Clinical trial NCT04530487
Conditions: Desmoplastic Small Round Cell Tumor Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor Recurrent Desmoplastic Small Round Cell Tumor Recurrent Malignant Peripheral Nerve Sheath Tumor Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Recurrent Rhabdomyosarcoma Refractory Desmoplastic Small Round Cell Tumor Refractory Malignant Peripheral Nerve Sheath Tumor Refractory Malignant Solid Neoplasm Refractory Neuroblastoma Refractory Rhabdomyosarcoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2020-08-19; Completion date: 2024-08-26
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial investigates side effects and how well donor stem cell transplant after chemotherapy works in treating pediatric and adolescent-young adults with high-risk solid tumor that has come back (recurrent) or does not respond to treatment (refractory). Chemotherapy drugs, such as fludarabine, thiotepa, etoposide, melphalan, and rabbit anti-thymocyte globulin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess tolerability of allogeneic hematopoietic stem cell transplantation (HCT) for patients with chemo-responsive recurrent/refractory solid tumors as defined by transplant-related mortality (TRM) at day 30 and the rate of grade III or higher organ toxicity (Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days.

SECONDARY OBJECTIVES:

I. Assess median time to platelet and neutrophil engraftment. II. Assess incidence of acute graft-versus-host disease (aGVHD) by day 100. III. Assess incidence of chronic GVHD (cGVHD) at day 100 and one year. IV. Assess rate of grade II organ toxicity through day 100. V. Assess rate of graft failure (primary and secondary) through day 100. VI. Assess rate of infectious complications through day 100. VII. Assess progression free survival (PFS) at day 100,180 and 365. VIII. Assess cumulative incidence of relapse, overall survival (OS) at 100 days and 1 year.

OUTLINE:

CONDITIONING REGIMEN: Patients receive thiotepa intravenously (IV) over 2-4 hours and etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -4 and -3.

TRANSPLANT: Patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive orally (PO). Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.

After completion of HSCT, patients are followed up for up to 1 year.

Arms: arm 1: CONDITIONING REGIMEN: Patients receive thiotepa IV over 2-4 hours, etoposide IV over 60 minutes on days -8 to -6, melphalan IV over 20 minutes on days -5 and -4, and fludarabine phosphate IV over 1 hour on days -5 to -3 in the absence of disease progression or unacceptable toxicity. Patients receiving umbilical cord transplant also receive rabbit anti-thymocyte globulin IV on days -3 and -4.

TRANSPLANT: Patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Beginning day -2, patients receive tacrolimus or cyclosporine IV continuously until able to receive PO. Patients continue tacrolimus or cyclosporine PO to day 60 and tapered to day 100. Patients also receive mycophenolate mofetil PO or IV every 8 hours until day 40 and tapered to day 90.
Interventions: intervention 1: Allogeneic Hematopoietic Stem Cell Transplantation intervention 2: Cyclosporine intervention 3: Etoposide intervention 4: Fludarabine Phosphate intervention 5: Lapine T-Lymphocyte Immune Globulin intervention 6: Melphalan intervention 7: Mycophenolate Mofetil intervention 8: Tacrolimus intervention 9: Thiotepa
Intervention descriptions: intervention 1: Undergo HSCT intervention 2: Given IV and PO intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV or PO intervention 8: Given IV and PO intervention 9: Given IV

Protocol documents:
Prot_SAP_001.pdf: 
 
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A PILOT STUDY OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR 
PEDIATRIC AND ADOLESCENT-YOUNG ADULTS PATIENTS WITH HIGH RISK SOLID TUMORS 
 
 
 
Principal Investigator:   Jeremy Connors, MD       University Texas at MD Anderson 
 
 
Co-Investigators: 
Jonathan Gill, MD 
University Texas at MD Anderson 
Priti Tewari, MD 
Demetrios Petropoulos, MD 
Najat Daw, MD 
Douglas Harrison, MD 
University Texas at MD Anderson 
University Texas at MD Anderson 
University Texas at MD Anderson 
University Texas at MD Anderson 
 
 
 
 
Biostatistician: 
Clark Andersen 
Jian Wang 
University Texas at MD Anderson 
University Texas at MD Anderson 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table of Contents: 
Pages 
 
i. 
Face sheet 
1 
ii. 
Table of Contents 
2 
iii. 
Synopsis                                                                                        3 
1. 
Purpose 
3 
2. 
Objectives 
3 
3. 
Hypotheses 
4 
4. 
Trial design 
4 
5. 
Definitions 
6 
6. 
Background 
9 
7. 
Patient and Donor Selection 
13 
8. 
Enrollment on Study 
17 
9. 
Treatment Regimen and Procedures                                           17 
10. 
Drug Formulation and Administration 
21 
11. 
Standard Observations 
29 
12. 
Monitoring 
31 
13. 
Adverse event reporting requirements 
33 
14. 
Statistical Considerations 
35 
15. 
Data and Safety Monitoring Plan                                                  38 
16. 
Confidentiality of Study Data                                                        38 
17. 
Informed Consent Process                                                            39 
18. 
References                                                                                      40 
19. 
Appendix A: Bearman Regimen-Related Toxicities Scale          43 
20. 
Appendix B: Standard Observations and Interventions             44 


 
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Synopsis: A PILOT STUDY OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR 
PEDIATRIC AND ADOLESCENT-YOUNG ADULTS PATIENTS WITH HIGH RISK SOLID TUMORS 
Primary Objectives:  The primary objectives are to assess tolerability of allogeneic HCT for patients with 
chemo-responsive recurrent/refractory solid tumors as defined by transplant-related mortality (TRM) at day 
30 and the rate of grade III or higher organ toxicity (Bearman Regimen-Related Toxicities Scale) attributable 
to conditioning occurring within 30 days. 
 
Secondary Objectives: Assess: (i)Median time to platelet and neutrophil engraftment,(ii)incidence of acute 
graft-versus-host disease (aGVHD) by day 100, (iii)incidence of chronic GVHD(cGVHD) at day 100 and one 
year (iv)rate of grade II organ toxicity through day 100,(v)rate of graft failure (primary and secondary) through 
day 100,(vi)rate of infectious complications through day 100,(vii)progression free survival (PFS) at day 100,180 
and 365, (viii) cumulative incidence of relapse,(ix) overall survival(OS) at day 100 and 365.   
 
Eligibility Criteria:  Patients aged 0-25 years, confirmed diagnosis of a malignant recurrent/refractory solid 
tumors with chemo- responsive disease, an available suitable HCT donor and patients have adequate organ 
function to undergo the conditioning regimen as outlined in section 7.0. Up to 200 patients will be enrolled.  
Method: This is a non-randomized, non-blinded ,phase II clinical trial. Patients will be assigned to one of two 
arms based on the HCT donor and the stem cell source that is available as detailed in section 7.3.A non 
radiation based conditioning regimen will be used as detailed in section 9.1.Patients will receive standard 
supportive care as per best clinical practice in addition to the required observations detailed in Appendix B.  
 
1.0 
Purpose 
 
This is a pilot study of allogeneic hematopoietic stem cell transplantation (HCT) among patients 
with chemo-responsive recurrent/refractory solid tumors.  
 
2.0 
Objectives 
 
2.1 
Primary Objectives 
To assess tolerability of allogeneic HCT for patients with chemo-responsive 
recurrent/refractory solid tumors as defined by transplant-related mortality (TRM) at day 30 
and the rate of grade III or higher organ toxicity (Bearman Regimen-Related Toxicities 
Scale)[1] attributable to conditioning occurring within 30 days.  
 
2.2 
Secondary Objectives: 


 
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Assess 
              I. Median time to platelet and neutrophil engraftment. 
             II. Incidence of acute graft-versus-host disease (aGVHD) by day 100 
             III. Incidence of chronic GVHD(cGVHD) at day 100 and one year 
            IV. Rate of grade II organ toxicity through day 100 
            V. Rate of graft failure (primary and secondary) through day 100. 
            VI. Rate of infectious complications through day 100. 
             VII. Progression Free Survival (PFS) at day 100,180 and 365 
VIII. Cumulative incidence of relapse, overall survival (OS) at 100 days and 1 year.   
 
3.0 
Hypotheses 
 
Allogeneic HCT may be a consideration for the treatment of patients with recurrent/refractory 
chemo- responsive solid tumors. High dose chemotherapy may reduce tumor burden and 
associated inhibitory immune escape signals. Allogeneic HCT confers a Graft- Versus-Tumor effect 
(GvT) to eliminate residual disease after conditioning chemotherapy which may decrease disease 
recurrence and improve overall survival [2].   
 
 
 
4.0 Trial Design 
 
This is a non randomized, non blinded, phase II clinical trial in which eligible patients (see section 7.2 and 
7.3) will be enrolled to receive one of the two treatments based on the availability of the donor stem cell 
source as outlined in section 7.4. Up to 20 pediatric and AYA patients (Age 0-25) will be enrolled for each 
treatment group. Assessment of the tolerability will be conducted in each treatment group.   
 
 
 
 
 
 
 
 
 


 
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Figure 1: A Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Pediatric and Adolescent-
Young-Adult Patients (age 0-25) with High Risk Solid Tumors  
 
 
 
VP-16: Etoposide 
CSA: Cyclosporine 
MMF: Mycophenolate Mofetil       ATG: Anti-Thymocyte Globulin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient with Chemo Responsive Recurrent/Refractory Solid Tumor
Matched Related Donor
Thiotepa/Melphalan/Fludarabine/VP-16
Tacrolimus/CSA + MMF
Matched Allogeneic Umbilical 
Cord Donor
Thiotepa/Melphalan/Fludarabine/VP-16
Rabbit Thymoglobulin (ATG) 
1.25 mg/kg (Day -4)
Rabbit Thymoglobulin (ATG)
1.75 mg/kg (Day -3)
Tacrolimus/CSA + MMF
Matched Unrelated Donor
Thiotepa/Melphalan/Fludarabine/VP-16
Rabbit Thymoglobulin (ATG)
1.25 mg/kg (Day -4)
Rabbit Thymoglobulin (ATG)
1.75 mg/kg (Day -3)
Tacrolimus/CSA + MMF


 
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5.0 Definitions 
 
5.1 Engraftment: Engraftment is defined as recovery of blood counts (neutrophil and platelet 
engraftment, as defined in 5.1.1) with cells of donor origin, documented by either bone marrow 
or peripheral blood chimerism assays after hematopoietic cell transplant. 
5.1.1 Neutrophil engraftment. Neutrophil engraftment is defined as the first day of 
three consecutive days when the absolute neutrophil count (ANC) is >500/mm3. 
            
 
 Platelet engraftment.        Platelet engraftment is defined as the first of three 
consecutive days when the platelet count is >20 K/uL (and the patient has not 
received a platelet transfusion for seven days preceding the first day). 
 
5.1.2. Donor chimerism. Donor cells in either peripheral blood or bone marrow, as 
documented by fluorescent in situ hybridization (FISH), for 
sex-mismatched 
donor/recipients)   or   short-tandem   repeat   testing   (STR)   for   sex-matched donor 
recipient pairs. 
 
5.2 Immunological function 
5.2.1 T lymphocyte recovery.   T lymphocyte recovery is defined as absolute number  of donor-
derived CD3+ T lymphocytes >100/mm3. 
5.2.2. Mitogen-specific T lymphocyte function recovery. Mitogen-specific T lymphocyte function is 
defined as proliferative responses to phytohemagglutinin (PHA) 
>25,000 CPM of titrated thymidine incorporation. 
5.2.3 Antigen-specific B lymphocyte function recovery. Antigen-specific B lymphocyte function is 
defined as normal titers of specific antibody to immunization with tetanus toxoid (TET) 
and not receiving IVIG for at least 3 months. 
 
5.3 Toxicity 
5.3.1 Acute conditioning regimen related toxicity is defined according Bearman Regimen-
Related Toxicities Scale) Grade III or higher of the following organs are to be documented: 
5.3.1.1 Hepatic 
5.3.1.2 Pulmonary 
5.3.1.3 Renal 
5.3.1.4 Cardiac 
5.3.1.5 Bladder 
5.3.1.6 Central Nervous System 
5.3.1.7 Mucosal (stomatitis) 
5.3.1.8 Gastrointestinal 
 
 
 
5.4 Acute and Chronic Graft Versus Host Disease 


 
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Acute Graft-Versus-Host Disease (aGVHD): Acute graft-versus-host disease usually develops within  
the first three months after transplantation and may appear as a characteristic dermatitis which may  
be accompanied by cholestasis and/or enteritis. Staging of acute GVHD will follow the  
Glucksberg staging criteria. 
 
Chronic Graft-Versus-Host Disease: Chronic graft-versus-host disease is typically a  
late complication of HCT characterized by a connective-tissue disease-like syndrome and usually,  
but not always, occurring greater than 100 days following transplantation. Occasionally, its onset  
may closely follow aGVHD (known as progressive presentation of cGVHD). 
Initial symptoms of cGVHD frequently include nausea and anorexia with ocular and oral sicca.  
Rash characteristically appears with pigmentary changes progressing to sclerosis and  
contractures. Other organs may be involved.  Symptoms may mimic those seen in patients 
with scleroderma and other autoimmune disorders. Chronic GVHD will be assessed by the criteria 
set up by the National Institutes of Health Consensus Development Project on criteria for clinical 
trials in cGVHD. The following organs are evaluated for grading of cGVHD: 
               5.4.1 Skin: Assessment of skin for erythematous maculopapular rash,  
                        scleroderma, hypertrophy or atrophic changes of skin, hyperpigmentation  
                         or hypopigmentation, lichen planus or lichenoid reactions 
5.4.2 Joints and fascia: Tightness, contractures and decrease range of motion 
5.4.3 Eyes: Xerophthalmia and photophobia. 
5.4.4  Mucosa: Erythema, lichenoid changes, and ulcers of mucosal surfaces of the 
mouth, vagina. 
5.4.5 Gastrointestinal: Anorexia, nausea, vomiting, abdominal pain and weight loss  
may be manifestations of GI involvement. Esophageal stenosis and dysmotility may 
also be a GVHD presentation. 
5.4.6 Liver function abnormalities with cholestasis and fibrosis, resulting in elevated 
serum levels of bilirubin, alkaline phosphatase, and hepatic transaminases and 
transferases. 
5.4.7 Obliterative bronchiolitis (OB) may occur as a pulmonary manifestation of 
cGVHD. 
5.4.8 Genital tract: Vaginal scarring, labial agglutination, phimosis or urethral scarring. 
 
 
5.5 Sinusoidal Obstructive Syndrome (SOS) will be diagnosed and graded according to  
Pediatric and AYA modified EBMT Consensus Criteria 
 
 


 
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5.6 Chronic toxicities                                                                                                               
Chronic toxicities are defined as those occurring at least 100 days post HCT and will be monitored       
and graded using the Common Terminology Criteria (CTCAE) version 5.0. The CTCAE v5.0 will be 
used as it allows standardized reporting of adverse events through the use of assigned uniformed 
terminology and severity grading. The following specific toxicities that represent common chronic 
effects related to HCT will also be monitored:              
              5.6.1     Chronic GVHD (see above 5.4). 
5.6.2 Hypogammaglobinemia (see B lymphocyte recovery above 5.2). 
5.6.3 Learning disability and/or neurocognitive dysfunction. Determined by both school 
performance and appropriate battery of age-appropriate neurocognitive tests. 
 
 
 
5.7 
EVALUATION OF RESPONSE 
 
This study will use the revised (RECIST 1.1) Response Evaluation Criteria in Solid Tumors[3]. 
PET scan, bone marrow examinations, and/or tumor specific markers may be used as described 
below.   
 
5.8 
Response criteria  
5.8.1 Complete Response (CR): disappearance of all lesions. For lymph nodes reduction of the 
short axis to 10 mm or less, and no new lesions 
5.8.2 Partial Response (PR): At least a 30% decrease in the total tumor burden.  Reference is 
disease measurement prior to starting treatment, and no new lesions   
5.8.3 Progressive Disease (PD): At least 25% increase in the total tumor burden.  Reference is 
disease measurement prior to starting treatment.  
5.8.4 Stable Disease (SD): Changes that do not meet definition of CR, PR, or PD. 
 
 
5.9 
Response Criteria for Solid Tumors with FDG-PET positive lesions 
 
A ‘positive’ FDG-PET scan lesion is one that is FDG avid with an uptake greater than twice that of 
the surrounding tissue on the attenuation corrected image. Patients without measurable disease with 
only FDG-PET positive lesions will have disease evaluated by FDG-PET response. 
 
 
FDG-PET Response 
Complete response: resolution of all FDG-PET positive lesions 
Incomplete response: resolution of at least one positive FDG-PET lesions with persistence of other 
FDG-PET lesions 


 
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Stable Disease: No change in FDG-PET scan in number of positive lesions 
Progressive disease Development of new FDG-PET positive lesion and/or massive unequivocal 
increase of FDG-PET lesions.    
 
          5.9.2  Response Criteria for tumors with only bone marrow metastasis or elevated tumor 
markers. 
Patients without measurable disease with only bone marrow metastasis or elevated tumor marker 
will have disease evaluated by bone marrow or tumor marker response. 
 Bone marrow metastasis is defined by the presence of metastatic disease identified on a bone 
marrow aspirate or biopsy sample prior to initiation of therapy 
Elevated tumor marker is defined by a level above upper limit of normal for age and sex 
 
5.9.3 Tumor Marker or Bone Marrow Response 
 Complete response: resolution of bone marrow metastasis and/or normalization of tumor markers. 
 Incomplete response/stable disease: does not meet definition of complete response nor 
progressive disease. 
Progressive disease: For patients with no measurable disease at baseline will only contribute to 
overall progression disease if develops new measurable disease that can be used to compare 
subsequent responses 
 
6.0 Background 
 
            Allogeneic HCT/Immunotherapy for high-grade solid tumors: 
 
Relapsed, and/or metastatic solid tumors are associated with a 5-year survival as low as <35%. 
Outcomes for these patients have failed to significantly improve over the past two decades despite 
the use of novel agents, increased chemotherapy dose intensity, new chemotherapy combinations 
and high dose chemotherapy requiring autologous stem cell rescue. The addition of novel agents 
such as cixutumumab and temozolamide to an already dose intensified regimen for newly diagnosed 
patients with rhabdomyosarcoma metastatic at sites other than regional lymph nodes, resulted in a 
3 year event free survival (EFS) of 16% and 18% and OS of 47 and 33% respectively[4].The EURO-
E.W.I.N.G 99  and Ewing-2008 trials compared the effect of consolidation therapy with  combined 
high dose chemotherapy- Busulfan/Melphalan (BuMel) followed by autologous stem cell 
transplantation versus standard chemotherapy- vincristine/dactinomycin/ifosfamide (VAI)for patients 
with localized high risk  Ewing sarcoma. Three year EFS rates for VAI and BuMel followed by 
autologous stem cell transplantation were 56.7% and 69% respectively with this benefit being 
sustained at 8 years where the EFS was 47.1% vs 60.7% respectively[5]. While The International 
Society of Pediatric Oncology European Neuroblastoma (SIOPEN) group added a combination of 


 
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topotecan, vincristine, and doxorubicin to patients who failed induction therapy with only 6.4% of 
patients achieving clinical remission.[6] 
With approximately 25% of children and young adults presenting with metastatic disease, the 
development of new modalities of cancer therapy including hematopoietic stem cell therapy (HCT) 
for these tumors is therefore essential to the improvement of patient outcomes 
 
The ability to rescue a patient with hematopoietic progenitor cells allows the use of very high-doses 
of chemotherapy that could overcome resistance.  Autologous transplants have been viewed more 
favorably because the high morbidity/mortality due to GVHD with allogeneic transplants. The 
research, however shows inconclusive data to support high-dose chemotherapy with autologous 
stem-cell rescue and as mentioned above, finds about 20-30% overall and event free survival [7, 8]. 
With autologous HCT, adequate collection depends, on the bone marrow reserve after chemo and/or 
radiotherapy, and bone/bone marrow involvement with disease. Marrow that has been irradiated may 
be unable to mobilize sufficiently to provide the increased number of cells needed for collection. 
Furthermore, if disease has disseminated to the bones and bone marrow, subsequent fibrosis may 
reduce the marrow’s efficacy. Finally, disseminated bone marrow disease may increase the risk of 
potential contamination of an autologous stem cell collection. For these patients, it becomes 
unlikely to obtain an adequate autologous stem cell source. At present, it is not possible to separate 
a malignant cell from a peripheral stem cell harvest leaving the potential risk of re-infusing malignant 
cells after the high-dose therapy leading to disease recurrence. Therefore, these patients are not 
ideal candidates for marrow-ablative therapy with autologous HCT 
 
This paradigm is shifting with new advancements in allogeneic transplant management [9]. There is 
evidence to suggest that allogeneic immune effect can be seen in solid tumors [10-14]. A group in 
Spain performed allogeneic HCT among 6 patients with a variety of high-risk solid tumors 
(neuroblastoma, Ewing sarcoma, desmoplastic tumor, nasopharyngeal carcinoma, and embryonal 
rhabdomyosarcoma) and found response among all 6 patients, with 3 developing complete 
response (CR), 2 developing partial response, and 1 patient having stable disease for greater than 
9 months. Three patients remained alive in CR at a median follow-up of 15 (4-65) months[15]. Lang 
et al reported allogeneic HCT for treatment of solid tumors. Four patients with neuroblastoma (NB), 
a patient with rhabdomyosarcoma (RMS), and a patient with Ewing sarcoma (EWS) were included 
in this study. All patients entering transplant had significant tumor burden. All patients had primary 
engraftment at a median of 11 days. One patient had secondary graft failure. Acute GVHD grade 
II was seen in 4 patients while 2 experienced limited cGVHD; no TRM occurred. Four patients died 
from progression while two are alive, with an overall median survival of 6 (2-11) months [16].  
GvT effect in allogeneic transplants is clearly a benefit over autologous transplants. There is 
emerging clinical evidence which suggests a clinically meaningful GvT effect following allogeneic 


 
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HCT in Ewing sarcoma and rhabdomyosarcoma [17-24].  
Donor T lymphocytes in the allograft, reactive to host histocompatibility antigens, can directly kill 
human cancer cells in vitro and in vivo. This can occur even after donor T lymphocytes are rejected 
and suggests that host lymphocytes might mediate the anti- tumor effect of donor allogeneic 
lymphocytes[25]. 
Donor lymphocyte infusion (DLI) has been reported to induce GvT after allogeneic HCT in a patient 
with multiply-relapsed rhabdomyosarcoma to sustain remission.  At 31 months post- transplant, this 
patient remained disease-free[24]. In a case-report, Donker et al reported a patient with stage IV 
rhabdomyosarcoma who at 4 years post-allogeneic transplant remains in CR[23]. Baird et al 
reported a clinical trial of 23 sarcoma patients who underwent reduced intensity HCT [26] (44). 
All patients had successful donor engraftment. Five of 23 patients remained alive (OS of 30% at 
3 years), including 3 of 7 (42%) transplanted without gross disease (median survival 14.5 versus 
29.0 months from HCT). Koscielniak et al reported long-term remission in a patient with Ewing 
sarcoma after HCT[21]. Capitini et al reported response of metastatic Ewing sarcoma after 
allogeneic HCT[18]. Hosono et al reported clinically significant GvT effect in a patient with pulmonary 
Ewing sarcoma who failed high-dose chemo with autologous transplantation[19].  
Additionally, tumors have evolved sophisticated mechanisms to avoid immune detection. They may  
down-regulate expression of MHC class I and other proteins involved in antigen presentation.[27-
29] Tumors can also decrease, or shed, expression of proteins that are recognized by the immune  
system (immunoediting) and they can by-pass death mechanisms by elevating expression levels of 
survival factors, such as anti-apoptotic proteins (survivin, BCL-XL), metastatic proteins (VEGF, 
MMPs) and proliferation factors (EGFR, c-Myc). The transcription factor STAT3 is upregulated in a 
number  of tumors and controls expression of some of these genes.[30]  Tumor cells adapt to 
immune recognition by down regulating expression of antigens, and can also adapt to 
chemotherapy by increasing expression of adenosine-triphosphate binding cassette (ABC) pumps 
to actively secrete intracellular drugs.[31] However chemotherapies have the potential to enhance 
cancer vaccine-induced immune responses by lowering the defenses of the tumor[32],  targeting 
the immune system to reduce tumor-induced immune suppressive cells and/or targeting the tumor 
to increase immunogenicity (increase MHC or antigen expression) and/or directly stimulating 
effector response by activating T cells.  
Some chemotherapy agents/combinations, such as fludarabine,[33] may induce significant and 
relevant T cell depletion and seems to generate a micro milieu suitable for subsequent T cell 
activation.  Hence, high-dose chemotherapy may lower the defences of the  
tumor and allow a suitable micro milieu for subsequent allogeneic donor immune-surveillance.   
Effective combination treatments hinge on our understanding of the role of the immune system in 
tumor rejection. Combining chemotherapies and immunotherapies effectively to attack the tumor 
from multiple sides may enhance our ability  to quickly and thoroughly eliminate enhance our ability  


 
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to quickly and thoroughly eliminate cancer.[34] 
 
Cord blood (CB) natural killer (NK) cells represent another promising effector cell immunotherapy  
due to their recognition of malignant cells without the need for a known target and their potential to 
expand exponentially.[35] Natural killer cells have documented activity against 
medulloblastoma.[36, 37]However, complete elimination of tumor by autologous NK cells is unlikely 
as the inhibitory signals from the tumor generally render their own NK cells incapable of inducing 
potent cytolytic activity. Although most NK cell clinical trials have used allogeneic peripheral blood 
(PB) as  a cell source [38], in vitro studies suggest that umbilical cord blood (CB) NK cells may 
possess better cytolytic ability.[39, 40]  The use of cord blood as a source of allogeneic NK cells is 
also advantageous because: (a) they can be ex vivo expanded to clinically useful cell numbers; and 
(b) they allow a  higher chance of identifying HLA-compatible and KIR-mismatched products 
because of their immediate availability in established cord blood banks. Such a readily available 
“off-the-shelf” source of NK cells greatly enhances the feasibility of using these cells as therapy.[35]   
In this study, for patients lacking matched related donors, cord blood graft(s) or matched unrelated 
donor (MUD) grafts will be used as an alternative donor source.  This study may inform the design 
of future pivotal studies regarding use of HLA-compatible and KIR-mismatched products as well as 
CB derived NK cells in combination with HCT. 
 
Finally more precise patient selection, pre-transplant work-up, the use of reduced intensity 
preparative regimens and better supportive care medications to aide with side-effects/GVHD has led 
to improved overall survival post HCT.[41-44] 
Taken altogether, the main advantages of the proposed approach can be summarized as 
follows: 
- 
Overcome the challenges in autologous bone morrow/PBSC collection in patients who 
are heavily pre- treated and/or have disseminated disease within the bone/bone 
marrow. 
- 
Use of radiation sparing thiotepa based regimen 
- 
Eliminate the risk of autologous graft contamination with tumor cells. 
- 
Provide GvT to eliminate residual disease after conditioning chemotherapy. 
 
The main potential risks are GVHD, risk for post-HCT infections and delayed immune recovery. 
The use of allografting with the proposed regimen combines the benefits of high dose 
chemotherapy and an immune approach to disease therapy 
 
 
7.0 
Patient (Recipient) and Donor Selection: 
 


 
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7.1 
Recipient inclusion criteria 
7.1.1 Pathological criteria, including malignant recurrent/refractory solid tumors. This would 
include: 
7.1.1.1 Ewing’s sarcoma with the following translocations*: 
EWS-FLI1 
EWS-ERG 
EWS-ETV1 
EWS-ETV4 
EWS-FEV 
FUS-ERG 
FUS-FEV 
7.1.1.2  Ewing-like sarcoma with the following translocations*: 
EWS-NFATC2 
EWS-POU5F1 
EWS-SMARCA5 
EWIS-PATZ1 
EWS-SP3 
CIC-DUX4 
 
BCOR-CCNB3 
*Additional translocations may be considered based on changes in classification and discussion with the PI  
7.1.1.3 Peripheral PNET  
7.1.1.4 Malignant peripheral nerve sheath tumor, neurofibrosarcoma 
7.1.1.5 Rhabdomyosarcoma 
7.1.1.6 Neuroblastoma (patients who are ineligible for tandem autologous 
transplant or who are at least 3 months post autologous HCT) 
7.1.1.7 Desmoplastic small round cell tumor (DSRCT)- both new diagnoses as 
well as recurrent/refractory disease 
7.1.1.8 Synovial Sarcoma 
 
 
7.1.2 Extent of disease eligibility: Patients must have chemo-responsive disease, defined as; 30% 
or greater decrease in the tumor target lesions when compared to its pre-treatment 
evaluation.  Patients with complete response will be eligible to participate. 
 
7.1.3 Available suitable HCT donor as defined below. 
 
 
7.1.4 Eligible patients must have adequate organ function to tolerate the chemotherapy 
conditioning regimen and the HCT, as measured by: 
7.1.4.1 Renal: creatinine clearance or GFR ≥50 ml/min/1.73m2, and not requiring dialysis 
7.1.4.2 Pulmonary: Diffusing Capacity of lung for carbon monoxide (DLCO) (corrected for 
hemoglobin) ≥ 50% predicted. If unable to perform pulmonary function tests, then 
O2 saturation ≥ 92% in room air. 


 
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7.1.4.3 Bilirubin ≤3x upper limit of normal (ULN) and ALT and AST ≤ 5x for age (with the 
exception of isolated hyperbilirubinemia due to Gilbert’s syndrome). 
7.1.4.4 Patients will be 0 – 25 years of age. 
 
7.1.5 Non-English speakers will be eligible to participate in this study 
 
7.2 
Recipient exclusion criteria 
7.2.1 Lack of histocompatible suitable related donor/ graft source as defined in 7.4 
7.2.2 End-organ failure that precludes the ability to tolerate the transplant procedure, including 
conditioning regimen 
7.2.3 Renal failure requiring dialysis 
7.2.4 Congenital heart disease resulting in congestive heart failure 
7.2.5 Ventilatory failure: requires invasive mechanical ventilation 
7.2.6 HIV infection 
7.2.7 Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet clinical 
symptoms progress); stable, controlled disease with treatment is not an exclusion criteria 
7.2.8 A female of reproductive potential who is pregnant, planning to become pregnant during the 
study, or is nursing a child 
7.2.9 Any patient who does not fulfill the inclusion criteria listed above 
7.2.10 Patient, parent, guardian or LAR unable/unwilling to provide consent and when indicated, 
assent 
 
7.3 
Vulnerable populations 
a. There will be pediatric patients as the patients may experience prolongation of life. Adequate 
safeguards as outlined in the HRP-416 checklist will be followed to protect their rights and 
welfare.  
b. When possible, the research will be explained to the child compatible with the child’s 
understanding. 
• 
Any person that has not achieved the age of 18 is considered a child. 
 
• 
For research conducted in the state, HRP-013 - SOP - LARs, Children, and 
Guardians to be aware of which individuals in the state meet the definition of 
“children” will be followed. 
 
• 
Research will not be conducted outside of the state. 
 
• 
Parental permission will be obtained from one or both parents as determined by the 
IRB. 
 
• 
In the event a LAR is used, we will follow consent SOP-04_Informed Consent Process 
and HRP-013_SOP Legally authorized representative. 
 
• 
Assent will be obtained per the SOP-04_informed consent process. 
 
• 
Assent will be documented per the SOP-04_informed consent process. 


 
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c. This research may involve adults unable to consent as this vulnerable population may 
experience prolongation of life. Adequate safeguards as outlined in the HRP-417 checklist 
will be followed to protect their rights and welfare.  
• 
For this population this will include: 
 -  when appropriate, the IRB would allow a legally authorized representative or family 
member to sign proxy informed consent, if that person is authorized to make 
decisions about medical care for the subject.  The investigator should document in the 
medical and research record who is legally authorized to make medical decisions. 
• 
-The investigator will provide detailed information of the risks and benefits of the research to 
the proxy and the subject (if the subject can possibly understand).  The protocol should be 
based on good science and sound research design with the potential for significant beneficial 
results 
• 
Patients have medical decision-making capacity if they can demonstrate 
understanding of the situation, appreciation of the consequences of their decision, 
and reasoning in their thought process, and if they can communicate their wishes. 
• 
For patients of who carry a diagnosis of a genetic condition leading to a lack of 
decision making capacity (e.g. Trisomy 21), no further evaluation will be required.  For 
patients without a known diagnosis, further evaluation will be made based on the 
patient’s history including possible evaluation by neurology or neuro-psychology to 
determine decision-making capacity. A determination of lack of decision-making 
capacity shall be made after an appropriate medical evaluation that concludes there is 
little or no likelihood that the participant will regain decision-making capacity in a 
reasonable period of time. 
• 
Physician will do the following:  
(1) assessment of any language or communication barriers interfering with the 
patient's understanding 
(2) identification and treatment of any reversible causes of incapacity 
(3) a directed interview to assess the elements of consent 
 
• 
For research conducted in the state, HRP-013 - SOP - LARs, Children, and 
Guardians to be aware of which individuals in the state meet the definition of “legally 
authorized representative” will be followed. 
• 
Research will not be conducted outside of the state. 
• 
Assent will be required of some of the subjects.  Assent will be obtained on subjects 
that have the capacity to provide assent.   
• 
Documentation of assent will be documented in the note documenting the consent 
process. 
• 
Subjects will be particularly closely monitored. 
• 
Subjects will be withdrawn if they appear to be unduly distressed. 
 
 
 
 
 
7.4 
Donor Selection 
HCT will be done using stem cell sources in the following order of preference: 
7.4.1 
Matched related donor bone marrow (10 of 10 HLA alleles [HLA-A, B, C, DR, and 
DQ]. Matched related donor PBSC is allowed only if collection of BM is not available 


 
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or refused by parents/donor. 
7.4.2 
Umbilical Cord Blood (UCB) 
Related 
7.4.2.1 Single Matched allogeneic umbilical cord blood (UCB): (Single Cord) Related 
• 
High-resolution matching at A, B, DRB1 (minimum 4/6) 
• 
Patients must have one CB unit available which is matched with 
the patient at 4/6, 5/6, or 6/6 HLA class I (serological) and II 
(molecular) antigens. The cord must contain a minimum of 2.5 x 
10e7 total nucleated cells/Kg recipient body weight (pre-thaw), with 
optimal goal of 4.0 x 10e7 total nucleated cells/Kg 
7.4.2.2 Double Matched allogeneic umbilical cord blood (UCB): (Double Cord) Related 
• 
High-resolution matching at A, B, DRB1 (minimum 4/6) 
• 
Patients who lack an appropriately matched single cord unit ), with 
an optimal dose of 4.0 x 10e7 total nucleated cells/Kg recipient 
body weight (pre-thaw)  as defined above (7.3.2.1), may receive 
two CB units which are matched with the patient at 4/6, 5/6, or 6/6 
HLA class I (serological) and II (molecular) antigens. Each cord 
must contain at least 1.5 x 10e7 total nucleated cells/Kg recipient 
body weight (pre-thaw) to achieve a cumulative cell dose of at least 
3.0 x 10e7 with the goal to be above 4.0 x 10e7 total nucleated 
cells/Kg 
 
Unrelated 
7.4.2.3 Single Matched allogeneic umbilical cord blood (UCB): (Single Cord) Unrelated 
• 
High-resolution matching at A, B, DRB1 (minimum 4/6) 
• 
Patients must have one CB unit available which is matched with 
the patient at 4/6, 5/6, or 6/6 HLA class I (serological) and II 
(molecular) antigens. The cord must contain a minimum of 2.5 x 
10e7 total nucleated cells/Kg recipient body weight (pre-thaw), with 
optimal goal of 4.0 x 10e7 total nucleated cells/Kg 
7.4.2.4 Double Matched allogeneic umbilical cord blood (UCB): (Double Cord) 
Unrelated 
• 
High-resolution matching at A, B, DRB1 (minimum 4/6) 
• 
Patients who lack an appropriately matched single cord unit ), with 


 
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an optimal dose of 4.0 x 10e7 total nucleated cells/Kg recipient 
body weight (pre-thaw)  as defined above (7.3.2.3), may receive 
two CB units which are matched with the patient at 4/6, 5/6, or 6/6 
HLA class I (serological) and II (molecular) antigens. Each cord 
must contain at least 1.5 x 10e7 total nucleated cells/Kg recipient 
body weight (pre-thaw) to achieve a cumulative cell dose of at least 
3.0 x 10e7 with the goal to be above 4.0 x 10e7 total nucleated 
cells/Kg 
7.4.3 
Matched unrelated donor bone marrow (10 of 10 HLA alleles [HLA-A, B, C, DR, 
and DQ]. Matched unrelated donor PBSC is allowed only if collection of BM is not 
available or refused by parents/donor. 
 
8.0 
Enrollment on the Study: 
 
Principal investigators or designee will review each patient’s eligibility prior to patient 
enrollment. Patients are considered enrolled on this study after all of the following: (i) 
patient, and/or parent(s) or legal guardian (s) consent (and assent when appropriate) for the 
patient to undergo the transplant procedure under this study protocol, (ii) patient meets all 
inclusion/exclusion criteria, and patient subsequently undergoes HCT under this study. 
 
9.0  Treatment Regimen and Procedure: 
 
Potential subjects will initially undergo screening for eligibility and a request for financial clearance will 
be submitted, once obtained, a written informed consent and assent (when appropriate) for HCT on 
this protocol will be obtained by the principal investigator or study designees prior to initiation of the 
conditioning regimen. 
 
 
 
 
 
9.1    TREATMENT SCHEMA 
 
Day 
Conditioning Regimen 
GVHD Prophylaxis 
 
-8 
Thiotepa 300 mg/m2 IV (10 mg/kg for < 12 Kg) 
Etoposide 100 mg/m2 IV (3.3 mg/kg for < 12 Kg) 
 
-7 
Thiotepa 300 mg/m2 IV (10 mg/kg for < 12 Kg), 
Etoposide 100 mg/m2 IV (3.3 mg/kg for < 12 Kg) 
 


 
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-6 
Thiotepa 300 mg/m2 IV (10 mg/kg for < 12 Kg), 
Etoposide 100 mg/m2 IV (3.3 mg/kg for < 12 Kg) 
 
-5 
Melphalan 70 mg/m2 IV (2.3 mg/kg for < 12 Kg), 
Fludarabine 30 mg/m2 
 
-4 
Melphalan 70 mg/m2 IV (2.3 mg/kg for < 12 Kg), 
Fludarabine 30 mg/m2 
 
(UCB and MUD: rATG 1.25 mg/kg) 
 
-3 
Fludarabine 30 mg/m2 IV 
(UCB and MUD: rATG 1.75 mg/kg) 
 
-2 
Rest 
Start Tacrolimus1 0.05 
mg/kg 
-1 
Rest 
 
0 
HSC Infusion 
Start MMF
2 15 mg/kg q8hr 
1Cyclosporine (CSA) may be substituted for Tacrolimus: 
• 
Age ≤ 6 years old: (CSA) 6 mg/kg IV QD in divided doses (e.g. 2 mg/kg 
q8hrs). 
• 
Age > 6 years old: (CSA) 3 mg/kg IV QD in divided doses (1.5mg/kg 
q12hrs) 
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9.2 
   HSC processing and administration will be performed per institutional SOP. 
 
9.3 
 Graft-Versus-Host Disease prophylaxis and treatment 
9.3.1 
GVHD prophylaxis. All patients will receive a calcineurin inhibitor per 
institutional practice to prevent GVHD. 
9.3.1.1 
Calcineurin inhibitor: The patient will receive a calcineurin inhibitor (CI), either 
tacrolimus or cyclosporine (CSA), starting on Day -2 sufficient to maintain a 
serum trough level of approximately 7-12 ng/dl for tacrolimus, or 150-300 ng/dl 
for CSA. 
 
                  Tacrolimus will begin on Day –2 pre-HCT at a starting dose of 0.05 mg/ kg/ day as 
a continuous infusion. 
 
       Cyclosporine (CSA) may be substituted for Tacrolimus: 
• 
Age ≤ 6 years  old: 6 mg/kg IV QD in divided doses (e.g. 2 mg/kg q8hrs) 
• 
Age > 6 years old: 3 mg/kg IV QD in divided doses (1.5 mg/kg q12hrs) 
 
Tapering schedule for Calcineurin inhibitors (if no active GVHD): Recipients of 
Matched (10/10 allele matched) related Donors 
• 
Start taper at Day +60 at approximately 20% of the original therapeutic 
dose/week to be and complete by Day +100. 
 
Recipients of all other donors 
• 
Start taper at Day +100 at approximately 10% of the original therapeutic 
dose/week to be completed by Day +180. 
 
 
 
 
 
 
 
 
 


 
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9.3.1.2 
Mycophenolate mofetil (MMF) 
                   MMF will be given at 15 mg/kg q 8 hours (45 mg/kg/day; max.3g/day) PO, 
or IV if indicated (i.e. first dose 4-6 hours following stem c e l l  infusion) to Day 
+40 post-transplant. MMF will be given until Day +40 post-transplant and then 
tapered by 10% per week to be discontinued by Day +90. 
                   Taper for both Tacrolimus (CSA)/MMF may be halted or modified as clinically 
indicated or with the development of any evidence of GVHD at the evaluation 
of the treating physician. 
                    For 
patients 
with 
suspected 
recurrence 
a 
more 
rapid 
taper 
of 
immunosuppression can be done at the discretion of the treating physician. 
 
9.3.1.3 
Rabbit Anti-thymocyte globulin (rATG)  
rATG will be given on days -3 and -4 to patients receiving umbilical cord blood 
transplants. 
 
 
9.3.2 GVHD treatment: If clinical GVHD develops, then further immunosuppressive 
treatment may be required. The individual aspects of each case would affect the 
choice of immunosuppression. Therefore, the method of immunosuppression, if 
necessary, would be decided on a case-by-case basis, using standard treatments 
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9.4 
Duration of participation on the study 
Patients should be followed and remain in the hospital until there is evidence of engraftment 
of donor cells and there is recovery from the side effects of the transplant procedure, per 
institutional guidelines. Monitoring parameters will be performed weekly until day 42 or longer, 
if the engraftment process is delayed. If the patient is engrafted and stable enough to be 
discharged from the inpatient facility, patients will be followed as outpatients at regular 
intervals. Study assessment data will be collected around the weeks of Day +100, +180, +270 
and +365 post-transplant (please refer to Section 11.3). Subject participation will continue for 
1 year post- HCT under this study. Patients are considered off-study only if death occurs, they 
withdraw consent/assent, and/or are confirmed lost to follow-up after a 12- month period of 
effort to locate the patient. 
 
10.0 Drug Formulation and Administration 
 
10.1 
  Fludarabine (FLUDARA®) 
10.1.1Source and Pharmacology 
Supplier: Berlex Laboratories, Inc. FLUDARA FOR INJECTION contains fludarabine 
phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D- 
arabinofuranosyladenine (Ara-A) that is relatively resistant to deamination by adenosine 
deaminase. The chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2- fluoro-9-
(5-O-phosphono-ß-D-arabinofuranosyl). Fludarabine phosphate is rapidly dephosphorylated 
to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active 
triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA polymerase 
alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis. The 
mechanism of action of this antimetabolite is not completely characterized and may be multi-
faceted. 
 
10.1.2 Formulation and Stability 
Each vial of sterile lyophilized solid cake contains 50 mg of the active ingredient fludarabine 
phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH range for 
the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection USP results 
in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous 
administration. FLUDARA FOR INJECTION is supplied in a clear glass single dose vial (6 
mL capacity) and packaged in a single dose vial carton in a shelf pack of five. 
 
10.1.3 Solution Preparation 
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Injection USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid 
cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 
25 mg of fludarabine phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 
7.7. The pH range for the final product is 7.2-8.2. In clinical studies, the product has been 
diluted in 100 cc or 125 cc of 5% Dextrose Injection USP or 0.9% Sodium Chloride USP. 
 
10.1.4 Storage and Stability 
FLUDARA is supplied as a white, lyophilized solid cake. Each vial contains 50 mg of 
fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust pH to 7.7. The 
pH range for the final product is 7.2-8.2. Store under refrigeration, between 2°-8° C (36°-46° 
F). 
 
10.1.5 Administration: 
FLUDARA will be administered by the central venous catheter over 1 hour, daily for 3 days. 
Patients will receive antiemetics prior to administration of this chemotherapy. 
 
10.2 Thiotepa 
10.2.1 Source and Pharmacology 
Thiotepa is a cytotoxic agent of the polyfunctional type, related chemically and 
pharmacologically to nitrogen mustard. The radiomimetic action of thiotepa is believed to 
occur through the release of ethylenimine radicals which, like irradiation, disrupt the bonds of 
DNA. One of the principal bond disruptions is initiated by alkylation of guanine at the N-7 
position, which severs the linkage between the purine base and the sugar and liberates 
alkylated guanines. Thiotepa is desulfurated by cytochrome P-450 enzymes such as 2B1 
and 2C11 which catalyze the conversion of thiotepa to tepa. 
Tepa is less toxic than thiotepa and has been demonstrated to produce alkali-labile sites 
in DNA, rather than cross-links. These findings indicate that tepa reacts differently from 
thiotepa and produces monofunctional alkylation of DNA. A second metabolite of thiotepa, a 
mercapturic acid conjugate, is formed via glutathione conjugation. Monochlorotepa is the third 
metabolite found in the urine. 
 
10.2.2 How supplied and storage 
Thiotepa for Injection USP, for single use only, is available in vials containing 15 mg of 
nonpyrogenic, sterile lyophilized powder. Store in a refrigerator at 2° to 8°C (36° to 46°F). 
PROTECT FROM LIGHT AT ALL TIMES. 
 
10.2.3 Dosage and Administration 
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drug concentration of approximately 10 mg/mL. (As per manufacturer’s information: Actual 
content per vial 15.6 mg; withdrawable amount 14.7 mg/1.4 mL; approximate reconstituted 
concentration: 10.4 mg/mL). When reconstituted with Sterile Water for Injection, solutions 
of thiotepa should be stored at refrigerated temperatures 2°-8°C (36°-46°F) and used 
within 8 hours. The reconstituted solution is hypotonic. For administration by intermittent or 
continuous infusion, the reconstitution solution should be further diluted with Sodium 
Chloride Injection or 5% Dextrose Injection to a concentration of between 1-5 mg/mL. 
Thiotepa 1 mg/mL in 0.9% sodium chloride is nearly isotonic. Reconstituted solutions 
further diluted with Sodium Chloride Injection should be used immediately. In order to 
eliminate haze, filter solutions through a 0.22 micron filter [Polysulfone membrane (Gelman’s 
Sterile Aerodisc®, Single Use) or triton- free mixed ester of cellulose/PVC (Millipore’s 
MILLEX®-GSFilter Unit)] prior to administration. Filtering does not alter solution potency. 
Reconstituted solutions should be clear. Solutions that remain opaque or precipitate after 
filtration should not be used. 
 
10.3 Antithymocyte Globulin (Rabbit) (rATG)  
10.3.1 Source & Pharmacology:  
Antithymocyte globulin (rabbit) is a polyclonal antibody which appears to cause  
immunosuppression by acting on T-cell surface antigens and depleting CD4 lymphocytes. 
Its onset of action (T-cell depletion) occurs within 24 hours with a half-life of 2-3 days. 
Its resulting lymphopenia may persist for up to 1 year. 
 
10.3.2 How Supplied 
rATG for injection is available in sterile multiple dose vials of 25mgs each. Its pH: 6.5 to 
7.2 when reconstituted and it contains glycine, mannitol and sodium chloride. 
 
10.3.3 Dosage and Administration 
Store intact vial at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light.  
Allow vials to reach room temperature, then reconstitute each vial with 5 mL sterile water 
for injection (SWFI). Rotate vial gently until dissolved; resulting concentration is  
5 mg/mL of thymoglobulin. Further dilute dose to a final concentration of 0.5 mg/mL  
(e.g., one vial [25 mg] in 50 mL saline or dextrose); in adults, total volume is usually  
50 to 500 mL depending on total number of vials needed per dose. 
Mix by gently inverting infusion bag once or twice. Reconstituted product is stable 
for up to 24 hours at room temperature; however, the product contains no preservative  
and room temperature storage is not recommended. Immediate use is recommended 
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Infuse the first dose over at least 6 hours in adults and 6-12 hours in 
pediatric patients; subsequent doses may be infused over at least 4 hours.  
Infuse through a high-flow vein (central line). Administer through an in-line 
0.22 micron filter. Premedication with corticosteroids, acetaminophen, and/or an 
antihistamine 1 hour prior to infusion may reduce the incidence and 
severity of infusion-related reactions.  
Reducing the infusion rate may minimize infusion reactions. 
No dosing adjustments are required for renal or hepatic impairment 
 
10.4 Etoposide (VP-16) 
10.4.1Source and Pharmacology 
Etoposide is a semisynthetic derivative of podophyllotoxin that forms a complex with 
topoisomerase II and DNA which results in single and double strand DNA breaks. Its 
main effect appears to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 
hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted in the 
urine. In children, approximately 55% of the dose is excreted in the urine as etoposide in 
24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² or about 35% of the 
total body clearance over a dose range of 80 to 600 mg/m². 
 
10.4.2 How Supplied 
Etoposide for Injection is available in sterile multiple dose vials. The pH of the clear, nearly 
colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30mg 
benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, 
and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened vials of 
Etoposide are stable until expiration date on package at room temperature (25°C). 
 
10.4.3 Dosage and Administration 
Etoposide will be given through an IV. Preparation, administration, and monitoring will be 
according to standard practice procedures. 
 
10.5 Melphalan 
10.5.1 Source and Pharmacology 
Melphalan is a derivative of nitrogen mustard, it is a bifunctional alkylating agent which causes 
miscoding, cross-linkage of DNA and single-strand breakage of DNA. It inhibits glycolysis, 
respiration and protein synthesis. It is not phase specific. After IV administration the μ t½ 
is 8 minutes and the b t½ is 2 hours. Oral absorption is erratic, but averages 60% of IV dose. 
Initial half-life after oral dose is 90 minutes. Dosage may need reduction in patients with renal 
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10.5.2 How Supplied 
For injection, it is supplied as 50mg sterile, lyophilized powder with 10ml special diluent for 
reconstitution. After reconstitution to 5 mg/mL, shake until clear solution obtained. 
 
10.5.3 Dosage and Administration 
Prior to administration, further dilute the solution with 0.9% sodium chloride to a concentration 
no greater than 0.45 mg/mL. Intact packages and reconstituted solutions should be stored 
at room temperature (15°-30°C), protected from light. The manufacturer recommends 
melphalan administration should be completed within 60 minutes of reconstitution. IV 
infusion over 20 minutes and good IV hydration with 3000 mL/m2 of D5W 1/2 normal saline 
24 hours after melphalan infusion. Lasix may also be given to maintain urine output. 
 
10.6 Cyclosporine A (cyclosporine, CYA, CSA, Sandimmune®, Neoral®, Gengraf®) 
10.6.1Source and Pharmacology 
Cyclosporine (CSA) is a lipophilic fungal peptide consisting of 11 amino acids. CSA is a potent 
immunosuppressive agent, which prolongs survival of allogeneic transplants involving skin, 
heart, kidney, pancreas, bone marrow, small intestine, and lung. CSA binds to a cellular 
protein, cyclophilin, which, like tacrolimus, then binds to calcineurin. The inhibition of 
calcineurin inhibits the transcription of IL-2, the action of which stimulates the proliferation of 
activated T-lymphocytes. The terminal half-life of CSA is approximately 19 hours (ranges 
from 10-27 hours). Ninety-nine percent of CSA is metabolized. Elimination is primarily biliary 
with approximately 6% excreted in the urine. In the circulation, CSA is mainly bound to high, 
low, or very low density lipoproteins and to chylomicrons. Only a small fraction circulates 
unbound. The volume of distribution varies from 3.5 L/kg to 13 L/kg, with higher 
concentrations of drug found in the liver, lymphocytes, kidney, heart, lung, pancreas, fat, 
neural, and muscle cells. CSA clearance rates have been shown to be higher in pediatric 
patients and for patients <25 years old. The absorption of CSA from the gastrointestinal 
tract is incomplete and variable, exhibiting large intra- and inter-patient variability. Drugs that 
stimulate or inhibit hepatic P-450 enzymes will alter clearance of CSA; thus, close attention 
to potential drug interactions is crucial. 
 
10.6.2 Formulation, Stability and Storage 
IV formulation: Cyclosporine (Sandimmune®) is available as a (50 mg/mL) 5 mL ampoule 
containing 650 mg polyoxyethylated castor oil (cremophor) and 32.9% alcohol. It should be 
stored at temperatures below 30°C (86°F) and protected from light. 
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capsules, or in a 100 mg/mL oral solution Inactive ingredients include: Sandimmune® Capsule 
= Dehydrated alcohol, sorbitol, glycerol, corn oil, gelatin, polyoxyethylated glycolysed 
glycerides; Sandimmune® Solution = Olive oil, dehydrated alcohol, polyoxyethylated 
glycolysed glycerides. 
Cyclosporine USP modified (microemulsion) (Neoral®, Gengraf®) 25 mg, 100 mg capsule, 
100 mg/mL oral solution. Inactive ingredients include: Neoral® capsule and solution = 
dehydrated alcohol, corn oil, polyoxyl 40 hydrogenated castor oil, α- tocopherol, gelatin, and 
propylene glycol. Gengraf® Capsule and solution = dehydrated alcohol, gelatin, polyethylene 
glycol, polyoxyl 35 castor oil, polysorbate 80, propylene glycol, and sorbitan monooleate. 
 
Store capsules in the original unit-dose container at controlled room temperature 15°- 30°C 
(59°-86°F). Store oral solutions in the original container at controlled room temperature 68°-
77°F (20°-25°C). Do not store in the refrigerator. Once opened, the contents must be used 
within two months. At temperatures below 68°F (20°C), the solution may form a gel; light 
flocculation or the formation of a light sediment may also occur. There is no impact on product 
performance or dosing using the syringe provided. Allow to warm to room temperature 77°F 
(25°C) to reverse these changes. 
 
NOTE: Sandimmune®, Neoral® and Gengraf® ARE NOT BIOEQUIVALENT. Liquid 
formulations of each trade name are equivalent to capsules of that same trade name. 
Conversion from one trade name product to another is generally done at a 1:1 ratio, but 
requires close monitoring. Conversions from IV to PO are usually done at a 1:3 ratio, but 
should be monitored closely. Adjusting emulsion products to the same trough concentration 
as other oral products results in greater total exposure to the drug. 
 
10.6.3 Solution Preparation 
Dilute IV concentrate 1 mL (50mg) of Cyclosporine for Injection in 20 mL-100 mL 0.9% Sodium 
Chloride Injection or 5% Dextrose Injection (0.5 - 2.5 mg/mL). Diluted infusion solutions are 
stable for 24 hours at room temperature under fluorescent light. 
 
10.6.4 Administration 
The Cremophor® EL (polyoxyethylated castor oil) contained in concentrate for IV infusion can 
cause phthalate stripping from PVC. It is highly recommended that glass bottles and non-
PVC tubing be used to minimize patient exposure to DEHP. Monitor closely for an acute 
allergic reaction for the first 30 minutes and at frequent intervals thereafter. Note: 
Cyclosporine absorbs into plastics and can give falsely high serum or blood concentrations if 
blood samples are collected from the same line through which Cyclosporine was 
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Oral: Administer at a consistent time of day and at consistent intervals with regard to meals. 
Do not use plastic or Styrofoam cups. If diluted with juice or milk, use a glass container and 
rinse with additional diluent, and then consume to ensure that complete dose has been taken. 
Do not use water or cleaning agents on the dosing syringe. To improve palatability, mix 
Sandimmune® with milk, chocolate milk or orange juice; mix Neoral® or Gengraf® with 
orange juice or apple juice, but NOT milk. After mixed, have patient consume immediately. 
DO NOT MIX GRAPEFRUIT JUICE with any CSA product. 
 
10.7 
Tacrolimus 
10.7.1 Source and Pharmacology 
Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. 
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant 
models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, 
skin, cornea, and limb. Experimental evidence suggests that tacrolimus binds to an 
intracellular protein, FKP-12. A complex of tacrolimus- FKBP-12, calcium, calmodulin, 
and calcineurin is then formed, and the phospatase activity of calcineurin is inhibited. 
This effect may prevent the dephosphorylation and translocation of nuclear factor of 
activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for 
the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is 
the inhibition of T-lymphocyte activation (i.e., immunosuppression). 
 
10.7.2 Formulation and Stability 
Prograf injection (tacrolimus injection) 5 mg (for IV infusion only). Supplied as a sterile 
solution in 1 mL ampoules, containing the equivalent of 5 mg of anhydrous tacrolimus 
per mL. 
 
10.7.3 Dosage and Administration 
The usual dose of the drug is 0.05 mg/kg to 0.1 mg/kg/IV per day to achieve the trough 
level of 10-15mg/ml. Orally, the patient needs to be started on 0.15 to 0.2 mg/kg q12 
hours to achieve the same trough level. The dose may have to be decreased if other 
nephrotoxic agents are being administered. 
 
10.7.4 
Preparation for Administration/Stability 
Tacrolimus will be stored in glass or polyethylene containers and should be discarded after 
24 hours. The diluted infusion solution should not be stored in a PVC container due to 
decreased stability and the potential for extraction of phthalates. In situations where more 
dilute solutions are utilized (e.g., pediatric dosing, etc.), PVC-free tubing should, likewise, 
be used to minimize the potential for significant drug absorption onto the tubing. Parenteral 


 
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drug products should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. Due to the chemical instability of 
tacrolimus in alkaline media, Prograf injection should not be mixed or co-infused with solutions 
of pH 9 or greater (e.g., Ganciclovir or Acyclovir). 
Store between 5° C and 25° C (41° F and 77° F). Prograf capsules (tacrolimus capsules) 5 
mg, oblong, grayish/red, branded with white “5 mg” on the capsule cap and containing the 
equivalent of 5 mg anhydrous tacrolimus. 
 
10.8 Mycophenolate mofetil (MMF, Cellcept® Myfortic®) 
10.8.1 Action and Pharmacology 
MMF is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate 
dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide 
synthesis without incorporation into DNA. Because T- and B- lymphocytes are critically 
dependent for their proliferation on de novo synthesis of purines, whereas other cell types 
can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA 
inhibits proliferative responses of T- and B- lymphocytes to both mitogenic and allo-specific 
stimulation. 
 
10.8.2 Formulation and Stability 
Capsules, 250 mg and 500 mg Store at 25°C (77°F); excursions permitted to 15° to 30°C 
(59° to 86°F). Dispense in light-resistant containers, such as the manufacturer's original 
containers. Oral Suspension Supplied as a white to off-white powder blend for constitution to 
a white to off-white mixed-fruit flavor suspension. Storage: Store dry powder at 25°C (77°F); 
excursions permitted to 15° to 30°C (59° to 86°F). Store constituted suspension at 25°C 
(77°F); excursions permitted to 15° to 30°C (59° to 86°F) for up to 60 days. Storage in a 
refrigerator at 2° to 8°C (36° to 46°F) is acceptable. Do not freeze. Intravenous Supplied in a 
20 mL, sterile vial containing the equivalent of 500 mg mycophenolate mofetil as the 
hydrochloride salt in cartons of 4 vials: Store powder and reconstituted/infusion solutions at 
25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). 


 
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In the setting of marrow transplantation, several etiologies may contribute to alterations 
in gastrointestinal and hematologic parameters; therefore, MMF dose adjustments are 
not encouraged. 
 
10.8.3 Administration Guidelines 
Initial dosage will be IV or PO with switch to PO when tolerated. Starting doses will be 
15 mg/kg/day Q 8 hours (total dose 45 mg/kg/day, maximum 3 g/day; IV same as 
PO dose) beginning day 0 with the first dose given approximately 4-6 hours after the 
stem cell infusion. 
 
11.0 
Standard Observations 
Frequent clinical and laboratory evaluation will be performed to provide appropriate medical 
care to the patients as per standard practice. For this study’s assessment laboratory data 
will be collected once weekly or as defined below for analysis. Please refer to appendix B for 
summary of required observations 
 
 
11.1 Baseline/Pre-Conditioning 
Baseline laboratory testing must be done within 7 days prior to the start of the conditioning 
regimen. 
All baseline imaging, cardiac evaluation and pulmonary evaluation must be done within 28 
days prior the start of the conditioning regimen. Baseline/pre conditioning evaluation is 
summarized in Appendix B  
11.1.1 History, physical examination, pregnancy test for females of reproductive 
potential, weight, height, BSA and head circumference (if appropriate for age). 
11.1.2 CBC, differential, platelet count, ABO and Rh typing. 
11.1.3  Liver function tests (bilirubin, ALT). 
11.1.4  Renal function tests (creatinine, BUN, creatinine clearance or GFR). 
11.1.5 Cardiac evaluation: echocardiogram, MRI or MUGA with ejection fraction 
( or shortening fraction) as appropriate. 
11.1.6 Pulmonary function evaluation: CT chest and pulmonary function tests (if 
age appropriate and feasible) or O2 Saturation in room air. 
11.1.7 Serology for CMV, Hep. B &C, HSV, VSV, HTLV and HIV (if HIV NAT testing 
not obtained). 
11.1.8 NAT testing for HIV/HCV. (HIV and HCV PCRs may replace serology or    
NAT testing). 
11.1.9 Immune assessment: Immunophenotyping (CD3, CD4, CD8, CD19, CD56, 
CD4+/CD45RA+, 
CD4+/CD45RO+), 
lymphoproliferative 
responses 
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mitogens, Quantitative Immunoglobulins (IgG, IgA, IgM). 
11.1.10 Archived blood sample for short tandem repeat (STR) and/or FISH analyses of 
blood to document a genetic marker that can be used to distinguish donor and 
recipient cells as per standard of care (as clinically appropriate). 
11.1.11 Blood sample for circulating tumor cells prior to the start of conditioning 
regimen to be sent to Dr.Shulin Li’s lab 
11.1.12 Karnofsky or Lansky score (age appropriate) 
11.1.13 Evaluation of other disease specific manifestations/sites as clinically 
appropriate which may include: Imaging (e.g. MRI, PET/CT, Bone scan, 
skeletal surveys); LP/CSF analysis and bone marrow aspirate/biopsy. Bone 
marrow aspirate and biopsy will be obtained prior to HCT to evaluate for 
disease by morphology. 
 
11.2 During Conditioning 
11.2.9 History, physical examination, pregnancy test for females of reproductive potential, 
weight, height, BSA and head circumference (if appropriate for age). 
            CBC and serum chemistries, Tacrolimus or CSA level (as clinically appropriate) starting 
one day after initiation of tacrolimus, until levels are stable on oral dosing or until 
discharge. 
Evaluation required during conditioning is summarized in Appendix B 
 
11.3 
Post-Transplant 
After transplant, frequent clinical and laboratory evaluation will be performed to provide 
appropriate medical care to the patients. Post-transplant evaluation summarized in Appendix 
B The post-transplant data will be captured once a week for the assessment of the study. 
In the first year, studies scheduled for Days +100, +180, +270 and +365 can be performed 
at any Day ± 15 of the scheduled test. 
11.3.1 Weekly CBC, differential (after WBC >500/mm3) until ANC = 500/mm3 for 3 
consecutive days; 
Post-engraftment: CBC and platelet count weekly until discharge; 
Post-discharge: CBC and platelet count weekly until PRBC and platelet transfusion 
independent and at Days +100, +180, +270, and +365. Differential must be done if 
WBC < 500/mm3 at any time post-engraftment and at Days 
+100, +180, +270, and +365 
11.3.2 Donor chimerism study at Day +28 ± 3 days (if engrafted for neutrophils) and at 6 
months and at 1 year. 
11.3.3 Bone marrow aspirate on Day +42 (+/- 3 days) for patients who do not have an 
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11.3.4 Weekly assessment for toxicity: Mucositis and SOS until Day +30 or until resolution 
(whichever is longer). 
11.3.5 Perform and document: Karnofsky/Lansky performance score, GVHD, history and 
physical examination weekly for 6 weeks, twice a month until Day +100, 
                          then Day +180, +270, and +365. 
11.3.6 CBC, renal and liver function tests weekly for 6 weeks; cardiac function tests 
(echocardiogram), pulmonary assessment, thyroid function tests, height, 
weight, head circumference (if age appropriate) at one year follow-up as 
part of the study. However, it is recommended as general part of a general 
long-term follow-up to assess yearly for a minimum of 4 years. 
11.3.7 
Immune assessment: Immunophenotyping (CD3, CD4, CD8, CD19, CD56), 
lymphoproliferative responses to mitogens, quantitative Immunoglobulins (IgG, IgA, 
IgM) will be monitored at Days +100, +180, +270, +365 post-transplant.  
11.3.8 Three months, 6 months, 9 months, and 12 months post-tetanus immunization, 
lymphoproliferative responses to tetanus and antibody titer to tetanus. 
11.3.9 Evaluation of disease specific manifestations/sites as clinically appropriate/per 
standard disease assessment which may include: Imaging (e.g. MRI, PET/CT, 
Bone scan, skeletal surveys); LP/CSF analysis and bone  marrow 
aspirate/biopsy on at least on Day +100 with subsequent testing on Days 
+180,+270 and 1 year post-HCT. 
 
12.0 Monitoring 
 
12.1 
Supportive Care                                                                                                                
Before, during and after the transplant, subjects of this study will require standard 
supportive care. Programmatic supportive care guidelines will be adhered to, but 
may vary with the condition or problems of individual patients. Supportive care will 
include red blood cell and platelet transfusion; antibiotic treatment of bacterial, 
fungal and viral infections; prevention of bacterial, fungal and viral infections, 
including Pneumocystis jiroveci; administration of prophylactic and therapeutic 
intravenous immunoglobulin (IVIG); isolation; treatment of hepatic sinusoidal 
obstruction syndrome/veno-occlusive disease; and treatment of mucositis. 
Aggressive supportive care improves outcome, particularly in high-risk patient 
populations receiving very intensive chemotherapy as incorporated in this protocol. 
These supportive care guidelines are provided for institutional consideration,  
in order to optimize patient care as well as to encourage uniformity in the treatment 
of this study population. 
 
 


 
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12.2 
General Guidelines 
12.2.1 Complete blood counts (Hemoglobin, platelet count, WBC and ANC) should be 
monitored after blood counts drop (i.e. ANC <1000, platelets <50,000), daily for in- patients 
until blood count recovery commences. Hospitalization is required until the patient achieves 
and sustains an absolute neutrophil count (ANC) of at least 500/μL for at least five days. 
Growth factors (e.g. granulocyte colony stimulating factor) can be used at the discretion of 
the treating physician. 
12.2.2  Blood Products 
• 
Irradiated and leukodepleted platelets must be transfused to maintain a platelet count 
above 20,000/mm3. 
• 
Irradiated and leukodepleted packed red blood cells must be transfused to maintain a 
hemoglobin > 8 g/dL. 
• 
All blood products should be leukodepleted and irradiated and/or prepared in a 
manner to prevent the occurrence of acute graft-versus-host disease with the 
exception of blood stem cells or bone marrow. 
12.2.3 Prophylactic Antimicrobial Therapy is required for viral, fungal and bacterial 
infections 
HSV/VZV Viral prophylaxis with acyclovir IV or Valacyclovir is strongly recommended 
(dosing per institutional standards). Prophylaxis for cytomegalovirus (CMV) with 
intravenous ganciclovir (10 mg/kg/day) during conditioning through Day -2 and then 
high dose acyclovir (1500 mg/m2/day) is recommended. After engraftment and when 
patients are able to tolerate oral medications, oral acyclovir or valganciclovir 
depending on pre-HCT CMV serology may be used for viral prophylaxis; this should 
be continued for at least one year after HCT. 
IV caspofungin (25 mg/m2 daily for infants, 70 mg/m2/day on day 1 then 50 
mg/m2/day after for children and adolescents). This may be transitioned to oral 
posaconazole or voriconazole following engraftment and when clinically appropriate. 
IV liposomal amphoterecin B (3-5 mg/kg/day) is strongly recommended as fungal 
prophylaxis for patients with a history of invasive fungal infection. 
Weekly surveillance with viral polymerase chain reactions (PCR) and 
galactomannans should be performed. 
Trimethoprim-sulfamethoxazole (5 mg/kg/day) or pentamidine for pneumocystis 
jiroveci pneumonia (PJP) prophylaxis should be initiated from admission until Day -2 
then restarted at Day +30 (or at the time of engraftment) until one year post-HCT or 
until appropriate T-cell recovery is achieved. 
IVIG replacement per the institutional guidelines.  
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until patients achieved acceptable evidence of immune reconstitution. 
12.2.4 Sinusoidal obstruction syndrome/Veno-occlusive disease prophylaxis: Prophylaxis 
with oral ursodeoxycholic acid should also be considered from admission until Day 
+28. Patients who develop SOS/VOD should be promptly started on defibrotide 
definitive treatment per institutional guidelines. 
 
 
12.3 
Pre-Transplant assessment as outlined in 11.1 
 
 
12.4    Post-Transplant weekly assessment as outlined in 11.3 
 
 
12.5   Post-Transplant monthly assessment as outlined in 11.3 
 
 
13.0 
Adverse Event Reporting Requirements 
 
13.1  Assessment of the Adverse Events Severity. 
The severity of the adverse events (AEs) will be graded according to the Common 
Terminology 
Criteria v5.0 (CTCAE). Events not included in the CTCAE chart will be scored as follows: 
General grading: 
Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment required 
beyond prophylaxis. 
Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment. 
Grade 4: Life Threatening: discomfort that represents immediate risk of death. 
 
 
13.2 
Casualty Assessment. 
For the purpose of this study the treatment plan (preparative regimen followed by allogeneic 
stem cell transplantation) is defined as the “transplant package”; therefore adverse events 
known to be caused by components of the transplant package and its direct consequences will 
be scored as definitive related. Adverse events known to be related to drugs used for the 
treatment of GVHD and infection episodes will be scored as probable related. When the 
relationship of the adverse event cannot be ruled out with certainty the AE may be considered 
possible related. Adverse events known to be related to drugs used for supportive treatment 
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The principal investigator will be the final arbiter in determining the casualty assessment. 
 
13.3 
List of most common expected adverse events. 
1. Infections in the presence or absence of neutropenia: fungal, bacterial and or viral 
infections. 
2. Fever: Non-neutropenic or neutropenic without infection 
3. Acute graft versus host disease (aGVHD): most commonly manifested by skin rash, 
diarrhea and abnormal liver function tests could also present with some degree of fever, upper 
gastrointestinal symptoms (nausea and vomiting) mucositis and eye dryness. 
4. Gastrointestinal (GI tract): the GI tract manifestations could be not only due to direct 
damage from the preparative regiment but also be a manifestation of GVHD or infections. 
Therefore, the time course and its presentation are crucial when assessing these as adverse 
events. Nausea/vomiting, mucositis, diarrhea when presented within first 7 to 10 days most 
likely will be related to the preparative regimen. 
5. Skin rash: not related to GVHD could be caused by chemotherapy used for the preparative 
regimen or antibiotics used a supportive treatment. 
6. Transaminitis: liver function test elevation. 
7. Pulmonary events:  Idiopathic pneumonia syndrome, pneumonia and/or pleural effusions 
8. Cytokine Storm/ engraftment syndrome: most likely caused by released cytokines. 
9. Hemorrhagic cystitis: not related to chemotherapy agents used in the proposed preparative 
regimen is most likely caused by viral infection. 
10. Thrombotic thrombocytopenic purpura (TTP). 
11. Sinusoidal obstruction syndrome  
12. Fluid overload due to hydration required for conditioning regimen, blood product 
transfusions and or IV alimentation 
13. Graft failure. 
14. Chronic GVHD. 
15. For the purpose of this study the following events would not be considered adverse events 
and would not be recorded in the database: 
1. Flu-like symptoms not associated with infection 
2. Abnormal laboratory findings considered associated to the original disease 
3. Isolated changes in laboratory parameters such as electrolyte, magnesium and metabolic 
imbalances, uric acid changes, elevations of ALT, AST, LDH and alkaline phosphatase. 
 
13.4  Adverse events considered serious. 
1. Prolonged hospitalization due to infections and/or organ failure requiring extensive 
supportive care (i.e. dialysis, mechanical ventilation). 
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3. Graft Failure/ rejection. 
4. Any expected or unexpected event resulting in an irreversible condition and/or leading to 
death. 
 
13.5  Adverse events data collection. 
From the start of preparative regimen up to D+100 the collection of adverse events will reflect 
the onset and resolution date and maximum grade; beyond this point some events considered 
related to chronic GVHD or late complications post-transplant  may be recorded only with the 
first date of their awareness with no grade or resolution date. 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. 
 
13.6 
 AE and Protocol Deviations Reporting Requirements. 
Adverse events will be reported accordingly to MDACC (HSRM chapter 15.001) and SCT&CT 
Department (HSRM chapter 15.053) policy and procedures. This study will be conducted in 
compliance however in the event of any protocol deviations or violations these will be reported 
accordingly to MDACC (HSRM chapter 25). 
 
 
14.0 
Statistical Considerations 
 
14.1 Overview 
This is a pilot study of allogeneic hematopoietic stem cell transplantation in high risk solid 
tumors. The study plans to enroll a maximum of 20 patients in each of the two groups: 1) 
Patients with a matched related donor, 2) Patients with a matched allogeneic umbilical cord 
donor. The primary objective is to assess the tolerability in each treatment group by transplant-
related mortality (TRM) at day 30, as well as the rate of grade III or higher organ toxicity 
(Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 
days. Secondary objectives are listed in section 2.0. Specifically, the primary endpoints 
include the TRM at day 30 and the rate of grade III or higher organ toxicity within 30 days. The 
secondary endpoints include time to platelet and neutrophil engraftment, incidence of aGVHD 
by day 100, incidence of chronic GVHD at day 100 and one year, rate of grade II organ toxicity 
through day 100, rate of graft failure (primary and secondary) through day 100, rate of 
infectious complications through day 100, progression free survival at day 180 and cumulative 
incidence of relapse, overall survival, and progression-free survival at 100 days and 1 year. 
 
14.2  Statistical Considerations and Analysis Methods 
We will use Bayesian monitoring rules to monitor the 30-day TRM rate and stop the trial if there is 
strong evidence at any time that this rate exceeds 20%. Formally, we will stop accrual if at any time: 


 
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Pr (Day 30 TRM> 0.20 | Data) > 0.80. We assume a Beta (0.4, 1.6) prior distribution for the probability 
of TRM corresponding to a 20% mean, and assume a constant rate of 20% for the standard of care. 
Stopping boundaries and operating characteristics were generated using the Department of 
Biostatistics’ Bayesian Toxicity Monitoring Shiny version v2.1.1.2 
(https://biostatistics.mdanderson.org/shinyapps/BTOX/). Patients will be monitored in cohorts of size 
5. The stopping boundaries for this rule corresponding to the probability criterion above are: 
 
No of total Patients (Cohorts of 
5) 
Discontinuation if No of 30-day TRM is: 
5 
3-5 
10 
4-10 
15 
5-15 
20 
6-20 
 
Corresponding operating characteristics for toxicity stopping rule for 30-day TRM: 
 
True 30-day TRM Rate 
Prob. of Early Stop 
Avg. N Patients 
.1 
.02 
20 
.15 
.09 
19 
.2 
.21 
18 
.25 
.36 
16 
.3 
.53 
15 
.35 
.68 
13 
.4 
.81 
11 
 
Similarly for rate of grade III or higher organ toxicity attributable to conditioning occurring 
within 30 days, we will stop the trial if there is strong evidence at any time that this rate 
exceeds 30%. Formally, we will stop accrual if at any time: Pr (Day 30 grade III or higher 
organ toxicity > 0.30 | Data) > 0.80. We assume a Beta (0.6, 1.4) prior distribution for the 
probability of toxicity corresponding to a 30% mean, and assume a constant rate of 30% for 
the standard of care. Stopping boundaries are: 
 
No of total Patients (Cohorts of 
5) 
Discontinuation if No of 30-day grade III or 
higher organ toxicity is: 
5 
3-5 
10 
5-10 
15 
7-15 
20 
8-20 


 
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Corresponding operating characteristics for toxicity stopping rule for 30-day grade III or 
higher organ toxicity: 
 
True Grade III or Higher Organ Toxicity 
Rate 
Prob. of 
Early Stop 
Avg. N Patients 
.2 
.08 
19 
.25 
.15 
18 
.3 
.26 
17 
.35 
.39 
15 
.4 
.53 
14 
.45 
.66 
12 
.5 
.78 
10 
 
 
14.3 Analysis Methods 
 
The proportion of patients with 30-day TRM and the proportion of patients with 30-day grade III or 
higher organ toxicity will be reported together with the corresponding 95% Bayesian credible interval.  
Given 20 patients with the stopping criteria thresholds of 20% and 30%, respectively, corresponding 
95% Bayesian credible intervals span (.07, .40) and (.13, .51).   
 
The 100-day and 1-year rates of relapse, overall survival (OS) and progression-free survival (PFS) 
will be calculated and illustrated from the time of transplant by the method of Kaplan and Meier[45].  
The same approach will be applied to the time to failure of platelet and neutrophil engraftment. The 
progression free survival at day 180 will be assessed using the method of Kaplan and Meier.  
 
The 100-day rates of acute and chronic GVHD with the competing risk of relapse will be estimated 
using the method of Gooley[46].  The same approach will also be applied to 100-day and 1-year 
chronic GVHD and 30-day TRM. The 100-day rates of grade II organ toxicity, primary and secondary 
graft failure, and infectious complications will be reported as counts with percentages. 
Frequency counts and percentages will also be presented of subjects with serious adverse events 
and adverse events leading to withdrawal. All other safety parameters will be summarized using 
descriptive statistics or frequency counts. All time-to-event modeling will include corresponding 
illustrations. Other statistical approaches might be employed.  
 
15.0 Data and Safety Monitoring Plan 
 
This study is monitored by the MDA DSMC. 


 
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16.0 Confidentiality of Study Data 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a 
specific study participant will be held in strict confidence within the research team. No personally 
identifiable information from the study will be released to any unauthorized third party without prior 
written approval of the sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 
Access to Study Records 
Study records may be accessed by IRB approved study personnel, or authorized inspectors. The 
study monitor, other authorized representatives of the sponsor or funding agency, representatives of 
the Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
 
Methods of Storage of Study Records 
All data collected from MD Anderson Cancer Center (MDACC) sources will be maintained in 
REDCap. Study staff will have role based restricted access to REDCap, according to project 
responsibilities. Only those with data entry permissions can add records. The PI or a delegate will 
review the conditions under which data will be released to recipient- investigators. Each application 
for use will need IRB approval and consents, if appropriate. The level of identifiability will determine 
the process for review and approval as well as the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the offices of the PI or 
other delegated study staff, in a locked cabinet or other comparable controlled environment, and will 
be accessible only to authorized study team members or authorized inspectors.   
 
Duration of Study Record Storage 
The study participant’s contact information will be securely stored internal use during the study. At the 
end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency requirements. 
 
Sharing of Study Records 
There are no plans to share study data with entities external to MD Anderson Cancer Center, aside 
from authorized inspectors as applicable (i.e. authorized representatives of the sponsor or funding 
agency, representatives of the Institutional Review Board (IRB), regulatory agencies or 
representatives from companies or organizations supplying the product).  If data will be shared, IRB 
approval will be sought, and applicable inter-institutional agreements executed, prior to data sharing.   
 
 
17.0 
Informed Consent Process 
Each subject / legal representative or proxy consenter will have ample time and opportunity to 
ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. Only if the 
subject / legal representative or proxy consenter voluntarily agrees to sign the informed 
consent form and has done so, may he/she enter the study.  Additionally, the investigator and 
other information provider (if any) will personally sign and date the form.  The subject / legal 


 
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representative or proxy consenter will receive a copy of the signed and dated form. The signed 
informed consent statement is to remain in the investigator site file or, if locally required, in the 
patient’s note/file of the medical institution. In the event that informed consent is obtained on 
the date that baseline study procedures are performed, the study record or subject’s clinical 
record must clearly show that informed consent was obtained prior to these procedures. 
The informed consent form and any other written information provided to subjects / legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to 
the protocol that necessitates a change to the content of the subject information and / or the 
written informed consent form.  The investigator will inform the subject / legal representative or 
proxy consenter of changes in a timely manner and will ask the subject to confirm his/her 
participation in the study by signing the revised informed consent form.  Any revised written 
informed consent form and written information must receive the IEC/IRB`s approval / favorable 
opinion in advance of use. 
Consent Process and Documentation 
Please select one of the following: 
☒ This protocol will follow the SOP 04_Informed Consent Process. SOP 04 has been read 
by the research staff and investigators. 
☐ 
This protocol will follow SOP 04_Informed Consent Process with the following changes: 
________. SOP 04 has been read by the research staff and investigators. 
Informed consent may be obtained using the following methods: (check all that apply): 
☒ Remote consent 
☒ In-person consent 
 
18.0  References 
 
1. 
Bearman, S.I., et al., Regimen-related toxicity in patients undergoing bone marrow 
transplantation. Journal of Clinical Oncology, 1988. 6(10): p. 1562-1568. 
2. 
Llosa, N.J., et al., Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-
Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients. Biol Blood 
Marrow Transplant, 2017. 23(12): p. 2127-2136. 
3. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
4. 
Malempati, S., et al., The addition of cixutumumab or temozolomide to intensive multiagent 
chemotherapy is feasible but does not improve outcome for patients with metastatic 
rhabdomyosarcoma: A report from the Children's Oncology Group. Cancer, 2019. 125(2): p. 290-
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E.W.I.N.G.99 and Ewing-2008. J Clin Oncol, 2018: p. JCO2018782516. 
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Amoroso, L., et al., Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma 
Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study. 
Cancer Res Treat, 2018. 50(1): p. 148-155. 
7. 
Meyers, P.A., et al., High-dose melphalan, etoposide, total-body irradiation, and autologous stem-
cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve 
prognosis. J Clin Oncol, 2001. 19(11): p. 2812-20. 
8. 
Brissot, E., et al., Improvement of overall survival after allogeneic hematopoietic stem cell 
transplantation for children and adolescents: a three-decade experience of a single institution. 
Bone Marrow Transplant, 2016. 51(2): p. 267-72. 
9. 
Thiel, U., et al., Allogeneic stem cell transplantation for patients with advanced 
rhabdomyosarcoma: a retrospective assessment. Br J Cancer, 2013. 109(10): p. 2523-32. 
10. 
Kasow, K.A., et al., Possible allogeneic graft-versus-tumor effect in childhood melanoma. J 
Pediatr Hematol Oncol, 2003. 25(12): p. 982-6. 
11. 
Ruggeri, L., et al., Effectiveness of donor natural killer cell alloreactivity in mismatched 
hematopoietic transplants. Science, 2002. 295(5562): p. 2097-100. 
12. 
Takada, S., et al., Three AML patients with existing or pre-existing intracerebral granulocytic 
sarcomas who were successfully treated with allogeneic bone marrow transplantations. Bone 
Marrow Transplant, 1999. 23(7): p. 731-4. 
13. 
Ueno, N.T., et al., Rapid induction of complete donor chimerism by the use of a reduced-intensity 
conditioning regimen composed of fludarabine and melphalan in allogeneic stem cell 
transplantation for metastatic solid tumors. Blood, 2003. 102(10): p. 3829-36. 
14. 
Venstrom, J.M., et al., KIR and HLA genotypes are associated with disease progression and 
survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. 
Clin Cancer Res, 2009. 15(23): p. 7330-4. 
15. 
Perez-Martinez, A., et al., Natural killer cells can exert a graft-vs-tumor effect in haploidentical 
stem cell transplantation for pediatric solid tumors. Exp Hematol, 2012. 40(11): p. 882-891 e1. 
16. 
Lang, P., et al., Haploidentical stem cell transplantation in patients with pediatric solid tumors: 
preliminary results of a pilot study and analysis of graft versus tumor effects. Klin Padiatr, 2006. 
218(6): p. 321-6. 
17. 
Burdach, S., et al., Allogeneic and autologous stem-cell transplantation in advanced Ewing 
tumors. An update after long-term follow-up from two centers of the European Intergroup study 
EICESS. Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and 
St. Anna Kinderspital, Vienna, Austria. Ann Oncol, 2000. 11(11): p. 1451-62. 
18. 
Capitini, C.M., et al., Unusual sites of extraskeletal metastases of Ewing sarcoma after allogeneic 
hematopoietic stem cell transplantation. J Pediatr Hematol Oncol, 2009. 31(2): p. 142-4. 
19. 
Hosono, A., et al., Segregated graft-versus-tumor effect between CNS and non-CNS lesions of 
Ewing's sarcoma family of tumors. Bone Marrow Transplant, 2008. 41(12): p. 1067-8. 
20. 
Kido, A., et al., Allogeneic and autologous stem cell transplantation in advanced small round cell 
sarcomas. J Orthop Sci, 2010. 15(5): p. 690-5. 
21. 
Koscielniak, E., et al., Graft-versus-Ewing sarcoma effect and long-term remission induced by 
haploidentical stem-cell transplantation in a patient with relapse of metastatic disease. J Clin 
Oncol, 2005. 23(1): p. 242-4. 
22. 
Lucas, K.G., C. Schwartz, and J. Kaplan, Allogeneic stem cell transplantation in a patient with 
relapsed Ewing sarcoma. Pediatr Blood Cancer, 2008. 51(1): p. 142-4. 
23. 
Donker, A.E., et al., Metastatic rhabdomyosarcoma cured after chemotherapy and allogeneic 
SCT. Bone Marrow Transplant, 2009. 43(2): p. 179-80. 


 
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Ohta, H., et al., Allogeneic hematopoietic stem cell transplantation against recurrent 
rhabdomyosarcoma. J Pediatr Hematol Oncol, 2011. 33(1): p. e35-8. 
25. 
Ellman, L., et al., Mechanisms involved in the antileukemic effect of immunocompetent allogeneic 
lymphoid cell transfer. Cancer Res, 1972. 32(1): p. 141-8. 
26. 
Baird, K., et al., Reduced-intensity allogeneic stem cell transplantation in children and young 
adults with ultrahigh-risk pediatric sarcomas. Biol Blood Marrow Transplant, 2012. 18(5): p. 698-
707. 
27. 
Vitale, M., et al., HLA class I antigen and transporter associated with antigen processing (TAP1 
and TAP2) down-regulation in high-grade primary breast carcinoma lesions. Cancer Res, 1998. 
58(4): p. 737-42. 
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Vitale, M., et al., HLA class I antigen down-regulation in primary ovary carcinoma lesions: 
association with disease stage. Clin Cancer Res, 2005. 11(1): p. 67-72. 
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33. 
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36. 
Fernandez, L., et al., In vitro Natural Killer Cell Immunotherapy for Medulloblastoma. Front Oncol, 
2013. 3: p. 94. 
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to target medulloblastoma. Expert Rev Anticancer Ther, 2016. 16(6): p. 573-6. 
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Completed Clinical Trials. Cancer Invest, 2018. 36(8): p. 431-457. 
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(TE671) than lymphokine activated killer cells from peripheral blood. Childs Nerv Syst, 2004. 
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40. 
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Clinical Applications. Front Immunol, 2017. 8: p. 329. 
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Aoyama, Y., et al., Successful treatment with reduced-intensity stem cell transplantation in a case 
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42. 
Leonard, J.T. and B. Hayes-Lattin, Reduced Intensity Conditioning Allogeneic Hematopoietic 
Stem Cell Transplantation for Acute Lymphoblastic Leukemia; Current Evidence, and Improving 
Outcomes Going Forward. Curr Hematol Malig Rep, 2018. 13(4): p. 329-340. 
43. 
Marsh, R.A., et al., Reduced-intensity conditioning significantly improves survival of patients with 
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representations of old estimators. Stat Med, 1999. 18(6): p. 695-706. 
 


19.0   Appendix A: Bearman Regimen-Related Toxicities Scale 
 
 
 
 
 
*Grade IV regimen related toxicity is defined as fatal toxicity  
 
 


 
20.0 APPENDIX B: STANDARD OBSERVATIONS  & INTERVENTIONS 
 
Observation/Intervention 
Baseline 
During Conditioning 
Post-Transplant 
Weekly for 6 
weeks 
2x’s/mo Week 7 - Day+100 
Day +180 
Day +270 
Day +365 
History 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Weight, Height, and BSA 
X 
X 
X 
X 
X 
X 
X 
Head Circumference (if age appropriate) 
X 
X 
X 
X 
X 
X 
X 
Karnofsky/Lansky Score (as age appropriate) 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
GvHD Assessment Score 
X 
X 
X 
X 
X 
Serum Chemistries 
X 
X 
X 
X 
X 
X 
X 
Liver Function Test 
Bilirubin 
X 
X 
X 
X 
X 
X 
X 
ALT 
X 
X 
X 
X 
X 
X 
X 
Renal Function Test 
Creatinine 
X 
X 
X 
X 
X 
X 
X 
BUN 
X 
X 
X 
X 
X 
X 
X 
Creatinine Clearance or 
GFR 
X 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
 
 
Pre 
engraftment 
Post- 
Engraftment 
Post- 
Discharge 
Day 
Weekly 
Weekly 
Weekly 
+100 
+180 
+270 
+365 
CBC/Dif 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ABO/Rh 
X 
Immune 
Assessment 
Immunophenotyping 
(CD3, CD4, CD8, CD19, 
CD56) 
X 
X 
X 
X 
X 
Lymphoproliferative 
Responses to Mitogens  
X 
X 
X 
X 
X 
Quantitative 
Immunoglobulin 
(QuIGs = IgG, IgA, IgM) 
X 
X 
X 
X 
X 
Anti- tetanus antibody 
titers 
X 
X 
X 
X 
X 
Circulating tumor cells sample 
 
X 
 
 
 
 
 
Archived Blood Sample for STR and/or FISH Analyses 
X 


Post-Tra 
 
Observation/Intervention 
Baseline 
During Conditioning 
 
1 Year Post-Transplant 
Cardiac Evaluation 
Echo 
X 
X 
MRI or MUGA 
w/ejection fraction (or 
shortening fraction) as 
X 
X 
Pulmonary Function 
Evaluation 
CT Chest 
X 
X 
PFT (if age appropriate 
& feasible) or O2 
Saturation in room 
X 
X 
Thyroid Function Tests 
X 
Serology 
CMV 
X 
Hep B&C 
X 
HSV 
X 
VSV 
X 
HTLV 1&2 
X 
HIV (if HIV NAT 
testing not obtained) 
X 
NAT Testing for HIV/HCV 
X 
Day +42 
Done as clinically appropriate/per standard disease 
assessment 
Day +100c 
Day +180 
Day +270 
Day +365 
Evaluation of Other 
Disease Specific 
Manifestations/Sites* 
Imaging 
X 
X 
X 
X 
X 
LP/CSF Analysis 
X 
X 
X 
X 
X 
Bone Marrow 
Aspirate/Biop
X 
Aspirate if ANC < 500m3 
by Day +42 
X 
X 
X 
X 
Pre- 
Transplant 
Weekly starting 1 day after initiation of tacrolimus/CSA, until stable levels on oral dosing or until discharge 
Tacrolimus or CSA 
Level 
X 
X 
Taperc 
Day +60 to Day +100 
Day +100 to D+180 
20% of original therapeutic dose/wk 
10% of original therapeutic dose/wk 
Donor Chimerism (D+28 only if engrafted by then) 
Xd 
X 
X 
Weekly assessment until Day +30 or until resolution (whichever is longer) 
Toxicity 
Mucositis 
X 
VOD 
X 


 
 
 
 
* When applicable to primary disease 
a  Only if clinically indicated 
b Post-discharge: CBC and platelet count weekly until PRBC and platelet transfusion independent and at Days +100, +180, +270, and +365 
c  If no active GvHD, then begin taper as follows: 
Recipients of matched related donors start taper at Day +60 at approximately 20% of the original therapeutic dose/week to be and complete by Day +100. 
Recipients of other donors start taper at Day +100 at approximately 10% of the original therapeutic dose/week to be completed by Day +180 as possible. 
d Donor chimerism study done on D+28 can be done ±3 days if engrafted for neutrophils 
 
 
 
 

ICF_000.pdf: 
Protocol 2020-0496 
March 18, 2024 
Page 1 of 29 
 
Informed Consent 
 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION IN 
RESEARCH 
 
A Pilot Study of Allogeneic Hematopoietic Cell Transplantation for 
Patients with High Risk Solid Tumors 
2020-0496 
 
 
Study Chair:  Jeremy Connors 
 
_________________________ 
_____________________ 
Participant’s Name 
 
 
Medical Record Number  
 
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary. 
 
This research has been reviewed and approved by an Institutional Review Board 
(IRB - a committee that reviews research studies). 
 
STUDY SUMMARY 
 
If you are reading and signing this form on behalf of a potential participant, please 
note:  Any time the words "you," "your," "I," or "me" appear, it is meant to apply to 
the potential participant. 
 
The goal of this clinical research study is to learn about the safety and effectiveness 
of a combination of drugs (fludarabine, thiotepa, etoposide, melphalan, and rabbit 
anti-thymocyte globulin [rabbit ATG]) followed by an allogeneic hematopoietic stem 
cell transplant (HSCT) when given to patients with recurrent (has come back) or 
refractory (has not responded to treatment) high-risk solid tumors.  
 
This is an investigational study. Fludarabine, thiotepa, etoposide, melphalan, and 
rabbit ATG are all FDA approved and commercially available. However, it is 
considered investigational to use these drugs together, at these doses, to treat high-
risk solid tumors. Their use in this study is for research purposes only.  
 
The study doctor can explain how the study drugs are designed to work. 
 


Protocol 2020-0496 
March 18, 2024 
Page 2 of 29 
The study drug combination and stem cell transplant may help to control the 
disease. Future patients may benefit from what is learned. There may be no benefits 
for you in this study.  
 
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment. You may not want to take part in 
this study because you will be hospitalized and/or required to stay within 1 hour of 
the clinic for an extended amount of time. You may also experience side effects 
associated with the study drugs. 
 
You can read a list of potential side effects below in the Possible Risks section of 
this consent. 
 
You will receive the study drug combination over a period of 6 days. You will have 
follow-up visits for 1 year after your stem cell transplant. 
 
You and/or your insurance provider will be responsible for the cost of the study 
drugs and the stem cell transplant you receive during this study. 
 
You may choose not to take part in this study. Instead of taking part in this study, 
you may choose to receive the standard treatment for the disease as determined by 
your primary treatment team outside of this study. You may receive other 
investigational therapy, if available. The study doctor will discuss the possible risks 
and benefits of these treatments. You may choose not to have treatment for cancer 
at all. In all cases, you will receive appropriate medical care, including treatment for 
pain and other symptoms of cancer. 
 
1. STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this 
study. The following tests and procedures will be performed to help the study doctor 
decide if you are eligible: 
• You will have physical exam. 
• Blood (about 1-2 teaspoons) will be drawn for routine tests, immune system 
testing, circulating tumor cell (CTC) testing, tests to check your blood type, 
and tests to check for viruses such as cytomegalovirus (CMV), hepatitis B 
and C, herpes simplex virus (HSV), varicella-zoster virus (VSV), human t-
lymphotropic virus (HTLV), and HIV (the AIDS virus). CTC testing checks the 
number of tumor cells in the blood. 
• Blood (about 1-2 teaspoons) will also be drawn for use in distinguishing 
between your cells and the donor’s cells after your transplant. 
• You will have an echocardiogram (ECHO), MRI, or MUGA scan to check your 
heart function.  
• You have a CT scan of your chest to check your lung function. If the doctor 
thinks it is needed, you may also have a pulmonary function (breathing) test. 


Protocol 2020-0496 
March 18, 2024 
Page 3 of 29 
• You will have tests/procedures to check the status of the disease. Depending 
on the disease and what the study doctor thinks is needed, this may include: 
o Imaging scans (such as a PET scan) 
o Bone marrow aspirate/biopsy - to collect a bone marrow 
biopsy/aspirate, an area of the hip or other site is numbed with 
anesthetic, and a small amount of bone marrow and/or bone is 
withdrawn through a large needle. 
o Blood may be drawn for tumor marker testing – tumor markers may be 
related to the status of the disease. 
• If you are able to become pregnant, blood (about 1 teaspoon) will be used for 
a pregnancy test. To take part in this study, you must not be pregnant. 
 
The study doctor will discuss the screening test results with you. If the screening 
tests show that you are not eligible to take part in the study, you will not be enrolled. 
Other options will be discussed with you. 
 
Up to 40 participants will be enrolled in this study. All will take part at MD Anderson. 
 
Study Drug Administration 
Negative days are days before your stem cell transplant. Day 0 is the day you 
receive your stem cell transplant. Positive days are days after your stem cell 
transplant. 
 
You will be admitted to the hospital during this study. You will have a central line 
placed in your vein (called a Hickman catheter) before you start receiving the study 
drug combination. The Hickman catheter allows the study staff to draw blood daily 
without having to stick you with a needle many times. The catheter will also be used 
to give you blood, blood products, the stem cell infusion, antibiotics and other 
medicines, and nutrition through your vein. You will be kept in strict isolation in order 
to protect you from outside germs that cause infections. 
 
In the days leading up to the stem cell transplant, you will receive fludarabine, 
thiotepa, etoposide, melphalan, and (if you are receiving an umbilical cord blood or 
matched unrelated donor transplant) rabbit ATG. This drug combination is called 
conditioning chemotherapy. These drugs are not intended to treat the disease 
directly but instead help prepare your body to receive the stem cell transplant.  
 
On Days -8, -7, and -6, you will receive thiotepa and etoposide by vein. The thiotepa 
infusion should take about 2 – 4 hours. The etoposide infusion should take at least 
60 minutes. 
 
On Days -5 and -4, you will receive melphalan and fludarabine by vein. The 
melphalan infusion should take about 20 minutes. The fludarabine infusion should 
take about 1 hour. 
 
On Day -3, you will receive fludarabine alone by vein over about 1 hour. 
 


Protocol 2020-0496 
March 18, 2024 
Page 4 of 29 
If you are receiving an umbilical cord blood or matched unrelated donor transplant 
only, on Days -3 and -4, you will also receive rabbit ATG by vein. The first infusion 
may take at least 6 hours for adults and 6-12 hours in pediatric patients. The second 
infusion may take at least 4 hours. 
 
On Days -2,  you will start to receive either tacrolimus or cyclosporine to help lower 
your chance of developing graft-versus-host disease (GVHD), described below in 
the Possible Risks section. You will receive the drug by vein as a continuous (non-
stop) infusion every day until you are able to take it by mouth. You will continue to 
take tacrolimus/cyclosporine by mouth every day. It is expected that you will take 
this drug until about Day 60-100, depending on what kind of donor the stem cells 
came from, but it may be longer if the study doctor thinks it is needed. You will then 
be tapered off (gradually stop taking) tacrolimus or cyclosporine. The study doctor 
will discuss with you which drug you will take and how long/how often you will 
receive it.  
 
On Day 0, you will have your stem cell transplant. You will receive the stem cells by 
vein. The study doctor will discuss with you how long the stem cell transplant will 
take.  
 
You will also start taking mycophenolate mofetil (MMF) to help prevent GVHD. You 
will take it 3 times every day, about 8 hours apart. You will take it until about Day 60-
100, depending on what kind of donor the stem cells came from, but it may be longer 
or shorter if the study doctor thinks it is needed. 
 
During this study, you will also be given standard drugs to help decrease the risk of 
side effects. You may ask the study staff for information about how the drugs are 
given and their risks. 
 
During this study, you may also receive platelet/blood infusions and/or be fed by vein 
for several weeks. The study doctor will discuss these procedures with you, if 
needed.  
 
Between 4 and 8 weeks after your transplant, your new bone marrow should be 
creating enough red blood cells, white blood cells, and platelets and the new 
immune system should be developing as well. The study doctor will release you from 
the hospital when you have enough blood cells that are working properly. 
 
Study Visits 
 
Each day during your conditioning chemotherapy: 
• You will have a physical exam.  
• Blood (about 3 teaspoons) will be drawn for routine tests.  
• If you can become pregnant, blood (about 1 teaspoon) will be collected for a 
pregnancy test. 
 


Protocol 2020-0496 
March 18, 2024 
Page 5 of 29 
Blood (about 3 teaspoons) will be drawn for routine tests daily after your stem cell 
transplant until the study doctor thinks your blood cell counts have recovered.   
 
One (1) time a week for Weeks 1-6: 
• You will have a physical exam. 
• Blood (about 3 teaspoons) will be drawn for routine tests. 
 
One (1) time a week until you are discharged from the hospital, then 1 time a 
week until you no longer require blood and/or platelet transfusions, blood 
(about 3 teaspoons) will be drawn for routine tests. 
 
On Day 28: 
• Blood (about 2 – 3 teaspoons) will be drawn to determine the number of 
donor cells are present in your body following the transplant. 
 
On Day 42: 
• You will have a bone marrow aspirate to check the status of the disease. 
 
Two (2) times a month from Day 42 to Day 100: 
• You will have a physical exam. 
 
On Day 100: 
• Blood (about 3 teaspoons) will be drawn for routine tests and immune system 
testing. 
• You will have tests/procedures to check the status of the disease. This may 
include the imaging scans, spinal tap, and/or bone marrow biopsy/aspirate as 
described in Screening Tests.  
 
On Day 180: 
• You will have a physical exam. 
• Blood (about 4 teaspoons) will be drawn for routine tests, immune system 
testing, and tests to determine the number of donor cells are present in your 
body following the transplant. 
• You will have tests/procedures to check the status of the disease. This may 
include the imaging scans, spinal tap, and/or bone marrow biopsy/aspirate as 
described in Screening Tests.  
 
On Day 270: 
• You will have a physical exam. 
• Blood (about 4 teaspoons) will be drawn for routine tests and immune system 
testing. 
• You will have tests/procedures to check the status of the disease. This may 
include the imaging scans, spinal tap, and/or bone marrow biopsy/aspirate as 
described in Screening Tests.  
 
On Day 365: 


Protocol 2020-0496 
March 18, 2024 
Page 6 of 29 
• You will have a physical exam. 
• You will have an ECHO, MRI, or MUGA scan to check your heart function. 
• You will have a pulmonary function test to check your lung function. 
• Blood (about 4 teaspoons) will be drawn for routine tests, immune system 
testing, and tests to determine the number of donor cells that are present in 
your body following the transplant. 
• You will have tests/procedures to check the status of the disease. This may 
include the imaging scans, spinal tap, and/or bone marrow biopsy/aspirate as 
described in Screening Tests.  
 
 
2. POSSIBLE RISKS 
 
While on this study, you are at risk for side effects. You should discuss these with 
the study doctor. The more commonly occurring side effects are listed in this form, 
as are rare but serious side effects. You may also want to ask about uncommon side 
effects that have been observed in small numbers of patients but are not listed in 
this form. Many side effects go away shortly after treatment is stopped, but in some 
cases side effects may be serious, long-lasting or permanent, and may even result 
in hospitalization and/or death. 
 
Side effects will vary from person to person, and some may occur after you have 
stopped receiving treatment. Tell the study staff about any side effects you may 
have, even if you do not think they are related to the study drugs/procedures. 
 
Fludarabine, thiotepa, etoposide, melphalan, rabbit ATG, tacrolimus, and 
mycophenolate mofetil may each cause low blood cell counts (red blood cells, 
platelets, and/or white blood cells):   
• A low red blood cell count (anemia) may cause difficulty breathing and/or 
fatigue. You may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, 
bruising, stroke, and/or digestive system bleeding). You may need a platelet 
transfusion.   
• A low white blood cell count increases your risk of infection (such as 
pneumonia and/or severe blood infection). Infections may occur anywhere and 
become life-threatening. Symptoms of infection may include fever, pain, 
redness, and/or difficulty breathing. 
 
Fludarabine Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• fever 
• fatigue 
• pain 
• loss of appetite 
• nausea 
• vomiting 
• weakness 
• difficulty breathing 
• cough 
• infection 


Protocol 2020-0496 
March 18, 2024 
Page 7 of 29 
• low blood cell count 
(red, white, 
platelets) 
 
Occasional (occurring in 3-20% of patients) 
 
• chest pain (possibly 
due to heart trouble) 
• heart failure 
• heart attack 
• fast and/or irregular 
heartbeat 
• blood clots in a vein 
(possible pain, 
swelling, and/or 
redness) 
• vein inflammation 
• swelling  
• chills 
• stroke 
• headache 
• difficulty sleeping 
• skin rash and/or 
itching 
• sweating 
• hair loss (partial or 
total) 
• high blood sugar 
(possible diabetes) 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• diarrhea/constipatio
n 
• digestive system 
bleeding 
• gallstones 
• blood in the urine 
• difficult and/or 
painful urination 
• inability to urinate 
• abnormal liver tests 
(possible liver 
damage) 
• abnormal sensation 
(such as pins and 
needles) 
• vision problems 
• hearing loss 
• sore/swollen throat 
• lung 
damage/inflammatio
n (possible difficulty 
breathing) 
• coughing up blood 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• build-up of fluid in 
the tissue around 
the heart 
• weakness in wall of 
artery (possible 
serious bleeding 
complications) 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• bleeding in the brain 
• abnormal brain 
function (affecting 
balance and 
coordination) 
• progressive 
multifocal 
leukoencephalopath
• painful blisters 
• very severe 
blistering skin 
disease (with ulcers 
of the skin and 
digestive tract) 
• very severe 
blistering skin 
disease (loss of 
large portion of skin) 
• dehydration 
• abnormal pancreas 
tests 
• bladder 
inflammation with 
bleeding (possible 
pain and/or urge to 
urinate) 
• nerve damage 
affecting the eye 
and/or causing wrist 
weakness 
• paralysis 
• blindness 
• inflammation of an 
eye nerve 
• kidney failure 
• high blood levels of 
uric acid (possible 
painful joints and/or 
kidney failure) 
• bleeding in the lungs 
and/or airways 
• failure to breathe 
• low oxygen level in 
the blood (possible 
lightheadedness)  


Protocol 2020-0496 
March 18, 2024 
Page 8 of 29 
y (PML – a disease 
with brain damage 
that may likely result 
in paralysis and/or 
coma, which may be 
permanent, or 
death) 
• mental status 
change 
• coma 
• seizure 
• abnormal salts, 
minerals, and/or 
acids in the blood 
(possible weakness, 
swelling, fatigue, low 
blood pressure, 
organ failure, heart 
problems, changes 
in mental status, 
and/or seizure) 
• bone marrow failure 
due to abnormal 
tissue growth 
• destruction of red 
blood cells and 
platelets due to 
abnormal antibodies 
• anemia due to 
destruction of red 
blood cells 
• condition causing 
increased bleeding 
and/or bruising 
• liver failure 
• nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function) 
• life-threatening 
allergic reaction 
(such as difficulty 
breathing, low blood 
pressure, and/or 
organ failure) 
• breakdown products 
of the cancer cells 
entering the blood 
stream (possible 
weakness, low blood 
pressure, muscle 
cramps, kidney 
damage, and/or 
other organ 
damage) 
 
Fludarabine may rarely cause you to develop another type of cancer (such as skin 
cancer and/or acute myeloid leukemia [a type of blood cancer]. 
 
Frequency Unknown 
 
• testes/sperm damage 
• graft-versus-host disease (when 
transplanted donor tissue attacks 
the tissues of the recipient's body) 
 
Thiotepa Side Effects 
 
It is not known how often the following side effects of thiotepa may occur. 
 
• chills 
• fatigue 
• fever 
• headache 
• weakness 
• dizziness 
• hair loss (partial or 
total)  
• skin rash 
• lightening of skin 
• hives 
• nausea/vomiting 
• stopped menstrual 
cycle 
• decreased production 
of sperm 
• difficult and/or painful 
urination 
• inability to urinate  
• low blood cell counts 
(red, white, platelets) 
• blood in the urine  
• swelling of the vocal 
cords 
• difficulty breathing due 
to narrowing of the 
airways 
• wheezing 
• nosebleed 
• infection 
• life-threatening 
allergic reaction (such 
as difficulty breathing, 


Protocol 2020-0496 
March 18, 2024 
Page 9 of 29 
• abdominal pain 
• loss of appetite 
• blurry vision 
• painful red eyes 
low blood pressure, 
and/or organ failure) 
• injection site pain 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• liver damage (possible caused by 
blood clots) 
• bladder inflammation (possible pain, 
bleeding, and/or urge to urinate) 
 
Thiotepa may rarely cause you to develop another type of cancer (such as acute 
myeloid leukemia, a type of blood cancer). 
 
Etoposide Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• hair loss (partial or 
total) 
• nausea 
• vomiting  
• low blood cell counts 
(red, white, 
platelets) 
 
Occasional (occurring in 3-20% of patients) 
 
• loss of appetite 
• diarrhea  
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• liver damage 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• low blood pressure 
(possible 
dizziness/fainting)  
• heart attack 
• decreased blood 
supply to the heart 
• blood vessel spasm 
(possible blockage 
of blood flow) 
• blood vessel 
inflammation 
(possible bleeding 
and/or bruising) 
• fever 
• brain injury that may 
be reversible 
(possible headache, 
• severe sunburn-like 
rash at site of 
previous radiation 
(called radiation 
recall) 
• very severe 
blistering skin 
disease (with ulcers 
of the skin and 
digestive tract) 
• very severe 
blistering skin 
disease (loss of 
large portion of skin)  
• enlarged bowel 
(possible abdominal 
pain) 
• nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function)  
• blindness  
• inflammation of an 
eye nerve 
• lung inflammation 
and/or damage 
(possible difficulty 
breathing) 
• blue skin 
• drug leakage from 
the injection site 
(possible hardened 
tissue and/or tissue 
death)  


Protocol 2020-0496 
March 18, 2024 
Page 10 of 29 
confusion, seizures, 
and/or vision loss) 
• seizure 
• failure of the ovaries 
to produce 
hormones (possible 
stopped menstrual 
cycle) 
• abnormal blood 
acid/base balance 
(possible organ 
damage) 
• closing of the throat 
• allergic reaction, 
possibly life-
threatening (such as 
difficulty breathing, 
low blood pressure, 
and/or organ failure)  
 
High-dose etoposide also may cause the following side effects.  It is not known how 
often these side effects may occur.  
 
• symptoms of drunkenness (possible flushing and/or dizziness) 
 
High-dose etoposide may cause you to develop another type of cancer (such as 
leukemia, a type of blood cancer). 
 
Melphalan Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• swelling (arm/leg) 
• fever 
• fatigue 
• dizziness 
• low blood levels of 
potassium (possible 
weakness and/or 
muscle cramps)  
• low blood levels of 
phosphate (possible 
bone damage) 
• diarrhea 
• nausea 
• vomiting 
• loss of appetite 
• constipation 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• abdominal pain 
• abnormal taste 
• upset stomach 
• low blood cell counts 
(red, white, platelet) 
 
Occurring in 1-10% of patients 
 
• bright red blood in the 
stool  
• stopped menstrual 
cycle 
• kidney failure  
• allergic reaction that 
may be life threatening 
(such as difficulty 
breathing, low blood 
pressure, and/or organ 
failure) 
 
Frequency Unknown 
 


Protocol 2020-0496 
March 18, 2024 
Page 11 of 29 
• blood vessel 
inflammation (possible 
bleeding and/or 
bruising) 
• flushing 
• tingling 
• hormonal deficiency 
that affects the body's 
ability to control blood 
pressure and react to 
stress 
• inability to have 
children 
• decreased testes 
function  
• liver damage, possibly 
due to blood clots 
• jaundice (yellowing of 
skin and/or eyes)  
• abnormal kidney test 
(possible kidney 
damage) 
• damage to DNA 
(possible new form of 
cancer) 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• bone marrow failure  
• lung damage (possible 
difficulty breathing) 
• lung inflammation 
(possible difficulty 
breathing) 
• tissue death at the 
injection site caused by 
drug leakage 
 
ATG Side Effects 
Treatment with ATG may cause the body to make human antibodies to the rabbit- 
or horse-based antibody, depending on which one you receive. If you receive other 
drugs in the future that contain rabbit or horse proteins, you could develop an 
allergic reaction to those drugs. 
 
Rabbit ATG Side Effects 
 
It is not known how often the following side effects may occur. 
 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
• high blood pressure 
• swelling (arm/leg) 
• fast heartbeat 
• dizziness 
• fever 
• chills 
• headache 
• high blood levels of 
potassium (possible 
kidney failure) 
• abdominal pain 
• nausea 
• diarrhea 
• low blood cell counts 
(white and/or platelets) 
• weakness 
• pain 
• difficulty breathing 
• infusion site 
pain/swelling/redness 
 
Rabbit ATG may cause cytokine release syndrome. This involves a release of a 
large amount of proteins into the blood stream. This may cause changes in blood 
pressure and heartbeat, flu-like symptoms (nausea, fever, and chills), and/or affect 
your lung/liver/kidney function. It may also cause certain brain-related symptoms, 
such as dizziness, weakness, confusion, difficulty speaking, and/or decreased 
brain function (possible paralysis and/or coma). 
 


Protocol 2020-0496 
March 18, 2024 
Page 12 of 29 
Tacrolimus Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• high blood pressure 
• swelling 
• headache 
• difficulty sleeping 
• fever 
• itching and/or skin rash 
• abnormal salts, 
minerals, and/or acids 
in the blood (possible 
weakness, swelling, 
fatigue, low blood 
pressure, organ failure, 
heart problems, 
changes in mental 
status, and/or seizure) 
• high blood sugar 
(possible diabetes) 
• low blood sugar 
• high blood levels of fat 
(possible heart disease 
and/or stroke) 
• diabetes 
• diarrhea 
• abdominal pain 
• nausea/vomiting/upset 
stomach 
• constipation 
• loss of appetite 
• fluid in the abdomen 
• low blood cell counts 
(red, white, platelets) 
• abnormal liver tests 
(possible liver damage, 
and possibly due to 
scarring and/or blood 
clots) 
• tremors 
• weakness 
• abnormal sensation 
(such as pins and 
needles) 
• pain 
• abnormal kidney test 
(possible kidney 
damage) 
• difficulty breathing 
(possibly due to lung 
damage) 
• build-up of fluid around 
the lungs 
• infection 
 
Occasional (occurring in 3-20% of patients) 
 
• chest pain (possibly 
due to heart trouble) 
• build-up of fluid in the 
tissue around the heart 
• fatigue 
• dizziness 
• inflammation of the 
stomach and/or 
intestines 
• decreased urine output 
• cough 
• lung inflammation 
 
 
Exact frequency unknown but occurring in fewer than 15% of patients 
 


Protocol 2020-0496 
March 18, 2024 
Page 13 of 29 
• low blood pressure 
(possible dizziness/ 
fainting) 
• abnormal EKG 
• irregular/fast/slow 
heartbeat 
• heart and/or lung failure 
• heart attack 
• enlarged heart 
• decreased blood supply 
to the heart 
• decreased blood supply 
to the brain caused by 
stroke 
• blood vessel disorder 
(possible tissue death) 
• increased amount of 
blood 
• vein inflammation 
• blood clots in a vein 
(possible pain, swelling, 
and/or redness) 
• abnormal blood clotting 
• stroke 
• flushing 
• fainting 
• abnormal dreams 
• difficulty thinking 
• inability to speak  
• memory loss 
• difficulty writing 
• loss of coordination due 
to brain dysfunction 
• difficulty walking 
• chills 
• confusion 
• mood swings or 
changes (such as 
agitation, anxiety, 
depression, and/or 
nervousness) 
• nightmares 
• hallucinations (seeing or 
hearing things that are 
not there) 
• sweating 
• skin sores 
• wound healing problems 
• abnormal blood 
acid/base balance 
(possible organ 
damage) 
• Cushing's syndrome 
(possible weakness, 
diabetes, and/or bone 
weakness) 
• low blood levels of iron 
(possible low blood red 
cell counts and/or weak 
fingernails) 
• high blood levels of uric 
acid (possible painful 
joints and/or kidney 
failure) 
• dehydration 
• throat inflammation 
(possible esophageal 
sore) 
• mouth blisters/sores 
• increased appetite 
• cramps 
• difficulty swallowing 
• gas 
• abdominal wall 
inflammation 
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen) 
• slow emptying of food 
from the stomach into 
the intestines 
• stomach ulcer 
• intestinal blockage 
• fluid-filled sac in the 
pancreas 
• inflammation and 
bleeding of the pancreas 
(possible abdominal 
pain and/or tissue 
death) 
• high red blood cell count 
(possible headache, 
dizziness, and/or stoke) 
• anemia due to 
destruction of red blood 
cells  
• blockage of the bile tract 
(possible body yellowing 
and/or abdominal pain) 
• liver damage 
• jaundice (yellowing of 
skin and/or eyes) 
• leg cramps 
• muscle pain, twitching, 
tightness, and/or 
spasms 
• painful joint 
inflammation 
• joint disease (possible 
pain)  
• loss of bone strength 
(possible broken bones) 
• immune response that 
causes the body to 
attack itself (causing 
muscle weakness) 
• nerve damage (loss of 
motor or sensory 
function) that is possibly 
due to pressure on the 
nerves 
• paralysis 
• walking/balance 
problems (possible 
falling)  
• vision problems (such 
as blurry vision and/or 
lazy eye) 
• painful red eyes 
• hearing loss 
• ear pain  
• ringing in the ears 
• kidney failure 
• infection-related kidney 
damage (possible 
kidney failure) 


Protocol 2020-0496 
March 18, 2024 
Page 14 of 29 
• psychosis (loss of 
contact with reality) 
• seizure 
• acne 
• hair loss (partial or total) 
• shedding and scaling of 
the skin (possible fatal 
loss of bodily fluids) 
• hair growth 
• skin sensitivity to 
sunlight or sunlamps 
• change of skin color 
• weight gain/loss 
• bladder inflammation 
(possible pain, bleeding, 
and/or urge to urinate) 
• difficult, frequent, and/or 
painful urination 
• inability to produce urine 
• blood in the urine 
• vaginal inflammation 
• rectal disease  
• increased risk of 
bleeding 
• back-up of urine into the 
kidney 
• death of kidney tissue 
(possible kidney failure) 
• voice changes 
• sore throat 
• hiccups 
• collapsed lung and/or 
fluid in the lung (possibly 
difficulty breathing) 
• runny nose 
• flu-like symptoms 
• allergic reaction 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
 
Tacrolimus may cause you to develop another type of cancer (such as bladder, 
thyroid, or skin cancer). 
 
Rare but serious (occurring in fewer than 3% of patients) 
 


Protocol 2020-0496 
March 18, 2024 
Page 15 of 29 
• sudden stopping of the 
heart 
• multiple blood clots 
(possible organ 
dysfunction and/or 
failure) 
• DIC (breakdown of the 
blood clotting system) 
(possible severe 
bleeding, organ 
dysfunction, and/or 
organ failure) 
• abnormal blood clotting 
in small blood vessels 
(possible stroke and/or 
other organ damage)  
• tissue swelling 
• coma 
• difficulty forming or 
speaking words 
• anxiety disorder 
causing inability to 
speak 
• decreased brain 
function (possible 
paralysis and/or coma) 
• brain injury that may be 
reversible (possible 
headache, confusion, 
seizures, and/or vision 
loss)  
• progressive multifocal 
leukoencephalopathy 
(PML – a disease with 
brain damage that may 
likely result in paralysis 
and/or coma, which 
may be permanent, or 
death) 
• delirium (loss of contact 
with reality) 
• very severe blistering 
skin disease (with 
ulcers of the skin and 
digestive tract) 
• very severe blistering 
skin disease (loss of 
large portion of skin) 
• inflammation and 
bleeding of the 
pancreas (possible 
abdominal pain) 
• decreased bone 
marrow function and 
inability to make red 
blood cells 
• destruction of red blood 
cells (possible kidney 
damage and/or failure) 
• increase in white blood 
cells 
• breakdown of muscle 
tissue (possible kidney 
failure) 
• liver failure 
• blindness 
• damage to an eye 
nerve (possible vision 
changes) 
• deafness 
• failure to breathe 
• increased blood 
pressure in the lungs 
(possible difficulty 
breathing and/or heart 
failure) 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
• multiorgan failure 
• graft-versus-host 
disease (when 
transplanted donor 
tissue attacks the 
tissues of the 
recipient's body) 
 
Tacrolimus may rarely cause you to develop another type of cancer (such as 
lymphoma [a type of lymph node cancer] or leukemia [a type of blood cancer]).  
 
Tacrolimus also may cause heart damage.  It is not known how often this may occur. 
 
Cyclosporine Side Effects 
 
Common (occurring in more than 20% of patients)     
 
• high blood pressure 
• headache 
• hair growth 
• nausea 
• tremors 
• decreased kidney 
function 
 


Protocol 2020-0496 
March 18, 2024 
Page 16 of 29 
Cyclosporine may commonly cause an increased risk of infection, such as a viral or 
bacterial infection or pneumonia. This infection may occur anywhere. It may become 
life-threatening. Symptoms of infection may include fever, pain, redness, and 
difficulty breathing. 
 
Occasional (occurring in 3-20% of patients) 
 
• swelling 
• high blood levels of fat 
(possible heart disease 
and/or stroke) 
• diarrhea 
• thickened gums 
• abdominal pain 
• upset stomach 
• female reproductive 
disorder 
• abnormal sensation 
(such as pins and 
needles) 
• leg cramps 
 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• 
abnormal blood 
clotting in small blood 
vessels (possible 
stroke and/or other 
organ damage) 
• 
increased pressure in 
the skull (possible 
headache, vision 
changes, and/or 
mental status 
changes) 
• 
brain damage that 
may be reversible 
(possible headache, 
confusion, seizures, 
and/or vision loss)  
• 
loss of 
consciousness 
• 
progressive multifocal 
leukoencephalopathy 
(PML – a disease 
with brain damage 
that may likely result 
in paralysis and/or 
coma, which may be 
permanent, or death) 
• 
abnormal salts, 
minerals, or acids in 
the blood (possible 
weakness, swelling, 
fatigue, low blood 
pressure, organ 
failure, heart 
problems, changes in 
mental status, and/or 
seizures)   
• 
destruction of red 
blood cells (possible 
kidney damage 
and/or failure) 
• 
blockage of the bile 
tract (possible body 
yellowing and/or 
abdominal pain) 
• 
abnormal liver tests 
(possible liver 
damage and/or 
yellowing of the 
skin/eyes) 
• 
breakdown of muscle 
tissue (possible 
kidney failure) 
• 
swelling of the eye 
nerve (possible vision 
loss) 
• 
fluid in the lung 
(possible difficulty 
breathing) 
• 
life-threatening 
allergic reaction 
(such as difficulty 
breathing, low blood 
pressure, and/or 
organ failure) 
 
Cyclosporine may cause you to develop another type of cancer, such as lymphoma 
(a type of lymph node cancer). 
 
 


Protocol 2020-0496 
March 18, 2024 
Page 17 of 29 
Mycophenolate Mofetil Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• high blood pressure 
• low blood pressure 
(possible 
dizziness/fainting) 
• swelling (such as 
arm/leg/face) 
• chest pain (possibly due 
to heart trouble) 
• fast heartbeat 
• headache 
• dizziness 
• difficulty sleeping 
• fever 
• anxiety  
• skin rash  
• abnormal salts, 
minerals, and/or acids in 
the blood (possible 
weakness, swelling, 
fatigue, low blood 
pressure, organ failure, 
heart problems, changes 
in mental status, and/or 
seizure) 
• high blood sugar 
(possible diabetes) 
• high blood levels of fat 
(possible heart disease 
and/or stroke) 
• nausea/vomiting 
• diarrhea/constipation 
• abdominal pain 
• loss of appetite 
• upset stomach  
• fluid in the abdomen 
• increase in infection-
fighting cells 
• low blood cell counts 
(red, white, platelets) 
• abnormal liver tests 
(possible liver damage) 
• pain 
• weakness 
• tremors 
• abnormal sensation 
(such as pins and 
needles)  
• decreased kidney 
function 
• abnormal kidney test 
(possible kidney 
damage) 
• difficulty breathing 
(possibly due to 
narrowing of the 
airways) 
• build-up of fluid around 
the lungs 
• cough 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
 
Mycophenolate mofetil may cause long-lasting anemia. Mycophenolate mofetil may 
cause a viral or bacterial infection.   
 
Occasional (occurring in 3-20% of patients) 


Protocol 2020-0496 
March 18, 2024 
Page 18 of 29 
• irregular/slow heartbeat 
• extra heartbeats 
• sudden stopping of the 
heart 
• heart failure 
• build-up of fluid in the 
tissue around the heart 
• decreased blood 
circulation 
• abnormal blood clotting 
• blood clots in an artery 
and/or vein (possible 
organ damage such as 
stroke and/or heart 
attack) 
• blood vessel spasm 
(possible blockage of 
blood flow) 
• increased risk of 
bleeding 
• flushing 
• seizure 
• mood changes or 
swings (such as 
agitation, confusion, 
depression, and/or 
nervousness) 
• delirium and/or 
psychosis (loss of 
contact with reality) 
• hallucinations (seeing or 
hearing things that are 
not there) 
• difficulty thinking 
• fainting 
• chills and fever 
• fatigue/lack of energy 
• sleepiness 
• sweating 
• pale skin 
• acne 
• hair loss (partial or total) 
• hair growth 
• itching 
• thickened skin 
• diabetes 
• low blood sugar 
• abnormal blood 
acid/base balance 
(possible organ 
damage) 
• Cushing's syndrome 
(possible weakness, 
diabetes, and/or bone 
weakness) 
• digestive system 
bleeding due to 
digestive system 
irritation 
• thirst/dehydration  
• abdominal swelling  
• difficulty swallowing 
• gum disease 
• thickened gums 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• dry mouth 
• inflammation of the 
stomach and/or 
intestines 
• stomach ulcer 
• weight gain or loss 
• gas 
• paralysis of the 
intestines 
• tarry or coffee ground-
like blood in the stool 
• frequent and/or painful 
urination 
• inability to urinate 
• blood in the urine 
• decreased urine output 
• swelling of the scrotum 
• impotence 
• prostate disorder 
• increased amount of 
blood 
• wound healing problems 
• painful joint inflammation 
• joint disorder 
• muscle tightness 
• numbness 
• nerve damage (loss of 
motor or sensory 
function) 
• loss of bone strength 
(possible broken bones) 
• leg cramps 
• cataracts (clouding of 
the lens of the eye) 
• vision problems 
(possible teary eyes, 
lazy eye, and/or painful 
red eyes) 
• deafness 
• ear pain 
• ringing in the ears 
• back-up of urine into the 
kidney 
• high blood levels of uric 
acid (possible painful 
joints and/or kidney 
failure) 
• kidney failure 
• death of kidney tissue 
(possible kidney failure)  
• voice changes 
• sore throat/throat 
inflammation 
• collapsed lung and/or 
fluid in the lung (possibly 
difficulty breathing) 
• increased blood 
pressure in the lungs 
(possible difficulty 
breathing and/or heart 
failure) 
• runny nose 
• interrupted breathing 
• lung inflammation 
(possible difficulty 
breathing)  
• nosebleed 
• coughing up blood 


Protocol 2020-0496 
March 18, 2024 
Page 19 of 29 
• skin sores 
• blistering skin rash 
• cyst (fluid-filled lump) 
• underactive thyroid 
gland (possible weight 
gain, heart failure, 
and/or constipation) 
• high red blood cell count 
(possible headache, 
dizziness, and/or stoke) 
• liver damage  
• jaundice (yellowing of 
skin and/or eyes) 
• hiccups 
• fast breathing 
• flu-like symptoms 
 
MMF may occasionally cause you to develop another type of cancer (such as skin 
cancer). 
 
Rare but serious (occurring in fewer than 3% of patients)     
 
• heart valve damage 
• progressive multifocal 
leukoencephalopathy 
(PML – a disease with 
brain damage that may 
likely result in paralysis 
and/or coma, which may 
be permanent, or death) 
• hole in the intestines 
(possibly leaking 
contents into the 
abdomen) 
• inability to process food 
due to stomach and/or 
intestinal damage 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• decreased bone marrow 
function and inability to 
make red blood cells 
• infection-related kidney 
damage (possible 
kidney failure) 
• lung damage (possible 
difficulty breathing) 
 
MMF may rarely cause you to develop lymphoma (cancer of the lymph nodes). 
 
Frequency Unknown 
 
• birth defects 
• pregnancy loss 
 
 
Using the study drugs together may cause side effects that are not seen when 
each is given alone. The study drug combination may also increase the frequency 
and/or severity of the side effects listed above. 
 
Other Risks 
The allogeneic stem cell transplant infusion may cause allergic reactions and/or 
shortness of breath. The donor cells may fail to grow and multiply in your body (graft 
failure). If this occurs, you may have a high risk of infections and/or bleeding. You 
may need frequent blood transfusions. Graft failure can be treated with growth 
factors or a second transplant, but these treatments do not work all the time. 
 
Once inside your body, the cells from your donor may react against your normal 
tissues, causing a reaction called graft-versus-host disease (GVHD). Acute GVHD 
may occur within the first several months after the transplant and may cause skin 
rash, diarrhea, and/or liver damage. Chronic GVHD may develop after the third 


Protocol 2020-0496 
March 18, 2024 
Page 20 of 29 
month after the transplant and is considered a long term complication involving the 
lungs, eyes, mouth, liver, skin, joints, digestive system, and/or muscles.   
 
Veno-occlusive disease (liver damage caused by blood clots) is a common 
complication that results from high doses of chemotherapy. Patients who experience 
this develop swelling, weight gain, jaundice (yellowing of skin and/or eyes), 
abnormal liver function, abdominal swelling, and stomachache or shoulder pain. 
These usually occur in the first month after transplant. Although most patients 
recover completely, veno-occlusive disease can lead to death. If you develop these 
symptoms, you will receive drugs to treat them. 
 
Some complications of transplantation may occur many years later. Some children 
experience delays in growth. There may be hormonal problems that affect your 
thyroid or damage to the ovaries or testes, which lead to infertility. Your hormone 
level will be monitored yearly following your transplant. The chemotherapy can also 
affect any organ system including your heart, lungs and kidneys. You may develop 
cataracts, which are cloudy spots on the lens of the eyes that blur vision. They can 
occur many years after the transplant. If you notice a change in your eyesight 
following transplant, you should notify your doctor immediately. If children do not 
have their adult teeth at the time of transplant, their tooth development may be 
delayed. Tooth decay and gum disease are also common. It will be important to see 
a dentist regularly following transplant. Some children will develop learning 
disabilities, growth problems, bone problems, nervous system problems, and 
psychosocial issues following their transplant. 
 
Blood draws may cause pain, bleeding, and/or bruising. You may faint and/or 
develop an infection with redness and irritation of the vein at the site where blood is 
drawn. Frequent blood collection may cause anemia (low red blood cell count), which 
may create a need for blood transfusions. 
 
Having bone marrow biopsies/aspirates performed may cause pain, bruising, 
bleeding, redness, low blood pressure, swelling, and/or infection at the site of the 
biopsies. An allergic reaction to the anesthetic may occur. A scar may form at the 
biopsy site. 
 
Spinal taps may cause headaches, sensitivity of the eyes to light, nausea, vomiting, 
confusion, drowsiness and/or pain at the injection site. They may cause fever, 
infection, and/or bleeding. Spinal taps may cause inflammation/bleeding around the 
brain and/or the covering of the spinal cord, which can lead to nerve damage. In rare 
instances, spinal taps may cause seizures, leakage of spinal fluid, and/or blockage of 
spinal fluid, which can lead to brain swelling. Severe infections of the spinal fluid or 
bleeding within the brain can result in coma and/or death. Repeated spinal taps may 
result in learning or memory difficulties. 
 
EKGs/ECHOs may cause discomfort while lying on the exam table, and the tape on 
the EKG pads may cause skin irritation.  
 


Protocol 2020-0496 
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MUGA scans may cause allergic reactions to the radioactive tracer, injection site 
soreness, and/or swelling. They may cause damage to cells or tissue from being 
exposed to the radiation used in the scan. These side effects may occur in less than 
10% of patients. 
 
CT scans send x-rays through the body at many different angles.  You will be 
exposed to a small dose of radiation.  All radiation adds up over a lifetime and may 
increase the risk of new cancer forming.  Some people may feel “closed in” while 
lying in the scanner.  However, the scanner is open at both ends, and an intercom 
allows you to talk with doctors and staff.  If you feel ill or anxious during scanning, 
doctors and/or radiology technicians will give comfort, or the scanning will be 
stopped.  Solution may also be given by vein to make the x-ray pictures more 
accurate.  This may cause an uncomfortable feeling of warmth, nausea, and/or 
severe allergic reactions.  The solution injection may also cause pain, bleeding, 
bruising, hives, and/or itching. 
 
A PET scan may cause you to feel “closed in” while lying in the scanner. However, 
the scanner is open at both ends and an intercom allows you to talk with doctors and 
staff. If you feel ill or anxious during scanning, doctors and/or technicians will give 
comfort or the scanning will be stopped. 
 
The PET scan exposes your body to radiation. The radioactive solution does not 
remain in your system for a long period of time. However, you should wait 2 hours 
before holding an infant or getting close to a pregnant woman to avoid exposing 
them to radiation. You should drink fluids after the scan to help remove the solution 
from your system. 
 
During the MRI, you may feel mild vibrations throughout your body. The machine will 
produce a loud knocking noise. This is normal. You will be given earplugs to protect 
your ears. Some people, especially those who tend to feel uncomfortable in small or 
closed spaces, may feel “closed in” and become anxious while in the scanner. The 
scanner has an intercom, which will allow you to speak to the staff during the 
procedure. If you feel ill or anxious during scanning, tell the MRI staff and the 
scanning will be stopped if you wish. The MRI will require a catheter to be inserted 
into one of your veins in order to inject the MRI contrast agent. This may cause skin 
irritation, bleeding, and/or infection.  You may have an allergic reaction to the 
contrast agent. 
 
The magnetic field used in MRI scanning may harm you if you have certain types of 
metal in your body (as might be found in pacemakers, neurostimulators, or certain 
clips). It may cause problems with devices, such as pacemakers. If you have metal in 
your body or devices such as a pacemaker, you should discuss this with the study 
doctor. 
 
Although every effort will be made to keep study data safe, there is a chance that 
your personal health information could be lost or stolen, which may result in a loss 
of confidentiality. 


Protocol 2020-0496 
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This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so 
you should not become pregnant, breastfeed a baby, or father a child while on this 
study. You must use birth control during the study if you are sexually active. 
 
Birth Control Specifications: Talk to your study doctor about appropriate methods of 
birth control during this study. 
 
Males: Tell the doctor right away if your partner becomes pregnant or suspects 
pregnancy. 
 
Females: If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant will result in your removal from this study.   
 
 
3. COSTS AND COMPENSATION  
 
If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care. However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson for this injury. You may also 
contact the Chair of MD Anderson’s IRB at 713-792-6477 with questions about 
study-related injuries. By signing this consent form, you are not giving up any of your 
legal rights. 
 
Certain tests, procedures, and/or drugs that you may receive as part of this study 
may be without cost to you because they are for research purposes only. However, 
your insurance provider and/or you may be financially responsible for the cost of 
care and treatment of any complications resulting from the research tests, 
procedures, and/or drugs. Standard medical care that you receive under this 
research study will be billed to your insurance provider and/or you in the ordinary 
manner. Before taking part in this study, you may ask about which parts of the 
research-related care may be provided without charge, which costs your insurance 
provider may pay for, and which costs may be your responsibility. You may ask that 
a financial counselor be made available to you to talk about the costs of this study. 
 
Samples that are collected from you in this study may be used for the development 
of treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit. 
 


Protocol 2020-0496 
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There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research.  
 
You will receive no compensation for taking part in this study.  
 
Additional Information  
 
4. You may ask the study chair (Dr. Jeremy Connors, at 713-792-6624) any questions 
you have about this study. You may also contact the Chair of MD Anderson's 
Institutional Review Board (IRB - a committee that reviews research studies) at 713-
792-6477 with any questions that have to do with this study or your rights as a study 
participant. 
 
5. You may choose not to take part in this study without any penalty or loss of benefits 
to which you are otherwise entitled. You may also withdraw from participation in this 
study at any time without any penalty or loss of benefits. If you decide you want to 
stop taking part in the study, it is recommended for your safety that you first talk to 
your doctor. It may be dangerous to suddenly stop study treatment, and the study 
doctor can discuss ways to safely withdraw. If you withdraw from this study, you can 
still choose to be treated at MD Anderson. 
 
If you stop being in the research, already collected data may not be removed from 
the study database. The study staff may ask if they can continue collecting the 
results of routine care from your medical record. If you agree, this data will be 
handled the same as research data.  
 
6. This study or your participation in it may be changed or stopped without your 
consent at any time by the study chair, the U.S. Food and Drug Administration 
(FDA), the Office for Human Research Protections (OHRP), or the IRB of MD 
Anderson. 
 
7. You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study and you may be asked to sign 
another informed consent and authorization form stating your continued willingness 
to participate in this study. 
 
8. MD Anderson may benefit from your participation and/or what is learned in this 
study.  
 
 
Future Research 
 
Data 
Your personal information is being collected as part of this study. These data may be 
used by researchers at MD Anderson and/or shared with other researchers and/or 
institutions for use in future research. 
 


Protocol 2020-0496 
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Samples  
Samples (such as blood and/or tissue) are being collected from you as part of this 
study. Researchers at MD Anderson may use any leftover samples that are stored at 
MD Anderson in future research.  
 
Before being used or shared for future research, every effort will be made to remove 
your identifying information from any data and/or research samples. If all identifying 
information is removed, you will not be asked for additional permission before future 
research is performed. 
 
If you do not want your samples or data to be used for future research, tell the study 
doctor. You may withdraw your samples at any time by telling your study team. If you 
decide to withdraw your samples, they will be returned to the lab they came from or 
destroyed. However, the data and test results already collected from your samples 
will be kept and may be used. 
 
In some cases, all of your identifying information may not be removed before your 
data or research samples are used for future research. If future research is 
performed at MD Anderson, the researchers must get approval from the 
Institutional Review Board (IRB) of MD Anderson before your data and/or research 
samples can be used. At that time, the IRB will decide whether or not further 
permission from you is required. The IRB is a committee of doctors, researchers, 
and community members that is responsible for protecting study participants and 
making sure all research is safe and ethical. 
 
If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples. 
 
Genetic Research 
Research samples collected from you as part of this study may be used for genetic 
research, which may include whole genome sequencing. Whole genome sequencing 
is a type of testing in which researchers study your entire genetic makeup (DNA). 
This may help researchers learn how changes in the ordering of genes may affect a 
disease or response to treatment. If genetic research is done with your samples, 
those who have access to those samples may be able to identify you. The results of 
this research may also be able to be linked to you. The same level of data protection 
that covers your individual data does not apply to summary results (when data from 
the whole study is combined). 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most 
employers to discriminate against you based on your genetic information. This law 
generally will protect you in the following ways: 
• Health insurance companies and group health plans may not request your 
genetic information that we get from this research. 
• Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums. 


Protocol 2020-0496 
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• Employers with 15 or more employees may not use your genetic information 
that we get from this research when deciding to hire, promote, or fire you or 
when setting the terms of your employment. 
 
Be aware that this federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
Nor does this federal law prohibit discrimination based on an already known genetic 
disease or disorder. 
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A. During the course of this study, MD Anderson will be collecting and using your PHI, 
including identifying information, information from your medical record, and study 
results. For legal, ethical, research, and safety-related reasons, your doctor and the 
research team may share your PHI with: 
• Federal agencies that require reporting of clinical study data (such as the FDA, 
National Cancer Institute [NCI], and OHRP) 
• The IRB and officials of MD Anderson 
• Study monitors and auditors who verify the accuracy of the information 
• Individuals who put all the study information together in report form 
 
The results of this research may be published in scientific journals or presented at 
medical meetings, but your identity will not be disclosed. 
 
B. Signing this consent and authorization form is optional but you cannot take part in 
this study or receive study-related treatment if you do not agree and sign. 
 
C. MD Anderson will keep your PHI confidential when possible (according to state and 
federal law). However, in some situations, the FDA could be required to reveal the 
names of participants. 
 
Once disclosed outside of MD Anderson, federal privacy laws may no longer protect 
your PHI. 
 
D.  The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed 
from the study and the data collected about you up to that point can be used and 
included in data analysis. However, no further information about you will be 
collected. If you withdraw from the study, the study staff may ask if they can continue 
collecting the results of routine care from your medical record. 
 
E. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this 
Web site at any time. 
 


Protocol 2020-0496 
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CONSENT/AUTHORIZATION 
(Adult Participants Only) 
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think 
about it, ask questions, and talk about it with others as needed. I give the study chair 
permission to enroll me on this study.  By signing this consent form, I am not giving up 
any of my legal rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
_________________________________         
PRINTED NAME OF PARTICIPANT                 
 
LEGALLY AUTHORIZED REPRESENTATIVE (LAR) 
The following signature line should only be filled out when the participant does not have 
the capacity to legally consent to take part in the study and/or sign this document on his 
or her own behalf. 
 
_____________________________________________________ 
_________ 
SIGNATURE OF LAR 
DATE 
 
 
 
PRINTED NAME and RELATIONSHIP TO PARTICIPANT 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under this protocol. 
 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for non-English speakers utilizing the  
short form consent process (VTPS) and patients who are illiterate. 
 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits 
and risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 
 


Protocol 2020-0496 
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PARENT/GUARDIAN PERMISSION 
I have read and understand the description of this research. I have had a chance to 
discuss the study and ask questions.  My questions have been answered. I give 
permission for my child or ward to take part in this study. 
 
 
______________________________________________  
  
_________ 
SIGNATURE OF PARENT/GUARDIAN 
  
DATE 
 
 
 
 
PRINTED NAME OF PARENT/GUARDIAN 
 
______________________________________________  
  
_________
 
 
SIGNATURE OF PARENT/GUARDIAN  
 
 
 
 
DATE 
Signature of Other Parent (Optional, unless required by the IRB.) 
 
 
 
PRINTED NAME OF PARENT/GUARDIAN 
 
__X__ The IRB has determined that the signature of both parents is required. 
 
If not obtaining both parental signatures, please indicate reason below: 
 
____Other parent is deceased, unknown, incompetent, or not reasonably available. 
 
____Parent/Guardian signing above has sole legal responsibility for the care and 
custody of the child. 
 
____The IRB has determined that the signature of both parents is NOT required. 
 
 
 


Protocol 2020-0496 
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ASSENT OF MINOR 
(Entire section must be completed if the participant’s intellectual age is at least 7 
and less than 18 years. Participants with an intellectual age of 7 - 12 are not 
required to sign.) 
 
If written assent is not obtained on an age-appropriate participant, check reason why 
not: 
 
____ 1.) The participant’s intellectual age is less than seven. 
____ 2.) The participant dissented, but the participant's parent(s)/guardian felt that the 
intervention(s) or procedure(s) involved in the research hold out the possibility of a 
direct benefit that is important to the health and/or well being of the participant and is 
available only in the context of this research study. 
____ 3.) Other: ____________________________________________________ 
 
I have been told what I will be asked to do in this study. 
 
I have been told that I do not have to be in this study.  If I decide not to be in this study, 
no one will be mad at me.  I may quit at any time, but if I do, I may need to take a 
different treatment. 
 
I have had a chance to talk about the study and ask the study doctor questions. All of 
my questions have been answered.  I agree to be in this study and do what I am asked 
to do so long as I want to stay in this study.  I agree that the study doctor can put me on 
this study. By signing this paper, I am not giving up any of my legal rights. I have been 
given a copy of this document. 
 
___________________________________________________ 
  
_________ 
SIGNATURE OF MINOR (Age 13-17) 
DATE 
 
_____________________________________________________ 
PRINTED NAME OF MINOR 
 
 


Protocol 2020-0496 
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TRANSLATOR 
I have translated the above informed consent as written (without additions or 
subtractions) into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
 
_____________________       _______________________________   ___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line.)