A Phase I/II Clinical Trial of "Off-the-shelf" NK Cell Administration in Combination With Allogeneic SCT to Decrease Disease Relapse in Patients With High-risk Myeloid Malignancies Undergoing Matched Related, Matched Unrelated, One Antigen Mismatched Unrelated, or Haploidentical Stem-cell Transplantation
Phase: PHASE2
Conditions: Myeloid Malignancies, Acute Myeloid Leukemia, Myelodysplastic Syndrome, Chronic Myeloid Leukemia
Sponsor: M.D. Anderson Cancer Center

 
A Phase II Clinical Trial of “Off-the-shelf” NK cell administration in combination 
with allogeneic SCT to decrease disease relapse in patients with high-risk Myeloid 
malignancies undergoing Matched related, Matched unrelated, One antigen 
mismatched unrelated, or Haploidentical 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, Radiation Oncology Department 
3 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
 
 
Institution Study Number:  2021-0329 
Financial Supporter:   Kiadis Pharma 
IND Holder:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  27750 
Principal Investigator:  Jeremy Ramdial, MD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0423 
Houston, TX 77030 
Telephone: 713-745-0146 
Fax: 713-794-4902 
jlramdial@mdanderson.org 
 
Co-Chairs:  Richard Champlin, MD1 
 
 
Collaborators:  Bouthaina S. Dabaja, MD2 
Peter Thall, PhD3 
Roland L.Bassett, Jr., MS3 
 

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Table of Contents  
1.0 
OBJECTIVES ............................................................................................................................................... 4 
1.1  
PRIMARY OBJECTIVE ............................................................................................................................................. 4 
1.2  
SECONDARY OBJECTIVES ........................................................................................................................................ 4 
2.0 
BACKGROUND AND RATIONALE ................................................................................................................. 4 
2.1 
ALLOSCT FOR AML, MDS, AND TKI RESISTANT/INTOLERANT CML .............................................................................. 4 
2.2 
NATURAL KILLER CELLS .......................................................................................................................................... 5 
2.3 
CLINICAL EXPERIENCE USING INFUSION OF NK CELLS AFTER TRANSPLANT ......................................................................... 6 
2.4 
RATIONALE FOR USE OF THIRD PARTY EXPANDED NK CELLS ........................................................................................... 8 
2.5 
KDS-1001 DESCRIPTION ..................................................................................................................................... 10 
2.6 
KDS-1001 NONCLINICAL EXPERIENCE ................................................................................................................... 10 
3.0 
PATIENT ELIGIBILITY ................................................................................................................................. 10 
3.1 
   INCLUSION CRITERIA ......................................................................................................................................... 10 
3.2 
EXCLUSION CRITERIA ........................................................................................................................................... 12 
4.0 
EVALUATION DURING STUDY ................................................................................................................... 12 
4.1      OUTSIDE PHYSICIAN PARTICIPATION DURING TREATMENT ............................................................................................. 17 
5.0 
TREATMENT PLAN ................................................................................................................................... 17 
6.0 
ENDPOINTS .............................................................................................................................................. 20 
7.0 
STATISTICAL CONSIDERATIONS ................................................................................................................ 24 
7.1       PRELIMINARIES ................................................................................................................................................... 24 
7.2 
SAMPLE SIZE ..................................................................................................................................................... 24 
7.3   
TIME-TO-FAILURE MONITORING RULE ................................................................................................................... 24 
7.4 
DATA ANALYSES ................................................................................................................................................. 25 
8.0 
CRITERIA FOR REMOVAL FROM THE STUDY .............................................................................................. 26 
9.0 
REPORTING REQUIREMENTS .................................................................................................................... 26 
10.0 
ADVERSE EVENTS AND DATA COLLECTION ............................................................................................... 31 
10.1 
COMMON TERMINOLOGY CRITERIA ADVERSE EVENTS (CTCAE) .................................................................................. 31 
10.2 
TIME FOR AE COLLECTION ................................................................................................................................... 33 
10.3  
AE REPORTING .................................................................................................................................................. 33 
10.4       DATA COLLECTION .............................................................................................................................................. 33 
10.5 
CONCOMITANT MEDICATIONS ............................................................................................................................... 34 
11.0 
REGULATORY CONSIDERATIONS .............................................................................................................. 34 
11.1  
INSTITUTIONAL REVIEW BOARD ............................................................................................................................ 34 
11.2  
STUDY CONDUCT ............................................................................................................................................... 34 
11.3 
SUBJECT PRIVACY ............................................................................................................................................... 34 
11.4 
WRITTEN INFORMED CONSENT ............................................................................................................................. 35 
12.0 
BACKGROUND DRUG INFORMATION ....................................................................................................... 35 
13.0 
REFERENCES ............................................................................................................................................ 38 
APPENDIX 1. .................................................................................................................................................................. 40 
APPENDIX 2. .................................................................................................................................................................. 48 
 

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1.0   Objectives 
 
1.1  
Primary Objective 
 
Assess the safety and effectiveness of “off the shelf” third party NK cells in 
combination with allogeneic SCT in patients with myeloid malignancies.   
 
1.2  
Secondary Objectives 
 
i. To assess NK cell related toxicities 
ii. To estimate the proportion of patients with engraftment/graft failure. 
iii. To assess the rate of leukemia relapse, disease-free survival (DFS), overall 
survival (OS), and GVHD-free, Relapse-free survival (GRFS) after 
transplantation by one year. 
iv. To estimate the non-relapse mortality (NRM) at day 100, day 180 and 1 year 
post-transplant. 
v. To estimate the cumulative incidence of grade 2-4 and grades 3-4 aGVHD    
 
at day 100. 
vi. To assess the rate of chronic GVHD within the first-year post transplantation. 
vii. To assess rate of BK, CMV, and Adenovirus infections. 
viii. To assess MRD.  
ix. To assess immune reconstitution post-transplant. 
 
2.0   Background and Rationale 
 
2.1 
AlloSCT for AML, MDS, and TKI resistant/intolerant CML 
 
Acute myeloid leukemia, myelodysplastic syndrome, and TKI resistant CML 
continue to be among the most aggressive forms of blood cancer. Allogeneic 
hematopoietic stem cell transplantation (alloSCT) remains one of the most 
effective treatments available. Much of the benefit of AlloSCT is due to the 
immune-mediated graft-versus-leukemia effect to prevent relapse1-4. Nevertheless, 
disease relapse remains the most important cause of treatment failure after 
alloSCT.  
 
A potential solution to reduce the risk of relapse may be found in Natural Killer 
(NK) cells, which have a demonstrable ability to eliminate leukemic and virally 
infected cells.   However, naturally produced NK cells seen in patients early post-
transplant are functionally impaired. A potential solution would be to provide donor-
derived, expanded and activated NK cells in the peri-transplant setting. This is a 
challenge, since patients have aggressive disease characteristics and patient-
specific donor NK cells require a substantial time to expand, donor NK cells from 
the same donor as the stem cell donor may not confer optimal anti-leukemic 

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reactivity, and patient specific manufacture of NK cells is expensive.  
 
Administration of off-the-shelf third party NK cells in the peri-transplant period may 
allow for minimizing delays in treatment and also provide the benefit to select a 
donor conferring effective NK cell alloreactivity to enhance the graft versus 
leukemia effect and decrease relapse.  Large numbers of expanded NK cells may 
be produced from one donor improving cost effectiveness. 
 
2.2 
Natural Killer Cells 
 
Natural killer (NK) cells are a unique class of lymphocytes, with cytotoxic, and 
immunoregulatory function which can mediate potent antileukemia effects5-7. NK 
cells are regulated by Killer-cell Immunoglobulin-like Receptors (KIR) receptor-
ligand interactions and mediate cytotoxicity against certain HLA class I 
mismatched targets8. Alloreactive NK cells have been reported to enhance 
engraftment, reduce GVHD and prevent relapse of leukemia post transplant5-7. 
This study will utilize NK cells from third party donors as adjuvant treatment to 
eradicate leukemia and prevent disease relapse after transplantation. 
Natural killer cells have both cytotoxic and immunoregulatory functions. Human NK 
cells are characterized by expression of CD56 with or without CD16, and the 
absence of T-cell receptor and CD3 expression5,6. There are 2 subtypes of NK 
cells: CD56dimCD16bright cells, which compose 90% of the NK cells from 
circulation which have cytotoxic function, and express MHC class I allele-specific 
KIRs, and the CD56brightCD16neg cells present in small numbers in the peripheral 
blood but 100% in lymphoid tissues, and secrete immunoregulatory cytokines, like 
interferon (IFN) gamma, and promote adaptive immune responses. NK cell 
cytotoxicity can be upregulated by increased secretion of cytokines including 
interleukin (IL)-2 (IL-2) and IL-15, whereas IL-12 and IL-18 increase IFN-γ 
secretion by NK cells5. NK cell reactivity is governed by activating and inhibitory 
receptors. By the “missing ligand model” initially described by Karre in 1986, killing 
of tumor cells by NK cells occurs when there is a missing signal (or missing self) 
on the target cells9. Several inhibitory receptors and putative activation receptors of 
the NK have been characterized and they can be classified as lectin-like receptors 
(CD94) receptors and KIR10-12.  
 
In man, some HLA class I molecules expressed on the target cells are ligands of 
the CD94 and KIR receptors. The interactions between NK receptors molecules 
are specific for different HLA isotypes, for example, the inhibitory receptor KIR2 
DL4 interacts with HLA-G molecules. KIRs interact with groups of alleles of HLA-C 
and HLA-B. It is of interest that the KIR2DL1 receptor interacts with alleles of the 
HLA-C locus that have the amino acid lysine (Lys) at residue 80 (C-lys-80) while 
the receptors KIR2DL2 and KIR2DL3 interact with alleles of HLA-C that have 
asparagine (Asn) at residue 80 (C-asn-80). Interestingly, the substitutions Lys/Asn 
at residue 80 define a bi-allelic system in all alleles of HLA-C in which all the alleles 
of this locus carry either of these amino acids. The alleles of HLA-B locus present 
also different capacities to interact with the receptor KIR3DL1; only the HLA-B 

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alleles carrying the supertypic serologic epitope HLA-Bw4 (encoded in the amino 
acid stretch spanning residues 77-83) interact with KIR3DL110-12. Therefore, in an 
allogeneic transplantation setting, in which the donor and recipient are mismatched 
in the alleles of HLA-B or in HLA-C, the NK cells from the donor may not be 
inhibited by the target cells of the recipient that lack the appropriate HLA alleles 
which interact with the KIR receptors.  
 
In allogeneic bone marrow transplants the graft-versus-leukemia effect has been 
attributed in part to NK cells not being uninhibited due to the lack of the appropriate 
HLA ligand in the recipient. It is important to note that the KIR genes are encoded 
as a haplotype block (KIR loci) on chromosome 19q. The KIR haplotypes differ in 
gene content between individuals and some individuals may lack some KIR genes. 
The NK repertoire therefore may vary from individual to individual and will depend 
on the HLA phenotype and in the KIR haplotype gene composition. 
 
Allogeneic stem cell transplantation confers an immune mediated graft-vs.-
leukemia effect. NK cells have been shown to mediate a potent antileukemia effect 
against myeloid leukemias. As indicated above, inhibitory KIRs recognize HLA-C 
and -Bw antigens, when the corresponding ligand (HLA molecule) is present, 
cytotoxicity is inhibited; when the ligand is absent, cytotoxicity occurs (based on 
the “missing ligand” principle)13. Thus, NK cytotoxicity is most marked when NK 
cells react against a target missing the relevant class of HLA class I molecules. 
Velardi et al. have studied the results of T-cell depleted haploidentical transplants 
from alloreactive or nonalloreactive donors based upon this “missing ligand” 
principle14, and demonstrated that patients predicted to have alloreactive NK cells 
had no relapses compared to a 75% relapse in recipients of nonalloreactive 
transplants15. 
 
2.3 
Clinical experience using infusion of NK cells after transplant 
 
Several lines of evidence suggest that increased numbers of alloreactive NK cells 
would have benefit in the transplant setting, despite the fact that retrospective 
results vary depending on patient population, underlying diseases, conditioning 
regimens, graft composition and cell dose, degree of T-cell depletion, post-
transplant immunosuppressive regimens and differing methods of determining 
alloreactivity16.   Ruggeri et al. reported a retrospective evaluation of NK 
alloreactivity in transplanted patients15 and supportive NK models. This group 
analyzed 92 patients with high risk leukemia who received a haplotype 
mismatched hematopoietic stem cell transplant (HSCT) and reported that NK cell 
alloreactivity improved engraftment, protected from graft-versus-host disease 
(GVHD) and reduced the rate of relapse17. In mouse xenograft models it was 
demonstrated the role of alloreactive NK cells in eradicating human leukemia, 
improved engraftment by targeting host T lymphocytes, and reduced GVHD by 
eliminating recipient-type dendritic cells18. In addition, the NK cell dose of the 
infusion product has been associated with better outcomes following matched 
sibling transplants19. 

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A number of small prospective studies published mostly in abstract format (listed in 
Table 2), have reported on the safety of NK cell infusion. This experience has been 
recently reviewed by us6. A study of patients infused with NK cells post-transplant 
was reported by the Duke University group on non-expanded NK cells20. They 
infused a total of 51 NK cell-enriched donor lymphocyte infusions (DLIs) to 30 
patients following a 3-6/6 HLA matched T-cell-depleted non-myeloablative 
allogeneic transplant using with alemtuzumab part of the conditioning regimen20. 
Eight weeks following transplantation, donor NK cell-enriched DLIs were 
processed using a CD56+ selecting column, with up to 3 fresh infusions allowed. 
Fourteen matched and 16 haploidentical transplant patients received a total of 51 
NK cell-enriched DLIs. The median number of CD3- CD56+ NK cells infused was 
10.6×106 cells/kg and 9.21×106 cells/kg for matched and mismatched, 
respectively. The median number of contaminating CD3+CD56－ T-cells infused 
was 0.53×106 and 0.27×106 cells/kg in the matched and mismatched setting, 
respectively. All but 2 subjects had donor engraftment accounting for >80% of their 
hematopoiesis at the time of first infusion. After a median follow-up of 12 months 
for matched sibling donor transplants, and 27 months for the haploidentical 
transplants, 1 year overall survival was 43% and 42%, respectively18. Evaluating 
outcomes by disease, 1-year survival was 50% for the 19 patients with myeloid 

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diseases 29% for patients with lymphoid diseases. Only 1 patient each in the 
matched (n=14) or mismatched (n=16) groups experienced severe aGVHD with 
little other toxicity attributable to the infusions. Importantly, long-term responders 
had improved T-cell phenotypic recovery and improved duration of responses and 
overall survival after multiple NK cell-enriched infusions20. 
 
Finally, our group showed feasibility and safety of infusing high doses of ex vivo–
expanded NK cells after haploidentical HSCT without adverse effects, increased 
GVHD, or higher mortality, and was associated with significantly improved NK-cell 
number and function, lower viral infections, and low relapse rate posttransplant21. 
No infusion reactions or dose-limiting toxicities occurred. All patients engrafted with 
donor cells. Seven patients (54%) developed grade 1-2 acute GVHD (aGVHD), 
and  in later follow-up one developed grade 3-4 aGVHD and one developed 
chronic GVHD22, and a low incidence of viral complications was observed. One 
patient died of nonrelapse mortality; 1 patient relapsed. All others were alive and in 
remission at last follow-up (median, 14.7 months). NK-cell reconstitution was 
quantitatively, phenotypically, and functionally superior compared with a similar 
group of patients not receiving NK cells.   
 
2.4 
Rationale for use of third party expanded NK cells 
 
Kiadis Pharma is developing natural killer (NK) cells for oncologic therapeutic 
indications. KDS-1001 is an off-the-shelf donor-derived NK cell investigational 
immunotherapy manufactured with donor material obtained from an allogeneic 
donor. The expected efficacy and safety of KDS-1001 is derived from the known 
efficacy and safety profile of NK cells expanded using mbIL-21 and 4-1BBL 
expressing feeder cells. FC21-NK cells continue to be used worldwide in clinical 
trials in various tumor indications (See below).  
 
NK cells produced by utilizing the FC21 platform are used in multiple clinical trials 
in adults and pediatric population (Table 2). Three phase 1 clinical trials have been 
completed in adults: NCT0172909119, NCT0190413620, and trial NCT01823198 
in myeloid malignancies (unpublished, 22 patients). Upon positive outcomes of the 
phase 1 parts, two of these studies (NCT01729091 and NCT01904136) continued 
with a phase 2.  
 
Following the promising results in the phase 1 trials, FC21-NK cells are currently 
being used in 5 ongoing trials in pediatric and adults patients with: 
• relapsed/refractory AML - NCT0178747423 
• relapsed/refractory AML - NCT0280909224 
• relapsed/refractory AML - NCT0422068425 
• solid tumors including hepatocellular carcinoma - NCT02008929 
• non-small cell lung cancer - NCT02370017 
 
In addition to these trials, feeder cell expanded NK cells are being utilized in 
pediatric trials treating solid tumors such as neuroblastoma (NCT02573896, 
NCT03242603 and NCT03209869) and brain tumors (NCT0227171126). 

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Published (interim) efficacy and safety results for these studies are summarized in 
Table 2. 
 
 
 
There are several limitations to patient specific donor-derived, expanded NK cells. 
The cells must be manufactured from individual donors at great expense and take 
approximately one month to produce. This process requires an extra visit from the 
donor. Available donors may not have the optimal HLA and KIR genes to generate 
optimal anti-leukemic activity. Additionally, the inevitable possibility of failure in 
manufacturing of patient-specific therapeutics would leave patients without an 
alternate source of NK cells. 
 
An alternate is to produce expanded NK cells from selected third-party donors. 
Such cells would be banked and could be immediately available and be selected to 
confer maximal alloreactivity against the patient’s leukemia. 
 
We have shown that 108 expanded third party NK cells/kg can be safely infused 
with an autologous stem cell transplant and not produce graft failure or GVHD23. 
Similarly 1x108 NK cells per kg, third party cord blood derived NK cells can be 
infused on day -2 prior to allogeneic transplantation from HLA matched unrelated 
donors for treatments of myeloid leukemias without graft failure or an increase in 
the expected rate of acute GVHD20. In both of our studies the rate of relapse of the 
malignancies was low.  
 
In this study, we will examine the safety and potential efficacy of third party ex vivo 
expanded NK cells administered as adjunctive therapy to allogeneic HSCT with the 
goal of preventing leukemia relapse. Doses up to 108 NK cells/kg have been safely 
used in the aforementioned studies. This study will administer 3x107 NK cells/kg as 
a feasible dose to produce for therapeutic purposes (NK cells may be formulated 

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so that actual dose administered is +/- 20%) [Weight-based dosing bands]. If a 
patient’s weight exceeds 125 kg, the patient will receive the dose for a 125 kg 
patient). 
 
2.5 
KDS-1001 description 
 
The investigational product for this study is K-NK cells that will be manufactured 
and packaged by Kiadis Pharma Netherlands B.V. (Kiadis Pharma). This product is 
referred to as KDS-1001.  
KDS-1001 is composed of NK cells from a universal donor, expanded ex vivo 
using PM21 membrane particles. PM21 particles are formed from the plasma 
membranes of K562.mbIL21.41bbl (CSTX002) feeder cells.   
KDS-1001 is an NK cell suspension for intravenous administration and will be 
supplied frozen in cryobags, formulated at 5 x 107 viable NK cells/mL.  
 
2.6 
KDS-1001 Nonclinical experience 
 
In comparative in vitro studies, PM21 membrane particles effectively stimulated 
expansion of NK cells at rates similar to methods using feeder cells expressing 
mbIL-21 and 4-1BBL (FC21) and expressed the expected NK cell activation and 
inhibitory surface receptors, including the receptors NKG2D, NKp46 and CD16.  
PM21-NK cells and FC21-NK cells showed similarly potent cytotoxic activity 
against human leukemia target cells at relatively low effector concentrations. 
Likewise, PM21-NK cells and FC21-NK cells both secreted high amounts of anti-
tumor cytokines upon stimulation with cytokines or K562 human leukemia cells. 
Finally, PM21-NK cells and FC21-NK cells displayed similar activity towards tumor 
cells in a transgenic cancer mouse model. 
Refer to the IB, section 4, for the details from non-clinical in-vitro and in-vivo 
studies. 
 
3.0   Patient Eligibility 
 
3.1 
Inclusion criteria 
 
1) 
Patients ages 18 to 70 years old at the time of enrollment.  
2) 
Patients weighing at least 42 kg 
3) 
Patient with the hematologic malignancies described below, as well as an HLA 
matched related donor, HLA matched unrelated donor, a haploidentical related 
donor, or a one antigen mismatched unrelated donor. HLA matching includes 
HLA A, B, C, and DR-B1.   
4)   Patients must have one of the following diseases: 
 
Acute myeloid leukemia (AML): 
 
a.    With one or more high-risk features defined as: 
(i)  
Greater than 1 cycle of induction therapy required to achieve 
remission; 
(ii)  Preceding myelodysplastic syndrome (MDS); 

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(iii)  Presence of FLT3 mutations or internal tandem duplication or other 
mutations designated as adverse-risk by the ELN Leukemia Net AML 
Classification (see Appendix 2):  
Adverse: 
• 
t(6;9)(p23.3;q34.1)/DEK::NUP214 
• 
t(v;11q23.3)/KMT2A-rearranged#  
• 
t(9;22)(q34.1;q11.2)/BCR::ABL1  
• 
t(8;16)(p11.2;p13.3)/KAT6A::CREBBP  
• 
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, 
MECOM(EVI1)  
• 
t(3q26.2;v)/MECOM(EVI1)-rearranged  
• 
−5 or del(5q); −7; −17/abn(17p)  
• 
Complex karyotype,** monosomal karyotype††  
• 
Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, 
STAG2, U2AF1, and/or ZRSR2‡‡  
• 
Mutated TP53a 
 (iv)  FAB M6 or M7 classification; 
(v)   Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving 
3q,    9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 
abnormalities]; or other mutations designated as adverse-risk by the 
ELN criteria;  
(vi)  Treatment-related AML 
(vii)  Primary induction failure with partial response to therapy who 
 
achieve adequate cytoreduction 
(viii) Aplastic/hypoplastic marrow with or without detectable persistent 
disease after induction chemotherapy or after salvage chemotherapy. 
(ix)   Have minimal residual disease by flow cytometry, FISH, detection of 
disease related mutations or cytogenetic abnormality after first 
course of induction chemotherapy 
(x)    Have relapsed after prior allogeneic hematopoietic transplant 
 
AND 
 
b.  Patients must be in one of the following 
(i) 
CR: complete remission,  
(ii) 
CRi: CR with incomplete hematologic recovery, or  
(iii) MLFS: morphological leukemia-free state with less than 5% bone           
marrow blasts. 
(iv)   Primary induction failure with response to therapy who achieve 
adequate cytoreduction 
  (v)    Aplastic/hypoplastic marrow without detectable persistent    disease 
after induction chemotherapy or after salvage chemotherapy 
 
       
Myelodysplastic syndromes (MDS): 
a. 
De novo MDS with intermediate or high-risk IPSS scores, chronic 
myelomonocytic leukemia (CMML) or treatment-related MDS.  Patients 

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with intermediate-1 features should have failed to respond to 
hypomethylating agent therapy. . 
 
Patients must have less than 10% bone marrow blasts 
 
Chronic myeloid leukemia (CML): 
a.  Failed to achieve cytogenetic remission or have cytogenetic relapse after 
treatment with at least 2 tyrosine kinase inhibitors, or 
b.  Accelerated phase or blast phase at any time, or  
c.  Intolerant of available TKIs 
 
5) 
Performance score of at least 70% by Karnofsky or 0 to 1 by ECOG. 
 
6)   Adequate major non-hematopoietic organ system function as demonstrated 
by: 
a.  Serum creatinine clearance equal or more than 50 ml/min (calculated with 
Cockcroft-Gault formula). 
b.  Bilirubin equal or less than 1.5 mg/dL except for Gilbert’s disease. ALT or 
AST equal or less than 200 U/L for adults. Conjugated (direct) bilirubin 
less than 2x upper limit of normal. 
c.  Left ventricular ejection fraction equal or greater than 45%. 
d.  Diffusing capacity for carbon monoxide (DLCO) equal or greater than 60% 
predicted corrected for hemoglobin. 
7) 
 Ability to understand and willingness to sign the written informed consent 
document.  
8) 
Sexually active males and females of childbearing potential must agree to use 
a form of contraception considered effective and medically acceptable by the 
Investigator while on study. 
 
3.2 
Exclusion criteria 
 
1) 
HIV positive; active hepatitis B or C. 
2) 
Uncontrolled infections; PI is the final arbiter of this criterion. 
3) 
Liver cirrhosis. 
4) 
CNS involvement within 3 months prior to the transplant. 
5) 
Positive pregnancy test in a woman with child bearing potential defined 
as not post-menopausal for 12 months or no previous surgical sterilization. 
6) 
Inability to comply with medical therapy or follow-up. 
7) 
Patient with a known history of allergic reactions to any constituents of the 
product, including a known history of allergic reactions to cellular products or 
DMSO. 
8) 
Other malignancy/cancer diagnosis with active disease or in remission and <2 
years ago, not including nonmelanoma skin cancer 
9) 
Requiring systemic corticosteroids with prednisone dose >10 mg or equivalent. 
10) KDS-1001 Donor specific antibodies (dsa) >3000 MFI units or C1q positive 
 
4.0   Evaluation During Study 

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Evaluation Prior to Transplant (baseline) 
Standard work up for transplant as well as disease assessment is done prior to study 
entry as part of diagnostic or routine pre-transplant evaluation.  
 
Evaluation During Study 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other 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.  The following tests are standard of care pre-transplant 
tests and not protocol specific. The results are used to determine transplant eligibility and 
should not be repeated prior to the beginning of treatment, unless the treatment is 
delayed for more than 30 days after consenting: 
 
• CBC, differential and platelets 
• Bilirubin, serum creatinine and creatinine clearance, ALT, albumin, electrolytes, LDH, 
alkaline phosphatase 
• Infectious diseases panel (hepatitis serology (B, C), HIV, HTLV, I/II, CMV, TPHA 
screen), toxoplasma serology,  
• PT and PTT 
• ABO and Rh typing 
• Bone marrow aspiration and biopsy with cytogenetics, flow cytometry and molecular 
studies as clinically indicated 
• Chimerism analysis baseline 
• Serum pregnancy test in females of childbearing potential 
• Pulmonary function test with DLCO 
• Echocardiogram or multigated acquisition scan (MUGA) to assess Left ventricular EF  
• Chest X ray and ECG 
• Serum for donor-specific anti-HLA antibodies (DSA) if clinically indicated 
Standard Post Transplant Evaluations 
Patients will receive standard supportive care and monitoring as clinically indicated for 
allogeneic hematopoietic transplantation.  Patient evaluations and testing follow our 
standard practice and are performed to monitor engraftment, identify and manage 
toxicities and infections, and to assess disease status: 
1. Chimerism studies from peripheral blood performed on separated T-cells and myeloid 
cells. 
2. At each visit, a physical examination and adverse event documentation including 
GvHD assessment.   
3. Transplant Panel from the peripheral blood T-cell subsets, B-cell immune 
reconstitution, +/- NK cell studies collected at same time as correlatives. 

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4. Disease specific assessment as per standard of care and SCT&CT guidelines 
including bone marrow aspirate with cytogenetics and molecular studies if clinically 
indicated. 
Study staff will contact study participants regarding their health status once a year starting 
12 months post 100 days post transplant. 
 
Blood samples for correlative studies will be sent to Dr. Katy Rezvani's laboratory (located 
in Zeyad Building), Phone 713-563-1894, Pager: 713-404-3858). 
 
A total of 2cc/kg up to 60cc will be required, 5 (10cc) green top tubes and 1 (10cc) purple 
top tube. 
 
Sample collection for exploratory analyses 
Exploratory analyses with immunophenotyping for NK cell chimerism and persistence will 
be done as feasible.  Immune reconstitution studies or additional future research may be 
performed.   
 
Time points for sample collection for immunophenotyping for detection of NK cells and 
immune reconstitution are relative to day of transplant (day 0) approximately: Day -7, Day 
-2 (2-6 hours post first KDS-1001 infusion), Day +3 (2-6 hours pre-cyclophosphamide),  
Day +7 (2-6 hours pre- KDS-1001 administration), Day +8, +14, Day +28 (2-6 hours pre- 
KDS-1001 administration), and then on Days +35, and +60. 
 
Samples from bone marrow aspiration will also be studied at approximately day 28, day 
90, and for bone marrow aspirations if performed for suspicion of relapse. 
 
See Table 1 below for details. 

 
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Table 1. Schedule of Study Procedures and Assessments 
 
 
 
Baseline 
 
 
Day -7 
 
 
Day -2 
 
 
Day 0 
 
 
Day +2 
 
Day +7    
(±2 days) 
 
Day +14  
(± 5 days) 
 
Day +21  
(±5 days) 
 
Day +28  
(±5 days) 
 
Week 5 
(±5 days) 
 
Week 6 
(±2 wks) 
 
Week 7 
(±2 wks) 
 
Week 8 
(±2 wks) 
 
Week 9 
(±2 wks) 
 
Month 3 
(±2 wks) 
 
Month 6 
(±2 wks) 
 
Month 9 
(±2 wks) 
 
Month 12 
(±2 wks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History, physical exam, 
(height weight at 
baseline)1 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-Comorbidity Index 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky performance 
status 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
CBC2 differential, 
chemistry panel3, LDH 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
KDS-1001 
Administration 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Infusion-related toxicities 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Allogeneic SCT 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor-specific antibodies 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
CMVPCR 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adenovirus infection 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
Infection evaluation4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine BK PCR5 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
LVEF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO, FEV1, FVC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
 
 
 
Serum beta-HCG 
(females)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-ray and ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow aspirate, 
biopsy, flow cytometry, 
relevant cytogenetic and 
molecular studies7 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
GVHD assessments8 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE assessments9 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Sorted chimerisms from 
blood10 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Transplant Panel 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
Exploratory analyses  
(see previous page) 
 
X 
X 
 (2-6 hrs post-  
KDS-1001) 
 
 
X 
(D+3,  
2-6 hrs  pre 
cytoxan) 
X 
(D+7 ,  
-6 hrs pre- KDS-
1001, & D+8) 
X  
 
 
X 
  (2-6 hrs pre-  
KDS-1001) 
 
X 
(Day +35)_ 
 
 
X 
(Day +60) 
 
 
 
 
 

 
2021-0329                                                         Version 12.0,04 September 2024                                   Page 16 of 48 
 
 
 
 
1   Physical exam at baseline, within 14 days prior to initiation of conditioning and end of treatment visit should include vital signs and a complete physical examination, 
to include assessment according to standard techniques of general appearance, head, eyes, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, 
musculoskeletal, neurological, endocrine, dermatological and lymph nodes. Height and weight is required at baseline. It is not required to be repeated at the other 
time points.  At all other times, physical exam may be performed at the investigator’s discretion based on the patient’s status.  
2  Patients are evaluated according to standard practice in support of hematopoietic transplantation.  Evaluations generally include: CBC with differential performed 
three times weekly from Day 0 until ANC at least 500/mcL or greater for three days and platelet count at least 20,000/mcL or greater after nadir, while hospitalized. 
CBC then performed weekly through Day 63 post-transplant and then every other week until Day 100 post-transplant, then at Days 180, 270, and 365 post-
transplant.  Only those labs listed on the Summary of Required Clinical Assessments table for each visit will be captured in the eCRF; all other lab results obtained 
between study visits will be collected and maintained by the site as part of SOC. The actual dates of PLT and ANC engraftment will also be captured in the eCRF. 
CBC with differential needs to be collected and reported in CRF at all visits where research blood samples are collected for cryopreserved Biorepository samples to 
be used for future NK cell persistence studies. 
3 Blood chemistries include: serum creatinine, albumin, bilirubin, alkaline phosphatase, AST and ALT. Blood chemistries performed twice weekly until hospital 
discharge. Blood chemistries performed weekly after hospital discharge until Day 63 post-transplant, then every other week through Day 100 post-transplant, and 
then at Days 180, 270 and 365 post-transplant.  Only those labs listed on the Summary of Required Clinical Assessments table for each visit will be captured in the 
eCRF; all other lab results obtained between study visits will be collected and maintained by the site as part of SOC. 
4 Infectious disease assays should be performed per institutional guidelines. CMV shall be monitored per SOP as NK cells are derived from a CMV (+) donor 
5 Urine BK PCR can be done more frequently based on symptoms, or earlier based on institutional guidelines.    
6  Pregnancy test must be performed ≤ 14 days before the start of the transplant conditioning regimen. Pregnancy test is required for females of child-bearing potential 
and may be performed per institutional practices. 
7 Evaluation of disease: (A) For acute leukemia MDS, evaluation for malignant disease includes a bone marrow aspirate and biopsy for histology and cytogenetics. A 
bone marrow biopsy should be performed no more than 30 days prior to the initiation of conditioning.   
8 GVHD assessments are performed weekly from Day +7 through Day +63 post-transplant, and then at Days +100, +180, +270, and +365 post-transplant. GVHD 
assessment on days 7 and 28 must be done within 24 hours prior to NK infusion. The GVHD assessment will include a review of all abnormalities experienced 
during the entire assessment period and the highest stage for each abnormality during the assessment period will be recorded on the GVHD eCRF.  The Chronic 
GVHD Provider Survey will record GVHD symptoms present in the last week and be completed by a clinician on the day of the assessment.  
9  AEs and SAEs will be reported from Day -2 (1st dose of KDS-1001) through100 days post transplant. All SAEs must be reported to the IND Office (refer to Section 
9).  
10 Chimerism may be evaluated in whole blood or blood cell fractions if sufficient cells are available, including CD3 and CD33 or CD15 fraction, according to 
institutional practice. The actual measurement dates may be within +/- 7 days of the recommended time points. Remaining DNA sample after chimerism studies 
may be used for correlative studies   
11 Day 100 DLCO if clinically indicated. 

 
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4.1      Outside Physician Participation During Treatment 
 
1. 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 
2. 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. 
3. 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. 
4. 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. 
5. A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
6. 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. 
7.   The home physician will be requested to report to the MDACC physician investigator all life-
threatening events within 24 hours of documented occurrence. 
8.   Patients will be evaluated either in person or remotely via telemedicine. 
 
5.0   Treatment Plan 
 
In this study the transplant day is referred to as day zero (D0), treatment plan activities prior 
or after D0 are denoted as day minus (D-) or day plus (D+). 
 
The NK product on this trial will be manufactured by Kiadis Pharma per their OTS protocol. 
T cell spec corresponds to max 1% of the target formulated NK cells.  The T-cell dose of 
each infusion should be ≤ 5.0 x 105 viable CD3+ cells/kg over approximately 30 minutes. 
 
Treatment plan by day 
 
D-8  Admit/ Hydration. 
  
D-7  to D-6 Melphalan Administration: Patients < age 60 receive melphalan 140 mg/m2 IV 
split into two doses (70 mg/m2 IV each day).   
 
Patients age 60-70 receive melphalan 100 mg/m2 IV (infused per package insert) split 
into two doses (50 mg/m2 IV each day).  
 
D-7  to D-4   Fludarabine Administration.  Fludarabine will be administered at the dose of 40 
mg/m2 IV daily for four doses on days -7 to -4. Patients weighing within 20% above 
their ideal body weight will be dosed according to actual body weight. Patients 
weighing more than 20% above their ideal body weight will be dosed according to the 
adjusted body weight. Formula to calculate adjusted body weight: Adjusted BW (Kg) = 
IBW + 0.5 (Actual body weight-IBW).  
 
 
 

 
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D-3 TBI 200 cGy on D-3.  
 
D-2  NK cell (KDS-1001) administration 
 
KDS-1001 is an NK cell suspension for intravenous administration and will be 
supplied frozen. The patient will receive 3x107 (+/- 20%) NK cells/kg IV on D-2.  
 
Prior to administration of KDS-1001 
30 minutes prior to KDS-1001 administration, patients may be pre-medicated with 
diphenhydramine hydrochloride 25 mg IV or PO, acetaminophen 650 mg PO, or the 
preferred pre-medications, according to institutional policy or investigator discretion. 
- 
Patients should have vital signs q15 minutes throughout the administration, monitored 
q1 hour for 4 hours after the completion of administration. 
- 
To be eligible to receive the first administration of KDS-1001, patients must meet the 
following requirements at the time of the administration or must be removed from 
study: 
o 
No systemic corticosteroids within 72 hours of KDS-1001 dosing (≥10mg/day 
prednisone or equivalent). 
o 
Steroids should be avoided for at least 7 days after the administration, unless 
clinically required.  
o 
No uncontrolled infection or fever greater than or equal to 38.5◦C (101.3 degrees 
F) within 24 hours.  
- 
AE assessment will be performed at every visit. 
 
Should the patient experience a reaction while study medication is being administered, the 
injection will be interrupted and the patient evaluated. The treating physician may 
administer acetaminophen and/or diphenhydramine per institutional standards or may 
consider stopping the injection. 
 
D-1  Rest 
 
D0  Donor Hematopoietic stem cell transplant Infusion of a non T-cell depleted graft (from 
bone marrow or peripheral blood).  
 
D+3 and D+4   Post Transplant Cyclophosphamide Administration with Mesna: 
 
Patients will receive a dose of Mesna 10 mg/kg IVPB just prior to the first dose of 
cyclophosphamide, that will be repeated every 4 hours for a total of ten (10) doses. 
Patients will also receive ondansetron (or a comparable anti-emetic) prior to each dose of 
Cyclophosphamide (Cy). 
 
Patients will receive Cyclophosphamide at a dose of 50 mg/kg per dose. Patients will 
receive mesna and cyclophosphamide according to ideal body weight or actual weight, 
whichever is lower. 
 
It is recommended to receive IV fluids at a rate of 1.5-2 ml/kg/hr starting 2 hours before 
each dose of Cy and continued for a total of 10 hours, then resuming the previous IV fluids.  

 
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D+5 GvHD prophylaxis with Tacrolimus and Mycophenolate Mofetil should be started per 
standard practice. Tacrolimus start 0.015 mg /kg (based on IBW (adjusted to a level 5-15 
ng/mL) IV daily then continued PO for at least 6 months post transplant. The dose may be 
modified as clinically indicated. Mycophenolate mofetil (MMF) 15 mg/kg (max. 1000mg per 
dose, based on actual body weight) p.o. TID.  It is recommended to discontinue MMF after 
day +35 and to start tapering tacrolimus at D+180, tapering off over at least 3 weeks.  
Immunosuppressive treatment can be modified as clinically indicated.  
 
G-CSF and Supportive Care Antimicrobial prophylaxis as per standard practice. 
 
D+7 and D+28 (with flexibility per table 1) Second and Third KDS-1001 administration (As 
on D-2).  
NK cell administration: To be able to receive the subsequent KDS-1001 administration(s) 
patients must meet the following requirements: 
 
     1. No uncontrolled infection or fever >38.5 C within 24 hours 
     2. No active GVHD requiring systemic steroid treatment.   
3. No systemic corticosteroids within 72 hours of KDS-1001 dosing (≥10mg/day 
prednisone or equivalent). 
4. Steroids should be avoided for at least 7 days after the administration, unless 
clinically required.  
 
30 minutes prior to KDS-1001 administration, patients may be premedicated with 
diphenhydramine 25 mg intravenous piggyback (IVPB) or PO, acetaminophen 650 mg PO, 
or the preferred pre-medications, according to institutional policy or investigator discretion. 
 
Epinephrine and antihistamines should be available at the patient’s bedside during the NK 
cell administration to help treat any allergic reaction that might occur. 
 
For day 28 infusion, patient must have recovered neutrophils> 1.0 x 109/liter.  
On day +28 infusion, vital signs should be monitored q15 minutes throughout the 
administration and q1 hour x 1 after infusion. 
 
If patients do not meet these criteria on the planned day 7 infusion, the cells can be given 
within the next week if the problem resolves; for the day 28 NK cell infusion, they may 
receive the NK cells within two weeks if the problem resolves and patients meet these 
criteria.  
 
If possible, corticosteroids should be avoided within prior 72 hour period prior to NK cell 
administration (less than 0.5mg/kg prednisone or equivalent) and for 7 days after the 
administration.  Corticosteroids may be administered if clinically necessary at the discretion 
of the attending physician.  
 
D+7  Filgrastim or biosimilar filgrastim 5mcg/kg/day (rounded  to the nearest vial) s.q. once 
a day daily until neutrophil recovery. 
 

 
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Antimicrobial prophylaxis will be employed according to the departmental standard practice. 
The recommended supportive care guidelines may be modified at the discretion of the 
patient’s attending physician as clinically indicated.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0   Endpoints 
 
The period of active treatment is from study entry to day +100 post transplant.  After that 
time, patients are monitored for development of chronic GVHD, relapse and survival.  
 
Primary endpoint 
The primary endpoint is the composite adverse event Failure = graft failure, grade 3-4 
GVHD, relapse or non-relapse death within 100 days post-transplant. 
 
Secondary endpoints  
 
i. 
All grade 1-5 adverse events during or within 24hours of KDS-1001 administration 
including CRS and infusion related toxicity will be tabulated (CTCAE v5.0) 
ii. 
All grade 1-5 adverse events starting Day -2 (first KDS-1001 administration) through 
100 days post transplant will be tabulated (CTCAE v5.0). 
iii. 
Donor cell engraftment and graft failure will be assessed with donor/recipient 
chimerism studies at day+28 and day+100.  
iv. 
Day+100, Day+180 and 1-year post-transplant:  
NK Cells (KDS-1001) 
Tacro/MMF beginning day 5 
GCSF beginning day 7 
Stem Cell Collection 
Day 0 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
28 
Marrow Collection/Infusion 
Melphalan 140 mg/m
2  (Age < 60) 
Melphalan 100 mg/m
2  (Age 60 - 70) 
Fludarabine 40 mg/m
2 
Cyclophosphamide 50 mg/kg 
Admit / Hydration 
TBI 200 cGy 
Stem Cell 
Processing 

 
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a. Time to relapse or Death (Kaplan Meyer curves for DFS and OS) 
b. Cumulative incidences for Relapse and NRM 
c. Cumulative incidences for grade 2-4 and grade 3-4 acute GVHD, and chronic 
GVHD 
d. GRFS  
v. 
All grade 2 and higher infections will be described. Cumulative incidence of CMV 
reactivation, symptomatic BK hemorrhagic cystitis and Adenovirus infection at 
day+100 and day+180 will be described.  
vi. 
Immune reconstitution of T and NK cells and function of NK cells post-transplant at 
day+28, day+100 and 1-year post-transplant 
 
Definitions for endpoints 
Active treatment administration is defined from the first day of treatment 
administration as outlined in the treatment plan through the NK administrations. 
Active treatment period is defined from the first day of treatment administration 
through 30 days post the third NK administration. 
Follow-up period is defined from 31 days post the third NK administration until one year of 
treatment completion. 
Engraftment is defined as the evidence of donor derived cells (more than 95%) 
by chimerism studies in the presence of neutrophil recovery by day +28 and day+100 post 
stem cell infusion. 
 
Other definitions used to assess engraftment: 
Neutrophil recovery is defined as a sustained absolute neutrophil count (ANC) 
> 0.5 x 109/L for 3 consecutive days. 
Engraftment date is the first day of three (3) consecutive days that the ANC 
exceeds 0.5 x109/L. 
Delayed engraftment is defined as the evidence of engraftment beyond day 28 
post SC infusion achieved after the administration of therapeutic (high dose) 
hematopoietic growth factors. 
Primary Graft failure is defined as failure to achieve an ANC > 0.5 x 109/L for 3 
consecutive days by day 28 post SC infusion, with no evidence of donor derived cells by 
bone marrow chimerism studies and no evidence of persistent or relapsing disease. 
Secondary graft failure is defined as a sustained declined of ANC <0.5 x 109/L 
for 3 consecutive days after initial documented engraftment with no evidence of disease 
progression. 
Autologous reconstitution is defined by the presence of ANC > 0.5 x 109/L 
without evidence of donor-derive cells by bone marrow chimerism studies. This can occur 
at initial engraftment or later after initial engraftment has been documented. 
Acute GVHD will be graded according to tables below. Time of onset of acute grades II-IV 
and III-IV GVHD will be recorded, as well as the maximum grade achieved. 

 
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Chronic GVHD will be reviewed as defined by the NIH 2014 Consensus(see Appendix 1) 
Conference Criteria to calculate the NIH global severity scores of mild, moderate and 
severe chronic GVHD.  
CMV reactivation is defined as infection in a patient with previous evidence of CMV 
infection who has not had virus detected for an interval of at least 4 weeks during active 
surveillance.  
Symptomatic BK hemorrhagic cystitis is defined as grade 1 by the presence of 
microscopic hematuria, grade 2 with patient-reported macroscopic hematuria, grade 3 with 
the passage of clots, grade 4 macroscopic hematuria with clots and an elevated creatinine 
secondary to obstruction as described by Bedi et al. 
 
Disease Response as per CIBMTR criteria and documented in EPIC by the patient’s 
treating physician. 
 
A. For AML/MDS/CMML: 
Complete remission (CR): 
BM < 5% blasts (absence of blasts with Auer rods). 
ANC > 1000/ul. 
Platelet count >100 x 10e9/ul (independent of red cell transfusions). 
Red blood cell transfusion independence. 
Absence of extramedullary disease. 
Marrow CR (CRi) (incomplete hematologic recovery). 

 
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BM < 5% blasts (absence of blasts with Auer rods). 
ANC < 1000/ul or Platelet count <100 x 10e9/ul. 
Absence of extramedullary disease. 
No Response (NR) or Disease Progression/Relapse 
BM > 5% leukemia blasts 
Persistent presence of blasts in peripheral blood. 
Presence of extramedullary disease. 
Primary induction failure with response to therapy shown by adequate cytoreduction 
including <5% blasts or aplastic/hypoplastic marrow with no extramedullary disease and no 
blasts in peripheral blood detectable. 
 
B. For CML: 
Cytogenetic Response 
Complete: No Ph positive metaphases. 
Major: 0-35% Ph positive metaphases. 
Partial: 1-34% Ph positive metaphases. 
Minor: 35-90% Ph positive metaphases. 
Complete Hematologic Response 
Complete normalization of peripheral blood counts with leukocyte count <10x109 
/L. 
Platelet count <450x109/L. 
No immature cells in peripheral blood. 
No signs and symptoms of disease with disappearance of palpable splenomegaly. 
 
Partial Hematologic Response 
Same as complete hematologic response, except for: 
Presence of immature cells. 
Platelet count < 50% of the pretreatment count, but >450x109/L. 
Persistent splenomegaly, but < 50% of the pretreatment extent. 
 
Molecular Response: 
Complete molecular response: BCR-ABL mRNA undetectable by RT-PCR. 
Major molecular response equal or more 3-log reduction of BCR-ABL mRNA. 
 
Relapse of CML is defined as cytogenetic relapse, detection of t(9;22).  
 
Non-relapse mortality (NRM) is defined as death from any cause other than 
relapse disease. 
 
Disease free survival (DFS) is defined as the interval between day of transplant 
and day of death or disease progression. 
 
Overall Survival (OS) is defined as the interval between day of transplant and 
day of death. 
 
 
 

 
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7.0   Statistical Considerations 
 
7.1 
Preliminaries    
 
This is a single-arm Phase II trial of 3rd party natural killer (NK) cells at a fixed dose of 3 x 
107 +/- 20% cells/kg added to an allogeneic stem cell transplant for AML/MDS/CML.  The 
primary endpoint is the composite adverse event Failure = [graft failure, grade 3-4 GVHD, 
relapse or non-relapse death within 100 days post-transplant].  The stopping rule for time-
to-failure (defined as graft failure, gr 3-4 GHVD, relapse or non-relapse death) will be 
implemented per Section 7.3. 
 
The secondary endpoint is T= time to relapse or death = RFS time.   
 
7.2 
 Sample Size 
 
The maximum sample size will be 24, and the anticipated accrual rate is 2 patients/month.  
This sample size will ensure that, for example, if p = Pr(T> 3 months) follows a non-
informative beta(.65, .35) prior and 21/24 patients have T> 3 months, then the posterior of p 
will be beta(21.65, 3.35) with 95% credible interval .71 -- .97 for p. 
 
7.3   Time-to-Failure Monitoring Rule 
 
To avoid waiting 100 days (3 months) to evaluate each patient to perform safety 
monitoring, the design will be based on T with 3 months follow-up, applying the design of 
Thall et al24.  The failure rate will be monitored as follows:  Denote S = standard historical 
therapy, and E = the experimental NK cell therapy.  Assume that T associated with S 
follows an exponential distribution with median mS and that T associated with the E follows 
an exponential distribution with median mE.  Under a Bayesian model, both mS and mE 
are assumed to follow Inverse Gamma (a, b) priors, denoted IG(a, b).  It will be assumed, 
based on historical experience, that Pr(T > 3 months) has mean .65,  which corresponds to 
median(T) = 4.83 months under the assumption of exponentially distributed T. It is desired 
that, in this trial, Pr(T > 3 months) ≥ 0.85, which corresponds to a median(T ) = 12.80 
months or longer.  For priors, we assume that mS ~ IG (13.73, 61.51), which has mean = 
4.83 months and variance = 2.0 months, and that mE ~ IG (3, 9.66), which has the same 
mean = 4.83 months and the much larger variance = 23.33 months, reflecting little prior 
knowledge about E.  Possibly right-censored values of T for patients treated with E in the 
trial will be monitored continuously throughout the trial.  
 
Early Stopping Rule. Accrual to the trial will be terminated early if, at any time, 
Pr(mE > mS + 100 days| data) < 0.05 
 
The accrual rate is expected to be approximately 2 patients per month, with each patient’s 
follow-up continued until all patients have been followed for 3 months from their date of first 
NK cell administration. This rule was constructed under the assumption that that true mE = 

 
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12.80 months or larger is acceptable, but smaller values are undesirable.  The operating 
characteristics (OCs) of this time-to-failure stopping rule were computed using the program 
One-Arm TTE v 3.0.8 developed by the Department of Biostatistics at M.D. Anderson 
Cancer Center, available at the website:  
 
https://biostatistics.mdanderson.org/SoftwareDownload/.   
 
The OCs of the stopping rule, based on 1000 replications of the trial for each assumed true 
median failure time, are summarized in Table 2.  These operating characteristics assume 
that trial monitoring occurs at the time of each new patient accrual. 
 
Table 2. Operating characteristics of the time-to-failure stopping rule 
True  
Median of T (months) 
True  
Pr (T > 3 months) 
Pr (Stop Early) 
Mean Sample 
Size 
 
 
 
 
3.48 
0.55 
0.96 
9.1 
4.83 
0.65 
0.70 
13.9 
7.23 
0.75 
0.33 
18.9 
12.80 
0.85 
0.10 
22.1 
40.54 
0.95 
0.02 
23.7 
 
If grade ≥ 3 CRS or Grade ≥ 3 infusion reactions occur, we will report this event to the IRB 
and hold the study for review.  The protocol will not resume until approved to proceed by 
the IRB.  The study will also be stopped if an excess rate of cytomegalovirus (CMV) viremia 
occurs >70% (4 or more of the first 5 patients or >70% of patients thereafter). 
 
7.4 
Data Analyses 
 
The distributions of time to failure and RFS time will be estimated using the method of 
Kaplan and Meier25.  Each of these distributions also will be estimated as functions of 
patient baseline covariates, including age, disease type,  and whether the patient had 
active disease at transplant, by fitting a Bayesian survival time regression model26,27, with 
the distribution chosen based on preliminary goodness-of-fit analyses. 
 
Failure event times will be monitored continuously during the trial, using the Biostatistics 
Department Clinical Trial Conduct (CTC)  website. 
The stopping rule will be applied each time a new patient is accrued, or each time a patient 
has a "failure" event, to decide whether the trial should be stopped or not.  The data for 
each patient at each time the rule is applied will consist of 2 statistics: (1) time from 
initiation of the patient’s treatment to the event or last follow up time, (2) an indicator of 
whether the patient had a "failure" event at last follow up. 
Each patient's (1) date of enrollment, (2) date of a failure event if it occurs, will be 
immediately entered into the CTC software, which will be set up  for the trial on the CTC 
website prior to enrollment of the first patient.  If a patient is followed for 100 days without a 
failure, then that patent's data will be considered complete for the purpose of applying the 
monitoring rule. 

 
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All secondary endpoints will be tabulated using mean, median, and range for numerical 
valued variables, and counts and percentages for binary or categorical variables.  Kaplan-
Meier plots will be used to estimate the distributions of all possibly right-censored time-to-
event variables. 
The Investigator is responsible for completing safety summary reports and submitting them 
to the IND Office Medical Affairs and Safety Group for review and approval. These should 
be submitted after the first 4 evaluable patients complete 100 days post transplant and 
every 4 evaluable patients thereafter.  Subjects who are considered to be evaluable for 
efficacy have received three KDS-1001 infusions, undergone SCT, and completed 100 
days post SCT assessment.  
 
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 
 
1.  Disease progression requiring further treatment. 
2.  Prolonged cytopenia requiring treatment beyond GCSF. 
3.  Unexpected pattern of toxicity. 
4.  Patient withdrawal of the informed consent. 
5.  Patient is noncompliant with treatment schema. 
6.  After one year of treatment completion. 
 
9.0   Reporting Requirements 
 
Adverse event definition 
 
An adverse event (AE) 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. An AE (also referred to as an adverse experience) 
can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug (study medication), and 
does not imply any judgment about causality. An AE can arise with any use of the drug 
(e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose.  
 
An AE or suspected adverse reaction (AR) is considered “unexpected” if it is not listed in 
the Reference Safety Information (RSI) of the IB or is not listed at the specificity or severity 
that has been observed. 
 
Medical conditions/diseases present before starting study drug are only considered AEs if 
they worsen after starting study drug. Abnormal laboratory values or other abnormal 
assessment findings constitute AEs or SAEs only if they induce clinical signs or symptoms, 
are considered clinically significant, require medical or surgical intervention, or leads to 

 
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study medication discontinuation, delay or interruption.  
 
The severity of the AEs will be graded according to the Common 
Terminology Criteria v5.0 (CTCAE) from the start of the first NK cell administration up to 
100 days from the last NK administration. Events not included in the CTCAE chart will be 
scored as follows: 
 
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. 
Grade 5:  Death 
 
Known adverse events  
No clinical data have been reported yet with KDS-1001. From the clinical experience with 
other (expanded) NK cell preparations to date the overall conclusion is that NK cell 
infusions are safe and well tolerated, even in very high doses and repeated administration 
(refer to Table 3). AEs associated with infusion of allogeneic, expanded NK cells are the 
following:    
 
Common (within 1-2 days of receiving drug) 
- 
Flu-like symptoms, including fever, chills, cough, dyspnea, myalgia, arthralgia, fatigue, 
headache. 
- 
Cryoprotectant (DMSO) associated adverse events, including unusual taste or odor, 
increased or decreased blood pressure, tachycardia, and headache. 
Uncommon/rare (within 1-2 days of receiving drug) 
- 
Acute infusion reaction, including fever, chills, cough, dyspnea, hypoxia, pulmonary 
edema, hypotension, tachycardia, angioedema, bronchospasm, rash, pruritis, myalgia, 
headache, hematuria, renal insufficiency. 
The above common and uncommon AEs are anticipated to be ≤ Grade 3 events, occur in 
the first 24 hours after NK cell infusion, are responsive to supportive care, and resolve 
within 72 hours. In addition, in rare cases CRS and GVHD were reported. 
 
• 
Cytokine release syndrome 
CRS was reported in one of the studies in 2 of 16 patients receiving non-expanded IL 2-
activated NK cells from haploidentical donors33. If symptoms of cytokine release syndrome 
are observed treatment should be initiated according to institutional standards.  See 
Neelapu et al, Nature 2017;15:47. 
 
• GVHD 
In general, the role of NK cells in mediating GVHD has been the subject of much debate. 

 
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The contribution of NK cells in the development of GVHD remains elusive due to conflicting 
evidence emerging from a variety of different experimental approaches42,43. It is 
hypothesized that presumed sub-optimal timing of NK cell infusion with respect to timing of 
HSCT engraftment, and a more rapid T cell (CD3+ cell) engraftment observed in patients 
who developed GVHD may have contributed to the development of GVHD in certain 
studies with NK cells, while a number of other studies have promoted the notion that NK 
cells, in allogeneic adoptive transfer settings, help prevent GVHD by suppressing 
alloreactive T cells.  
 
GVHD may also occur from contaminating T cells in the NK cell product. NK preparations 
with a T cell content of less than 1% were not associated with GVHD20. CD3+ lymphocytes 
present in the KDS-1001 product is limited by the release specifications for the final 
product.  If grade 2 or greater acute GVHD occurs, it will be initially treated with 
corticosteroids (prednisone 2 mg/kg or equivalent).  Additional immunosuppressive 
treatment will be given as clinically indicated.  See Department GVHD treatment guidelines. 
 
• CMV infection 
CMV positive donors are selected for the manufacturing of KDS-1001 based on the 
observed correlation of higher NKG2C expression on NK cells sourced from these donors. 
The risk of the CMV virus passing from the donor to the recipient via the NK cell product, 
although very small, cannot by excluded48,49. Between 50 and 80% of people in the US 
have had a CMV infection before age 40-50. In persons with normal immune systems, 
CMV infection normally does not pose a risk. CMV monitoring and, if needed, treatment is 
recommended according to institutional guidelines. 
Table 3. Overview of AEs Reported after Infusion of Allogeneic NK Cell Therapies 
Common 
Occasional 
Rare 
• Flu-like symptoms 
• Fever 
• Chills 
• Cough 
• Dyspnea 
• Myalgia 
• Arthralgia 
• Fatigue 
• Headache 
• Cryoprotectant (DSMO) 
associated: 
• Unusual taste 
• Increased or decreased blood 
pressure 
• Tachycardia 
• Headache 
 
• Acute infusion reaction 
• Fever 
• Chills 
• Cough 
• Dyspnea 
• Hypoxia  
• Pulmonary edema 
• Hypotension 
• Tachycardia 
• Angioedema 
• Bronchospasm 
• Rash 
• Pruritus 
• Myalgia 
• Headache 
• Hematuria 
• Renal insufficiency 
• Cytokine release syndrome 
• Graft-versus-host disease 
(GVHD) 
 
 
 
 
Serious Adverse Event (SAE) Reporting Requirements for M D Anderson 

 
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Sponsor Single Site 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 event 
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 on Reporting Adverse Events for Drugs and 
Devices”. 
 
Serious adverse events will be captured from Day -2 (first KDS-1001 
administration) through 100 days post transplant, unless the participant 
withdraws consent.  
 
Serious adverse events will be captured from the time of the first protocol-specific 
treatment until 100 days after the last KDS-1001 administration, 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. 
 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the 

 
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IND Office within 5 working days of knowledge of the event regardless of the 
attribution. 
 
Death or life-threatening events that are unexpected, possibly, probably or 
definitely related to drug must be reported (initial or follow up) to the IND Office 
within 24 hours of knowledge of the event  
 
Additionally, any serious adverse events that occur after the 100 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. 
 
OnCore will be utilized for safety reporting to the IND Office and MD Anderson 
IRB.  
All events reported to the supporting company must also be reported to the IND 
Office. 
  
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor 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. 
 
 
Investigator Reporting to Kiadis:   
 
Initial SAEs and/or subsequent follow-up reports will be reported to Kiadis on the 
MDACC Institution Adverse Event Report Form at the time it is submitted to MDACC 
IND Office. SAE reports should be for a single subject.  
 
Email report to:   
CL-CPV-Receipt@sanofi.com   
 
Copy:  
Dr. Klaudia Traudtner  
Head of Safety and Pharmacovigilance, GPV Oncology  
Email: Klaudia.Traudtner@sanofi.com    
 
Periodic safety reporting:   
WW-GPV-GlobalPeriodicReports@sanofi.com    
 
Events not considered to be SAEs are hospitalizations that are expected, such as: 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition; 

 
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• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
studied indication and has not worsened since signing the informed consent; 
• Hospitalization for a procedure that is planned (i.e., planned prior to starting of 
treatment on study) must be documented in the source document and the CRF.  
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
 
 
10.0  Adverse Events and Data Collection 
 
For the purpose of this study, the investigational component of the treatment plan is [KDS-
1001]. Therefore, serious and unexpected AEs occurring  from Day -2 (first KDS-1001 
administration) through 100 days post transplant, as defined below, will be reported 
according to MDACC policy and procedures below to BMTWeb The end of active treatment 
is the completion of the three NK cell administrations]. AEs or SAEs that are considered 
causally related to the KDS-1001 administration need to be reported throughout the entire 
study period. Pregnancy of a female patient or partner of a male patient should be followed 
until either termination of the pregnancy for whatever reason or birth. 
 
Serious adverse events must be followed until clinical recovery and laboratory test have 
returned to values within normal range progression of the event has stabilized, or there has 
been acceptable resolution of the event. SAEs determined to be due to progression of the 
underlying disease should be recorded but not be subject to expedited reporting. All SAEs 
related to the disease but unrelated to the study medication administration should be 
reported annually to the FDA and IRB. 
 
10.1 Common Terminology Criteria Adverse Events (CTCAE)  
 
A descriptive terminology developed by the National Cancer Institute (NCI) for use in 
reporting adverse events. The CTCAE includes a grading (severity) scale for each adverse 
event term.  A copy of CTCAE version 5.0 can be downloaded from the CTEP website. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 
Grade – Severity of the adverse event. Grades were developed using the following guidelines: 
 
Grade 0 – No adverse event or lab values within normal limits  
1 – Mild adverse event 
2 – Moderate adverse event  
3 – Severe adverse event 
4 – Life-threatening or disabling adverse event  
5 – Fatal adverse event 
 
Abnormal laboratory values not included in the CTCAE guidelines will be defined per 
protocol. 

 
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The relationship/attribution of each AE to the investigational product will be assessed by 
the investigator after careful consideration of all relevant factors such as (but not limited to) 
the underlying study indication, coexisting disease, concomitant medication, relevant 
medical history, pattern of the AE, temporal relationship to the study medication and 
dechallenge or rechallenge according to the following guidelines: 
 
Possibly, Probably, or Definitely Related: there is a reasonable possibility and/or evidence 
that the study drug caused the event if One or more of the following criteria apply: 
 
• The event follows a reasonable temporal sequence from administration of 
investigational product; 
• The event could not be reasonably attributed to the known characteristics of the 
patients clinical state, environment, or toxic factors or other modes of therapy, 
administered to the patient; 
• The event follows a known pattern of response to investigational product; 
• The event disappears or decreases on cessation or reduction in dose of the 
investigational product. In some situations, an AE will not disappear or decrease in 
intensity upon discontinuation of the investigational product despite other clear 
indications of relatedness. 
 
Unlikely, or Not Related: There is no reasonable possibility that the investigational product 
caused the event if one or more of the following criteria apply: 
 
• The event does not follow a reasonable temporal sequence from administration of 
study drug; 
• The event could be reasonably attributed to the known characteristics of the patient’s 
clinical state, concurrent illness, environment, or toxic factor or other modes of therapy 
administered to the patient; 
• The event does not follow a known pattern of response to investigational product; 
• The event does not disappear or decrease on cessation or reduction in dose of the 
study drug, and it does not reappear or worsen when the investigational product is re-
administered. 
 

 
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10.2 Time for AE Collection 
 
Adverse events will be collected Day -2 (first KDS-1001 administration) through 100 days 
post transplant. 
 
AEs or SAEs that are considered causally related to the KDS-1001 administration 
need to be reported whenever they occur. Pregnancy of a female patient or partner 
of a male patient should be followed until either termination of the pregnancy for 
whatever reason or birth. 
 
10.3  AE reporting  
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all AEs and assigning attribution for each event on all subjects 
enrolled in this study.  
 
10.4     Data collection 
 
Collection of AEs will reflect the onset and resolution date and maximum grade. 
Indeterminate events should be labeled as such and followed until resolution. If a 
patient is taken off the study while an event is still ongoing, the event will be 
followed until resolution unless another therapy is initiated. Pre-existing medical 
conditions will be recorded only if an exacerbation occurs during the active 
treatment period. 
 
 
 
Patients will be registered in MD Anderson’s Clinical Trial Management System, 
OnCore. 
 
Adverse events and protocol specific data will be entered into BMTWeb. BMTWeb will be 

 
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used as the electronic case report form for this protocol. 
Events not to be considered AEs in this study are those related to the 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 monitored. 
 
10.5  Concomitant medications 
 
Patients treated in this study 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 (but side effects of concomitant 
medications should be considered when making a causality assessment of any 
AE or SAE during the study at the discretion of the P.I.). All antiviral therapy will be 
captured in the medical record.  
 
11.0  Regulatory considerations 
 
11.1  Institutional Review Board 
 
This protocol and the proposed ICF must be reviewed and approved by the FDA and 
IRB prior to the start of the study. No modifications to the protocol will be made without 
the approval of the sponsor (MDACC IND Office) and the IRB prior to implementation.  
 
It is the investigator’s obligation to maintain a regulatory file, and to make this available 
for review by sponsor representatives as part of the study monitoring process. 
 
During the study, the investigator shall make timely and accurate reports to the FDA 
and IRB on the progress of the trial, at intervals not exceeding 1 year. 
 
11.2  Study Conduct  
 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH Guidelines for GCP and 
applicable regulatory requirements.   
 
The investigator will ensure that all persons involved in the conduct of the study are 
informed about the protocol, protocol amendments, study procedures, and study-related 
duties. 
 
11.3 Subject Privacy  
 
To maintain subject confidentiality and to comply with applicable data protection and 
privacy laws and regulations, all data provided to the sponsor or designee, study 

 
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reports, and communications relating to the study will identify subjects by assigned 
subject numbers, and access to subject names linked to such numbers shall be limited 
to the site and the study physician and shall not be disclosed to the sponsor or 
designee. 
 
11.4 Written Informed Consent  
 
The investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study. The investigator will 
ensure that the subject is given full and adequate oral and written information about the 
nature, purpose, and possible risk and benefit of the study. Subjects must also be notified 
that they are free to discontinue from the study at any time. The subject should be given the 
opportunity to ask questions and allowed time to consider the information provided. The 
subject’s signed and dated ICF must be obtained before conducting any study procedures. 
A copy of the signed ICF must be given to the subject.  
 
12.0   Background Drug Information 
 
12.1    All drugs listed below are available commercially. Refer to the FDA approved 
package inserts for complete product information, pharmacology, including how 
supplied, storage and stability, special precautions, reconstitution, and 
administration instructions. Dose rounding/standardization is permitted as per 
institutional policy for all commercially available chemotherapy and supportive 
care agents. 
 
12.1.1   Fludarabine (Fludara™) 
Fludarabine is a fluorinated nucleoside analog. 
 
Mechanism of Action: After phosphorylation to fluoro-ara-ATP the drug appears to 
incorporate into DNA and inhibit DNA polymerase alpha, ribonucleotide reductase 
and DNA primase, thus inhibiting DNA synthesis. 
 
Known Side Effects: pancytopenia, immunosuppression, autoimmune hemolytic 
anemia have (rarely) been reported, and recurred when patients were retreated with 
the drug. GI toxicity: Nausea, vomiting, anorexia, weakness. CNS toxicity: agitation, 
visual disturbances, confusion, coma, peripheral neuropathies. With high dose use 
confusion, blindness, coma and death have been reported. Please refer to the 
package insert for a complete listing of all toxicities. 
 
12.1.2   Melphalan 
 
Melphalan is an alkylating agent, which is a derivative of mechlorethamine.  
 
Mechanism of Action: Melphalan inhibits DNA and RNA synthesis via formation of 

 
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carbonium ions; cross-links strands of DNA. Melphalan acts on both resting and rapidly 
dividing tumor cells. 
 
Known Side Effects: Dose limiting toxicity is expected to be hematological when used without stem 
cell support. Other toxicities seen frequently following melphalan in preparative regimens for bone 
marrow transplantation include: peripheral edema, fatigue, dizziness, hypokealemia, 
hypophosphatemia, diarrhea, nausea, vomiting, constipation, mucositis, stomatitis, dyspepsia, 
fever, renal failure, amenorrhea, hematochezia, hypersensitivity reaction, SIADH, veno-occlusive 
disease (VOD)/sinusoidal obstruction syndrome (SOS). Please refer to the package insert for a 
complete listing of all toxicities. 
 
12.1.3   Cyclophosphamide (Cytoxan™) 
 
Cyclophosphamide is an alkylating agent. 
 
Mechanism of Action: Cyclophosphamide prevents cell division by cross-linking 
DNA strands and decreasing DNA synthesis. It is cell cycle phase non-specific. 
Cyclophosphamide also possesses potent immunosuppressive properties. It is a 
pro-drug metabolized by the liver to active metabolites. 
 
Known Side Effects: Hematologic: Leukopenia, anemia, alopecia. GI: Nausea, 
vomiting, increased AST, ALT, mucositis, and diarrhea. Neurologic: Headache, 
dizziness. Cardiovascular: Cardiomyopathy, non-specific ST changes on EKG. 
Please refer to the package insert for a complete listing of all toxicities. 
12.1.4   Mesna (sodium -2-mercapto ethane sulphonate, Mesnex™) 
Mesna is a prophylactic agent used to prevent hemorrhagic cystitis induced by the 
oxazophosphorines (cyclophosphamide and ifosfamide). It has no intrinsic 
cytotoxicity and no antagonistic effects on chemotherapy. 
 
Mechanism of Action: Mesna binds with acrolein, the urotoxic metabolite produced by the 
oxazophosphorines, to produce a non-toxic thioether and slows the rate of acrolein 
formation by combining with 4-hydroxy metabolites of oxazophosphorines. 
 
Known Side Effects: At the doses used for uroprotection, mesna is virtually non-
toxic. However, adverse effects which may be attributable to mesna include nausea 
and vomiting, diarrhea, abdominal pain, altered taste, rash, urticaria, headache, joint 
or limb pain, hypotension and fatigue. Please refer to the package insert for a 
complete listing of all toxicities. 
 
12.5  Adoptive NK Cell Therapy 
 
NK Cells Expanded with mbIL-21 and 4-1BBL (KDS-1001) 
Ex-vivo expansion of NK cells using a modified K562 cell line that expresses mbIL-21 and 
4-1BB ligand (FC21-NK) allowed infusion of large number of NK cells to patients12. FC21-
NK continue to be used worldwide in clinical trials. Adoptive transfer of these donor derived 

 
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expanded NK cells was safe up to doses of 1 x 108 NK cells/kg and resulted in clinical 
relevant response rates such as reducing tumor burden and relapse rates (Section 5.3). 
Although the feeder cell system enabled the robust generation of large numbers of highly 
active NK cells to perform clinical trials, the expansion process was refined through the 
development of PM21 membrane particles, which can as effectively stimulate expansion of 
NK cells13. PM21 particles are formed from the plasma membranes of K562.mbIL21.41bbl 
(CSTX002) feeder cells. 
 
KDS-1001 comprises allogeneic donor NK cells which have been expanded ex vivo using 
PM21 membrane particles. The use of PM21 particles circumvents the direct use of feeder 
cells. Similar expansion and pharmacological activity of expanded NK cells using feeder 
cells or PM21 particles has been demonstrated in in vitro and in vivo nonclinical studies 
(Section 4.1). Therefore, KDS-1001, expanded using the PM21 particles, is expected to 
have a similar clinical activity and safety profile as the mbIL-21 and 4-1BBL feeder cells 
expanded NK cells used in several oncology indications. 
 
Use of PM21 particle expanded haploidentical NK cells (K-NK002), produced using the 
same manufacturing process, is cleared by the FDA and is currently being investigated in 
an ongoing clinical trial (NK-REALM, NCT04395092) as adjunctive treatment for patients 
with high risk myeloid malignancies undergoing a haploidentical hematopoietic stem cell 
transplantation (HSCT). In that study the NK cells are from the same donor as stem cells 
for the transplant. Kiadis Pharma is developing KDS-1001 as an off–the-shelf drug product 
from material from allogenic donor for immediate availability to the patient. Off the shelf 
Kiadis NK cells are cleared by the FDA for use in patients with solid tumors and in the 
infectious disease area.  
 
In conclusion, NK cells expanded using the mbIL-21 and 4-1BBL are safe and clinically 
effective as a cancer therapy. The Kiadis off-the-shelf production process developed for 
KDS-1001 allows to make NK-cell therapy products rapidly available for a broad patient 
population across a potentially wide range of oncology indications. 
 
 
 

 
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27. 
Ibrahim JG CM-H, Sinha D. . Bayesian Survival Analysis: Springer, NY; 2001. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 1.  
 
Chronic GVHD organ scoring from the 2014 NIH consensus as defined per Jagasia 
et al, 2015 
 
Mild chronic GVHD 
 
  1 or 2 organs involved with no more than score 1 plus 
 
  Lung score 0 
 
Moderate chronic GVHD 
 
  3 or more organs involved with no more than score 1 
    OR 
 
  At least 1 organ (not lung) with a score of 2 
    OR 
 
  Lung score 1 
 
Severe chronic GVHD 
 
  At least 1 organ with a score of 3 
 
    OR 
 
  Lung score of 2 or 3 
 
Key points: 
In skin: higher of the two scores to be used for calculating global severity. 
 
In lung: FEV1 is used instead of clinical score for calculating global severity. 
 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-
GVHD documented cause, that organ is not included for calculation of the global severity. 
 
If the abnormality in an organ is attributed to multifactorial causes (GVHD plus other 
causes) the scored organ will be used for calculation of the global severity regardless of 
the contributing causes (no downgrading of organ severity score). 
 
 
 
 
 
 
 

 
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Figure 1. Organ Scoring of Chronic GVHD  
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
PERFORMANCE 
SCORE:  
 
KPS   ECOG   LPS 
 
 
ϒ  Asymptomatic 
and fully active 
(ECOG 0; KPS or 
LPS 100%) 
ϒ  Symptomatic, 
fully ambulatory, 
restricted only in 
physically 
strenuous activity 
(ECOG 1, KPS or 
LPS 80-90%) 
ϒ  Symptomatic, 
ambulatory, capable
of self-care, >50% 
of waking hours out
of bed (ECOG 2, 
KPS or LPS 60-
70%)  
ϒ  Symptomatic, 
limited self-care, 
>50% of waking 
hours in bed (ECOG 
3-4, KPS or LPS 
<60%) 
SKIN† 
 
SCORE % BSA  
 
 
 
 
 
GVHD features to be scored  
by BSA: 
Check all that apply: 
ϒ Maculopapular 
rash/erythema 
ϒ Lichen planus-like features 
ϒ Sclerotic features 
ϒ Papulosquamous lesions 
or 
    ichthyosis 
ϒ Keratosis pilaris-like GVHD
ϒ  No BSA   
involved 
 
 
 
ϒ  1-18% BSA  
 
ϒ  19-50% BSA   
ϒ  >50% BSA 
SKIN FEATURES  
SCORE: 
 
 
ϒ No sclerotic 
features 
 
 
 
 
ϒ Superficial  
   sclerotic features 
“not hidebound” 
(able to pinch) 
Check all that apply: 
ϒ Deep sclerotic            
features  
ϒ “Hidebound”               
(unable to pinch)  
ϒ Impaired mobility  
ϒ Ulceration 
 
Other skin GVHD features (NOT scored by BSA) 
Check all that apply: 
ϒ Hyperpigmentation 
ϒ Hypopigmentation 
ϒ Poikiloderma 
ϒ Severe or generalized pruritus 
ϒ Hair involvement 
ϒ Nail involvement 
 
 
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_____________________________ 
MOUTH 
Lichen planus-like 
features present: 
ϒ Yes 
ϒ No 
ϒ  No symptoms  
ϒ  Mild 
symptoms with 
disease signs 
but not limiting 
oral intake 
significantly 
ϒ  Moderate 
symptoms with 
disease signs 
with partial 
limitation of oral 
intake 
ϒ  Severe symptoms 
with disease signs on 
examination with major 
limitation of oral intake 
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_____________________________ 
 
 
 
 
 
 
 
 

 
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Figure 1. Organ Scoring of Chronic GVHD  (continued) 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
EYES 
 
Keratoconjunctivitis 
sicca (KCS) 
confirmed by 
ophthalmologist: 
   ϒ  Yes 
   ϒ  No 
ϒ  Not examined 
 
 
 
ϒ  No 
symptoms  
       
ϒ  Mild dry eye 
symptoms not 
affecting ADL 
(requirement of 
lubricant eye 
drops  < 3 x per 
day)  
 
ϒ  Moderate dry 
eye symptoms 
partially affecting 
ADL (requiring 
lubricant eye drops 
> 3 x per day or 
punctal plugs), 
WITHOUT new 
vision impairment 
due to KCS 
ϒ  Severe dry eye 
symptoms significantly 
affecting ADL (special 
eyeware to relieve 
pain) OR unable to 
work because of ocular 
symptoms OR loss of 
vision due to KCS 
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
GI Tract 
 
Check all that 
apply: 
ϒ  Esophageal web/ 
proximal stricture or 
ring 
ϒ  Dysphagia 
ϒ Anorexia 
ϒ Nausea 
ϒ Vomiting 
ϒ Diarrhea 
ϒ Weight loss >5%* 
ϒ   No 
symptoms 
ϒ Symptoms 
without significant 
weight loss* 
(<5%)  
ϒ  Symptoms 
associated with 
mild to moderate 
weight loss*  
(5-15%) OR 
moderate 
diarrhea without 
significant 
interference with 
daily living  
ϒ Symptoms associated 
with significant weight 
loss* >15%, requires 
nutritional supplement 
for most calorie needs 
OR esophageal dilation 
OR severe diarrhea with 
significant interference 
with daily living  
 
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
LIVER 
 
 
ϒ  Normal total 
bilirubin and ALT 
or AP        < 3 x 
ULN 
ϒ Normal total  
bilirubin with ALT 
>3 to 5 x ULN or  
AP > 3 x ULN 
ϒ  Elevated total 
bilirubin but          
<3 mg/dL or      
ALT > 5 ULN 
ϒ  Elevated total         
bilirubin > 3 mg/dL 
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
LUNGS** 
 
Symptom score: 
 
 
 
ϒ No symptoms 
 
 
 
ϒ  Mild symptoms 
(shortness of 
breath after 
climbing one flight 
of steps) 
 
ϒ  Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground) 
 
ϒ  Severe symptoms 
(shortness of breath  at 
rest; requiring 02) 
Lung score: 
  % FEV1 
ϒ  FEV1≥80% 
ϒ FEV1 60-79% 
ϒ  FEV1 40-59% 
ϒ  FEV1 <39% 
Pulmonary function tests  
   ϒ   Not performed  
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
(specify):_____________________________ 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 1. Organ scoring of chronic GVHD (continued) 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
JOINTS AND FASCIA 
 
P-ROM score 
(see below) 
Shoulder (1-7):___ 
Elbow (1-7): ____ 
Wrist/finger (1-7):___ 
Ankle (1-4):___ 
ϒ  No 
symptoms 
ϒ  Mild tightness of 
arms or legs, 
normal or mild 
decreased range of 
motion (ROM) AND 
not affecting ADL 
ϒ  Tightness of 
arms or legs OR 
joint contractures, 
erythema thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
of ADL 
ϒ  Contractures WITH 
significant decrease of 
ROM AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress self 
etc.)  
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
(specify):___________________________ 
 
 
 
 
 
GENITAL TRACT  
(See Supplemental 
figure‡)  
    ϒ  Not examined 
 
Currently sexually active  
ϒ  Yes 
ϒ  No  
  ϒ  No 
signs  
ϒ Mild signs‡ and 
females with or 
without discomfort  
on exam  
ϒ  Moderate signs‡ 
and may have  
symptoms with 
discomfort on exam 
ϒ  Severe signs‡ with   
     or without  
      symptoms   
ϒ Abnormality present but explained entirely by non-GVHD documented cause 
(specify):___________________________ 
 
 
 
 
 
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and 
assign a score to severity (0-3) based on functional impact where applicable none – 0,mild -1, moderate 
-2, severe – 3) 
ϒ Ascites (serositis)___ 
ϒ  Myasthenia Gravis___ 
 
ϒ Pericardial Effusion___ 
ϒ  Peripheral Neuropathy___ 
ϒ   Eosinophilia > 500/μl___ 
ϒ Pleural Effusion(s)___ 
ϒ  Polymyositis___ 
ϒ   Platelets <100,000/μl ___ 
   ϒ Nephrotic syndrome___ 
ϒ  Weight loss>5%* without GI 
symptoms ___ 
ϒ 
 
 
Others 
(specify):_____________ 
 
 
 
 
 
 
Overall GVHD Severity  
(Opinion of the evaluator) 
 
No GVHD 
 
Mild 
 
Moderate 
 
Severe 
 
 
 
 
 
 
Photographic Range of Motion (P-ROM) 
 
 
 
 
 
† Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous features scales. 
When a discrepancy exists between the percentage of total body surface (BSA) score and the skin feature score, 
OR if superficial sclerotic features are present (Score 2), but there is impaired mobility or ulceration (Score 3), the 
higher level should be used for the final skin scoring. 
* Weight loss within 3 months. 
**Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. FEV1 should 

 
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be used in the final lung scoring where there is discrepancy between symptoms and FEV1 scores. 
Abbreviations: ECOG (Eastern Cooperative Oncology Group), KPS (Karnofsky Performance Status), LPS 
(Lansky Performance Status); BSA (body surface area); ADL (activities of daily living); LFTs (liver function 
tests); AP (alkaline phosphatase); ALT (alanine aminotransferase); ULN (normal upper limit). 
‡ To be completed by specialist or trained medical providers (see Supplemental Figure). 

 
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Name:________________________________ Date of birth: ________Assessment date: ____________ 
 
 
 
      SCORE 
0 
        SCORE 1 
        SCORE 2 
SCORE 3 
GENITAL TRACT 
 
Check: 
 
 
 Male    
 Female 
  No 
signs  
 Mild signs and 
females may have 
symptoms* WITH 
discomfort on exam  
 Moderate signs   
and may have  
symptoms* with 
discomfort on exam 
 Severe signs with
or without symptoms
*  

2021-0329                    Version 12.0 
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Currently sexually active: 
 
 Yes    
 No  
 
Check all signs that apply: 
 
  Lichen planus-like features  
   
  Lichen sclerosis-like features  
 
  Vaginal scarring (female) 
 
  Clitoral/labial agglutination (female) 
 
  Labial resorption (female) 
 
 
 
 
 
  Erosions 
 
  Fissures 
 
  Ulcers 
 
  Phimosis (male) 
 
  Urethral meatus scarring/ stenosis (male) 
 
  Abnormality present but NOT  thought to represent GVHD (specify 
)
  Abnormality thought to represent GVHD PLUS other causes(specify cause): 
_______________________________  
*Genital symptoms are not specific to cGVHD and can represent premature gonadal failure or 
genital tract infection.   
 
If a gynecologist is unavailable, external examination may be performed to determine 
“discomfort on exam” as follows: 
a)Spread the labia majora to inspect the vulva for the above signs.  Touch the vestibular gland 
openings (Skene’s and Bartholin’s), labia minora and majora gently with a qtip.  Vulvar pain 
elicited by the gentle touch of a qtip is classified as discomfort on examination. Palpate the 
vaginal walls with a single digit to detect bands, shortening, narrowing or other signs of vaginal 
scarring. 
b)If the woman is sexually active, determine whether qtip palpation or gentle palpation of scarred 
ridges elicits pain similar to that which the woman experiences during intercourse. 
 
Female genitalia: Severity of signs: 
1) Mild (any of the following); erythema on vulvar mucosal surfaces, vulvar lichen-planus or 
vulvar lichen-sclerosis.  
2) Moderate (any of the following); erosive inflammatory changes of the vulvar mucosa, fissures 
in vulvar folds    
3) Severe (any of the following); labial fusion, clitoral hood agglutination, fibrinous vaginal 
adhesions, circumferential fibrous vaginal banding, vaginal shortening, synechia, dense 
sclerotic changes, and complete vaginal stenosis.   
 
Male genitalia: Diagnostic features include lichen planus-like or lichen sclerosis-like features 
and phymosis or urethral scarring or stenosis. Severity of signs:  
1) Mild: lichen planus-like feature;  
2) Moderate: lichen sclerosus-like feature or moderate erythema;   
3) Severe: phimosis or urethral/meatal scarring. 
 
 
 
 
 
 
 
 
 
 
 
Biopsy obtained: 
 Yes     
 No     Site  biopsied:______________GVHD confirmed by 

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histology: 
 Yes      
 No 
 
Change from previous evaluation:  
 No prior or current GVHD   
 Improved      
 Stable        
 Worse   
 N/A (baseline) 
 
 
Completed by (print name):_____________________________  
 
Date form completed: _____________ 
 
 
 
 
 
 
 

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Appendix 2.  
 
2017 ELN risk stratification by genetics 
Risk Category* 
Genetic abnormality  
 
 
 
Favorable 
t(8;21)(q22;q22.1); RUNX1-RUNX1T1 
inv(16)(p13.1q22) or t(16;16)(p13.1;q22; CBFB-MYH11 
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlowⴕ 
Biallelic mutated CEBPA 
 
 
 
 
Intermediate 
Mutated NPM1 and FLT3-ITDhighⴕ 
Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlowⴕ (without adverse-risk 
genetic lesions) 
t(9;11)(p21.3;q23.3); MLLT3-KMT2A‡ 
Cytogenetic abnormalities not classified as favorable or adverse 
 
 
 
 
 
 
 
 
 
 
Adverse 
 t(6;9)(p23.3;q34.1)/DEK::NUP214 
t(v;11q23.3)/KMT2A-rearranged#  
 t(9;22)(q34.1;q11.2)/BCR::ABL1  
 t(8;16)(p11.2;p13.3)/KAT6A::CREBBP  
 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1)  
 t(3q26.2;v)/MECOM(EVI1)-rearranged  
−5 or del(5q); −7; −17/abn(17p)  
 Complex karyotype,** monosomal karyotype††  
 Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or 
ZRSR2‡‡  
 Mutated TP53a 
Frequencies, response rates, and outcome measures should be reported by risk category, and, if 
sufficient numbers are available, by specific genetic lesions indicated. 
*Prognostic impact of a marker is treatment-dependent and may change with new therapies. 
ⴕ Low, low allelic ration (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment of FLT3-ITD 
allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve “FLT3-ITD” 
divided by area under the curve “FLT3-wild type”; recent studies indicate that AML with NPM1 
mutation and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should 
not routinely be assigned to allogeneic HCT. 57—59, 77 
‡ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene 
mutations.  
§ Three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated 
recurring translocations or inversions, that is, t(8:21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), 
inv(3) or t(3;3); AML with BCR-ABL1. 
ǁ Defined by the presence of 1 single monosomy (excluding loss of X or Y) in association with at least 1 
additional monosomy or structural chromosome abnormality (excluding core-binding factor AML).116