Clinical trial NCT01363128
Conditions: Acute Lymphoblastic Leukemia Adult Acute Lymphoblastic Leukemia in Complete Remission Burkitt Leukemia Burkitt Lymphoma CD20 Positive Childhood Acute Lymphoblastic Leukemia in Complete Remission Lymphoblastic Lymphoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2011-07-12; Completion date: 2020-04-08
Enrollment: 72 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well combination chemotherapy and ofatumumab work in treating patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with ofatumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy together with ofatumumab may be an effective treatment for acute lymphoblastic leukemia or lymphoblastic lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the clinical efficacy of the combination of hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone) + ofatumumab in patients with newly diagnosed acute lymphoblastic leukemia with any level of CD20 expression: event-free survival; overall response rate; overall survival.

SECONDARY OBJECTIVES:

I. To evaluate the safety of this combination.

OUTLINE:

COURSES 1, 3, 5, 7: Patients receive hyper-CVAD comprising cyclophosphamide intravenously (IV) over 3 hours every 12 hours on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 15 minutes on days 4 and 11; and dexamethasone IV over 30 minutes or orally (PO) once daily (QD) on days 1-4 and 11-14. Patients also receive ofatumumab IV over 4-6 hours on days 1 and 11 of courses 1 and 3.

COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 2 hours and then over 22 hours on day 1 and cytarabine IV over 2 hours every 12 hours on days 2-3. Patients also receive ofatumumab IV over 4-6 hours on days 1 and 8 of courses 2 and 4.

Treatment repeats every 21-28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive maintenance therapy for an additional 30 months.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 1 year.

Arms: arm 1: COURSES 1, 3, 5, 7: Patients receive hyper-CVAD comprising cyclophosphamide IV over 3 hours every 12 hours on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 15 minutes on days 4 and 11; and dexamethasone IV over 30 minutes or PO QD on days 1-4 and 11-14. Patients also receive ofatumumab IV over 4-6 hours on days 1 and 11 of courses 1 and 3.

COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 2 hours and then over 22 hours on day 1 and cytarabine IV over 2 hours every 12 hours on days 2-3. Patients also receive ofatumumab IV over 4-6 hours on days 1 and 8 of courses 2 and 4.

Treatment repeats every 21-28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may receive maintenance therapy for an additional 30 months.
Interventions: intervention 1: Cyclophosphamide intervention 2: Cytarabine intervention 3: Dexamethasone intervention 4: Doxorubicin Hydrochloride intervention 5: Laboratory Biomarker Analysis intervention 6: Methotrexate intervention 7: Ofatumumab intervention 8: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV or PO intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV intervention 7: Given IV intervention 8: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Phase II Study of the Hyper - CVAD Regimen in Combination with Ofatumumab as 
Frontline Therapy for patients with CD-20 positive Acute Lymphoblastic Leukemia
2010-0708
Core Protocol Information
Short Title 
Phase II Study of HCVAD – Ofatumumab in CD-20 + ALL
Study Chair: 
Elias Jabbour
Additional Contact:
Lori L. Smith
Vicky H. Zoeller
Leukemia Protocol Review Group
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Leukemia
Phone:
713-792-4764
Unit:
428
Study Manager:
Heather Schroeder
Full Title: 
Phase II Study of the Hyper - CVAD Regimen in 
Combination with Ofatumumab as Frontline Therapy for 
patients  with CD-20 positive Acute Lymphoblastic 
Leukemia
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase II
Version Status:
Activated -- Closed to new patient entry as of 03/07/2019
Version:
23
Document Status:
Saved as "Final"
Submitted by:
Lori L. Smith--2/13/2019 9:31:26 AM
OPR Action:
Accepted by:  Melinda E. Gordon -- 3/1/2019 12:19:44 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
 
   


 
 
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Phase II Study of the Hyper-CVAD Regimen in Combination with Ofatumumab 
as Frontline Therapy for patients with CD-20 positive Acute Lymphoblastic 
Leukemia 
 
1.0 Objectives 
1.1 Primary Objectives: To evaluate the clinical efficacy of the combination of 
hyper-CVAD + ofatumumab in patients with newly diagnosed acute lymphoblastic 
leukemia with any level of CD20 expression: 
- 
Event-free survival 
- 
Overall response rate 
- 
Overall survival 
1.2 Secondary Objectives: To evaluate the safety of this combination.  
 
2.0 Background 
 
2.1 Acute Lymphoblastic Leukemia (ALL) 
 
Adult ALL encompasses a heterogeneous group of lymphoid malignancies. 
Prognosis is related to age, karyotype, molecular profile, immunophenotype, and 
other disease features. Prognosis for pediatric ALL has improved significantly 
over the last several decades to current long-term survival rates of greater than 
80% [1]. However, long-term survival in adults is currently only 35% to 45% [2,3]. 
The predominant reason for failure is disease recurrence. 
 
Recent advances in treatment have been based on the pediatrics regimens. 
Murphy et al. designed an intensive, multi-agent chemotherapy program based 
on the concept of delivery of agents in rapid sequence in children with Burkitt's 
leukemias and lymphomas [4]. Because it was recognized that these 
lymphomas/leukemias have high growth fractions and doubling times as short as 
25 hours, cyclosphosphamide was fractionated in the induction phase in an 
attempt to encompass the entire generation time of the tumor as well as to 
provide a smoother induction with fewer metabolic complications [5]. The Total B 
regimen consists of cycles of fractionated high-dose cyclophosphamide 
(300mg/m2 q 12 hours for six doses), vincristine, and doxorubicin alternating with 
high dose methotrexate (1g/m2) and escalating doses of ara-C. Kantarjian et al 
modified this program, and developed the regimen of hyper-CVAD 
(hyperfractionated cyclophosphamide, vincristine, doxorubicin, and 
dexamethasone alternating with high dose methotrexate and ara-C) [6,7]. This 
regimen has significant activity in the treatment of Burkitt's disease, mantle cell 
lymphoma, multiple myeloma, lymphoblastic lymphoma, and aggressive chronic 
lymphocytic leukemia with or without Richter's transformation. Of the 2004 
patients with de novo ALL who were treated with hyper-CVAD protocol, 91% 
achieved a complete remission. The median time to achieve CR was 21 days 
with 81% of patients achieving CR after one course of chemotherapy. The 


 
 
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estimated five-year survival was 39%, and the estimated median survival time 
was 35 months.  
 
2.2 Rationale for the Combination of hyper-CVAD and immunotherapy 
 
Expression of CD20 was associated with a higher incidence of relapse, lower 3-
year complete remission duration (CRD) and lower 3-year overall survival (OS) 
rate. The independent adverse influence of CD20 expression on event-free 
survival (EFS) was observed in a multivariate analysis, particularly among the 
youngest group of patients [8].  
In order to improve the outcome of these patients, several modifications were 
incorporated. Among them the addition of anti CD20 monoclonal antibody, 
rituximab. The addition of rituximab to the hyper-CVAD program in patients with 
CD20 expression (≥20%) improved outcome compared to historical experience, 
with 3-year CRD rates (68% vs 28%, p<0.001) and OS rates (65% vs 35%, 
p=0.01) approaching those of the CD20 negative counterparts [8]. 
 
The improvement in the CRD and OS rates with the use of rituximab in the CD20 
positive patients (CD20 expression defined by a threshold ≥20%) means that 
currently, the outcome for these patients is identical to that of patients with CD20 
negative disease: 3-year EFS rates of 52% and 53%, respectively. Therefore, 
patients with lower expression of CD20 may benefit from monoclonal antibodies 
with higher and more potent binding capacity.  
 
2.3 Ofatumumab 
 
Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a 
unique small-loop epitope on CD20 and elicits potent in vitro complement-
dependent cytotoxicity (CDC), even in malignant B cells with low CD20 
expression levels. Ofatumumab was found to be more effective than rituximab in 
promoting lysis of opsonized B cells via classical pathway complement CDC. 
Classical pathway CDC is initiated by binding of C1q to aggregated IgG bound to 
cells. Taylor and colleagues have recently reported on the higher capacity of 
ofatumamab when compared to rituximab in promoting CDC [9]. In fact, their 
results indicated that binding of very small amounts of C1q to mAb-opsonized 
cells, far below the maximal C1q binding capacity of the cells, was sufficient to 
promote CDC. Greater CDC induced by ofatumumab compared with rituximab 
might be due in part to a higher level of binding of C1q to OFA-opsonized B cells. 
Also, cell-bound C1q was found to be more closely associated with ofatumumab 
(based on the co-localization studies), likely functioning more effectively to 
activate the classical C pathway and promote CDC.  
 
Ofatumumab has been shown to be safe and active in chronic lymphocytic 
leukemia (CLL). In a phase I/II study, 12 of 26 relapsed patients who had 
received 4 weekly infusions of up to 2,000 mg of ofatumumab responded [10]. 
Time to progression and time to next therapy was 161 and 366 days, 


 
 
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respectively. The interim results of a non-randomized phase III registration trial in 
patients with CLL who progressed after fludarabine and alemtuzumab (DR) or 
who are refractory to fludarabine and have bulky adenopathy (BFR) have been 
recently reported. The objective response rate ORR was 51% (34, 68%) for the 
DR group and 44% (30, 59%) for the BFR group. Median time to next CLL 
therapy was 9 months for the DR group and 8 months for the BFR group. The 
median OS was about 14 months for the DR group and 15 months for the BFR 
group [11]. A phase II study of ofatumumab combined with cyclophosphamide 
and fludarabine in previously untreated patients recently completed accrual. 
  
3.0 Background Drug Information 
 
3.1 Drug information for the following agents is attached as an appendix to the 
back of this protocol (Appendix E). 
 Cyclophosphamide 
 Doxorubicin 
 Vincristine 
 MESNA 
 Methotrexate 
 Cytarabine (Ara-C) 
 6-mercaptopurine 
 Filgrastim Product (G-CSF) 
 Pegaspargase 
 Dexamethasone 
 Prednisone 
 
3.2 Ofatumumab [12] 
 
The investigational (non-commercial) medicinal product (IMP) is a clear colorless 
liquid concentrate intended for intravenous infusion after dilution in sterile, 
pyrogen free 0.9% sodium chloride. During infusion the IMP will be filtered using 
a 0.2 mm in-line filter. Ofatumumab is formulated at 20 mg/mL adjusted to pH 6.5 
and supplied in 5  mL and 50 mL glass vials. The 5 mL vial of ofatumumab (20 
mg/mL) contains a total of 100 mg.  The 50 mL vial of ofatumumab (20 mg/mL) 
contains a total of 1000 mg.   
 
3.21 Ofatumumab IMP composition: (ingredient Quantity per mL Function) 
 
Ofatumumab drug substance 20 mg Active ingredient 
Sodium acetate, trihydrate 6.8 mg  
Edetate disodium, dihydrate (EDTA) 0.019 mg 
L-arginine 10 mg 
Sodium chloride 2.98 mg 
Hydrochloric acid to give pH 5.5 
Water for injection q.s. to 1 mL  


 
 
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3.22 Packaging and Labeling of Ofatumumab IMP 
 
The Ofatumumab IMP will be supplied to the site/pharmacy in cartons., Labeling 
will be according to local legal requirements. 
 
3.23 Storage of Ofatumumab IMP 
 
The IMP will be stored refrigerated (2-8°C) in a safe and secure place. The IMP 
will not be frozen. A temperature log with daily readings will be kept. Exact time 
of dilution will be written on the infusion bag label. The IMP will not be utilized 
after the expiry date printed on the label. Drug supplies will be kept in an 
appropriate restricted area, accessible only to the investigator, pharmacist or duly 
designated person. Returned, unused or expired 
ofatumumab will be destroyed according to MDACC guidelines. 
 
3.24 Ofatumumab Drug Accountability and Compliance Check. 
 
The investigator will ensure that a designated person receives IMP deliveries 
from Novartis 
 
3.25 Ofatumumab preparation: 
 
All doses of ofatumumab will be prepared in 1000 mL of 0.9% Sodium Chloride 
Injection, USP.   
 300 mg dose:  withdraw and discard 15 mL from a 1000 mL polyolefin bag 
of 0.9% Sodium Chloride Injection, USP.  Withdraw 5 mL from each of 3 
vials of ofatumumab (each vial containing 100 mg) and add to the bag.  
Mix diluted solution by gentle inversion. 
 2000 mg dose:  Withdraw and discard 100 mL from a 1000 mL polyolefin 
bag of 0.9% Sodium Chloride Injection, USP.  Withdraw 50 mL from each 
of 2 vials (each vial containing 1000 mg) of ofatumumab and add to the 
bag.  Mix diluted solution by gentle inversion 
 
Dose of 
ofatumumab 
Infusion bag 
size 
Volume of 
Sodium chloride 
0.9% to be 
removed from 
infusion bag 
Volume 
ofatumumab 
(number of 
ofatumab vials) 
300 mg 
1000 mL 
15 mL 
15 mL 
(3 vials, 5 mL/vial) 
2000 mg 
1000 mL 
100 mL 
100 mL 
(2 vials, 50 
mL/vial) 
 


 
 
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For intravenous administration, compatibility of the following components for 
ofatumumab in clinical studies (not for commercial product) has been 
established: 
 
Dosing component 
Material of 
construction 
Suggested vendor 
1L sodium chloride 0.9% 
bags 
Polyvinyl chloride (PVC) 
Baxter 
 
Polyolefin [polyethylene* 
(PE)/polypropylene (PP)] 
Baxter, B. Braun 
Administration set 
PVC 
Baxter 
 
PVC lined with 
polyethylene 
B. Braun 
Filter extension set 
Sterilizing-grade (0.22 
m) hydrophilic filter 
Durapore brand by 
Millipore 
 
Lines made of PVC, filter 
membrane material 
polyether sulfone 
Baxter 
 
Lines made of PVC lined 
with polyethylene, filter 
membrane material 
polyether sulfone 
Alaris/Cardinal Health 
*polyethylene (IUPAC name: polyethene. 
 
 
The following materials are needed when preparing and administering the 
infusion: 
 
 1000 mL sterile pyrogen free 0.9% saline (NaCl) infusion bag(s).  
 Ofatumumab 100 mg and 1000 mg vials (supplied by NOVARTIS) 
 Needles and syringes (50 mL sterile syringe) not supplied by NOVARTIS 
 Intravenous (IV) cannula (not required if subject has central venous 
access) [not supplied by NOVARTIS] 
 Infusion pump and infusion tubing set (not supplied by NOVARTIS) 
 In-line low protein binding, polyether sulfone filter 0.2 m (please make 
sure a spare filter is available in case the filter needs to be changed) [not 
supplied by NOVARTIS].  Please note that the commercial filters are 
sterilizing-grade (0.22 m) hydrophilic Durapore by Millipore.   
 


 
 
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Preparation of the 1000 mL infusion bags should be done on the day of planned 
infusion.  Store diluted solution between 2° C and 8° C.  Start infusion within 12 
hours of preparation.  Discard prepared solution after 24 hours. 
 
3.26 Ofatumumab administration: 
 
During Ofatumumab infusion the patient should be monitored closely and 
appropriate measurements should be performed according to institutional 
standards and whenever judged necessary.  There are no proposed or planned 
ofatumumab dose reductions for toxicities. Toxicities will be addressed by 
escalating premedication, slowing the infusion rate, or delaying planned dose as 
determined by institutional standards and the treating physician. 
 
 
3.27 Safety Advisory of Ofatumumab: Subjects who are HBsAg negative, anti-
HBc positive and HBV DNA negative may be included in the study but must 
undergo HBV DNA monitoring. Consult with a physician experienced in care and 
management of subjects with hepatitis B to manage/treat subjects who are anti-
HBc positive. Initiate anti-viral therapy if required. If a subject’s HBV DNA 
becomes positive during the study, notify the NOVARTIS medical monitor. For 
subjects who have not completed planned ofatumumab therapy, discuss with the 
medical monitor the risks and benefits of continuing or discontinuing ofatumumab 
before appropriate treatment decisions are made for that individual subject 
 
 
4.0 Patient Eligibility 
 
Inclusion Criteria: 
4.1 Patients of all ages with newly diagnosed, previously untreated CD-20+ ALL, 
or lymphoblastic lymphoma, Burkitt Leukemia/Lymphoma or having achieved 
CR with one course of induction chemotherapy.  
4.2 Failure to one induction course of chemotherapy (these patients will be 
analyzed separately). 
4.3 Performance status of 0, 1, or 2. 
4.4 Adequate organ function with creatinine less than or equal to 3.0 mg/dL 
(unless considered tumor related), bilirubin less than or equal to 3.0 mg/dL 
(unless considered tumor related). 
4.5 Adequate cardiac function defined as no clinically significant history of 
arrhythmia as determined by the PI and/or the treating physician, history of MI  
or clinically significant abnormal EKG, as determined by the PI and/or the 
treating physician, within 3 months prior to study enrollment.  Cardiac function 
will be assessed by history and physical examination.  
4.6 No active or co-existing malignancy (other than ALL or lymphoblastic 
lymphoma) with life expectancy less than 12 months due to that malignancy. 
 
 


 
 
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Exclusion criteria: 
1. Pregnant or nursing women.  
2. Known to be HIV+ 
3. Ph+ ALL 
4. Active and uncontrolled disease/infection as judged by the treating physician 
5. Unable or unwilling to sign the consent form 
6. Subjects who have current active hepatic or biliary disease (with exception of 
patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or 
stable chronic liver disease per investigator assessment) 
7. Treatment with any known non-marketed drug substance or experimental 
therapy within 5 terminal half-lives (calculated by multiplying the reported 
terminal half-life by 5) or 3 weeks prior to enrollment, whichever is longer, or 
currently participating in any other interventional clinical study 
 8. History of significant cerebrovascular disease in the past 6 months or ongoing 
event with active symptoms or sequelae 
 9. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), 
a HB DNA test will be performed and if positive the subject will be excluded.  
Consult with a physician experienced in care & management of subjects with 
hepatitis B to manage/treat subjects who are anti-HBc positive.  
 10. Positive serology for hepatitis C (HC) defined as a positive test  
for HCAb, in which case reflexively perform a HC RIBA immunoblot assay on the 
same sample to confirm the result 
 
 Female patients of child bearing potential will be required to use a barrier 
method of contraception which must be used independently or in addition 
to another form of contraception while on the study and for 30 days after 
the last dose of study medication. 
 Men must agree not to father a child and agree to use a condom if his 
partner is of child bearing potential while on study and until 30 days after 
the last dose of study medication. 
 
 
5.0 Treatment Plan 
 
Monitoring Plan: (2010-0708) Phase II Study of the Hyper - CVAD Regimen 
in Combination with Ofatumumab as Frontline Therapy for patients with 
CD-20 positive Acute Lymphoblastic Leukemia 
 
This monitoring plan will be used as a guide for monitoring the clinical study 2010-0708 
that is sponsored by M D Anderson Cancer Center.  The purpose of the plan is to 
provide guidance to ensure that the rights and wellbeing of human subjects are 
protected, the conduct of the trial is in accordance with the protocol, regulatory 
requirements, and good clinical practices (GCP) and that data reporting (including 
safety reporting to IRB, FDA, and MDACC) is accurate and complete. 
 


 
 
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1.  
Monitoring Visit Intervals 
 
The Clinical Research Monitor (CRM) will notify the site in writing of planned visits 
and the purpose of the visit to ensure the availability of medical records, study 
personnel and regulatory documents if they are scheduled for review. 
 
 
THE INITIAL MONITORING VISIT WILL OCCUR AFTER THE 
FIRST SUBJECT HAS COMPLETED THEIR FIRST COURSE OF 
TREATMENT. 
 
 
INTERIM 
SITE 
MONITORING 
VISITS 
WILL 
THEN 
BE 
CONDUCTED EVERY 8-12 WEEKS DURING THE ENROLLMENT 
PHASE OF THE STUDY.  
 
 
ADDITIONAL MONITORING VISITS MAY BE CONDUCTED IF: 
ENROLLMENT PROCEEDS MORE RAPIDLY THAN EXPECTED; 
DATA FORMS ARE NOT BEING COMPLETED IN A TIMELY 
MANNER AND/OR THE SITE IS NOT IN COMPLIANCE WITH THE 
PROTOCOL, FEDERAL AND STATE REGULATIONS, AND GCP. 
 
2.  
Enrollment  
 
The research team will be responsible for screening and enrolling all subjects. 
During scheduled monitoring visits protocol eligibility criteria will be reviewed for 
each pre-selected subject in order to verify that all criteria were met, and the 
subject was eligible for study participation. 
 
3.  
Monitoring Requirements 
 
The following procedures will be performed during each monitoring visit unless 
otherwise indicated: 
 
 The CRM will generate queries, and provide them in writing to the PI and 
research team. A meeting with the CRM and research team to discuss the 
queries will be encouraged. 
 Findings will be recorded in the Monitoring Visit Report. 
 A Follow-up Visit Memo will be submitted to the investigator indicating all 
outstanding issues and significant findings that require attention as well as 
any deviations/violations.   
 
For this phase II trial, subjects 1 and 2 will be monitored; and 30% of future 
accruals will be reviewed. Additional subjects may be monitored as needed and 
determined by the sponsor.  
 


 
 
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The Monitoring Log (which will be located in the regulatory binder) will be 
signed/dated by the CRM and the research team. 
 
3.1  SOURCE DOCUMENT VERIFICATION 
 
All existing source material including, but not limited to, progress notes, laboratory 
results, hospital admission records, discharge summaries, consultations, 
diagnostic testing results, and documentation of all clinic (including study-
specified) visits along with all other clinical data in support of case report form 
entries that comprise the study database will be compared and verified.   
 
CRMs will review 100% of the source documentation for the subjects selected for 
monitoring; and compare the case report form entries with the source documents 
to ensure that the data is complete, accurate, and all study procedures were 
conducted per protocol specifications. 
 
3.2 Informed Consent Process 
 
CRMs will verify that the current IRB-approved informed consent form was used 
to obtain informed consent, that the dates of signatures precede the performance 
of any study-related procedures and that all required signatures are present.  
Comparison of signature dates will be made against the required notation in the 
subjects’ medical record regarding the informed consent process between the 
subject and the individual obtaining consent.   
 
3.3 Study Drug Accountability/Administration 
 
Pharmacy records regarding study drug shipping, receipt, storage and return, 
documentation of destruction documents compared against physical inventory and 
dispensing records will be reviewed periodically throughout the study.   
 
For each subject the CRM will verify the following: 
 
 
dose modification scheme was adjusted accordingly 
 
that the appropriate dose and volume were prepared and 
administered  
 
that dose interruption/delay guidelines as outlined in the protocol 
were followed 
     
 
4. Subject Visits 
 
CRMs will verify that all subject visits have occurred within protocol accepted 
windows.  For missed visits and subjects who are lost-to-follow-up, the CRM will 
verify that the site recorded all attempts to contact the subject in source documents 


 
 
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and that protocol procedures for documentation were followed.  Substantial 
deviations from the protocol and data management guidelines will be reported to 
the investigator and documented in the Monitoring Visit Report. 
 
5.  Adverse Event Reporting 
 
CRM’s will verify AEs are graded using NCI Common Toxicity Grading Criteria (CTC) 
as noted in the protocol and that causality is appropriately assigned by the Principal 
Investigator.  The CRM will ensure serious adverse events are reported per sponsor 
and IRB guidelines. 
 
6. Concomitant Medication 
 
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. 
 
7. Laboratory Specimen Samples, Handling and Reporting 
 
CRM’s will verify that protocol specific laboratory tests are documented as having 
been obtained according to protocol. In addition, CRMs will verify the following: 
 
 documentation indicative of review and sign-off for laboratory results by 
the Principal Investigator or designee with any clinically significant 
results denoted as such. 
 
 
lab reports will be checked against data forms and results checked 
against NCI Common Toxicity Grading Criteria to ensure that 
clinically significant results are recorded by study personnel as 
adverse events as outlined in the protocol 
 
8. Response 
 
CRMs will verify that all response assessments will be obtained, handled and 
documented according to protocol 
 
9. Data Recording 
 
PDMS, the electronic case report forms (eCRF) will be utilized for this study.  The 
CRM will review the eCRF’s in comparison to all available source data during 
interim monitoring visits.  Queries will be generated by the CRM during the site 
visit and submitted to the research team for resolution. 
 


 
 
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10. Regulatory Document File Review 
 
Periodically throughout the trial the CRM will review the site's regulatory document 
file for updated information, accuracy and completeness. 
 
11. Monitoring Visit Reports 
 
Monitoring visit reports will be completed and forwarded to the IND Medical Monitor 
for review.  
 
Information will include, but not be limited to: 
 
 
enrollment updates 
 
inventory of informed consents and supportive source data 
 
status of completion of data forms and queries 
 
data quality issues 
 
new SAEs (including deaths) and updates on previously reported 
SAEs 
 
protocol compliance/protocol deviations 
 
compliance with all applicable regulations and GCP 
 
concerns/issues expressed by study site personnel 
 
premature terminations or subjects lost-to-follow-up 
 
The monitor will attempt to meet with the study coordinator at each visit, document 
discussions and note any follow-up that is required in a follow-up letter to the 
investigator.  
 
Status of previously identified issues will be addressed in subsequent visit reports, 
including actions taken.  
 
12.  Deviations/Violations 
 
Deviations/violations from the protocol and applicable regulations will be 
documented in the Monitoring Visit Report and reported to the investigator.  
 
13. Study Discontinuation 
 
 
After the last subject has been removed from the study, a final closeout visit will 
be conducted to ensure all data is complete and regulatory documents are in order.  
The CRM will generate a close-out visit report that will outline the status of all trial 
documents and data. 
 
5.1 General 
 
All patients are registered through CORE 


 
 
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No dose escalations beyond those specified in the protocol are allowed. Other 
variations to the treatment plan outlined are allowed if felt to be in the best clinical 
interest of the patient. Major deviations should be discussed with the Principal 
Investigator.   
Dexamethasone 40mg IV or PO on D1-4 of the induction course are encouraged 
to be completed despite any doses given as supportive care prior to start of 
protocol treatment, but omission of one or more of these doses in the best 
interest of the patient per the treating physician will not be considered a deviation 
and does not require discussion with the PI.  Patients with Burkitt 
Leukemia/Lymphoma will only receive induction, consolidation and intrathecal 
chemotherapy as per protocol. They will not receive maintenance therapy nor will 
they receive late intensification. 
 
 
After three major deviations, while the participants are on protocol treatment the 
course will be reviewed by the Principal Investigator for consideration of removal 
from study with monitoring for disease-free and overall survival only. 
 
Examples of these clinical scenarios include: 
1- Treatment delays (> 14 days from recovery) despite hematologic recovery for 
reasons of patients request or unavoidable social situations. Treatment delays to 
allow recovery from infections or other toxicities of therapy will not be considered 
deviations, as these are expected complications of the therapy. 
2- Dose reductions or alterations in the chemotherapy administration beyond 
those specified in the protocol for reasons of patient request or unavoidable 
social situations. Dose reductions performed for clinical reasons will not be 
considered deviations, as patients may have unique toxicities or tolerance not 
accounted for by standard dose reductions. 
3- Other clinical scenarios after approval by the Principal Investigator. 
 
5.2 Doses and Schedule 
General: 
 
Hyper-CVAD + ofatumumab consists of 8 cycles of dose intensive therapy with 
hyper-CVAD + ofatumumab (odd courses) alternating with high-dose 
methotrexate and cytarabine + ofatumumab (even courses) administered 
approximately every 21-28 days (may delay for recovery from myelosuppression 
or infection; or sooner if count recovery allows).   
 
1- Hyper-CVAD (courses 1, 3, 5, and 7) will alternate with high-dose 
methotrexate/cytarabine (courses 2, 4, 6, and 8) administered approximately 
every 21 days or later to allow for recovery from myelosuppression or infection; 
or earlier if count recovery allows. 
2- Anti-emetic therapy with each course of intensive chemotherapy as indicated. 
3- Filgrastim product (G-CSF) at 10 mcg/kg/day (rounded) or pegfilgrastim 6 mg 
as a single dose within 72 +/- 48 hours may be given after chemotherapy until 


 
 
2010-0708 
 
 
November 5, 2018 
13 
 
 
neutrophil recovery to at least 1 x 109/l or higher. G-CSF may be stopped earlier 
for bone pain or other related toxicity. 
Next course may be started when granulocytes >= 1 x 109/L and platelets >= 50 
x 109/L, following discontinuation of Filgrastim product (G-CSF). Courses may be 
started with dose reductions prior to full platelet recovery, if the treatment is 
delayed (e.g., 28 days or later from the start of last course).  Instances where lab 
results fall outside of above criteria in the time between evaluation of next course 
and the actual start of next course will not be considered a deviation.  Start of 
courses in the best interest of the patient outside these parameters need to be 
discussed with and approved by the PI with reasons documented. The choice of 
filgrastim product will be determined by the institutional formulary and patient’s 
insurance. 
 
4- Prophylactic antibiotics (e.g. levaquin, trimethprim-sulfamethoxazole, 
fluconazole, valacyclovir) may be given with each course as indicated until 
neutrophil recovery 500/L. Prophylactic antibiotics will vary based on the 
patients' tolerance and allergy status. 
5- Patients with newly diagnosed, active disease who are aged 60 years or older 
may receive the first induction course in the protective environment unless they 
refuse, are unable to be confined, and/or medical illness prohibits. Protective 
environment is optional. 
6- CNS prophylaxis: total number of prophylactic intrathecal treatments for 
previously untreated patients will be 8, except for patients with Burkitt’s 
Leukemia/Lymphoma will receive 16, two with each course.Intrathecal route 
preferred. 
7- Eight injections of ofatumumab will be administered: Day 1 and 11 +/- 2 days 
of cycles 1 and 3 and day 1 and 8 +/- 2 days of cycles 2 and 4 (The first dose 
given will be 300 mg, the subsequent doses will be 2000 mg). 
8- XRT to the chest for patients with bulky mediastinal disease when indicated. 
9- Maintenance therapy with POMP (6-MP, vincristine, methotrexate, 
prednisone) for approximately 30 months, interrupted by intensifications courses 
6 and 7 and courses 18 and 19 with hyper-CVAD + ofatumumab and 
methotrexate + pegaspargase. 
 
Hyper-CVAD (courses 1, 3, 5, 7): 
1- Cyclophosphamide (CTX) 300 mg/m2 IV over 3 h every 12 hrs x 6 doses days 
1,2,3 (total dose 1800 mg/m2). 
2- MESNA 600 mg/m2/d IV continuous infusion daily for 24 hrs, starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs after 
the last dose of CTX. 
3- Doxorubicin 50 mg/m2 IV over 24 hrs via central venous catheter on day 4 
after last dose of CTX given (infuse over 48 hrs in patients with reduced ejection 
fractions < 50%). May be given by shorter infusion if difficulty with central venous 
access. 
4- Vincristine 2 mg IV on day 4 +/- 2 days and day 11 +/- 2 days. 


 
 
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5- Dexamethasone 40 mg IV or p.o. daily on days 1-4 +/- 2 days and days 11-14 
+/- 2 days. 
6- Ofatumumab 2000 mg IV on day 1 and 11 +/- 2 days for courses 1 and 3. 
(Ofatumumab will be given at the dose of 300 mg on day 1 of cycle 1. 
Subsequent infusions will be given at the dose of 2000 mg).  
7- Pegfilgrastim 6 mg as a one time dose or filgrastim product (G-CSF) 10 mcg 
/kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily)  until post-nadir 
granulocytes > 1.0 x 109/L. 
8- CNS prophylaxis: Methotrexate 12 mg intrathecally (6 mg via Ommaya 
reservoir) on day 2 +/- 2 days. Cytarabine 100 mg intrathecally on day 7 +/- 2 
days. 
9- Tumor lysis prophylaxis with allopurinol, intravenous alkalinization, oral 
bicarbonate for course 1 and if indicated. Urate oxidase (Rasburicase) may be 
substituted for allopurinol. 
 
Suggested Dose Modifications: 
1- Vincristine 
50% reduction (1 mg): 
- Bilirubin > 2 mg/dL and </= 3 mg/dL 
- Grade 2 persistent neuropathy. 
Eliminate vincristine: 
- Grade 3-4 neuropathy 
- Ileus suspected to be related to vincristine 
- Bilirubin > 3 mg/dL 
2- Doxorubicin 
50% reduction: 
- Bilirubin 2 to </= 3 mg/dL 
75% reduction: 
- Bilirubin 3.1 to 5 mg/dL 
Eliminate doxorubicin: 
- Bilirubin > 5 mg/dL 
- Consider elimination in the first course in patients with small/large bowel or 
gastric involvement to reduce the length of myelosuppression and risk of 
perforation. 
Administer over 48 hrs: 
- LVEF (if known) < 50% 
 
High-Dose Methotrexate and Cytarabine (courses 2, 4, 6, 8): 
1- Methotrexate (MTX) 200 mg/m2 IV over 2 hrs followed by 800 mg/m2 over 22 
hrs on day 1. 
2- Cytarabine 3 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2,3. Reduce 
to 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2 and 3 for: 
a- Neurotoxicity (Grade 2 reversible cerebellar toxicity or other ara-C related 
CNS toxicity) with previous courses.  
b- Age 60 years or greater. 
c- Creatinine greater than or equal to 1.5 mg/dL. 


 
 
2010-0708 
 
 
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d- MTX > 20 mcM at time "0" (see below), confirmed on repeat sample. 
3- Leucovorin rescue 50 mg IV followed by 15 mg IV every 6 hours for 8 doses 
beginning 12 hrs +/- 2 hrs post MTX. Additional rescue allowed as indicated for 
elevated levels or delayed methotrexate clearance. 
Check MTX around time 0h, 24h, and 48h post completion of MTX unless 
cleared (e.g. 0.15 mcM or less). 
a- if > 20 mcM at time "0", hold ara-C and repeat level; if continues to be > 20 
mcM reduce ara-C to 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2, 3. 
b- if > 1 mcM at 24 hrs or > 0.1 mcM at 48 hrs, increase leucovorin rescue until 
serum MTX level is < 0.1 mcM.  
Clearance to levels 0.15 mcM or less is acceptable in patients with normal renal 
function. 
4- Consider oral acetazolamide 250 mg PO twice daily to promote MTX excretion 
if the urine pH is <7.0. 
5- Ofatumumab 2000 mg IV on day 1 and 8 +/- 2 days for courses 2 and 4. 
6- Pegfilgrastim 6 mg as a one time dose or filgrastim product (G-CSF) 10 
mcg/kg (rounded) subcutaneously daily (or 5 mcg /kg twice daily) until post-nadir 
granulocytes greater than or equal to 1.0 x 109/L. 
7- CNS prophylaxis: Ara-C 100 mg intrathecally day 5 + 3 days and Methotrexate 
12 mg intrathecally (6 mg if via Ommaya reservoir) day 8 +/-3 days. 
 
Suggested Dose Modifications: 
1- Cytarabine: 
- 1 g/m2 IV over 2 hrs every 12 hrs for 4 doses on days 2, 3: 
- Creatinine >= 1.5 mg/dL. 
- Time "0" MTX level > 20 mcM (on repeat level). 
- Age >= 60 years. 
- Grade 2 reversible cerebellar toxicity related to high-dose Ara-C. 
- 1 g/m2 IV continuous infusion days 2, 3: 
- Grade 2 reversible cerebellar toxicity related to ara-C 1 g/m2 or grade 3 
reversible cerebellar toxicity related to any dose of ara-C. 
2- Methotrexate: 
- 25% to 50% reduction: 
- Grade 3 or worse mucositis with previous methotrexate course. 
- 25% to 75% reduction: 
- delayed excretion and/or nephrotoxicity with previous methotrexate 
course. 
- 50% reduction: 
- pleural effusion or ascites (drain effusion if possible) 
- Calculated creatinine clearance: 
- 10 to 50 ml/min: reduce by 50% 
- < 10 ml/min: hold MTX 
 
 


 
 
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16 
 
 
Dosing modifications based on age and performance status will be permitted on 
cycles 1-8 and maintenance intensifications. Suggested dose adjustments as 
below: 
 
 
 
< 60 
60 – 74 
PS 0–2 
>74 
> 60, PS 3–4 
Cyclophosphamide 
(mg/m2) 
300 
250 
200 
Doxorubicin 
(mg/m2) 
50 
37.5 
25 
Vincristine (mg) 
2 
2 
1 
Dexamethasone 
(mg) 
40 
20 
20 
Methotrexate 
(mg/m2) 
200 
800 
100 
400 
50 
100 
Cytarabine (g/m2) 
3 
1 
0.5 
 
Note:  Age 60 – 64 with PS 0-1 may be treated with full doses (except for reduction 
of cytarabine to 1 g/m2 as per design) at the discretion of the treating physician   
 
Maintenance Therapy: 
1- Patients may be moved from the intensive chemotherapy to the maintenance 
phase prior to completion of 8 cycles of chemotherapy if significantly intolerant of 
the intensive chemotherapy after discussion with the Principal Investigator.  A 
maintenance cycle will be defined as 28 days. 
2- Maintenance chemotherapy with 6-mercaptopurine (6-MP), methotrexate 
(MTX), vincristine, and prednisone (POMP) for approximately 30 months (except 
for consolidations with hyper-CVAD + ofatumumab followed by 
MTX/pegaspargase [or vice versa] at Course 6 and 7 and MTX/pegaspargase 
followed by hyper-CVAD-ofatumumab [or vice versa] at course 18 and 19) 
beginning at level 0 (or lower dose level if previous toxicity warrants):    
- 6-MP 50 mg PO three times daily (TID),  
- MTX 20mg/m2 (rounded) PO weekly 
- Vincristine 2 mg IV approximately every 28 days 
- Prednisone 200 mg PO daily days 1 to 5 approximately every 28 days, starting 
with vincristine (if given). 
 
Suggested maintenance chemotherapy dose adjustments as below: 
 
Level 
MTX (mg/m2) (rounded) 
6-MP (mg/d) 
Vincristine (mg) 
Prednisone (mg) 
0 
20 
150 
2 
200 
-1 
15 
100 
1 
100 
-2 
10 
50 
0 
50 
-3 
5 
50 
0 
0 
 


 
 
2010-0708 
 
 
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17 
 
 
3- Dose adjustments for myelosuppression include MTX and 6-MP, but not 
vincristine or prednisone (the latter should remain 200 mg unless steroid 
myopathy or other uncontrolled significant toxicity occurs). Titrate to keep 
granulocytes >= 1 x 109/L and platelet count >= 50 x 109/L. 
4- Methotrexate 
- Decrease by one dose level for mucositis > grade 2. 
- Decrease by one dose level for bilirubin > 2.5 or elevation of transaminases >= 
5 x upper limit of normal. 
- Hold if granulocyte count nadir < 0.5 x 109/L or platelets < 10 x 109/L, resume 
with decrease in one dose level or lower depending on duration of cytopenias. 
5- 6-mercaptopurine 
- Decrease by one dose level for bilirubin > 2.5 mg/dL or elevation of 
transaminases >= 5 x upper limit of normal. 
- Hold if granulocyte count nadir < 0.5 x 109/L or platelets < 10 x 109/L, resume 
with decrease in one dose level or lower depending on duration of cytopenias. 
6- Vincristine 
- Decrease by one dose level for >= grade 2 peripheral neuropathy persisting for 
more than 2 weeks. 
- Discontinue for grade 3 or greater peripheral neuropathy. 
7- Note that the dose adjustments of POMP are guidelines, and the dosing needs 
to individualized to the patient, as differential toxicities between 6-MP and 
methotrexate may be difficult to discern. 
 
Continued antiviral prophylaxis to prevent herpes zoster is strongly encouraged. 
Consider antifungal prophylaxis during days of prednisone. Consider PCP 
prophylaxis. 
 
Early and Late Intensifications (interrupting maintenance phase as follows): 
-Two courses of chemotherapy months 6 (methotrexate + pegaspargase) and 7 
(hyper-CVAD + ofatumumab) of maintenance, repeated at months 18 
(methotrexate + pegaspargase) and 19 (hyper-CVAD + ofatumumab) of 
maintenance Hyper-CVAD may precede or follow MTX + pegaspargase.  
 
 
Methotrexate 100 mg/m2 day 1 IV over 2 hours and pegaspargase at a dose of 
2000 IU/m2 dose will be capped at 3,750 international on units day 2 by IV over 2 
hours and this dose will be reduced to 1000 IU/m2 on day 2 by IV over 2 hours on 
patients older than 60 years of age.Hyper- CVAD + ofatumumab 
Cyclophosphamide (CTX) 300 mg/m2 IV over 3 h every 12 hrs x 6 doses 
days 1,2,3 (total dose 1800 mg/m2). 
MESNA 600 mg/m2/d IV continuous infusion daily for 24 hrs, starting 
approximately 1 hour prior to CTX and completing by approximately 12 hrs 
after the last dose of CTX. 
Doxorubicin 50 mg/m2 IV over 24 hrs via central venous catheter on day 4 
after last dose of CTX given (infuse over 48 hrs in patients with reduced 
ejection fractions < 50%). May be given by shorter infusion if difficulty with 
central venous access. 


 
 
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Vincristine 2 mg IV on day 4 +/- 2 days and day 11 +/- 2 days. 
Dexamethasone 40 mg IV or p.o. daily on days 1-4 +/- 2 days and days 
11-14 +/- 2 days. 
Ofatumumab 2000 mg IV on day 1 +/- 2 days and day 11 +/- 2 days  
 
- Intensification course may be started when granulocytes >= 1 x 109/L and 
platelets >= 50 x 109/L following discontinuation of Filgrastim product (G-CSF). 
Courses may be started with dose reductions prior to full platelet recovery, if the 
treatment is delayed (e.g., 28 days or later from the start of last course.)  
Instances where lab results fall outside of above criteria in the time between 
evaluation of next course and the actual start of next course will not be 
considered a deviation.  Start of courses in the best interest of the patient outside 
these parameters need to be discussed with and approved by the PI with 
reasons documented 
- Intensifications may be eliminated or given alternate months of the maintenance 
therapy, depending on patient tolerance and/or clinical situation, with reasons 
documented. 
- Treating physician has discretion to repeat course 1 dose escalation of 
ofatumumab during maintenance intensification 
 
All infusion times are approximate.  Infusion time variations due to IV bag 
overfill/underfill and institutional policy on IV flush solutions will not result in a 
protocol deviation.  Administration of oral medications will be documented via 
diary or verbally by the patient. Occasional missed doses of an oral medication 
will not result in a protocol violation. 
 
5.3 Central Nervous System (CNS) Management 
 
1. Standard CNS prophylaxis with intrathecal methotrexate and ara-C with 
each course if no evidence of CNS disease. Total number of prophylactic 
intrathecal treatments:= 8, except for patients with Burkitt’s 
Leukemia/Lymphoma will receive 16, consisting of 2 intrathecal treatments 
with methotrexate and ara-C with each course until total number reached. 
Missed intrathecals (e.g., related to failed procedure attempts, scheduling 
issues, patient social situations) can be "made up" with subsequent 
courses of chemotherapy. All patients will receive 8 intrathecal treatments 
except for patients with Burkitt’s Leukemia/Lymphoma will receive 16. 
 
2. If the patient has been previously treated, and has had prior intrathecal 
therapy, or prior CNS disease, discuss management of CNS 
prophylaxis/therapy with the Principal Investigator. 
 
3. If active CNS disease: methotrexate alternating with ara-C twice weekly 
until CSF clear; then once weekly for 4 weeks, then back to prophylactic 
schedule. Consider XRT to the base of the skull, particularly with cranial 
nerve root involvement (cranial nerve palsies, except for instances where 


 
 
2010-0708 
 
 
November 5, 2018 
19 
 
 
intrathecal therapy alone is expected to produce a response (e.g., mental 
neuropathy, isolated lateral rectus palsy). Alternative methods of treating 
CNS disease are allowed if appropriate for the patient (e.g., intrathecal 
liposomal ara-C, topotecan, ifosfamide, radionucleotides or others). 
 
4. Additional intrathecal treatments done as prophylaxis may be allowed after 
discussion with the PI.  
 
5. Additional Intrathecal treatments done as clinically indicated during 
exploratory lumbar puncture for symptoms of suspected CNS relapse are 
allowed and will not be considered a deviation from the protocol.  
 
6. LPs done outside of window will not be considered a deviation if dose is 
made up (if clinically indicated). 
 
 
5.4 Mediastinal disease 
Patients with mediastinal lymphoblastic lymphoma and bulky mediastinal disease 
(defined as >= 7 cm) or residual mediastinal lymphadenopathy at the end of the 
intensive chemotherapy portion of the treatment should be considered for 
consolidative mediastinal irradiation after recovery from the last course of 
consolidation therapy and prior to the maintenance phase of therapy. 
 
5.5 Maintenance therapy 
Maintenance therapy is planned for all patients as described in section 5.2, 
unless toxicity prohibits. Patients may move to the maintenance phase of therapy 
prior to completion of cycles 2 to 8 if they develop side effects prohibiting further 
intensive chemotherapy. Patients who do not complete all therapy per protocol, 
but remain in remission, will not be considered off-protocol, but will be monitored 
for disease-free survival only. An end-of-treatment date will indicate completion 
of therapy. 
 
5.6 Monitoring Patients on Study 
1- The hyper-CVAD regimens have been conducted since 1992, and have 
accrued over 500 patients on similar induction-consolidation-maintenance 
phases. The treatment-associated side effects, both myelosuppressive and 
extramedullary are well-known, and have been described and reported. Known 
and anticipated side effects of this regimen (see Appendix D) will not be reported 
as individual ADRs, according to the Code of Federal Regulations and ICH 
guidelines - CGP Section 4.11.1, p. 24. This also complies with the NCI CTEP-
CTC guidelines which state that for expected events "grade 4 myelosuppression 
or other grade 4 events that do not require expedited reporting will be specified in 
the protocol." AEs will not be collected in the maintenance phase, only SAEs will 
be collected.   
 


 
 
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20 
 
 
  2- The Investigator or physician designee is responsible for verifying and   
  providing source documentation for all adverse events and assigning the   
  attribution for each event for all subjects enrolled on the trial. Adverse events  
  (event name, grade, start/stop date, and attribution will be documented in the  
  medical record and entered into the case report form).  PDMS/CORE will be  
  used  as the electronic case report form for this protocol 
 
3- Recognizing there will be instances where patients cannot receive all of their 
care at M.D. Anderson Cancer Center, the following monitoring plan is proposed: 
- All patients who are enrolled on the protocol, will receive their courses of 
therapy that incorporate ofatumumab.  
- Subsequent courses of therapy may be given by a local physician under 
direction of the M.D. Anderson Cancer Center treating physician or the Principal 
Investigator. The referring physician will be identified, contacted and the protocol 
details discussed. 
- It will be detailed that therapy should not be administered except at the direction 
of the Principal Investigator or treating physician at M.D. Anderson. A review of 
laboratory data, review of compliance with the program, and review of toxicities 
will be performed. The participants will be informed of the intended procedure, 
and that their physician will be asked to comply, or they may be removed from 
the protocol. 
4- Physicians will be requested to sign a letter stipulating these items, and 
indicating their willingness to participate in the therapy as requested. Direction of 
therapy will be documented in the patient's medical record. 
5- Documentation will be requested from outside physicians, including drug 
administration records to ensure that the orders were followed. Outside 
physicians will be asked to contact us for prior approval of any decisions or 
changes related to the chemotherapy.  However, dose holds by the patient or 
local physician due to illness or concern for injury that are initiated prior to 
speaking with MDACC treating physician but are then reported to the MDACC 
Treating physician will not be considered a deviation. Note that occasional 
missed doses of medication self – administered by patient will be not be listed as 
a deviation. 
 
6.0 Pretreatment evaluation 
Procedure 
Comments 
Schedule 
Informed Consent 
Obtain standard informed 
consent approved by IRB 
Within 14 days of therapy 
Medical History 
History of present illness, known 
allergies, prior cancer history as 
far as traceable, 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 


 
 
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21 
 
 
Hematology 
CBC with differential and platelet 
count 
Within 14 days of therapy 
Biochemistry 
at least creatinine, total bilirubin, 
uric acid, LDH, SGPT or SGOT 
Within 14 days of therapy 
Bone marrow 
Aspirate and/or biopsy with flow 
cytometry for confirmation of 
diagnosis and PCR testing for 
TCR gene rearrangements. 
Within 21 days of therapy 
Cardiology 
12-lead ECG 
Within 14 days of therapy 
Serology 
Hepatitis B & C 
Within 14 days of therapy 
Pregnancy test 
 Serum or urine, if female and of 
child-bearing potential only. 
Females able to bear children 
that has not been 
postmenopausal for at least 12 
consecutive months or who had 
not undergone surgical 
sterilization) 
 
Within 14 days of therapy 
Imaging studies 
Chest X-ray and/or PET/CT as 
clinically indicated 
Within 14 days of therapy 
 
 
 
7.0 Evaluation During Study 
Procedure 
Comments 
Schedule 
Hematology 
CBC with differential and 
platelet count 
Minimum of Weekly during courses 1 to 8; 
preferred at least monthly during 
maintenance (except at least weekly during 
intensification courses during maintenance).  
Delay of labs for up to 2 weeks after 3rd 
week of intensive cycle and up to 6 weeks 
in POMP maintenance will be permitted 
without being considered deviation. 
Biochemistry 
at least creatinine, total 
bilirubin, SGPT or SGOT 
At least once every 2 weeks during course 
1, then at least every 4 weeks during 
courses 2 - 8 of chemotherapy, and at least 
every 4 weeks during maintenance therapy 
Delay of labs up to 6 weeks in POMP 
maintenance will be permitted without being 
considered deviation. 
Physical 
Examination 
Focused physical examination 
Prior to each treatment course 
Bone marrow 
Aspirate and/or biopsy 
(immunophenotyping by flow 
cytometry as indicated). Will 
include PCR testing for MRD if 
applicable. 
 
 
Only patients with involvement 
of bone marrow at time of 
On day 14 +/- 3 days strongly encouraged, 
but no later than day 21 of the first course of 
chemotherapy for patients with involvement 
of marrow at diagnosis, then weekly +/- 3 
days until remission or lack of response 
established. Once in CR, marrows will be 
repeated every 4 months (+/- 1 month) 
including PCR testing for eventual 
assessment of minimal residual disease.  
Commented [SM1]: Clarified wording and windows to 
minimize deviations without compromising safety. 


 
 
2010-0708 
 
 
November 5, 2018 
22 
 
 
diagnosis, will require bone 
marrow assessments as 
specified 
 
For patients with evidence of Leukemia in 
peripheral blood the bone marrow maybe 
omitted after discussion with and approval 
of PI. 
Imaging studies 
Chest X-ray and or PET/CT 
At the time of maximum response and/or 
when clinically determined to be necessary. 
 
Post treatment follow up - Until 30 days post last dose of Ofatumumab patient 
will be followed for toxicity or until another treatment is received.  
 
Long term follow up - Every 3 months, for 1 year. After you are off treatment 
you will be called and asked a series of questions. 1. How are you feeling? 2. 
Have you had any side effects? 3. Have you taken any other drugs? 
 
 
8.0 Criteria for Response 
8.1 Acute lymphoblastic leukemia: 
Complete remission (CR): 
Normalization of the peripheral blood and bone marrow with 5% or less blasts in 
marrow with a granulocyte count of 1 x 109/L or above and a platelet count of 100 
x 109/L or above. Complete resolution of all sites of extramedullary disease is 
required for CR.   
Partial response (PR): 
As above, except for the presence of 6-25% marrow blasts. 
 
8.2 Lymphoblastic lymphoma (with extramedullary disease) except for patients 
with Burkitt’s Leukemia/Lymphoma: 
8.21 Objective response of bi-dimensionally measurable and uni-dimensionally 
measurable parameters: 
Complete response (CR): 
Complete disappearance of all known disease. 
Partial response (PR): 
50% or more decrease in tumor size using the sum of the product (bi-
perpendicular dimensions when available). This includes a 50% volume 
decrease in lesions measurable in three dimensions. 
No response (NR): 
No significant change (includes stable disease). Lesions decreased in size, but < 
50% or lesions with slight enlargement but < 25% increase in size. 
Progressive disease (PD): 
Appearance of new lesions. 25% or greater increase in size of exising lesions 
(increase 50% or greater if only one lesion is available and is 2 cm or less in 
size). 
8.22 Objective response for non-measurable parameters. 
CR, NR, and PD same as above but estimated. 
PR: definite improvement estimated to be at least 75% of lesion but not 
quantifiable by measurement. 
 


 
 
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23 
 
 
9.0 Evaluation of Toxicity 
Toxicities will be graded according to the NCI Expanded Common Toxicity 
Criteria (see Appendix F). 
 
10.0 Criteria for Removal from the Study 
Criteria for removal from study include, but are not restricted to, the following: 
10.1 Progressive disease. 
10.2 Non-compliance by the patient with protocol requirements. 
10.3 Patient's request to be removed from the study. 
 
11.0 Statistical Considerations 
This is a phase II study of Hyper-CVAD + ofatumumab in patients with CD-20 
positive acute leukemia (ALL). The primary objective is to evaluate the event-free 
survival (EFS), where the event-free survival will be measured from the start of 
therapy until failure to respond, relapse or death.  
 
Historical data suggested that the 3-year EFS rate in patients with CD-20 positive 
ALL was 50% with a median survival of 3 years. It will be promising if the 3-year 
EFS rate will increase to 65%-70% with the treatment of Hyper-CVAD + 
ofatumumab with a potential median survival of 4.8 to 5.8 years. Assuming the 
event-free survival time follows an exponential distribution, the estimated median 
event-free survival time was 3 years for historical standard treatment, and it is 
expected to improve the median event-survival time to 4.8 to 5.8 years in this 
study.  A maximum of 80 will be recruited for the study at a rate of < 1 patient per 
month, leading to a maximum accrual period of 1 year and five months. 
Assuming the median event-free survival time is 3 years, then the 95% credible 
interval with 80 patients would be (2.22, 4.05), while assuming median survival 
time is 4.8 years, then the 95% credible interval with 80 patients would be (3.56, 
6.49). The toxicity and efficacy will be monitored during the study, and all the 
data will be used to update the prior distributions for toxicity and efficacy 
parameters. The study will be stopped for toxicity and futility based on the 
following stopping rules.   
 
The primary endpoint time-to-event will be monitored using the method of Thall et 
al.[13] Let TE and TS represent the event-free survival time for the experimental 
treatment and standard treatment respectively. We assume that both  TE | mE 
and TS | mS follow exponential distributions with median mE and mS. We also 
assume that mE and mS have a inverse gamma distribution, with prior 
distributions of mS ~ IG(50, 1746) and mE ~ IG(3, 72). Throughout the trial, we 
will update the distribution on mE and will stop if at any point. 
                                            Prob(mE > mS |data) < 0.05    
 
Table 1: Operating characteristics (additional follow-up 1 year) 
 
True median Time to 
event (month) 
Pr(stop early) 
Average Number of Patients Treated 
(25th, 75th percentiles) 


 
 
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24 
 
 
10 
1 
23 (16, 28) 
20 
0.94 
49 (30, 68) 
25 
0.64 
61 (40, 80) 
30 
0.32 
71 (74, 80) 
36 
0.14 
75 (80, 80) 
40 
0.08 
77 (80, 80) 
45 
0.04 
79 (80, 80) 
58 
0.02 
79 (80, 80) 
 
 
In addition, toxicity will be monitored closely in all patients using the method of 
Thall et al.[14] The monitoring will be 7 interim looks. Denote the probability of 
toxicity by E, where non-hematologic toxicity is defined as any Grade 3 or 
greater complications attributable to Ofatumumab.  We assume E ~ beta (0.6, 
1.4).  We will stop the trail if at any point Pr(E > 0.30 | data)  >0.85. That is, we 
will stop the trial if, at any time during the study, we determine that there is more 
than 85% chance that the toxicity rate is more than 30%. Stopping boundaries 
corresponding to this stopping rule are listed in table 2. 
 
Table 2: Stopping boundaries for non-hematologic toxicity monitoring 
Among These Number of 
Patients  
Recommend Stopping if Toxicity 
Observed in n or more patients 
10 
5 
20 
13 
30 
22 
40 
30 
50 
38 
60 
47 
70 
55 
 
Table 3: The operating characteristics for non-hematologic toxicity monitoring are 
summarized in the following table 
True toxicity 
probability  
Probability 
of early stop 
Sample size 
percentiles (10, 25, 
50, 75, 90) 
0.1 
0.002 
 80  80  80  80  80   
0.2 
0.043 
 80  80  80  80  80   
0.3 
0.319 
10  30  80  80  80 
0.4 
0.841 
10  10  20  50  80 
0.5 
0.994 
10  10  10  20  30 
0.6 
1 
10  10  10  10  20 


 
 
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Analysis Plan: 
For discrete or categorical data, descriptive statistics will include tabulations of 
frequencies.  For continuous data, summary statistics including n, mean, 
standard deviation, median, minimum and maximum will be computed.  The 
posterior median time to event and it 95% credible interval will be estimated.  
Kaplan-Meier method, Log rank test and Cox proportional hazards regression 
modeling will be utilized to analyze event free survival and overall survival.    
 
This study will utilize the clinical conduct (CTC) website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct   maintained by the 
Department of Biostatistics to monitor event-free-surv 
 
 
12.0 Reporting Requirements 
12.1 See Appendix D for guidelines for reporting ADR's to the IRB. Adverse 
events should be reported for 30 days post last dose of Ofatumumab or until 
another treatment is received. 
 
12.2 Adverse Events Requiring Expedited Reporting: Serious unexpected 
adverse events (SUSARs) considered associated with therapy should be 
reported to the study nurse or the Principal Investigator [Elias Jabbour, M.D., 
Telephone (713) 742-4764] within 24 hours of observing or learning of the event. 
All AEs should be reported to the study nurse. 
 
12.3 Expected therapy-related events include those known toxicities or side 
effects related to the components of the chemotherapy. These grade 4 or less 
events will not be reported as individual SAEs, but will be summarized in the 
annual report to the IRB (see Appendix D): 
Hyperglycemia 
Electrolyte abnormalities 
Renal failure related to tumor lysis syndrome, methotrexate, or antibiotic therapy 
(e.g. AmBisome, aminoglycosides). 
Ara-C related central nervous system toxicity. 
Catheter-related deep venous thrombosis. 
Coagulation abnormalities during induction chemotherapy (e.g. chemical DIC or 
hypofibrinogenemia). 
Ileus related to vincristine. 
Hepatotoxicity related to methotrexate or antibioitic therapy (e.g. azole 
antifungals). 
Post lumbar puncture headaches. 
 
12.4 Events not considered to be serious events are hospitalizations for the 
routine treatment or monitoring of the studied indications, not associated with any 
deterioration in condition. 


 
 
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12.4.1 Treatment, which was elective or pre-planned, for a pre-existing condition 
that did not worsen. 
12.4.2 Treatment on an emergency, outpatient basis for an event not fulfilling any 
of the definitions of serious given above and not resulting in hospital admission. 
12.4.3 Serious Adverse Event Reporting (SAE) for M. D. Anderson-Sponsored 
IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
Death 
 A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse experience as it occurred. It does not include an 
adverse experience that, had it occurred in a more severe form, might 
have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
 A congenital anomaly/birth defect. 
 
 Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator or 
the IND Sponsor, IND Office. 
 
 All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or 
unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 


 
 
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 All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next 
working day) of knowledge of the event to the Safety Project Manager in 
the IND Office.  
 
 Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.  
 
 Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the 
participant withdraws consent. Serious adverse events must be followed 
until clinical recovery is complete and laboratory tests have returned to 
baseline, progression of the event has stabilized, or there has been 
acceptable resolution of the event. 
 
 Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
 Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
 It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal 
Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy 
 
 
12.5 Update of Adverse Event (AE) Data Capture Required as of 12/8/2015 
on all active treatment patients 
 
Adverse events are collected in accordance with the Leukemia Specific AE 
Recording Guidelines under Appendix D. In accordance with these guidelines, 
only unexpected AEs will be recorded in the Case Report Form (CRF). An AE is 
considered to be unexpected if it is “not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the 
current application, as amended” (21 CFR § 312.32, 2015). Events expected 
during leukemia therapy are also listed within the Leukemia Specific AE 
Recording Guidelines.  
 


 
 
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Abnormal hematologic values will not be captured in the CRFs or on the 
Leukemia AE Record. Only the highest grade per course of grade 3 or 4 
chemistry lab abnormalities will be captured on the AE Record as well. All 
Serious Adverse Events will be captured on the Leukemia AE Record as well as 
entered in the CRFs, regardless of expectedness. 
 
Any “unexpected” AE will have such noted in the comments section of the AE 
Records moving forward. The Principal Investigator will sign and date the AE log 
per each patient after the completion of each course.  
 
 
12.6 Novartis Adverse Events 
 
 
Adverse Events: 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
Events meeting the definition of an AE include: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments e.g., ECGs, radiological scans, vital 
signs measurements), including those that worsen from baseline, and felt to 
be clinically significant in the medial and scientific judgment of the 
investigator 
 
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition 
 
New conditions detected or diagnosed after investigational product 
administration even though it may have been present prior to the start of the 
study 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se will not 
be reported as an AE/SAE) 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the definition 
of an AE or SAE. 
Events that do not meet the definition of an AE include: 
 
Any clinically significant abnormal laboratory finding or other abnormal safety 
assessments that is associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the subject’s 
condition.  


 
 
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 
The disease/disorder being studied, or expected progression, signs, or 
symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the 
condition that leads to the procedure is an AE 
 
Situations where an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen 
 
B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an 
event in which the subject was at risk of death at the time of the event.  It 
does not refer to an event, which hypothetically might have caused death, if it 
were more severe. 
c. Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been 
detained (usually involving at least an overnight stay) at the hospital or 
emergency ward for observation and/or treatment that would not have been 
appropriate in the physician’s office or out-patient setting.  Complications that 
occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When 
in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
An overnight hospital stay due to slow infusion rates will not be considered a 
Serious Adverse Event. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s 
ability to conduct normal life functions.  This definition is not intended to 
include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption. 


 
 
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e. Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These should also be considered serious.  Examples of such 
events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Laboratory and Other Safety Assessment Abnormalities Reported as AEs 
and SAEs 
 Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, 
vital signs measurements), including those that worsen from baseline, and 
felt to be clinically significant in the medical and scientific judgment of the 
investigator are to be recorded as AEs or SAEs. 
 
 All events meeting liver stopping criteria must be recorded as an SAE.  
 
 However, any clinically significant safety assessments that are associated 
with the underlying disease, unless judged by the investigator to be more 
severe than expected for the subject’s condition, are not to be reported as 
AEs or SAEs. 
 
 B cell depletion, IgG below LLN, low CD19+ count, and 
hypogammaglobulinemia due to treatment with ofatumumab are not to be 
reported as AEs or SAEs. 
 
 Infusion related AEs may lead to a prolonged infusion time. Overnight stay 
at the hospital due to slow infusion rate is not to be reported as a SAE. 
 
 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAEs 
An event which is part of the natural course of the disease under study (i.e., 
disease progression) does not need to be reported as an SAE.  However, if the 
progression of the underlying disease is greater than that which would normally 
be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with investigational product or protocol 
design/procedures and the disease progression, then this must be reported as an 
SAE. 
 


 
 
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Time Period and Frequency of Detecting and SAEs 
 
Once an investigator determines that an event meets the protocol definition of an 
SAE, the SAE will be reported to NOVARTIS within 24 hours of being notified of 
the event. All SAEs regardless of relationship to investigational product will be 
collected from the first dose of investigational product to after the last dose of 
investigational product (30 days post last dose of Ofatumumab or until another 
treatment is received).  All SAEs regardless of causality will be collected for 30 
days post last dose of Ofatumumab or until another treatment is received. 
 
From the time a subject consents to participate in and completes the study all 
SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to 
NOVARTIS concomitant medication, will be reported promptly to NOVARTIS. 
 
Any SAE brought to the investigator’s attention after the subject has completed 
the study and considered by the investigator as possibly related to investigational 
product must be reported to NOVARTIS. 
 
Pregnancy 
 
Any pregnancy that occurs during study participation must be reported to 
NOVARTIS.   To ensure subject safety, each pregnancy must be reported to 
NOVARTIS within 2 weeks of learning of its occurrence.  The pregnancy must be 
followed up to determine outcome (including premature termination) and status of 
mother and child.  Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE.  Spontaneous abortions must be 
reported as an SAE. 
 
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the 
investigator as possibly related to the investigational product, must be promptly 
reported to NOVARTIS. 
 
In addition, the investigator must attempt to collect pregnancy information on any 
female partners of male study subjects who become pregnant while the subject is 
enrolled in the study. Pregnancy information must be reported to NOVARTIS as 
described above. 
 
1. Fax SAEs to Novartis via the following: 
Drug Safety & Epidemiology  at  Fax #: 877-778-9739 
(Should the designated SAE Fax# be non-functional please send SAEs to the 
designated SAE mailbox: clinicalsafetyop.phuseh@novartis.com) 
2. Novartis Coversheets must be attached to all SAE submissions 


 
 
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3. SAE Submissions must reference your Novartis Study Code 
COMB157DUS16T 
 
 
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10. Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of 
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12.  Arzerra (ofatumumab) [package insert].  Greenford, Middlesex, UK:  Glaxo 
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