged hospitalization (>10 
days). 
4.   Any expected or unexpected event resulting in an irreversible condition and/ 
or leading to death. 
 
SAEs will be reported to the PI or his designate, who in turn will notify the IRB 
following institutional policy. 
 
9.5 Additional reporting requirements per study sponsor 
The sponsor is responsible for compliance with expedited reporting requirements 
for serious and unexpected and related adverse events (SUSARs), for 
generation of SAE reports including narratives, and for periodic reporting to 
Amgen of SAEs  
 
Safety Data 
Requirements 
Suspected Unexpected Serious 
Adverse Reaction (SUSARs) 
Required (Sent to Amgen at time of 
regulatory submission) 
Serious Adverse Events (SAEs) 
Required (Cumulative listing to 
Amgen every 6 months) 
Adverse Events not meeting serious 
criteria 
Not required 
Events of Interest 
Not required 
Pregnancy/Lactation 
Required (Sent to Amgen within 10 
days of Sponsor awareness) 
Event listing for reconciliation 
Required at end of study 
*Specific requirements are to be outlined in the ISS Research Agreement 
Required Aggregate reports*: 
 
 
 
 


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Safety Data 
Timeframe for submission to 
Amgen 
Annual Safety Report 
(eg, EU Clinical Trial Directive [CTD] 
Annual Safety Report, and US IND 
Annual Report) 
Annually 
Other Aggregate Analyses 
(any report containing safety data 
generated during the course of a 
study) 
At time of ISS sponsor submission 
to any body governing research 
conduct (eg, RA, IRB, etc) 
Final (End of Study Report), 
including: 
• Unblinding data for blinded 
studies 
• Reports of unauthorized use of 
a marketed product 
At time of ISS sponsor submission 
to any body governing research 
conduct (eg, RA, IRB, etc) but not 
later than 1 calendar year of study 
completion 
*Specific requirements are to be outlined in the ISS Research Agreement 
 
 
 


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10.0 References 
 
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2. Fielding AK, et al. Prospective outcome data on 267 unselected adult patients 
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