Clinical trial NCT03072043
Conditions: Myelodysplastic Syndrome Acute Myeloid Leukemia Myeloproliferative Neoplasm Chronic Myelomonocytic Leukemia
Keywords: myelodysplastic syndrome (MDS) TP53 mutant myelodysplastic syndrome MDS/myeloproliferative neoplasm (MPN) chronic myelomonocytic leukemia (CMML) acute myeloid leukemia (AML)
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2017-05-18; Completion date: 2021-12-08
Enrollment: 55 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The main purpose of this study is to determine the safe and recommended dose of APR-246 in combination with azacitidine as well as to see if this combination of therapy improves overall survival.

Detailed description:
Participants will be treated for a total of 6 cycles. For participants responding or who have stable disease following cycle 6, treatment may continue until one of the following criteria applies:

* Inter-current illness that prevents further administration of treatment,
* Unacceptable adverse event(s),
* Participant decides to withdraw from the study, or
* General or specific changes in the participant's condition render the participant unacceptable for further treatment in the judgment of the investigator.
* Evidence of disease progression by the International Working Group (IWG) 2006 criteria.

Participants who wish not to continue treatment at time of disease assessment at end of cycle 6 will complete their end of treatment visit upon completion of cycle 6.

Arms: arm 1: Participants will receive intravenous infusions of APR-246 as a lead-in phase on days -14 to -11 starting at Dose Level 1 prior to starting cycle #1 of combination therapy with azacitidine. Combination therapy will consist of APR-246 on days 1-4 and azacitidine on days 4-10 (or days 4-5 and 8-12) of a 28 day cycle. arm 2: Participants will be treated with APR-246 administered at the maximum tolerated dose (MTD) with azacitidine on a 28 day cycle utilizing the same dosing schedule as in Phase 1b.
Interventions: intervention 1: APR-246 intervention 2: Azacitidine
Intervention descriptions: intervention 1: Phase 1b: Dose escalation of APR-246 via intravenous (IV) infusion, with starting dose of 50 mg/kg lean body weight (LBW). Phase 2: APR-246 at maximum tolerated dose (MTD). intervention 2: Azacitidine is administered subcutaneously (SC) or via IV at 75 mg/m\^2.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase 1b/2 Study to Evaluate the Safety and Efficacy of APR-246 in 
Combination with Azacitidine for the Treatment of TP53 Mutant Myeloid 
Neoplasms 
 
NCT03072043 
 
Amendment 6 
December 30, 2019 


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53 
Study Calendar 
Evaluation* 
Baseline/ 
Screening 
* 
Lead-in phase*** 
Cycle 1 
Cycle 2 and Subsequent 
Cycles 
Every 3 
Cycles 
End of 
Treatment 
**** 
Day 
-14 
Day 
-13 
Day 
-12 
Day-
11 
Day 
-10 
Day 
-7 
Day 
1 
Day 
2 
Day 
3 
Day 
4a 
Day 
8 
Day 
15 
Day 
22 
Prior to/ 
Day 1b 
Days 
1-4a 
Day 
8 
Day 
15 
Day 
22 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical history c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam d 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vital Signsd 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
 
 
X 
ECOG PS 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
APR-246 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
Azacitidinea 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Bone marrow Biopsy and 
Aspiration** 
X 
 
 
 
 
X
** 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Flow Cytometry and 
Cytogenetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
NGS Myeloid Panele 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Correlative Studiesf 
X 
 
 
 
 
X
** 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Response  
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Hematology g 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Blood chemistry h 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Pregnancy test i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKGj  
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Transfusion Log 
X 
 <-------------------------From 8 weeks prior to randomization throughout end of treatment date --------> 
<---------------------------Starting C1D-14 (post 1st dose) through 30 days post end of treatment---------> 
 
X 
Adverse events 
 
 
X 
APR-246 will be administered as monotherapy in the lead-in phase IV over 4 days (days -14 to -10) during the Phase 1b portion only***.  
For combination therapy, APR-246 is administered IV on days 1-4 of each 28 day cycle. 
a:   Azacitidine is administered SC or IV over 7 days starting day 4 (7 consecutive days, 4-10; or 2+5 (i.e., days 4-5 and 8-12)) 
 
b:   Day 1 evaluations for subsequent cycles are to be done within 7 days prior to next cycle drug administration. 
c:   Full medical history will be obtained by the APP/MD at baseline for safety and eligibility purposes, though only baseline medical history items will be 
recorded  on CRFs – this will include any issues/items from 4 weeks prior to screening date. 
d:   Physical exam and vital signs (including blood pressure, heart rate, respiration rate and temperature) will be completed for safety purposes though not  
recorded onto CRFs and items noted will be recorded as AEs where appropriate. Vitals will be collected prior to APR-246, 2 hours into infusion and at 
end of infusion (+/- 30 mins at all time points). 
e:   NGS myeloid panel will evaluate  recurrent gene mutations and TP53 VAF (secondary endpoints #4-6) at study entry and every 3 cycles from 
peripheral blood (PB) mononuclear cells (MNC).  If TP53 mutation is only present on BM analysis at screening, serial NGS myeloid panel can 
be performed on bone marrow MNC.  Samples will be sent to Genoptix as the central laboratory for mutational analysis.   
f:   Correlative studies (secondary endpoints #7-8) will be performed on BM MNC during screening, day #-10 of lead in phase and every 3 cycles. If 


 
 
 
54 
 
specimen not collected (e.g. dry tap), not considered deviation.   
g: Hematology including hemoglobin, WBC with differential, and platelet count.  
h: Blood chemistry including sodium, potassium, BUN, glucose, ALT/AST, alkaline phosphatase, total protein, total bilirubin, albumin, creatinine, and 
calcium. 
i: Pregnancy test; for women of childbearing potential, a negative pregnancy test (urine or serum) must be documented between Screening 
and first day of treatment on study.  Must be documented prior to 1st dose of medication on study  
j:   EKG prior to initial dose of APR-246 and after infusion on day -11 of the lead in phase. EKG will be performed on day 1 and at end of infusion on day 
4 of cycle 1 and then on day 1 evaluations of subsequent cycles. 
Concurrent medications will not be captured on CRFs but will be reviewed with subjects in clinic at start of cycle visits to determine if they are reveal any 
new AEs or SAEs. For patients with documented CR or PR at disease assessment following cycle 3, hematology and blood chemistry assessments will be 
required for D1 of each subsequent cycle and more frequently per the discretion of the treating physician. 
 
* All screening/baseline evaluations will be performed within 4 weeks prior to the start of APR-246 and azacitidine treatment.  All assessments are to be   
     performed on day 1 of each week. In the event that a visit or test cannot be scheduled on the exact visit day, a window of ±7  
     working days is allowable.   
   
**Bone marrow aspirate will be only be required for day #-10 in the phase 1b component of the trial.   In the phase 2 component, bone marrow assessment   
      completed within 1  month of signing consent will be accepted to fulfill screening requirement as long as it has been completed following the last MDS   
      treatment (excluding ESAs) and there are unstained core biopsy or clot sections available for p53 immunohistochemistry.   
***Lead-in phase will only be part of the Phase 1b portion of the study.  
 
****Continuation Phase: After completing cycle 6 response assessments, subjects who have stable disease or better may continue treatment with APR-
246 and azacitidine on 28 day cycles.  Bone marrow biopsy and aspirate will be repeated after every 3 cycles. A CBC and CMP will be obtained at Day 1 
of each cycle or more often per study investigator.  
 
End of Cycle 6 Evaluation and End of Treatment:  Subjects discontinuing treatment early should complete their end of treatment visit within 
approximately 28 days of their last dose of investigational product.  Physical exam, vital signs, adverse event reporting, CBC, and blood chemistry and 
BM aspirate and biopsy with cytogenetic and NGS analysis should be performed if feasible.  
 
Off Treatment assessment: includes best response, date of first response, date of loss of response, reason for discontinuation. 
 
Off study CRF: vital status, date of death/last contact, transformation to AML and the date of transformation to AML if applicable. 
 


 
 
 
55 
 
14. MEASUREMENT OF EFFECT 
 
Definitions:  Response and progression will be assessed according to modified International Working Group 
(IWG) 2006 criteria34 (Appendix B).   
 
15. STATISTICAL CONSIDERATIONS 
 
1. Study Design 
This study will be a multi-institution, open-label, phase Ib/II clinical trial conducted in 2 parts: a Phase 1b 
part followed by a Simon’s two-stage Phase 2 design. The study will assess the safety and efficacy of APR-
246 in combination with azacitidine for the treatment of TP53 mutant myeloid neoplasms. All patients will 
have pre-screening NGS on peripheral blood (PB) or bone marrow (BM) samples to determine TP53 
mutational status and therefore eligibility to participate in this study. A PB sample will be obtained prior to 
treatment for NGS by the central laboratory to evaluate baseline VAF and for serial analysis. The initial 
Phase 1b part will evaluate APR-246 administered with azacitidine. Cohorts of at least 3 evaluable patients 
will be enrolled using a modified 3 + 3 design. The MTD is defined as the dose level below which DLT is 
manifested in ≥33% of the patients or at dose level 1 if DLT is manifested in <33% of the patients.  
     Following completion of the Dose Finding Phase, we will conduct a dose expansion, whereby patients 
will be treated with APR-246 administered at the MTD with azacitidine on a 28 day cycle utilizing the same 
dosing schedule as in Phase 1b. All patients who complete at least one treatment cycle of APR-246 and 
azacitidine and who have at least one post-treatment clinical response assessment will be considered eligible 
for the efficacy-evaluable population and will be summarized for all efficacy variables.  Patients who fail to 
complete one treatment cycle will also be considered efficacy-evaluable if they show clear evidence of 
clinically significant disease progression. Patients who are not efficacy-evaluable will be replaced. A 
Simon’s two-stage minimax design will be applied, as follows: 
Stage 1: Enroll a total of 24 evaluable patients at the MTD (including patients who were enrolled during the 
Phase 1 part of the study).  If less than 6 of 24 patients achieve CR, then the study will be terminated early 
with the conclusion that the regimen does not warrant further investigation.  If 6 or more patients achieve 
CR, then enrollment will be permitted to continue to Stage 2.  
Stage 2: Enroll 21 more evaluable patients for a total of 45.  If less than 14 of 45 patients achieve CR, then 
there is insufficient evidence to support continued study of this treatment.  If at least 14 of 45 patients 
achieve CR, then there is sufficient evidence to support further study of APR-246 in combination with 
azacitidine in Phase 3. Up to 39 additional evaluable patients will be treated at the level of the MTD in the 


 
 
 
56 
Phase 2 portion of the trial.   
This rule has the following operating characteristics:  90% power, with alpha=0.05 under the null hypothesis 
that the proportion of patients achieving CR is ≤ 20% versus the alternative hypothesis that it is ≥ 40%.  This 
design has a probability of early termination equal to 0.66 if the true CR rate is 20%.  
 
2.  Statistical Analysis Methods 
Demographic and clinical variables for the study patients will be summarized using descriptive statistics 
(mean, standard deviation, median, inter-quartile range, range, frequency counts and percentages). Safety and 
efficacy data will be analyzed overall as well as separately for each dose cohort when appropriate. 
 
3. Safety Analysis 
This analysis will include all subjects who have received any protocol treatment, regardless of patient 
eligibility. The number (%) of subjects with adverse events, serious adverse events, and adverse events 
leading to treatment discontinuation will be reported.  Adverse events summary will be reported by type and 
severity.  Laboratory parameters will also be summarized using descriptive statistics.  
 
4. Efficacy Analysis: ITT 
This analysis will include all subjects who have received any protocol treatment, regardless of patient 
eligibility or duration of treatment. Those who have no response assessment data due to reasons such as drop 
out of the study, withdrawal consent, or lost to follow-up will be treated as non-responders for various 
response evaluations. The proportion of subjects achieving the primary endpoint will be summarized.  A 95% 
exact binomial confidence interval of the proportion will also be provided for all participants treated at the 
MTD. In addition, a second analysis of evaluable subjects will be performed. Evaluable subjects are defined 
as those who complete at least 3 cycles of therapy and complete the first on treatment bone marrow biopsy 
and aspirate to evaluate study drug response. 
 
Analyses of the following secondary endpoints will be performed as well: 
i. Duration of response defined as the time between achieving response and progression of disease. 
ii. OS at 8 months 
iii. Proportion of subjects achieving hematological improvement (HI), partial response (PR), complete response 
(CR), and/or marrow CR (mCR) by the IWG 2006 criteria (see appendix B) 
iv. Proportion of subjects who obtain a response as defined by IWG 2006 criteria with a baseline TP53 VAF ≥ 
20% versus < 20% or high versus low nuclear p53 protein expression 


 
 
 
57 
v. Correlation of TP53 VAF with nuclear p53 protein expression as determined by IHC 
vi. Proportion of subjects who achieve ≥ 50% reduction in TP53 VAF. 
vii. Progression free survival (PFS) and OS in clonal responders (≥ 50% reduction in TP53 VAF) versus non-
responders 
viii. Profile expression of genes related to p53-mediated signal transduction before and after APR-246 treatment 
ix. Profile ROS production before and after APR-246 treatment 
x. AML transformation according to World Health Organization (WHO) criteria 
xi. OS 
xii. LFS 
xiii. Determine recurrent gene mutations in ASXL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, 
ETV6, EZH2, GATA2, GNAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, NPM1, NRAS, PDGFRA, 
PDGFRB, PHF6, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, STAT3, 
STAT5b, TET2, TP53, U2AF1, WT1, and ZRSR2 at study entry and serially throughout treatment to assess 
changes in somatic mutation landscape. 
 
Preliminary data on the above endpoints will prove to be very useful for further investigation of this 
protocol’s treatment. Such data will be summarized appropriately in an exploratory fashion. Both point 
estimates and 95% confidence intervals will be reported, if feasible. Time-to-event endpoints such as OS and 
LFS will be summarized using the Kaplan-Meier product-limit method. 
 
16. Laboratory Correlates 
Unless otherwise specified, all laboratory correlates will be performed in the laboratory of Dr. Alan List or at 
Genoptix medical laboratory. 
1. Mutation analyses 
Genoptix medical laboratory (2110 Rutherford Rd, Carlsbad, CA 92008) will be the central laboratory for 
this study regarding molecular profiling. All patients will undergo baseline NGS for confirmation of TP53 
mutation, baseline TP53 VAF, and identification of additional somatic mutations. These analyses will not 
impact enrollment into the clinical trial. Importantly, there will be serial evaluation following cycle 3 and 
cycle 6 where NGS will be repeated to evaluate for clonal reduction of TP53 VAF as well as changes in the 
underlying mutational architecture of these patients. These analyses will be utilized for secondary endpoints 
#4-7. For correlative genomic studies that will be performed at Genoptix medical laboratory, 2-3 mL 
of peripheral blood will be obtained in a standard Vacutainer tube with EDTA (purple top) as 
anticoagulant. If TP53 mutation is only present on BM analysis at screening, serial NGS myeloid panel 


 
 
 
58 
can be performed on bone marrow MNC.  A FedEx shipping label will be included in the shipper box 
with a research specific requisition.   Recurrent gene mutations of ASXL1, BCOR, BRAF, CALR, CBL, 
CEBPA, CSF3R, DNMT3A, ETV6, EZH2, GATA2, GNAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NF1, 
NPM1, NRAS, PDGFRA, PDGFRB, PHF6, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, 
SRSF2, STAG2, STAT3, STAT5b, TET2, TP53, U2AF1, WT1, and ZRSR2 will be evaluated at each NGS 
analysis. DNA and RNA will be isolated from BM-MNC by the Ficoll method following cycle 3 and cycle 6 
and stored in the laboratory of Dr. Alan List. In patients who become negative for TP53 mutation by NGS 
(VAF sensitivity for this assay is 1% in patients with previously identified variants), we will perform PCR-
based barcoding or digital droplet PCR to identify rare variants in an effort to determine the depth of 
remission induced by treatment with APR-246 and azacitidine.  
2. Immunohistochemistry for p53 expression 
BM core biopsies will be centrally evaluated at Moffitt Cancer center by Dr. Ling Zhang to evaluate for p53 
protein expression as a biomarker of response, correlation with TP53 VAF, and serially over the course of 
treatment (secondary endpoints # 4-5). Three sections from each core biopsy will be obtained at baseline and 
following cycle 3 and 6 of therapy. To evaluate for p53 protein expression, p53 IHC will be performed using 
a standard protocol (p53 antibody, clone Bp53-11, Ventana Medical Systems, Tucson, AZ, USA). Nuclear 
p53 expression will be assessed quantitatively by percent p53 positivity and semi-quantitatively with an IHC 
score of stain intensity (0, 1+, 2+, and 3+) multiplied by percent positive hematopoietic cells. 
Shipping 
Bone marrow core biopsies will be shipped to the below address. 
       H. Lee Moffitt Cancer Center 
       Dr. Ling Zhang 
       12902 Magnolia Drive 
       Tampa, FL 33612 
       Phone: (813) 745-2852 
 
3. In vivo evaluation of APR-246 
As the primary mechanism of action of APR-246 is restoration of wild-type function of p53, we will utilize 
the lead in phase of APR-246 monotherapy to assess the activation of downstream targets of p53. An 
additional 20ml of bone marrow aspirate will be obtained in purple EDTA tubes at the pre-study bone 
marrow (prior to Cycle #1) and on day -10 following four days of APR-246 as well as at disease assessments 
(following cycle 3 and cycle 6; see study calendar). Utilizing the bone marrow aspirates, the mononuclear 


 
 
 
59 
cells will be collected with isolation of DNA and RNA as previously described and stored in the laboratory 
of Dr. Alan List. Evaluation of p53-mediated signal transduction will be analyzed using Qiagen human p53 
Signaling Pathway RT² Profiler PCR Array (secondary endpoint #8). As production of ROS leading to DNA 
damage is an additional mechanism of action of APR-246, we will evaluate for ROS production before and 
after APR-246 monotherapy via flow cytometry (CellROX® Deep Red Reagant, Life Technologies; 
secondary endpoint #9).  
 
i. Shipping  
Heparinized bone marrow aspirates should be shipped overnight on cool packs, wrapping the vials to insure 
the marrow does not freeze. Specimens must be shipped via next day delivery on the day the specimen is 
obtained. DO NOT USE DRY ICE OR WET ICE. A Fedex account number will be provided for overnight 
shipping. Call Kathy McGraw or the List laboratory at (813) 745-8271 on the day of expected shipment to 
confirm delivery date. Shipping can only be done Monday through Thursday for arrival Tuesday through 
Friday.  Saturday arrivals cannot be processed. Be sure all samples are labeled appropriately with patient 
identifier information and designation of bone marrow.   
 
Shipping Addresses: 
H. Lee Moffitt Cancer Center 
Kathy McGraw or David Sallman, Dr. Alan List Laboratory 
SRB3/23234List/x8271 
12902 Magnolia Drive 
Tampa, FL 33612 
Phone: 813-745-8271 
 
ii. Banking 
The residuals and/or derivatives of bone marrow and blood samples collected for the correlative studies will 
be retained in the List laboratory for possible use in approved future studies. If future use is denied or 
withdrawn by the patient, the samples will be removed from consideration for use in any future study. 
 
17. REGULATORY AND REPORTING REQUIREMENTS 
This research will be done in compliance with the applicable State and Federal laws and regulations and in 
compliance with ICH guidelines. The study description will be posted on the www.clinicaltrials.gov website 
in compliance with current regulations. The data and safety plan will be executed in accordance with ICH 


 
 
 
60 
guidelines and in compliance with policy and procedures at the H. Lee Moffitt Cancer Center & Research 
Institute. The following must be observed to comply with Food and Drug Administration (FDA) regulations 
for the conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
1. Informed Consent 
The investigator is responsible for patient care and for obtaining consent by the patient. Written informed 
consent must be obtained prior to entry of any patient. The original consent form signed and dated by the 
subject and by the person consenting the subject prior to the subject’s entry into the study must be 
maintained in the Investigator’s study files. 
 
2. Use of Specimens For Research 
The patient is free at any time in the future to decide not to provide specimens or to withdraw his/her 
specimens from further scientific research.  Such a decision will have no impact on his/her treatment or other 
aspects of participation in this study. 
 
3. Institutional Review 
No subject is to be enrolled on this protocol until the Center’s Institution Review Board has approved it. The 
protocol for this study has been designed in accordance with the general ethical principles outlined in the 
Declaration of Helsinki. The Investigator will be responsible for preparing documents for submission to the 
relevant IRB and obtaining written approval for this study. The approval will be obtained prior to the 
initiation of the study. The approval for both the protocol and informed consent must specify the date of 
approval, protocol number and version, or amendment number. Any amendments to the protocol after receipt 
of IRB approval must be submitted by the Investigator to the IRB for approval. The Investigator is also 
responsible for notifying the IRB of any serious deviations from the protocol, or anything else that may 
involve added risk to subjects. 
 
4. Drug Accountability 
For each drug supplied for a study, an accountability ledger containing current and accurate inventory 
records covering receipt, dispensing, and the return of study drug supplies must be maintained.  Drug 
supplies must be kept in a secure, limited access storage area under the recommended storage conditions.  
These Accountability Forms must be readily available for inspection and are open to FDA inspection at any 
time. 


 
 
 
61 
5. IND Safety Reporting Requirements 
 
This protocol is associated with an Investigational New Drug Application (IND) supported by Aprea. IND 
Safety Reports are required for any adverse experience associated (or possibly associated) with the use of 
investigational product(s) that is both serious and unexpected. To meet the IND Safety reporting 
requirements set forth in 21 CFR§312.32, an FDA Form 3500A (MedWatch form) will be completed and 
provided to the Moffitt Office of Institutional Regulatory Affairs for Investigational Drugs and Devices. All 
other adverse events will be reported to the FDA as part of the annual reporting requirement of the IND. 
     The initial report will include details of the current illness and serious adverse events, and an assessment 
of the causal relationship between the event and the investigational product(s). Information not available at 
the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the 
report) will be documented on the follow-up report. A final report to document resolution of the serious 
adverse event is required if it is not documented in the initial report. The Moffitt Office of Institutional 
Regulatory Affairs will provide the report to the FDA as an official submission to the IND. This will occur 
independently of any other use of the MedWatch form or required reporting of serious adverse events. 
Submission of the MedWatch form to any other agency, including the FDA, does not fulfill this IND Safety 
Reporting requirement. Follow-up to the safety report must also be submitted to the Office of Institutional 
Regulatory Affairs in a timely manner. Upon completion of the report, a copy of all initial and follow-up 
MedWatch forms will be scanned and emailed to the Office of Institutional Regulatory Affairs and a 
telephone call will be made to confirm receipt. For unexpected fatal or life threatening experiences associated 
with the use of the investigational product(s), the Office of Institutional Regulatory Affairs will be contacted 
upon notice of the event. Notification to the FDA will be made as soon as possible, but no later than 7 
calendar days after initial receipt of the information. 
 
6. Hospital/Clinic Records 
Hospital records for patients on this study are the responsibility of the investigator. They will be available for 
review by the sponsors of the trial, health care personnel involved in this study, the IRB, DHHS, and the 
FDA. 
 
7. Investigator Study Files 
The Principal Investigator is responsible for maintaining study files for a period of 2 years following the date 
a marketing application is approved for the drug for the indication for which it is being investigated; or if no 


 
 
 
62 
application is to be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and FDA is notified.  
The following documents should be kept in the study files:  
• A completed, signed FDA Form 1572 (Statement of Investigator) and copies of all current curricula vitae of 
all sub investigators listed on the Statement of the Investigator.  
• The original protocol and all amendments  
• Final IRB approval, annual renewals and all IRB correspondence  
• Blank Case Report Forms  
• Copy of all IRB approved Informed Consent forms with applicable version date  
• Updated laboratory certification and laboratory values (covering entire time of study) 
• Copy of all patient’s signed informed consent forms  
• The final completed case report form for all patients  
 
8. STUDY MONITORING 
The Protocol Review & Monitoring Committee will monitor this study. Regulatory documents and case 
report forms will be reviewed routinely by the MCC Clinical Research Monitoring Core for accuracy, 
completeness and source verification of data entry, validation of appropriate informed consent process, 
adherence to study procedures, and reporting of SAEs and protocol deviations according to MCC Monitoring 
Policies. As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain and have available for monitoring adequate case records (accurate source documents and CRFs) for 
the subjects treated under this protocol. CRFs will only be required for patients who have received at least 
one dose of study medication. In addition, the Investigator agrees to maintain all administrative documents, 
e.g., IRB/IEC correspondence, investigational product and supplies shipment manifests, monitoring logs, or 
Moffitt Cancer Center/designee correspondence. The PI will be primarily responsible for monitoring of 
adverse events, protocol violations, and other immediate protocol issues.  The study coordinator will collect 
information of subjects enrolled at Moffitt and other institutions through the use of electronic or paper AE 
forms, CRF forms, End of Study forms, and Informed Consent forms.  
 
Internal Monitoring 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. The Case Report Forms will be reviewed 
by Moffitt’s Internal Monitors, periodically, throughout the conduct of the trial. The monitoring will include 
source data verification, utilizing research subjects’ medical records. 


 
 
 
63 
 
On-site Audits  
The Investigator should promptly notify Moffitt Cancer Center or its authorized representative of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports received to Moffitt 
Cancer Center or its authorized representative. 
 
Data & Safety Monitoring Plan 
Identification of oversight responsibility:  
The PI has primary responsibility. 
The MCC Protocol Monitoring Committee (PMC): 
The PMC meets monthly and reviews accrual, patterns and frequencies of all adverse events, protocol 
violations and when applicable, internal audit results.  
Description of internal (PI) safety review and monitoring process: 
Responsible for identifying and reviewing adverse events biweekly: 
Principal Investigator  
Study team 
To be reviewed:  
Adverse events by grade (Gr. 3 or above using CTCAE v4.03) and attribution (expected or unexpected)  
Relationship to study drug/intervention  
Application of dose finding escalation/de-escalation rules  
Application of study designed stopping/decision rules  
Whether the study accrual pattern warrants continuation/action  
Protocol violations 
AEs will be reported along with all other data in the Oncore database. The PI or PI designate will report all 
adverse events to the Clinical Research Office (CRO). The CRO will report all SAEs to Aprea, and all 
reportable SAEs to the IRB.   AE information will be entered into the CRO database. AE information will be 
managed by the CRO and will be made available to the PMC or appropriate monitoring body by designated 
members of the PMC or the study statisticians.  
 
 
 
 
 


 
 
 
64 
 
 
 
 
 
 
 
18. REFERENCES 
1. Greenberg, P.L., et al. Myelodysplastic syndromes. Journal of the National Comprehensive Cancer 
Network : JNCCN 11, 838-874 (2013). 
2. Cazzola, M., Della Porta, M.G. & Malcovati, L. The genetic basis of myelodysplasia and its clinical 
relevance. Blood 122, 4021-4034 (2013). 
3. Greenberg, P.L., et al. Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic 
syndromes. Blood (2012). 
4. Greenberg, P., et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. 
Blood 89, 2079-2088 (1997). 
5. Kantarjian, H., et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events 
not considered in the original International Prognostic Scoring System. Cancer 113, 1351-1361 (2008). 
6. Margulies, M., et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 
376-380 (2005). 
7. Malcovati, L., et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: 
recommendations from the European LeukemiaNet. Blood 122, 2943-2964 (2013). 
8. Papaemmanuil, E., et al. Clinical and biological implications of driver mutations in myelodysplastic 
syndromes. Blood 122, 3616-3627; quiz 3699 (2013). 
9. Bejar, R., et al. Clinical effect of point mutations in myelodysplastic syndromes. The New England 
journal of medicine 364, 2496-2506 (2011). 
10. List, A., et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. The New 
England journal of medicine 355, 1456-1465 (2006). 
11. Kulasekararaj, A.G., et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with 
aberrations of chromosome 5, and correlate with adverse prognosis. British journal of haematology 160, 
660-672 (2013). 
12. Bally, C., et al. P-006 Prognostic value of TP53 gene mutations in higher-risk MDS treated with 
azacitidine (AZA). Leukemia Research 37, S25. 
13. Mallo, M., et al. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of 
cytogenetics and mutations. British journal of haematology 162, 74-86 (2013). 
14. Jadersten, M., et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease 
progression. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
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15. Fenaux, P., et al. Efficacy of azacitidine compared with that of conventional care regimens in the 
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Oncol 10, 223-232 (2009). 
16. Bally, C., et al. Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute 
myeloid leukemia treated with azacitidine. Leukemia research 38, 751-755 (2014). 
17. Bejar, R., et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic 
syndrome patients. Blood 124, 2705-2712 (2014). 


 
 
 
65 
18. Bejar, R., et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after 
hematopoietic stem-cell transplantation. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 32, 2691-2698 (2014). 
19. Sallman, D.A., et al. Impact of TP53 mutation variant allele frequency on phenotype and outcomes in 
myelodysplastic syndromes. Leukemia 30, 666-673 (2016). 
20. Desoutter, J., et al. Molecular prognostic factors in acute myeloid leukemia receiving first-line therapy 
with azacitidine. Leukemia (2015). 
21. Bejar, R., et al. TP53 Mutation Status Divides MDS Patients with Complex Karyotypes into Distinct 
Prognostic Risk Groups: Analysis of Combined Datasets from the International Working Group for 
MDS-Molecular Prognosis Committee, (2014). 
22. Hou, H.A., et al. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups 
show the mutation is stable during disease evolution. Blood cancer journal 5, e331 (2015). 
23. Wiman, K.G. Strategies for therapeutic targeting of the p53 pathway in cancer. Cell death and 
differentiation 13, 921-926 (2006). 
24. McGraw, K.L., et al. Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and 
adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia. 
Haematologica (2016). 
25. Muller, P.A. & Vousden, K.H. Mutant p53 in cancer: new functions and therapeutic opportunities. 
Cancer cell 25, 304-317 (2014). 
26. Bykov, V.J., Issaeva, N., Selivanova, G. & Wiman, K.G. Mutant p53-dependent growth suppression 
distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National 
Cancer Institute database. Carcinogenesis 23, 2011-2018 (2002). 
27. Nahi, H., et al. PRIMA-1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion. 
British journal of haematology 132, 230-236 (2006). 
28. AB, A. INVESTIGATOR’S BROCHURE (IB) APR-246. (2016). 
29. Wiman, K.G. Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. 
Oncogene 29, 4245-4252 (2010). 
30. Lambert, J.M., et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer 
cell 15, 376-388 (2009). 
31. Peng, X., et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a 
dedicated NADPH oxidase. Cell death & disease 4, e881 (2013). 
32. Mohell, N., et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. 
Cell death & disease 6, e1794 (2015). 
33. Lehmann, S., et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 
in refractory hematologic malignancies and prostate cancer. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology 30, 3633-3639 (2012). 
34. Cheson, B.D., et al. Clinical application and proposal for modification of the International Working 
Group (IWG) response criteria in myelodysplasia. Blood 108, 419-425 (2006). 
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neoplasms and acute leukemia. Blood 127, 2391-2405 (2016). 
 
 
 
 


 
 
 
66 
 APPENDIX A 
Performance Status Criteria 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 


 
 
 
67 
APPENDIX B 
 
RESPONSE CRITERIA FOR SUBJECTS WITH MDS AND CMML ACCORDING IWG 2006 
CRITERIA34 
 
 
ALTERING DISEASE NATURAL HISTORY 
Complete remission (CR) 
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines 
Persistent dysplasia will be noted 
Peripheral blood: 
Hemoglobin ≥ 11 g/dL 
Platelets ≥ 100 x 109/L 
Neutrophils ≥ 1.0 x 109/L 
Blasts 0% 
Partial remission (PR) 
All CR criteria if abnormal before treatment, except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood:  if HI responses, they will be noted in addition to marrow CR 
Stable disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 weeks 
Failure 
Death during treatment 
Disease progression characterized by worsening of cytopenias, increase in % of 
bone marrow blasts, or progression to a more advanced MDS FAB subtype than 
pretreatment 
Disease Progression (PD) 
For subjects with: 
Less than 5% blasts:  ≥ 50% increase in blasts to > 5% blasts 
5%-10% blasts:  ≥ 50% increase in blasts to > 10% blasts 
10%-20% blasts:  ≥ 50% increase in blasts to > 20% blasts 
20%-30% blasts:  ≥ 50% increase in blasts to > 30% blasts 
Any of the following: 
At least 50% decrement from maximum remission/response levels in 
granulocytes or platelets 
Reduction in hemoglobin (Hgb) concentration by ≥ 2 g/dL  
- Transfusion dependence 
CYTOGENETIC RESPONSE 
Complete 
Disappearance of the chromosomal abnormality without appearance of new ones 
Partial 
At least 50% reduction of the chromosomal abnormality 
HEMATOLOGICAL IMPROVEMENT (HI) 
Erythroid response (HI-E) 
(Pretreatment < 11 g/dL)  
Hgb increase by ≥ 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion 
number in the previous 8 weeks.  Only RBC transfusions given for a Hgb of ≤ 
9.0 g/dL pretreatment will count in the RBC transfusion evaluation 
Platelet response (HI-P) 
(Pretreatment < 100 x 109/L) 
Absolute increase of ≥ 30 x 109/L for subjects starting with > 20 x 109/L 
Increase from < 20 x 109/L to > 20 x 109/L and by at least 100% 
Neutrophil response (HI-N) 
(Pretreatment < 1.0 x 109/L) 
At least 100% increase and an absolute increase of > 0.5 x 109/L 


 
 
 
68 
PROGRESSION/RELAPSE CRITERIA FOR SUBJECTS WITH MDS/CMML  
ALTERING DISEASE NATURAL HISTORY 
Disease Progression (PD) 
For subjects with: 
Less than 5% blasts:  ≥ 50% increase in blasts to > 5% blasts 
5%-10% blasts:  ≥ 50% increase in blasts to > 10% blasts 
10%-20% blasts:  ≥ 50% increase in blasts to > 20% blasts 
20%-30% blasts:  ≥ 50% increase in blasts to > 30% blasts 
Any of the following: 
At least 50% decrement from maximum remission/response levels in granulocytes 
or platelets 
Reduction in hemoglobin (Hgb) concentration by ≥ 2 g/dL  
                            Transfusion dependence 
Disease transformation 
Transformation to AML (30% or more blasts) 
Relapse after CR or PR 
At least one of the following: 
Return to pretreatment bone marrow blast % 
Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets 
- Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
HEMATOLOGICAL IMPROVEMENT 
Progression/relapse after HI  
At least one of the following: 
At least 50% decrement from maximum response levels in granulocytes or 
platelets  
Reduction in Hgb by ≥ 1.5 g/dL 
- Transfusion dependence 
 
 
 


 
 
 
69 
APPENDIX C: 2016 WHO CLASSIFICATION FOR CMML AND MDS35 
WHO CMML 
 
 
 
 
 
 
 
 
 
 
 
 
#Not meeting WHO criteria for BCR-ABL1 CML, PMF, PV, or ET. No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2 (should be 
specifically excluded in cases with eosinophilia). If myelodysplasia is absent or minimal, CMML diagnosis can be made with acquired clonal cytogenetic/molecular 
genetic abnormality or monocytosis x 3 months when all other causes of monocytosis have been excluded. Blasts and blast equivalents include myeloblasts, 
monoblasts, and promonocytes. 
 
WHO MDS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytopenias defined as: hemoglobin < 10 g/dL; platelet count < 100 x 109/L; and absolute neutrophil count < 1.8 x 109/L.  
To be classified as dysplasia, >10% of any cell lineage must be dysplastic. PB monocytes must be < 1 X 109/L. †If SF3B1 
mutation is present. *Subclassified as MDS-RS with single or multi-lineage dysplasia (MDS-RS-SLD or MDS-RS-MLD). 
Pancytopenia with RS is classified as MDS-RS-MLD.   **Presence of Auer rods is classified as MDS-EB-2. *** Del(5q) 
alone or with 1 additional abnormality except -7 or del(7q). ****1% peripheral blasts needs to be confirmed on 2 separate 
occasions to make a diagnosis of MDS-U. MDS-U diagnosis is also made with SLD and pancytopenia or MDS defining 
cytogenetic abnormality in the absence of cytopenias.  
WHO Subtype 
Peripheral Blood 
Bone Marrow 
#Chronic Myelomonocytic Leukemia 
*CMML-0 
**CMML-1 
                              ***CMML-2 
 
*<2% blasts 
**≥2% and <5% blasts 
***≥5% and <20% blasts 
persistent monocytosis > 1 x 109/L 
   and >10% of differential 
+/- cytopenias 
Leukocytosis frequent  
* <5% blasts 
**≥5% and <10% 
blasts 
***<20% blasts 
>10% dysplasia in 
affected lineage 
***Auer Rods 
The absence of the 
Philadelphia 
chromosome of bcr-abl 
fusion gene. 
 
WHO Category 
Peripheral blood 
Bone marrow 
MDS with single lineage 
dysplasia (MDS-SLD) 
Cytopenia (1-2 lines) 
<1% blasts 
 
Dysplasia (1 line) 
< 5% blasts 
RS <15%/<5%† 
MDS with ring sideroblasts 
(MDS-RS)* 
Cytopenia (1-3 lines) 
< 1% blasts  
 
Dysplasia (1-3 lines) 
 < 5% blasts 
RS >15%/>5%† 
MDS with multi-lineage dysplasia 
(MDS-MLD) 
Cytopenia (1-3 lines) 
< 1%blasts 
 
Dysplasia (2-3 lines) 
< 5% blasts  
RS <15%/<5%† 
MDS with excess blasts type I & 
II  
(MDS-EB-1 & MDS-EB-2**)  
Cytopenia (0-3 lines) 
Type I: 2-4% blasts 
Type II: 5-19% blasts  
Dysplasia (1-3 lines) 
Type I 5-9% blasts 
Type II 10-19% blasts 
MDS with isolated del(5q)*** 
Cytopenia (1-2 lines) 
< 1% blasts 
Dysplasia (1-3 lines) 
< 5% blasts 
MDS unclassified 
( MDS-U)**** 
Cytopenia (0-3 lines) 
1% or < 1% blasts 
Dysplasia (1-3 lines) 
< 5% blasts