A Phase I/II Study of Recombinant Human Interleukin-7 to Promote T-Cell Recovery After Haploidentical and Cord Blood Stem Cell Transplantation
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Cord Blood Transplant Recipient, Myelodysplastic Syndrome, Myeloproliferative Neoplasm
Sponsor: M.D. Anderson Cancer Center

 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2018-0674 
Protocol Title 
A Phase I/II Study of Recombinant Human Interleukin-7 to 
Promote T-Cell Recovery after Haploidentical and Cord Blood 
Stem Cell Transplantation 
Protocol Version 14.0 
Version Date 
09 September 2022 
 
Protocol PI 
Gheath Al-Atrash, DO 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
143744 

 
 
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A Phase I/II Study of Recombinant Human Interleukin-7 to Promote 
T-Cell Recovery after Haploidentical and Cord Blood  
Stem Cell Transplantation 
 
 
 
 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
Institution Study Number:  2018-0674 
Study Drug Supplier:   Revimmune 
IND Sponsor:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  143744 
Principal Investigator:  Gheath Al-Atrash, DO, PhD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0423 
Houston, TX 77030 
Telephone: 713.563.3324 
Fax: 713.563.3364 
galatras@mdanderson.org 
 
Co-Chairs:  Elizabeth Shpall, MD1 
Katy Rezvani, MD, PhD1 
 
Collaborators:  Roland L. Bassett, Jr., MS2 
Chitra M. Hosing, MD1 
Partow Kebriaei, MD1 
Rohtesh Mehta, MD1 
Yago Nieto, MD, PhD1 
Amanda L. Olson, MD1 
Betul Oran, MD1 
Uday Popat, MD1 
Peter F. Thall, PhD2 
 
   

 
 
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Table of Contents 
 
 
1.0  
OBJECTIVES ........................................................................................................................................................... 3 
2.0 
BACKGROUND ...................................................................................................................................................... 3 
3.0 
PATIENT ELIGIBILITY .............................................................................................................................................. 8 
4.0  
TREATMENT PLAN AND STUDY DESIGN ................................................................................................................ 9 
5.0  
BACKGROUND DRUG INFORMATION .................................................................................................................. 10 
6.0 
EVALUATION DURING STUDY .............................................................................................................................. 12 
7.0 
STATISTICAL CONSIDERATIONS ........................................................................................................................... 14 
8.0  
CRITERIA FOR REMOVAL FROM THE STUDY ........................................................................................................ 16 
9.0  
ADVERSE EVENTS AND REPORTING REQUIREMENTS .......................................................................................... 16 
10.0  
REFERENCES ........................................................................................................................................................ 22 
 
  
 
 
 

 
 
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Protocol Body 
 
 
1.0  Objectives 
 
Primary Objective: 
 
· 
To determine the safety and establish the optimal biologic dose of CYT107. 
 
Secondary objectives: 
 
· 
To determine the rate of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and BK viral 
infections in umbilical cord blood stem cell transplantation (CBT) and haploidentical 
stem cell transplantation (haplo-SCT) patients who receive three doses of IL-7 
following engraftment. 
 
· 
To calculate the OS, PFS and, cumulative incidence of GVHD and cumulative incidence of 
relapse 
 
· 
To evaluate the effects of CYT107 on the recovery of T, NK and B cell populations and their 
functions in vitro; these data will be used to identify the optimal dose to move to a phase II 
trial. 
 
2.0 Background 
2.1 
Haploidentical and Cord blood transplantation 
 
Haploidentical stem cell transplantation (haplo-SCT) and umbilical cord blood stem cell 
transplantation (CBT) are being increasingly used as a source of hematopoietic stem and 
progenitor cells (HSPCs) for allogeneic stem cell transplant candidates lacking suitable matched 
donors. Although haplo-SCT and CBT  are successful in many patients, their efficacy have  been 
restricted by slow hematopoietic and immunologic reconstitution due to the quantitative and 
qualitative differences in the composition of the stem cell grafts.1-5  While the frequency of HSPCs 
is greater in CB units, CB grafts contain an average of 1-2 logs fewer total cells compared to 
peripheral blood (PB) or bone marrow (BM) allografts. Moreover, the vast majority of T, B and 
dendritic cells in CB grafts are immature,6;7 which likely explains the low rates of graft-versus-host 
disease (GVHD) seen after CBT given the degree of HLA-mismatches typically used.8;9  The use 
of double unrelated CBT (DUCBT) represents an important advance by allowing larger children 
and adult patients to be transplanted with an acceptable cell dose. In this setting, although two CB 
units are initially transplanted, only one provides prolonged engraftment and becomes the 
“dominant” engrafted unit. Yet, even following DUCBT, severe complications related to infections 
remain a major cause of morbidity and mortality.15-20  Similarly, immune recovery after haplo-SCT 
also tends to be less roubust in comparison with matched grafts, and affects B cells, T cells and 
their subsets.1-3   
 
 
 

 
 
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6
2.2 
Strategies to enhance T-cell reconstitution 
 
Interleukin-(IL-7) has a central role in T-cell development and survival; it enhances 
thymopoiesis, peripheral T-cell survival and expansion in murine models of allogeneic 
hematopoietic stem cell transplantation (allo-HSCT).2-5  
 Initial trials with recombinant human IL-7 
(r-hIL-7) demonstrated an expansion of CD4+ and CD8+ T cells in patients with solid tumors or 
HIV infection.21-25  A potential concern with IL-7 in allo-HSCT patients is the stimulation of 
GVHD. In preclinical mouse models, short courses of IL-7 did not induce GVHD in T-cell 
depleted bone marrow transplant (TCD-BMT) nor did it aggravate the development of GVHD 
after adding donor T cells.3  However, IL-7 when given longer and at higher dose to mice after 
TCD-BMT, did lower the threshold dose of T cells required to induce lethal GVHD.26 In a  
recent Phase I clinical study of r-hIL-7 in recipients of a T-cell depleted allo-HSCT, investigators 
at Memorial Sloan Kettering treated 12 patients with escalating doses of IL-7 administered 
weekly for 3 weeks after the patients had engrafted. They reported that the study drug was well 
tolerated with only one patient developing acute skin GVHD. At baseline, patients were 
profoundly lymphopenic. IL-7 induced a doubling in CD4+ and CD8+ T cells with no significant 
effect on CD4+CD25+FoxP3+ T cells, NK, or B cells. Importantly, they also demonstrated an 
increase in functional T cell recovery, including viral-specific T cells that recognize CMV. 
Enhanced T-cell receptor (TCR) diversity was also observed after treatment. The authors 
concluded that IL-7 can enhance immune recovery after a T cell–depleted allo-HSCT without 
causing significant GVHD or other serious toxicity. 
 
2.3 
Preliminary Studies 
 
Predictors of Non-Relapse Mortality and Overall Survival after CBT. We analyzed the 
outcome of 108 patients who underwent a DUCBT at our center for predictors of 3-year 
non-relapse mortality (NRM).28  In univariate analysis, the day 30 absolute lymphocyte counts 
(ALC30) were treated as dichotomous variables above or below 150 x 106 /L (upper limit of first 
quartile) and significantly affected NRM. The median (range) of ALC30 was 240 (10-2420) x 
106/L. There was no significant impact of age, sex, disease stage at the time of DUCBT, CMV 
serostatus, the occurrence of grade II-IV acute GVHD before day 30, total nucleated cell dose 
(TNC) dose, total CD34 dose, preparative regimen or CB manipulation on NRM. In multivariate 
analysis, ALC30 (HR = 2.3, P = 0.01) emerged as an independent factor strongly associated 
with NRM. Figure 1 shows the impact of ALC30 on NRM and OS in all patients. For patients 
with ALC30 > 150 x 106/L, overall survival at 3 years was 37% (95% CI 25-49) compared with 
25% (95% CI 11-40) for those with counts ≤ 150 x 106/L (P = 0.02). Similarly, ALC30 > 150 x 10
6
 
/L was related to a lower risk of NRM, 42% (95% CI 31-56%) vs 59% (95% CI 44-78%) (P = 
0.01) in patients with ALC30 £ 150 x 10 /L. The leading causes of NRM in both the groups 
(ALC30 £ 150 vs. ALC30 >150) included infections (50% vs. 52%, P=0.9) and GVHD (40% vs 
30%, P = 0.5 ). Further, there was no significant impact of ALC30 on the rate of grade II-IV 
aGVHD (P = 0.4), disease progression (P = 0.7) or progression-free survival (P = 0.07) at 2 
years. 

 
 
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CBT outcome based on ALC30. Impact of ALC30 £ or > 150 x 10
6/L on (A) OS; (B) NRM. 
 
Figure 2 
 
 
 
Figure 2. Prolonged T lymphopenia and relative expansion of NK cells and B cells following DUCBT. T 
(CD3+CD4+ and CD3+CD8+), B (CD19+), and NK (CD56+) cells were prospectively measured by 
6 
multiparameter flow cytometry on fresh samples; (A) frequencies; (B) absolute numbers (x 10 /L) for each 
immune subset are presented. At baseline and after DUCBT, CD4+ and CD8+ T cells were relatively reduced, 
whereas early B-cell and NK-cell recovery was evident. Surviving CB transplant recipients demonstrated 
rebound of CD4+ and CD8+ T cells at later intervals after transplantation. Error bars represent interquartile 
range. 
 
Lymphocyte subset analysis. In 65 patients for whom peripheral blood (PB) samples had 
been collected at days +30, +100, +180 or 1 year post-DUCBT, we further characterized 
immune subset recovery by measuring the frequencies and absolute numbers of CD4+ T cells, 
CD8+ T cells, CD56+CD3- NK cells, and CD19+ B cells (Figure 2). The absolute number of 
each cell subset was calculated by multiplying their frequencies as determined by flow 
cytometry by the absolute lymphocyte number (cells/μl) obtained from a diagnostic complete 
blood count performed on the same day. Lymphocyte reconstitution following DUCBT began 
with a rapid increase in both the absolute number and frequencies of NK cells over baseline 
norms, and remained increased at the different study intervals, though the percentage of NK 
cells declined as T-cell counts recovered. T cell reconstitution on the other hand was 
significantly delayed. CD4+ and CD8+ T cells declined after conditioning and were significantly 

 
 
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reduced by day 30 post-DUCBT. The median absolute number of CD8+ cytotoxic T cells was 6 
x 106/L (range 0-170) at 30 days and 11 x 106/L (range 0-1900) at 100 days post-transplant. The 
corresponding numbers of CD4+ helper T cells were 4 x 106/L (range 0-100) and 22 x 106/L 
(range 0-390), respectively. These results confirm that quantitative T cell recovery is delayed 
after DUCBT, with an inverted CD4/CD8 T cell ratio, and that this delay in T cell immunity is 
associated with a preferential rapid reconstitution of non-T lymphoid cells (e.g., NK cells and B 
cells). Patients who developed acute GVHD had a slower T and B cell recovery (data not 
shown)29, in keeping with previous reports following allogeneic stem cell transplantation.29
 
To assess the tempo of functional virus-specific T cell recovery after DUCBT, we stimulated 
PBMC from 46 transplant recipients with 15-mer overlapping peptides spanning T cell 
immunogenic antigens from a range of both latent (CMV, EBV, BKV) and community (AdV, 
Influenza and RSV) viruses as well as to SEB, which was used as a positive control. Prior to 
transplant the frequency of T cells reactive against SEB was highest (mean 424.5 SFC/2 x 105 
PBMCs), followed by CMV (mean 258 SFC in 39 seropositive donors), EBV (mean 33 SFC), 
AdV (mean 17 SFC), BKV (mean 13 SFC), Influenza (mean 8 SFC), and RSV (mean 10 SFC) 
(Figure 3). 
 
Figure 3 
 
 
 
Figure 3. Virus-specific T cell activity following DUCBT. (A) Frequencies of SEB, BKV (Large T and 
VP1), AdV (Hexon and Penton) AND CMV (IE1 and pp65)-specific T cells in seropositive and seronegative 
donors in PB samples collected from patients prior to and post-DUCBT using IFN ELIspot as readout. Each 
symbol represents individual patient and results represent the SFC/2 x 10 input cells. 
 
 
 

 
 
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As shown in Figure 3, T cell activity against SEB, CMV, EBV, and AdV was delayed for at least 
8-9 months following DUCBT (mean 200, 89, 28 and 24 SFC/2 x 105, respectively). All patients 
developed viral infections/ reactivations post-DUCBT. The most common causes of viral 
infection included CMV (59%), BKV (20%) and AdV (11%). The majority of these infections 
occurred within the first 100 days post DUCBT and nearly 50% of patients had infections with 
multiple viruses. 
 
Haplo-SCT 
Immune recovery following haplo-SCT also has been reported to be suboptimal for at least 1 year 
after stem cell transplantation in comparison with the immune recovery observed following fully 
matched transplants. 35-37  Furthermore, the absolute numbers of lymphocyte subsets were much 
lower after haplo-SCT in comparison with lymphocyte counts seen in normal individuls.35-37 
Sluggish recovery was reported for CD19+ B cells, which according to some studies remained 
under 100 cells/μL until 180 days after transplantation.37  Poor recovery was also reported in the T 
cell subsets.35-37  In one study, CD4+ helper T cells were shown to recover slowly after haplo-SCT 
and did not reach 400/μL  until 12 months after transplantation.37  Although CD8+ cytotoxic T cells 
recovered rapidly after haplo-SCT according to some studies, there was a significant inversion of 
the CD4:CD8 ratio, which was observed up to 12 months after transplantation.35-37   CD4–CD8– T 
cells recovered slowly and did not reach the normal value until 180 days after transplantation. 
Slow recovery was also demonstrated in regulatory T cells (CD4+CD25+ ).37  Unlike conventional 
T and B cells, regulatory T cells never reached normal levels at 12 months following haplo-SCT.  
In addition to absolute numbers and frequencies, immune cell function may be altered following 
haplo-SCT.  For example, one study demonstrated lower numbers of CD28-expressing T cells 1 
year following haplo-SCT.37  Moreover, a number of studies have shown that successful immune 
reconstitution after allo-HSCT significantly correlates with better post-transplant outcomes, 
including lower infection, relapse and less secondary malignancy rates.38,39 Moreover, rapid 
immune reconstitution specifically following haplo-SCT prognosticated for superior outcomes, 
suggesting that measures that could “normalize” immune recovery may improve  the outcomes for 
patients following haplo-SCT.40 
 
IL-7 and GVHD 
 
Previous studies with infusion of exogenous IL-7 have shown variable effects on GVHD. 
Whereas Alpdogan et al, using an allogeneic murine model with full MHC class I and II disparity, 
reported that IL-7 improves immune reconstitution without aggravating GVHD,
29  Sinha et al 
reported increased GVHD in a murine parent into an F1 model.
31  More recently, a small phase I 
study, the administration of IL-7 in the setting of T-depleted bone marrow allogeneic transplant 
appeared to be safe and associated with an increase in functional T cell recovery, including 
virus-specific T cells that recognize CMV.27   Thus, we propose that treatment with IL-7 after CBT 
and haplo-SCTwill be safe and will not increase the risk of graft-versus-host disease (GVHD) for 
several  reasons: i) the number of infused T cells after CBT is one-log lower than that infused 
after a bone marrow transplant and two-logs lower than a peripheral blood stem cell transplant 
(akin to a T-depleted graft); ii) all patients will receive serotherapy with ATG as part of their CBT 
conditioning and will therefore undergo in vivo T cell depletion; iii) in our CBT population, the 
median time to acute GVHD grade I-IV is 34 days (manuscript submitted). Administration of 
CYT107 can be initiated between day 60-180, and all patients with a prior history of aGVHD will 
be excluded from the study. 
 
 

 
 
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3.0 Patient Eligibility 
3.1 
Patient Inclusion Criteria 
 
1. Patient 18 years old or older. 
2. English and non-English speaking patients are eligible. 
3. Patient post a cord blood transplant (CBT) or haplo-SCT, mismatched unrelated donors 
(mMUDmatched), unrelated donors (MUDs), matched related donors (MRDs), both PB and 
marrow sources with documented absolute neutrophil engraftment. 
4. Patients with documented engraftment but require G-CSF to treat myelosuppression 
induced by drugs used to treat or prevent infection are eligible. 
5. Karnofsky performance status (KPS) > 60%. 
6. Adequate organ function: 
· 
Pulmonary: Absence of dyspnea or hypoxia (< 90% of saturation by pulse oximetry on 
room air). 
· 
Hepatic: Bilirubin </= 1.5 X ULN, AST (SGOT) and /or ALT (SGPT) </= 2.5 X ULN. 
PT/PTT < 1.5 X ULN. 
· 
Renal: Calculated Creatinine clearance > 50 mL/min/1.73 m2. 
7. Diagnosis of acute myeloid leukemia; myelodysplastic syndrome; chronic myeloid leukemia; 
myelofibrosis or myeloproliferative disease. 
8. Patients are allowed to enroll on this study if they are enrolled on another IND trial. 
 
3.2 
Patient Exclusion Criteria 
 
1. Pregnant or nursing. 
2. History of lymphoid malignancy (including Hodgkin disease, non-Hodgkin lymphoma, Acute 
Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia) or acute biphenotypic 
leukemia. 
3. Patients with acute GVHD > grade 2 at any time during the post-transplant course. 
4. Ongoing immunosuppressive therapy for the treatment of GVHD.  Patients receiving 
GVHD prophylaxis will be allowed on this study. 
5. History of EBV associated lymphoproliferation. 
6. Active uncontrolled viral, bacterial or fungal infection. 
7. History of autoimmune disease. 
8. Receiving systemic corticosteroid therapy at </=5 mg, budesonide is allowed. 
9. Uncontrolled hypertension. 
10. QTc prolongation (QTc > 470 ms) or prior history of significant arrhythmia or ECG 
abnormalities. 
11. Active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements. 
12. Patients with cognitive impairments and/or any past or current psychiatric illness that, in the 
opinion of the investigator, would interfere with adherence to study requirements or the ability 
and willingness to give written informed consent. 
 
 
 
 
 
 
 

 
 
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4.0  Treatment Plan and Study Design 
 
CYT107 will not be administered before Day 60 but could be started as late as Day 180 
post-CBT or haplo-SCT. 
 
The active treatment period will be from the first injection of CYT107 and for 30 days after the 
last injection. The follow-up period will be for three years after the last injection. 
 
Patients will be treated with CYT107 by intramuscular route (I.M.)* post CBT or haplo-SCT 
(from 60 to 180 days), with 1 of 3 doses below: 
 
· 
5 mcg/kg/dose for 3 doses, one week apart 
· 
10 mcg/kg/dose for 3 doses, one week apart 
· 
20 mcg/kg/dose for 3 doses, one week apart 
 
Enrollment of the first 3 participants will be staggered by 14 days. Accrual in between cohorts 
will be halted for 30 days after the last patient in each cohort has received the last dose of 
CYT107. 
* If the patient's platelet count is below 35,000, the product may be administered by 
subcutaneous route. 
 
All patients will receive foscarnet for the management of CMV infection as per Stem Cell 
Transplantation and Cellular Therapy Department's standard of care. 
 
Dose modifications 
 
Treatment will be permanently discontinued for patients developing grade 3 or 4 GVHD, 
secondary graft failure, disease relapse, PTLD, PML, grade 2-4 skin rash, or grade 3-4 
non-hematological toxicity attributable to CYT107. 
 
Patients who develop grade 2 non-hematological toxicity attributable to the CYT107 will have 
the next dose withheld until the toxicity resolves to grade 1. If the toxicity resolves within 2 
weeks the drug will be administered at the same dose, however if the toxicity takes more than 2 
weeks to resolve the drug will be administered at the next lower level, or permanently 
discontinued if the patient was already at the lowest level. If the toxicity takes more than 4 
weeks to improve to grade I, the CYT107 will be permanently discontinued 
 
For patients who at study entry have grade 0, 1 or 2 hematological toxicity and develop grade IV 
hematological toxicity attributable to the CYT107 will have the next dose withheld until the 
toxicity resolves to grade 2. If the toxicity resolves within 2 weeks the drug will be administer at 
the same dose, however if the toxicity takes more than 2 weeks to resolve the drug will be 
administered at the next lower level, or permanently discontinued if the patient was already at 
the lowest level. If the toxicity takes more than 4 weeks to improve to grade 2, the CYT107 will 
be permanently discontinued 
 
There are no planned dose modifications for patients who already have grade 3-4 hematological 
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5.0  Background Drug Information 
 
5.1 CYT107 (IL-7) 
 
Description 
 
CYT107 is a recombinant protein belonging to the class of growth factors and more specifically 
to the class of cytokines. CYT107 is a heavily glycosylated and sialylated form of recombinant 
human interleukin-7 expressed from a CHO cell line, composed of 152 amino acids, with an 
average molecular mass as determined by mass spectrometry of 22 kDa and a mean pI of 7. 
The molecular formula of the peptidic sequence only (non glycosylated) is 
C762H1241N213O228S11. The protein contains 3 disulfide bridges (Cys2- Cys 92, Cys 34- Cys 
129, and Cys 47- Cys 141) and 4 glycosylation sites (3N, 1O). 
 
Source 
 
CYT107 used in this clinical trial was manufactured under good manufacturing practice (GMP) 
criteria at a 600 L fermentation and purification scale by PATHEON (Princeton, NJ), for 
REVIMMUNE Inc. At clinical site, the product will be made available to the hospital pharmacy by 
CSM, Fargo, ND 58103. 
 
Formulation 
 
CYT107 is supplied in a 2 mL vial as 0.5 mL of CYT107 (1 mg) in 10 mM Sodium Acetate, 100 
mM NaCl, 50 mM glutamic acid. The pH of the solution is 5 and the osmolality is 320 40 mOsm. 
The concentration of CYT107 in solution is 2 mg/ml. 
 
Stability 
 
Stability studies will continue throughout the clinical study. Updated stability information will be 
periodically communicated to the hospital pharmacy. 
 
Special Handling 
 
There are no specific guidelines for safe handling of CYT107. Institutional guidelines for safe 
handling of proteins in general should be followed. 
CYT107 Preparation 
 
Syringes containing the CYT107 dose will be prepared by the hospital pharmacy. The product 
should be defrosted at least 1 hour before administration. Defrosted product (and possibly put in 
syringe) should be kept refrigerated at +4°C/+8°C until use and for no more than 8 hours. 
 
CYT107 flip-top vials will only be used if the solution is clear (following visual inspection), the 
vial is undamaged and the use by (expiration) date (if marked on the vial) has not been passed. 
Based on patient’s body weight on day of study entry, the appropriate number of vials of 
CYT107 drug product will be prepared and administered. (See Body Weight (BW) Calculation 
below.) CYT107 will be kept refrigerated until time of immediate administration to the patient. 

 
 
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To minimize the chance for contamination, sterile or septic technique should be carefully 
observed during CYT107 solution preparation (filling of the syringe) and administration. 
 
A flip-top vial is restricted for use by a single patient. Take no more than 0.5 mL into the syringe. 
The dose to be injected will be divided as necessary into intramuscular injections so that each 
injection will not exceed 0.5 ml in volume. (Dosing guidelines for ideal body weight make the 
requirement for multiple injections highly unlikely). 
 
Body Weight (BW) Calculation 
 
If patient is </= 20% of ideal body weight (IBW), use actual weight. 
 
In obese patients, a corrected weight will be used to calculate the final dose the patient will 
receive.  The corrected dose will be calculated and used if the patient’s actual weight give a 
Body Mass Index (BMI) at the upper limit of normal (i.e. BMI >30).   
 
BMI=weight (Kg)/[height(m)]^2   
 
A BMI calculator is provided by www.cdc.gov: 
 
https://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/english_bmi_calculator/bmi_calcul
ator.html 
 
If BMI >30 proceed with the following steps to determine the adjusted body weight for the dose 
calculation: 
• 
Determins Ideal weight (1 kg=2.2 lbs): 
o Males: 50 kg + (2.3kg/inch over 5 ft) 
o Females 45.5 kg + (2.3kg/inch over 5 ft) 
• 
Determine Adjusted Body weight: 
o Ideal Weight + 0.25 (actual weight - ideal weight)= Adjusted Body Weight 
 
CYT107 Presentation and Packaging 
 
CYT107 is supplied as a sterile colorless liquid in 2 cc glass vials that are packed individually in 
cardboard box. Labels are stuck on vial and box. 
 
The labeling is following local and GMP rules. The detailed description of labeling is provided in 
the Pharmacy Manual. 
 
CYT107 Storage Accountability and Return of Unused Product 
 
Study product will be stored frozen at -25°C to -10°C until used. 
 
The Investigational Pharmacy will maintain complete records of all study products received, 
stored and subsequently dispensed. 
 
Per MDACC standard, empty, partially used, and expired vials will not be retained. These vials will 
be discarded immediately upon use in accordance with waste stream policy. 
 
MD Anderson's Investigational Pharmacy Services will use its electronic accountability system 
in lieu of sponsor-provided accountability forms. 

 
 
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The detailed procedures to be followed are provided in the Pharmacy Manual. 
Study Drug Administration 
 
Each dose of CYT107 will be administered by a registered nurse. CYT107 will be administered 
by intramuscular route at the dose of 5, 10 or 20 mcg/kg based on the patient’s body weight and 
the dose escalation cohort. (See Body Weight (BW) Calculation above.) 
 
The detailed procedures to be followed are provided in the Pharmacy Manual including a table of 
volumes to be administered per patient total body weight. 
 
6.0 Evaluation During Study 
Every effort will be made to adhere to the schedule of events and all protocol requirements. 
Variations in protocol requirements that do not affect the rights and safety of the patient will not 
be considered as deviations. Such variations may include laboratory assessments completed 
outside of schedule and occasional missed required research samples. Missed samples for 
correlative studies will not constitute protocol deviations. 
For patients who have discharged to their home clinics, and are not being followed weekly at 
MD Anderson, labs and assessments will be collected as feasible in their home clinics or upon 
patient’s return to MDACC clinic.  Any missed time points will not be counted as protocol 
deviations. 
 
6.1 
Pre-Treatment Evaluations 
 
Within 2 weeks of first dose: 
 
1. BK, CMV, and EBV blood level by PCR 
2. EKG 
3. Oxygen saturation by pulse oximetry 
4. Creatinine 
5. AST, ALT, bilirubin 
6. PT/PTT 
7. Electrolytes 
8. Physical exam 
9. Medical history 
 
6.2 
Evaluation after CYT107 administered: 
 
Weekly until day +42 following CYT107: 
 
1. CBC, differential, platelets 
2. SGPT, calcium, glucose, uric acid, magnesium, serum bilirubin, BUN and creatinine, serum 
protein, albumin, ALT, alkaline phosphatase, electrolytes, tacrolimus levels. 
3. Physical examination 
4. Adverse event assessment 
 
6.3 
Viral Infections. Patients will be monitored for viral infections after the CYT107. 
 

 
 
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1. CMV by PCR will be assayed in the blood weekly from the start of IL-7 therapy until day 180 
from the start of IL-7 therapy. 
2. EBV PCR will be assayed in the blood every two weeks from day 60 until day 100 and then 
monthly until day 180 from the start of IL-7 therapy. 
3. BKV PCR will be assayed in the urine and blood if patients become symptomatic, as 
clinically indicated. 
 
6.4 
Correlative Studies 
 
Circulating lymphocyte subsets will be measured, using immune reconstitution lab, prior to 
administration of each dose of CYT107 and approximately days 21 and 28, and 100 days 
after the first injection in the MD Anderson CLIA-approved clinical flow cytometry laboratory. 
The lymphocytes subsets analyzed will be CD4 and CD8 subsets including naïve and 
memory T-cells based on expression CD45RO, CD62L and CCR7. T-regulatory cells, B-
cells and NK cells will also be evaluated. This studies will be used to help identify the 
optimal IL-7 dose for a subsequent phase-II trial.   
 
Correlative study samples will be obtained via MD Anderson laboratory protocol LAB99-062 
if patient consents.  
 
6.5 
Plasma Samples 
 
Plasma samples will be drawn to test for anti-CYT107 antibodies on approximately Days 0 (prior 
to IL-7 administration), 42, and 100 from the start of IL-7 therapy. The samples will be batched and 
sent to Revimmune for immunogenicity assays. 
 
6.6     Outside Physician Participation During Treatment 
 
a)  MDACC Physician communication with the outside physician is required prior to 
the patient returning to the local physician. This will be documented in the patient 
record 
b)  A letter to the local physician outlining the patient's participation in a clinical trial 
will request local physician agreement to supervise the patient's care.    
c)  Protocol required evaluations outside MDACC will be documented by telephone, 
fax or e-mail.  Fax and/or e-mail will be dated and signed by the MDACC 
physician, indicating that they have reviewed it. 
d)  Changes in drug dose and/or schedule must be discussed with and approved by 
the MDACC physician investigator, or their representative prior to initiation, and 
will be documented in the patient record. 
e)  A copy of the informed consent, protocol abstract, treatment schema and 
evaluation during treatment will be provided to the local physician. 
f)   Documentation to be provided by the local physician will include drug 
administration records, progress notes, reports of protocol required laboratory and 
diagnostic studies and documentation of any hospitalizations. 
g)  The home physician would only be alerting the Principal Investigator to a subject’s 
life-threatening event (much as a family member would) and the Principal 
Investigator would be assessing the event per the protocol. 
h)  Patients will be evaluated either in person or remotely via telemedicine. 
 

 
 
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7.0 Statistical Considerations 
 
7.1 Outcomes and Covariates 
 
7.1.1 Primary Outcomes 
 
Toxicity.  Dose limiting toxicity (DLT) is defined as any of the following events: grade 3 or 4 GVHD, 
secondary graft failure, disease relapse, development of PTLD, development of PML, grade 2 organ 
failure or grade 2-4 skin rash, fatigue, AST and ALT elevations, allergic anaphylaxis, or hemolytic 
anemia, attributable to CYT107,  or death, occurring within 42 days of the first CYT107 injection.  
 
Biological Responses. The absolute number and percentage of total White Blood Cells (WBCs)  
consisting of T-cells and of B-cells will be observed at 1, 3, 6, 9 and 12 months.   
 
7.1.2 Secondary Outcomes 
 
Progression-free survival time, Overall survival time, Cytomegalovirus occurrence and severity , 
Epstein-Barr virus occurrence and severity, BK virus occurrence and severity 
 
All time-to-event outcomes will be measured from the time of CYT107 administration, with a maximum  
follow up of at least 12 months. 
 
7.2 Baseline covariates  
 
Baseline patient covariates to be recorded at enrollment will include the following variables: 
 
Conditioning regimen received 
GVHD prophylaxis 
Type of donor 
Type of graft 
Time to engraftment from cell infusion 
Donor age 
Acute (grades 2 – 4) GVHD 
Patient age 
Time to neutrophil engraftment 
Time to platelet engraftment 
Disease (AML or MDS) 
 
7.3 Trial Conduct 
 
7.3.1 Dose Assignments 
 
Three dose levels of CYT107 will be considered: 5, 10, and 15 mcg/kg, hereafter denoted as 
dose levels 1, 2, and 3.  
 
Randomization, rather than conventional sequentially adaptive dose selection, is based on the 
fact that neither Pr(DLT) nor any biological outcomes are necessarily monotone increasing in 

 
 
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dose of the biological agent IL-7, and also the scientific goal to obtain unbiased comparisons 
between doses. 
 
 A maximum of 21 patients will be randomized among the three IL-7 3 doses, with the 
randomization constrained to have exactly 7 patients per dose.    Since 2 patients previously have 
been enrolled and assigned to d=1, a randomization sequence will be provided for assigning 
doses to the remaining 19 patients, 3 – 21.   
 
 
7.3.2 Within-Dose Safety Monitoring  Rule 
  
For each dose d = 1, 2, 3, denote p(d) = Pr(DLT at dose d).   Assume that each p(d) follows a 
beta(.35, .65) prior.  Applying the method of Thall et al.41, enrollment to dose d will be stopped if   
 Pr[p(d) > .35 | data ]   >  .85.   This criterion will be applied continuously starting at n = 3, which 
implies that accrual to d  should be stopped if [number of DLTs] / [number of patients evaluated] 
is greater than or equal to 3/3 or 4/5.  To apply this safety rule for each dose to 2 cohorts of size 3 
each may or may not require suspension of accrual.  For each dose (a)  once 1 or more pats in 
cohort 1 (pats #1,2,3) have “No toxicity” by day 42 of followup, cohort 2 may begin enrollment, 
and (b) once 2 or more pats in cohorts 1 and 2 combined (pats #1,2,3,4,5,6) have “No toxicity” by 
day 42 of follow up, the last patient 7 may be enrolled. This rule has the following operating 
characteristics.   
 
Operating characteristics of the within-dose safety monitoring rule 
 
True p(DLT | d) 
Pr(Stop accrual to d) 
Sample Size  Quartiles 
.35 
.163 
7,   7,   7 
.55 
.497 
4,   7,   7 
.60 
.601 
4,   6,   7 
.65 
.607 
3,   4,   7 
 
 
7.4 Enrichment 
 
If enrollment to a dose d is stopped early at n(d) = 3 or 6 before 7 patients are treated, then the 
remaining 7–n(d) =  1 or 4 patients will be randomized between the remaining  two doses.  If 
enrollment  to 2 doses is stopped early, then all remaining patients, up to Nmax = 21, will be 
treated at the one remaining dose.  If enrollment to  all 3 doses is stopped early, then the trial will 
be stopped with no dose selected. 
 
7.5 Data Analysis 
 
7.5.1 Tabulation 
 
Each primary and secondary variable will be tabulated by dose using summary statistics, 
consisting of counts and percentages for categorical variables and the sample median and range 
for numerical valued variables.   Kaplan-Meier plots34 will be used to estimate the PFS and OS 
distribution for each dose. 
 
7.5.2 Regression Modeling 
 

 
 
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Bayesian longitudinal regression models42 will be fit to the final data on each of the four biological 
response variables, as defined in section 1, including in each model a parametric function of time 
and the baseline covariates patient age, type of graft, and disease (AML vs MDS).  Preliminary 
analyses will include a smoothed plot of each longitudinal outcome variable as a function of time. 
 
7.5.3 Optimal Biological Dose Selection 
 
At the completion of the trial, when all patients have been followed up fully and all outcomes 
evaluated, the optimum biological dose (OBD) will be defined as the dose maximizing the sample 
mean percentage of WBCs that are T-cells, evaluated at one year of follow up. 
 
7.6 Trial Conduct 
 
The Biostatistics Department Clinical Trial Conduct Website will be used to assign a dose to each 
patient at enrollment.   This will be set up and overseen by a Research Statistician in the Biostat 
Dept to be designated by Dr. Thall prior to re-starting the trial at patient number 3, using a 
randomization sequence provided by Dr. Thall.   The Principal Investigator and designated 
personnel in the SCT Dept will be responsible for recording all baseline covariates and outcome 
variables and implementing the within-dose stopping rule in terms of DLTs. 
 
7.7 Summary Reports 
 
The investigator is responsible for completing a toxicity summary report and submitting it 
to the IND Office, Medical Affairs and Safety Group, for review and approval. This should 
be submitted after the first, the first three, and the first five evaluable patients per cohort, 
have completed 42 days post-first CYT107 injection. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder, 
under “Sponsor Correspondence”. 
 
8.0  Criteria for Removal from the Study 
 
Any patient can be removed from study for the following: 
- 
Patient withdrawal of the informed consent 
- 
Patient not being compliant 
- 
An increasing or unexpected pattern of toxicity is observed deemed unacceptable by 
the study chairman 
- 
 Grade 2-4 skin rash, grade 3 or 4 GVHD, secondary graft failure, disease relapse, 
PTLD, PML or grade 3-4 non-hematological toxicity attributable to CYT107 
- 
Disease progression 
- 
Investigator judgment when the well-being and best interest of the patient is compromised 
- 
Secondary Graft Failure 
- 
1 year after last injection. 
 
 
9.0  Adverse Events and Reporting Requirements 

 
 
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Adverse event definition: 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy and otherwise meet the criteria for a 
reportable adverse event as defined above. They are to be captured under the signs, symptoms 
or diagnoses associated with them. 
 
It is common for HCT recipients to experience multiple complications as part of the transplant 
itself that are unrelated to exposure to investigational agents. Symptoms of the original or 
targeted disease are not to be considered adverse events for this study except for 
hematological toxicities as defined below. From start of study treatment through 30 days from 
last dose of CYT107, symptoms related to the conditioning regimen will not be reported unless 
the event is both serious and considered by the investigator to also be possibly, probably, or 
definitely related to CYT107. After 30 days from the last dose of CYT107, adverse events 
should only be reported if they are both serious and probably or definitely related to CYT107. 
Events that are unlikely or unrelated to CYT107 are not required to be reported. Reporting of 
such events should include the investigator’s assessment as to whether the event should be 
attributed to any of the HCT procedure itself, CYT107, GVHD, or exposure to 
immunosuppressive agents. An event may be attributable to all, some, or one of these 
categories. 
 
Assessment of the Adverse Events Severity: 
The severity of the adverse events (AEs) will be graded according to the Common Terminology 
Criteria v4.0 (CTCAE). 
 
 
 
 
 
Treatment period: 
Active treatment period (ATP) is defined from the first injection of CYT107 through 30 days from 

 
 
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the last injection. 
 
Time for Adverse Event (AE) Collection: 
Adverse events will be collected from the first injection of CYT107 through 30 days from the last 
injection. AEs that occur up to 30 days from the last injection of CYT107 will be followed until 
resolution. 
 
The collection of adverse events will reflect the onset and resolution date and maximum grade. 
If a patient is taken off study while an event is still ongoing, this will be followed until resolution 
or the event has stabilized. 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. 
 
Adverse Event Reporting: 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events, and assigning attribution for each event on all subjects 
enrolled on this study. 
 
Adverse events will be documented and entered into the electronic case report form 
(REDCap/CORe). All protocol specific data will be entered into REDCap/CORe. 
 
Events not to be considered adverse events in this study are those related to original disease or 
expected in the post-allogeneic transplant period. 
 
Isolated changes in laboratory parameters such as electrolyte, magnesium and metabolic 
imbalances, uric acid changes, elevations of GPT, GOT, LDH and alkaline phosphatase will not 
be captured. 
 
Concomitant medications 
Patients treated on this protocol will require supportive care treatment (concomitant medications). 
These medications are considered standard of care and have no scientific contribution to the 
protocol; therefore no data will be captured on various medications needed or their side effects. All 
concomitant medications will be captured in the medical record. 
 
Causality Assessment. 
The principal investigator will be the final arbiter in determining the casualty assessment. 
 
List of most common expected adverse events: 
1. 
GVHD 
2. 
Secondary graft failure 
 
Serious Adverse Event Reporting (SAE) for MD Anderson-Sponsored IND Protocols 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
· 
Death 
· 
A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 

 
 
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· 
Inpatient hospitalization or prolongation of existing hospitalization 
· 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
· 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
· 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 
· 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported 
to the IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
· 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
 
· 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
 
· 
A copy of the eSAE report will also be sent to Michel Morre (michel.morre@revimmune.com) 
and to Revlimid (pv-revimmune@anticipsante.com), the supporter of CTY-107. 
 
· 
Serious adverse events will be captured from the time of the first injection of CYT107 
through 30 days from the last injection. Serious adverse events must be followed until 
clinical recovery is complete and laboratory tests have returned to baseline, progression of 
the event has stabilized, or there has been acceptable resolution of the event. 
 
· 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
 
Reporting to FDA 
 
· 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 

 
 
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AEs Attribution Assessment 
 
Events assessed as to be caused by the administration of CYT107 and its direct consequences 
will be assessed as definite related. 
 
When the relationship of the adverse event cannot be ruled out between the CYT107 and the 
drugs used as part of the treatment plan, as well as for GVHD, infections and supportive 
treatment, the event will be scored as probably or possible related. 
 
The principal investigator will be the final arbiter in determining the causality assessment. 
 
AEs Severity Assessment 
 
AEs will be assessed according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
 
Events not included in the CTCAE version 4.0 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. 
AEs Data Collection 
Redcap/Core will be used as the electronic database/case report form (CRF) for this protocol. 
 
During the active treatment period, expected and unrelated adverse events considered 
unexpected and related to CYT107 will be collected in electronic medical record (EPIC). SAEs 
and AEs that require dose modifications will be captured in REDCap. The data will reflect the 
onset and resolution date and maximum grade. Intermittent events should be labeled as such 
and followed until resolution. If a patient is taken off study while an event still ongoing, this will 
be followed until resolution or the event has stabilized. Pre-existing medical conditions will be 
recorded only if an exacerbation occurs during the ATP. Co-morbid events will not be scored 
and collected separately. 
 
Medical events not considered adverse events will not be documented in the CRF. They will be 
captured in the medical record. 
 
· 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of knowledge 
of the event). 

 
 
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· 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the event 
to the Safety Project Manager in the IND Office. 
· 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
A copy of the eSAE will also be sent to RevImmune, the supporter of CYT-107. 
· 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
· 
Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
· 
Patients who withdraw consent due to toxicities will be evaluable and considered treatment 
failures. 
 
 

 
 
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