A Phase II Study to Evaluate Safety and Efficacy of CB-103 in Combination With Venetoclax in Adolescent and Young Adult Patients With Relapsed/Refractory T-cell Acute Lymphoblastic Leukemia (T-ALL)
Phase: PHASE2
Conditions: Leukemia, Lymphoblastic, Leukemia
Sponsor: M.D. Anderson Cancer Center

 
 
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MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2021-0547 
Protocol Title 
A phase II study to evaluate safety and efficacy of CB-103 in combination 
with Venetoclax in adolescent and adult patients with relapsed/refractory 
T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic 
lymphoma (T-LBL) 
Protocol Phase 
Phase II  
Protocol Version 
3.0 
Version Date 
4/25/2024 
 
Protocol PI 
Miriam B Garcia, DO 
Departments 
Pediatrics & Leukemia 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
160223 
SNOMED CT 
91855006 
 
 

 
 
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TITLE OF STUDY:  
 
A phase II study to evaluate safety and efficacy of CB-103 in combination with 
Venetoclax in adolescent and adult patients with relapsed/refractory T-cell 
acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) 
 
Title (Abbreviated): CB-103 + Venetoclax in Relapsed/Refractory T-ALL or T-LBL 
 
 
Department: Department of Pediatrics Patient Care, Division of Pediatrics, & Department of 
Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 
Houston, TX 
Protocol Version: 2.0 
 
PRINCIPAL INVESTIGATORS 
Name 
Title 
Department 
Email 
Phone 
Miriam Garcia, DO 
Assistant Professor 
Pediatrics 
MGarcia@mdanderson.org 
(713) 657-9467 
Branko Cuglievan, MD 
Assistant Professor 
Pediatrics 
Bcuglievan@mdanderson.org 
(713) 563-1499 
Gautam Borthakur, MD 
Professor 
Leukemia 
GBorthak@mdanderson.org 
(713) 563-1586 
 
COLLABORATORS   
Name 
Title 
Department 
Email 
Phone 
David McCall, MD 
Assistant Professor  
Pediatrics  
dmccall1@mdanderson.org 
(713) 792-6604 
Cesar Nunez, MD 
Associate Professor  
Pediatrics  
cnunez@mdanderson.org 
(713) 745-0886 
Michael Roth, MD 
Professor  
Pediatrics  
mroth1@mdanderson.org 
(713) 792-7751 
Amber Gibson, DO 
Assistant Professor 
Pediatrics  
Algibson2@mdanderson.org 
(713) 745-8177 
Jeremy Connors, MD 
Assistant Professor  
Pediatrics  
jsconnors@mdanderson.org 
(832) 729-2910 
Irtiza Sheikh, MD 
Assistant Professor 
Pediatrics 
Ishekh1@mdanderson.org 
(832) 728-9791 
Dristhi Ragoonanan, MD 
Assistant Professor 
Pediatrics 
dragoonanan@mdanderson.org 
(713) 792-6620 
Priti Tewari, MD 
Associate Professor  
Pediatrics  
ptewari@mdanderson.org 
(713)-792-3497 
Demetrious Petropoulos, MD 
Professor  
Pediatrics  
dpetro@mdanderson.org 
(713)-792-3746 
 
BIOSTATISTICIANS 
 
Clark Andersen, MS 
Research Biostatistician, Biostatistics 
crandersen@mdanderson.org 
 
Jian Wang, PhD 
Assistant Professor, Biostatistics 
jianwang@mdanderson.org 
 
  
 

 
 
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TABLE OF CONTENTS 
1. OBJECTIVES .................................................................................................................................. 4 
2. BACKGROUND AND RATIONALE .................................................................................................. 4 
3. STUDY POPULATION .................................................................................................................... 9 
4. TREATMENT PLAN ...................................................................................................................... 12 
5. TREATMENTS ADMINISTERED .................................................................................................... 15 
6. DOSE MODIFICATIONS ............................................................................................................... 20 
7. CONCOMITANT THERAPY .......................................................................................................... 29 
8. STUDY  ASSESSMENTS …………………………………………………………………………………………………………. 30 
 STUDY CALENDAR ............................................................................................................ 34 
9. RESPONSE DEFINITIONS ............................................................................................................. 36 
10. REGULATORY REQUIREMENTS ................................................................................................. 41 
11. TREATMENT DISCONTINUATION ............................................................................................. 41 
12. STATISTICAL CONSIDERATIONS ................................................................................................ 43 
13. APPENDICES ………………………………………………………………………………………………………………….…… 47 
Appendix 1 QT Prolonging Drugs with Risk of Torsades de Pointes ……………………………. 47 
Appendix 2 Revised Criteria for Response Assessment ………………………………………………. 48 
14. REFERENCES ............................................................................................................................. 57 
 

 
 
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1. OBJECTIVES 
1.1. Primary Objectives: 
1.1.1. To characterize the safety and tolerability of CB-103 in combination with Venetoclax in 
adolescent (12 to 18 years) and  adult (19 to 60 years) patients with relapsed/refractory T-cell 
acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). 
 
1.1.2. To assess the efficacy of CB-103 in combination with venetoclax by the overall response 
rate (ORR), defined as complete remission (CR) plus CR with incomplete blood count recovery 
(CRi) [1] plus partial remission (PR) [2], in adolescent and adult patients with 
relapsed/refractory T-ALL/T-LBL. 
 
1.2. Secondary Objectives: 
1.2.1. To assess whether the ORR to CB-103 in combination with Venetoclax is dependent on 
pre‐treatment expression of Notch and/or BCL2 pathway. 
 
1.2.2. To determine the preliminary assessment of CB-103 in combination with Venetoclax by 
other efficacy parameters such as minimal residual disease (MRD), duration of response 
(DoR), overall survival (OS), and event‐free survival (EFS) in adolescent and adult patients with 
relapsed/refractory T-ALL/T-LBL. 
 
1.3. Exploratory Objectives: 
1.3.1. To explore potential correlations of ORR to treatment and additional pharmacodynamic 
(PD) markers, i.e., other oncogenic pathway activations that may co-occur at the start of 
treatment. 
 
1.3.2. To evaluate how many patients are able to transition to Hematopoietic Stem Cell 
Transplant (HSCT): 
1.3.2.1. Either  in the patients achieving CR after the induction and reinduction cycles; 
1.3.2.2. Or in the patients with PR or stable disease (SD) after the induction and 
reinduction. 
 
2. BACKGROUND AND RATIONALE 
2.1. T-ALL Background 
Approximately 15% and 25% of newly diagnosed cases of acute lymphoblastic leukemia (ALL) in 
children and adults, respectively, are T-cell ALL (T-ALL) and are historically linked with a poor prognosis 
[1,2]. T-ALL is characterized by an older age of onset than B-ALL, male sex preponderance, and inferior 
outcome in comparison to B-ALL [1]. Even with the most advanced treatment, the 5-year disease-free 
survival (EFS) of children is only around 75%, with about 30% of children with T-ALL still failing to 
respond, relapsing, or dying from the disease [3]. Traditional treatment regimens for adult acute 
lymphoblastic leukemia, including allogeneic hematopoietic cell transplantation, result in overall 
survival of approximately 40% [4]. 
 
2.2. Notch pathway and Notch inhibitors in T-ALL 
In T-ALL, the most frequent actionable mutation is Notch1 [5]. Notch pathway signaling is commonly 
activated by Notch1 and FBXW7 gene mutations in T-cell ALL, and these are the most commonly 
mutated genes in pediatric T-cell ALL [Board P D T IN. Childhood acute lymphoblastic leukemia 
treatment (PDQ®)[M]//PDQ Cancer Information Summaries. National Cancer Institute (US), 
2019].[15,148] Notch1-activating gene mutations occur in approximately 50% to 60% of T-cell ALL 
cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases, with the result 
that approximately 60% of cases have Notch pathway activation by mutations in at least one of these 
genes [6]. In T-ALL Notch1 and the strictly associated 𝛾𝛾-secretase inhibitors were tested in late-stage 

 
 
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disease, with some responses of short duration and considerable gut toxicity [7]. The best study 
reported one CR and an overall 32% response rate in 25 patients with relapsed disease [8]. 
 
2.3. CB-103 
2.3.1. Preclinical studies 
 
CB-103 is a first-in-class small molecule pan-Notch inhibitor with a novel mechanism of action 
directly targeting the Notch transcriptional activation complex by inhibition of the NICD-CSL 
interaction [9]. In contrast to the aforementioned inhibitors, pan-Notch inhibitor CB-103 is 
binding to the Notch-specific transcription complex in the cell nucleus and unfolds its effects 
at the transcription level of Notch target genes at the most downstream and central location. 
Thereby CB-103 can inhibit transcriptional activation of Notch-related target genes, regardless 
of the mechanism of activation, at the most downstream location in the cell nucleus. 
 
Pharmacodynamic (PD) and direct effect of CB-103 treatment on tumor proliferation and 
growth was studied ex vivo in 10 primary T-ALL patient blood samples and based on one of 
the Notch positive T-ALL patient samples in vivo in a patient derived (PDx) xenograft model of 
human T-ALL in NSG mice. CB-103 was shown to be effective both against primary human T-
ALL samples ex vivo and in patients' derived T-ALL xenografts in mice. 
 
In a pre-clinical study the potential additive or synergistic activity of CB-103 in combination 
chemotherapy agents was investigated in patient samples harbouring GOF mutations in 
NOTCH1 receptor. The effect of drug on cell proliferation/ cell death was determined by MTS 
and best dose/combination were confirmed by flow cytometry using Annexin V+ 7AAD 
staining or an alternative method. 
 
Combination drugs tested were: 
a. Nelarabine 
b. Cytarabine 
c. Gemcitabine 
d. HDAC6 inhibitor (ACY1215) 
e. Dexamethasone 
f. Vincristine 
 
The data revealed that in NOTCH mutated (GOF) T-ALL patient samples, CB-103 exhibit 
synergy with Cytarabine, Gemcitabine, Nelarabine, HDAC6 inhibitor and Vincristine (Table 1). 
This synergy between CB-103 and different chemotherapeutic agents enhances cell death in 
NOTCH + T-ALL leukemic blasts. 
 
More interestingly, a synergy between CB-103 and Cytarabine, Gemcitabine,and Nelarabine 
was observed also in one of the two patients with Notch wild-type T-ALL. 

 
 
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Table 1: Summary of drug combination effect on primary T-ALL samples: 
T-ALL 
sample 
NOTCH 
mutation 
Additional 
mutations 
         Combination drug and combination index (CI value). 
CI < 1 synergy; = 1 additive, >1 antagonsitic effect 
 
 
 
Cytar-
abine 
Nelarabine 
Gemcitabine 
HDAC6 
inhibitor 
(ACY1215) 
Vincristine 
Dexamethasone 
PDTALL39 
NOTCH1 
GOF 
P53 
<1 
<1 
<1 
<1 
nd 
Nd 
PDTALL19 
NOTCH1 
GOF 
- 
< 1 
<1 
<1 
<1 
nd 
>1 
PDTALL46 
NOTCH1 
GOF 
FBXW7 & 
P53 
<1 
<1 
<1 
<1 
<1 
nd 
PDTALL47 
NOTCH3 
GOF 
FBXw7 & 
P53 
<1 
<1 
<1 
<1 
nd 
nd 
PDTALL9 
Wildtype 
- 
>1 
>1 
>1 
>1 
nd 
nd 
PDTALL13 
Wildtype 
- 
<1 
<1 
<1 
Nd 
nd 
nd 
 
2.3.2. Clinical studies 
 
The clinical study, CB103-C-101 (NCT03422679) was a first-in-human (FIH) trial, open-label 
phase I/IIA study designed to evaluate safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary efficacy of CB-103 administered orally in adult 
patients with either locally advanced or metastatic solid tumours or haematological 
malignancies characterised by pathogenic activations of the NOTCH signalling pathway.  
In cohorts 1-8, CB-103 was given at increasing doses up to 500 mg (free base) once daily (QD). 
The dose of 500mg QD, given orally, was declared as provisional recommended phase 2 dose 
(RP2D). Starting with dose group 9, CB-103 was given twice daily (BID). In cohorts 9-12, 
increasing doses from 250 to 500 mg BID were explored. From dose group 10, an intermittent 
dosing schedule was introduced whereby CB-103 was administered twice daily on 5 days on 
treatment followed by two days off treatment break. 
The dose of 2x 500mg in an intermittent schedule (five days on treatment, two days off) was 
declared a safe dose by the Cohort Review Committee (CRC). An MTD was not reached in the 
study. The 2x 500mg dose in an intermittent schedule (5 days on treatment, 2 days off) was 
declared as RP2D based on the saturation in exposure observed at this dose level and the high 
levels of NOTCH target gene downregulation, which would not biologically support further 
escalating the dose, as well as the signs of clinical efficacy observed. FDA suggests that for ≥ 
12-year-old adolescent patients no weight-related clinically relevant effect on drug 
pharmacokinetics or safety are expected, ≥ 12-year-old adolescent patients enrolled in this 
trial may receive the same fixed daily dose as administered in adults (Clinical Growth Charts 
web page under National Center for Health Statistics at the Centers for Disease Control and 
Prevention website (https://www.cdc.gov/growthcharts/clinical_charts.htm). 
 
Overall safety data (N=79) indicates that CB-103 is well tolerated with 61% of all reported 
adverse events (AEs) being mild (Grade 1) or 27% moderate (Grade 2) in severity, and 11% 
Grade ≥3. Cumulatively, a total of 699 treatment emergent AEs has occurred in 76 patients 
since study initiation, of which 285 AEs (41%) in 60 patients were considered related to the 
study drug.  
Most of treatment-related AEs resolved without requiring medications or discontinuation of 
CB-103 dosing, and without sequelae. Overall, there have been no sign of cardiotoxicity and 
no QTc prolongation reported. The most common study drug-related AEs (≥10%) were 

 
 
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nausea (21.5%), dyschromatopsia (19.0%), anaemia (16.5%), blurred vision (15.2%), dyspepsia 
(12.7%), diarrhoea (12.7%), fatigue (11.4%), and vomiting (11.4%).   
Three SAEs were considered related to study drug (two drug-induced liver injury in two 
patients with progressive liver metastasis and Stevens-Johnson syndrome was diagnosed in a 
patient after she took amoxicillin/clavulanic acid). There were two DLTs. One patient in cohort 
8 (500mg) experienced one dose limiting toxicity (DLT). This was an elevation of the gamma-
glutamyl transferase (GGT), grade 3, that was asymptomatic and deemed not clinically 
significant by the investigator. One patient in cohort 11 (400mg BID) experienced visual 
impairment that led to treatment interruption which counts as DLT. After the patient switched 
to a once daily schedule, he continued treatment. No deaths due to drug-related AEs have 
been reported. 
Individual patients have been treated with CB-103 under compassionate use in combination 
with other drugs (anticancer drugs and drugs for the prevention of GVHD). The combination 
treatment did not alter the safety profile of CB-103 and did not increase or worsen toxicities 
associated with the combination drugs. There were further signs of efficacy, particularly two 
patients with r/r T-ALL that achieved complete response. 
 
 
In addition to demonstrating a favorable safety profile of CB-103, pharmacodynamic data 
have shown strong target engagement, down-regulation of key target genes as well as long-
term stable disease in patients with Notch-pathway activation in Adenoid Cystic Carcinoma 
(ACC) [10]. Taking together the fact that Notch activation is an important driver of multi-drug 
resistance [10], the confirmed effect on the target, and exceptional safety profile in cancer 
patients, CB-103 is an ideal drug to be used in combination with standard of care therapies to 
tackle multi-drug resistant cancer.  
 
2.4. Mitochondrial cell death pathway 
The apoptotic blocking provided by BCL-2 expression has been shown to have a central role in survival 
of leukemic cells [11]. The mitochondrial cell death pathway is initiated by proapoptotic BH3-only 
effector proteins, which activate the cell death proteins including BAX and BAK [12]. The survival of 
cells depends on antiapoptotic family proteins (BCL- 2, BCL-X, and MCL1) that bind and sequester BH3-
only effector protein, which in turn blocks activation of the cell death pathway. 
 
Using BH3 profiling, a mitochondrial assay that classifies blocks in the intrinsic apoptotic pathway, 
Moore et al. [13] provided evidence that cells in the ALL samples exhibit dependence on BCL-2 by 
demonstrating inhibition of BCL-2 and killing of leukemic cells using a proapoptotic pharmacologic 
inhibitor of Bcl-2/Bcl-xL, ABT-737. 
 
2.5. Venetoclax (ABT-199) 
Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor of B-cell lymphoma 2 
(BCL2), a key regulator of the intrinsic apoptotic pathway. Venetoclax has shown promising effects in 
hematologic malignancies including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia 
(AML) [14, 15, 16]. Recent preclinical studies have suggested that inhibition of BCL-2 may be a novel 
therapeutic strategy for patients with T-ALL [17]. 
 
Two clinical trials will study the efficacy of venetoclax in monotherapy in RR ALL. A phase I study is 
recruiting pediatric patients and young adults with RR ALL to address the safety and pharmacokinetics 
of venetoclax monotherapy (NCT03236857). Another phase 1 study with dose escalation is underway 
and recruiting participants and will analyze the safety and pharmacokinetics of venetoclax, navitoclax, 
and chemotherapy in recurrent ALL (NCT03181126). 

 
 
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2.6. Rationale of the CB-103 + Venetoclax (ABT-199) combination 
The combination of a 𝛾𝛾-secretase inhibitor and a BCL2 inhibitor showed synergistic antitumor effects 
in multiple myeloma, breast cancer, melanoma and non-small cell lung cancer cell lines [18, 19, 20,21, 
20]. This effect was mediated through a dramatic upregulation of the proapoptotic bcl-2 family protein 
Noxa [22].  
 
Noxa belongs to the BH3-only "sensitizer" protein family that act by displacing the BH3-only 
"activators" like Bid and Bim from the antiapoptotic proteins, allowing the activators to bind Bax and 
Bak [23]. Alternatively, antiapoptotic proteins could directly inhibit Bax and Bak activation [24]. It is 
well known that Noxa has a very high affinity for the antiapoptotic protein Mcl-1, but not Bcl-2, Bcl-
xL, or Bcl-w. While activation of Bax is controlled by Bcl-2, Mcl-1, and Bcl-xL, Mcl-1 also cooperates 
with Bcl- xL to sequester Bak and prevent its activation [25, 26]. Recent studies have indicated that 
targeting of both Mcl-1 and Bcl-xL is necessary in order to release Bak [27].  
 
In both human primary T-ALL patient cell samples and in mouse xenograft transplants of adenoid 
cystic carcinoma, CB-103 + BCL2 inhibitor combination showed potent synergistic effect versus either 
single agent (data on file, Cellestia AG). 
 
There is anecdotal evidence of the activity in human T-ALL of CB-103 combined with other targeted 
therapy from the compassionate use treatment of a 24-year old male patient (Data on file, Cellestia 
Biotech AG). The patient was diagnosed with T-ALL expressing a Notch1 mutation in 29% of blasts in 
May 2020: after achieving CR with the polychemotherapy GRAALL-2014 regimen in July 2020, the 
patient relapsed within a few months and  became refractory to a series of salvage therapies, including 
idarubicine, cytarabine, neralabine, daraturumab, and cyclophosphamide. When all standard 
treatments were exhausted, a sequential/combined therapy with agents specifically targeted to the 
genetic alterations most frequently detected in the leukemic cells (BCL2, ABL1, CD-28 and Notch1) 
was adopted as the last attempt to transition the patient to HSCT (Figure 1): the patient was again 
induced into remission and was successfully transplanted. 
 
Figure 1: Sequence of the combined agents and results on the circulating lymphocytes  
 
The number of circulating lymphocytes is plotted versus days from the initial retreatment for relapsing 
disease: the sequential use and timing of of the variously single or combined agents is shown as well. 
Vertical arrows represent daily administration of the corresponding durg during the second attempt 

 
 
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to induce a remission, while orizontal arrows indicate the duration of administration of the 
corresponding durg during the third attempt to induce a remission. 
 
The sequence of these events points out to: 
• 
the validity of a targeted therapeutical approach on the basis of the phenotypic/genetic 
biomarkers of the disease; 
• 
the possible contribution of a Notch inhibitor in at least abating the Notch1 mutated clone, 
that was present since the initial diagnosis; 
• 
the possibility of adding a Notch inhibitor to more than one other targeted agents without 
additional safety concerns and a potential additive efficacy.  
 
3. STUDY POPULATION 
3.1. Inclusion Criteria: 
3.1.1. Adolescent (12 to 18 years) and adult (19 to 60 years) patients who have relapsed or 
refractory T-cell lymphoblastic leukemia (T-ALL) or T-Cell lymphoblastic lymphoma (T-LBL) 
according to 2017 WHO classification [29] and NCCN v1 2021 [30]: 
 
Patients must have ≥ 5% blasts in the bone marrow as assessed by morphology on standard 
bone marrow biopsy and aspirate or less than 5% blasts in the bone marrow in presence of 
extramedullary relapse, excluding isolated central nervous system (CNS) relapse. However, if 
an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is 
unequivocal evidence of leukemia with ≥ 5% blasts in the peripheral blood.  
 
3.1.2. Patients are eligible independently of Notch pathway activation in the leukemic blasts: 
however, a fresh marrow/blood sample must be obtained before starting the study treatment 
to classify the patients as being either Notch positive or negative. 
 
3.1.3. Leukemic blasts must express of at least 2 of the following immune phenotyping: CD1a, 
CD2, CD3, CD4, CD5, CD7, CD8, CD34, TCRαβ, TCRγδ, cyCD3 
 
3.1.4. Patients have adequate performance status (ECOG ≤2) for patients ≥16 years old, 
Lansky score >50 for patients <16 years old. 
 
3.1.5. Patients must be 12 to 60 years of age inclusive when signing the informed consent. For 
patients < 18 years of age, parent or legally authorized representative (LAR) should be willing 
and able to give informed consent. Non-English speaking patients are eligible for whom 
consent process will follow institutional guidelines.   
 
3.1.6. Patients with CNS disease are eligible. 
 
3.1.7. Patients must have adequate organ function and laboratory results (obtained within 14 
days of enrollment): 
 
3.1.7.1. Direct  bilirubin ≤2 x upper limit of normal (ULN).  
 
3.1.7.2. Serum creatinine ≤ 1.5 x ULN; or if serum creatinine > 1.5 x ULN, then serum 
creatinine clearance (CrCl) ≥ 50 mL/min (estimated by Cockcroft-Gault formula). 
 
3.1.7.3. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤3 
x ULN; ≤5 x ULN in case of suspected leukemic liver involvement 
 

 
 
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3.1.8. Females of childbearing potential must have a negative serum or urine beta-human 
chorionic gonadotropin (β‐HCG) pregnancy test result within 14 days prior to the first dose of 
study drugs and must agree to use one of the following effective contraception methods 
during the study and for 30 days following the last dose of study drug. Effective methods of 
birth control include: 
 
3.1.8.1. Birth control pills, skin patches, shots, subdermal implants  
 
3.1.8.2. Intrauterine devices (IUDs) 
 
3.1.8.3. Condom or occlusive cap (diaphragm or cervical/vault caps) used with 
Spermicide  
 
3.1.8.4. Abstinence 
 
3.1.9. Males agree to inform study doctor right away if their partner becomes pregnant or 
suspects pregnancy. While in this study and for 30 days after the last treatment the patient 
agrees not to donate sperm for the purposes of reproduction. He agrees to use a condom 
while in this study and for 30 days after the last treatment. 
 
3.2. Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
3.2.1. Mixed phenotype leukemia (excluding T-ALL with myeloid antigen expression) 
 
3.2.2. History of another primary invasive malignancy that has not been definitively treated 
and in remission. Patients with non‐melanoma skin cancers or with carcinomas in situ are 
eligible regardless of the time from diagnosis (including concomitant diagnoses). 
 
3.2.3. Presence of clinically significant uncontrolled CNS pathology such as epilepsy, childhood 
seizure, paresis, aphasia, stroke, severe brain injuries, organic brain syndrome, or psychosis. 
 
3.2.4. Patients with a cardiac ejection fraction (as measured by either MUGA or 
echocardiogram) < 50% or with a history of absolute decrease in LVEF of ≥ 15 absolute 
percentage points are excluded. 
 
3.2.5. Medical history of cardiovascular disease such as: 
3.2.5.1. Clinically significant cardiac disease including congestive heart failure (NYHA 
class III or IV), arrhythmia or conduction abnormality requiring medication, or 
cardiomyopathy 
 
3.2.5.2. Clinically uncontrolled hypertension  
Age 
Blood Pressure 
12 to 13 
>120/80mmHg 
>13 
>140/90mmHg 
 
3.2.5.3. Complete left bundle branch block 
 
3.2.5.4. Right bundle branch block + left anterior hemiblock 
 
3.2.5.5. Congenital long QT syndrome 
 

 
 
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3.2.5.6. History or presence of sustained or symptomatic ventricular tachyarrhythmia, 
atrial fibrillation, or clinically significant resting bradycardia (< 50 bpm) 
 
3.2.5.7. Corrected QT interval using Fridericia formula (QTcF) > 450 ms for males and 
> 470 ms for females at the screening ECG 
 
3.2.5.8. QRS ≥ 110 ms 
 
3.2.5.9. History of symptomatic congestive heart failure 
 
3.2.6. Patients with uncontrolled, active infections (viral, bacterial, or fungal). Infections 
controlled on concurrent anti-microbial agents are acceptable. Anti-microbial prophylaxis per 
institutional guidelines is acceptable. 
 
3.2.7. Known active hepatitis B or C infection or known seropositivity for HIV.  
 
3.2.8. Liver cirrhosis or other active severe liver disease or suspected active alcohol abuse. 
 
3.2.9. Have conditions requiring chronic systemic (not inhaled) glucocorticoid use, such as 
autoimmune disease or severe asthma. Low doses of corticosteroids (10 mg prednisone 
equivalent a day) are permitted. 
 
3.2.10. Patients with unresolved nausea, vomiting, or diarrhea of CTCAE version 5.0, grade ˃ 
1 from prior therapy.  
 
3.2.11. Patients with impairment of GI function or GI disease presence that may significantly 
alter the absorption of CB-103 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection). 
 
3.2.12. Have current or recurrent (within 3 months) gastrointestinal disease, have conditions 
requiring chronic systemic glucocorticoid use, have active graft versus host disease, or have a 
second primary or prior malignancy that would affect the interpretation of study results.  Low 
doses of corticosteroids (10 mg prednisone equivalent a day) are permitted. 
 
3.2.13. Prior chemotherapy/radiotherapy/investigational therapy within 2 weeks before the 
start of study drugs with the following exceptions: 
 
3.2.13.1. Up to 5 days of glucocorticoids (10 mg of dexamethasone or equivalent/day) 
in combination with up to 3 doses of cyclophosphamide (200 mg/m2/day) are allowed 
as standard pre-phase treatment up to 1 day before start of study treatment. 
Cytarabine up to 2gm/m2 are also allowed as standard pre-phase treatment up to 1 
day before start of study treatment. 
 
3.2.13.2. Mercaptopurine may be dosed up to 5 days prior to first dose of CB103 
 
3.2.13.3. Vinca alkaloids may be dosed up to 5 days prior to first dose of CB103 
 
3.2.13.4. Prophylactic intrathecal (IT) chemotherapy may be dosed up to 1 day prior 
to first dose of CB103 
 
3.2.14. Females who are pregnant or lactating. 

 
 
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3.2.15. Male or female subjects of childbearing potential, unwilling to use an approved, 
effective means of contraception in accordance with institution's standards. 
 
3.2.16. Other severe, uncontrolled acute or chronic medical or psychiatric condition or 
laboratory abnormality that in the opinion of the Investigator may increase the risk associated 
with study participation or investigational product administration or may interfere with the 
interpretation of study results and/or would make the patient inappropriate for enrollment 
into this study.  
 
3.2.17. Patients who are unable or unwilling to comply with all study requirements for clinical 
visits, examinations, tests, and procedures. 
 
3.2.18. Patients must be excluded if they are currently enrolled in another ongoing clinical 
trial with anti-cancer investigational products 
 
4. TREATMENT PLAN 
4.1. Study Design 
This study is designed as a phase II open-label single-arm clinical trial to evaluate the efficacy and 
safety of CB-103 in combination with venetoclax in adolescent and adult patients with T-ALL/T-LBL 
with relapsed or refractory disease. 
 
Patients are eligible independently of Notch pathway activation in the leukemic blasts: however, a 
fresh marrow/blood sample must be obtained before starting the study treatment to classify the 
patients as being either Notch positive or negative. Notch pathway activation is defined presence of 
Notch1 gain-of-function (GOF) mutations, or FBXW7 loss-of-function (LOF) mutations, or Notch3 GOF 
mutations or Notch1 translocations detected by Next Generation Sequencing (NGS). Details on 
molecular alterations as signs of Notch pathway activation and the specific test method can be found 
in the laboratory manual. 
 
The study consists of three periods (Figure 2): 
• 
Screening period (including baseline assessments) 
• 
Treatment period (including an End-of-Treatment [EOT] visit) 
• 
Survival follow-up period 
 
Figure 2: Study design schema 
 
 
 
A cycle of treatment is defined as 28 days of treatment with CB-103 and Venetoclax. 
 
 

 
 
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4.2. Treatment Plan 
 
4.2.1. Induction cycle 
All eligible patients will receive the 1st cycle (induction cycle; day 1-28) with CB-103 and 
venetoclax. 
 
4.2.2. Reinduction cycle 
Patients achieving benefits from the treatment – benefit is defined as achieving at least 
stabilization of the disease - are eligible to receive a 2nd cycle (reinduction cycle, day 29-56) of CB-
103 and venetoclax at the same dose as in the induction cycle.  
In patients who did not attain a defined clinical response after the induction cycle i.e. non 
responders, a reinduction cycle of CB-103 and Venetoclax may be administered if there was no 
unacceptable toxicity. 
 
4.2.3. Maintenance 
Patients in CR or CRi after the reinduction cycle may continue to receive the combination CB-103 
and venetoclax until disease progression or bone marrow transplantation. 
 
Patients with PR or stable disease (SD) after the reinduction cycle may continue the treatment 
with the combination of CB-103 and venetoclax for a maximum of three additional cycles or until 
disease progression or bone marrow transplantation, whichevercomes first. 
 
4.3. Duration of Treatment and End of Study 
 
Patients will be followed-up for survival up to 2 years after they are enrolled onto the study. 
 
Estimated Study period: Q4 2022 – Q4 2025 
 
Collection of data will cease at the time when the last patient is removed from the study. 
 
Patients that are removed from the study during cycle 1 for any reason other than toxicity or disease 
progression will be replaced. 
 
Dose modifications/reductions are allowed in case of expected or observed unacceptable toxicity, at 
the discretion of treating physician or principal investigators. 
 
4.3.1. End of 1st Cycle (induction cycle) 
Patients are assessed for disease response on day 28 from the start of treatment (end of the 
induction cycle). 
 
If the day 28 marrow is not hypocellular (cellularity ≤ 15%) and the patient is showing at least 
stabilization of the disease or a clinical benefit in the investigator's judgement, the patient may 
enter the reinduction cycle of CB-103 and venetoclax. Patients are defined to have a clinical 
benefit, if they are in complete remission (CR) or complete remission with incomplete blood count 
recovery (Cri), or have a decrease in disease burden, including peripheral blasts or bone marrow 
blasts that do not meet the criteria for CR or Cri, or have no evidence of progression. 
 
If the day 28 marrow is hypocellular (cellularity ≤ 15%), then a repeat bone marrow biopsy is 
obtained between days 36 and 42 to assess response; if the repeat marrow is not hypocellular 
(cellularity ≤ 15%) and the patient is showing at least stabilization of the disease, the patient may 
enter the reinduction cycle of CB-103 and venetoclax. 

 
 
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If the peripheral counts do not recover (ANC < 1 x 109/L or platelets count < 60 x 109/L) and there 
is evidence of residual leukemia in the bone marrow, the patient may enter the reinduction cycle 
of CB-103 and venetoclax at the discretion of the treating physician, after a minimum of 4 weeks 
from the start of the last cycle. 
 
Patients who do not attain a defined clinical response after the induction cycle, may enter the 
reinduction cycle of CB-103 and venetoclax if there was no unacceptable toxicity.  
 
4.3.2. End of 2nd Cycle (reinduction cycle)  
Patients are assessed for disease response on day 56 from the start of treatment (end of the 
reinduction cycle): 
1. If the day 56 marrow is not hypocellular (cellularity ≤ 15%) and the patient is showing a 
CR or a CRi, the patient is eligible for maintenance with CB-103 and venetoclax until 
disease progression or bone marrow transplant in the absence of discontinuation criteria.  
2. If the day 56 marrow is hypocellular (cellularity ≤ 15%), then a repeat bone marrow biopsy 
is obtained between days 66 and 70 to assess response; if the repeat marrow is not 
hypocellular (cellularity ≤ 15%) and the patient is showing a CR or a CRi, the patient is 
eligible for maintenance with CB-103 and venetoclax until disease progression or bone 
marrow transplant in the absence of discontinuation criteria. 
3. Patients with PR or stable disease (SD) after the reinduction cycle may continue the 
treatment with the combination of CB-103 and venetoclax for a maximum of three 
additional cycles or until disease progression or bone marrow transplantation, whicher 
comes first. 
4. Non-responding patients, i.e patients without Cr or Cri or PR or SD after the reinduction 
cycle are discontinued from the treatment. 
 
 
4.3.3. End of Treatment  
 
Treatment will continue until discontinuation due to unacceptable toxicity, lack of response, 
relapse or progressive disease. This includes any of the following: 
 
1. Clinically significant progressive disease at any time. 
2. Death 
3. Possibility of undergoing allogeneic stem cell transplantation. 
4. Intercurrent illness that prevents further administration of treatment. 
5. Unacceptable adverse event(s), that are not manageable with dose adjustments and/or 
optimal medical management, or that, in the opinion of the Investigator, pose an 
unacceptable risk for the patient. 
6. Patient decision for study withdrawal. 
General or specific changes in the patient's condition that render the patient unacceptable for further 
treatment in the judgment of the Investigator, sponsor, or any regulatory body. 
 
 
End of Treatment (EoT) visit is to be done 5 days after the last dose of any study treatment, unless 
the patient starts any subsequent antitumor therapy (in which case the EoT visit should be 
performed before the start of the new therapy, whenever possible).  
 
4.3.4. Survival Follow-up  
 

 
 
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Patients will be followed-up for survival data up to 2 years after their study enrollment: survival 
status and any new anti-cancer therapy may be collected by phone every 3 months. 
 
 
5. TREATMENTS ADMINISTERED 
5.1. CB-103. CB-103 is a novel First-in-Class pan-Notch Protein-Protein Interaction (PPI) inhibitor 
directly targeting the assembly of the Notch transcription complex located in the nucleus of tumor 
cells. Thereby it inhibits transcription of Notch-related target genes at the most downstream location 
in the cell nucleus. 
 
The Investigational Medicinal Product (IMP) CB-103 will be provided in the form of capsules for oral 
treatment. 
 
More detailed information on the oral formulation of CB-103 can be found in the Investigator's 
Brochure. 
 
5.1.1. Description. CB-103 is produced under good manufacturing practice (GMP) conditions 
and analysed using state-of-the-art methods to ensure identity, purity and safety. CB-103 HCl 
is a white to off-white powder, soluble in water, with discrete polymorphism and a melting 
point around 173°C. Aqueous solubility is pH-dependent with higher values at lower pH. The 
active pharmaceutical substance is 6-(4-(tert-butyl) phenoxy) pyridin-3-amine hydrochloride 
with a molecular weight of 278.78 g/mol (hydrochloride) and 242.32 g/mol (free base). CB-
103 is provided to patients as capsules or oral suspension for oral administration.  
 
5.1.2. Nomenclature, structure and molecular weight.  
Chemical name: 6-(4-(tert-butyl)phenoxy)pyridin-3-amine hydrochloride Laboratory code: 
CB-103. 
 
Figure 3: Structure of CB-103 HCl 
 
 
 
Molecular Formula: C15H18N2O · HCl (hydrochloride); 
Molecular weight: 278,78 g/mol (CB-103 hydrochloride); 242.32 g/mol (CB-103 free base). 
 
5.1.3. Dosage and Administration.  
CB-103 will be administered orally as 500 mg twice a day (BID) for 5 days on and 2 days off, 
which has now been declared the RP2D in adults (section 2.3.2 Clinical Studies), until disease 
progression per investigator's judgement, or until unmanageable drug related toxicity, or as 
long as the patients are continuing to derive clinical benefits (section 4.2 Treatment Plan). For 
patients already enrolled prior to Protocol Version 2.0, they will be reconsented and offered 
the increased dose if it is felt to be safe and in the patient’s best interest by the treating 
physician, otherwise they may continue at their current dose of 500 mg daily.   
 

 
 
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In the event of vomiting, no re-dosing will be provided. According to FDA recommendations, 
as for ≥ 12-year-old adolescent patients no weight-related clinically relevant effect on drug 
pharmacokinetics or safety are expected, ≥ 12-year-old adolescent patients enrolled in this 
trial may receive the same fixed daily dose as administered in adults (Clinical Growth Charts 
web page under National Center for Health Statistics at the Centers for Disease Control and 
Prevention website (https://www.cdc.gov/growthcharts/clinical_charts.htm). 
 
CB-103 will be provided as capsules of 100 mg each. Patients will be instructed to swallow the 
CB-103 capsules whole with a glass of water (approx. 200 mL) in the morning, on an empty 
stomach, at least one hour before taking breakfast; in the evening, within 8 to 12 hours of the 
first intake, at least one hour before the evening meal. Capsules should not be chewed prior 
to swallowing. Capsules that are broken, cracked, or otherwise damaged should not be 
ingested. In the exceptional case of a patient who is unable to swallow capsules, the capsules 
can be opened and the contents may be mixed in a spoon with a bit of yogurt or fruit puree 
in order to swallow and follow with a glass of approximately 200mL of water (IMP Manual).  
 
5.1.4. Drug Preparation, Storage and Handling. All drug supplies should be stored in a secure, 
temperature-controlled area, which can be accessed only by the pharmacist, the Investigator, 
or another duly designated person. The investigational site will be supplied with study drug 
according to the site’s needs. Patients should be given a sufficient supply to last until their 
next study visit. Detailed storage conditions will be provided on the medication label and on 
the Pharmacy Manual. Detail drug preparation instructions are provided in the manufacturer's 
full prescribing information brochure. Unused portions of the study drug will be discarded 
properly as per the institutional policies. 
 
5.1.5. Drug Accountability. To ensure adequate records, CB-103 capsules will be accounted 
for as follows: 
• 
patients have a diary where they document the number of capsules taken each day; 
• 
patients are requested to return previously dispensed packages with the unused study 
drug as well as their completed patient diary to the clinic at each visit for accountability 
purposes even if they will not be dispensed with new medication at that visit; 
• 
the Investigator or designee will review the patient diary at Day 1 of each cycle.  
 
5.2. Venetoclax. Venetoclax is indicated for the treatment of patients with chronic lymphocytic 
leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least 
one prior therapy. 
 
Venetoclax is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic 
protein. Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, 
displacing proapoptotic proteins like BIM, triggering mitochondrial outer membrane permeabilization 
and the activation of caspases. In nonclinical studies, venetoclax has demonstrated cytotoxic activity 
in tumor cells that overexpress BCL-2. 
 
5.2.1. Description.  
Venetoclax is a selective inhibitor of BCL-2 protein. It is a light yellow to dark yellow solid with 
the empirical formula C45H50ClN7O7S and a molecular weight of 868.44. Venetoclax has very 
low aqueous solubility. Venetoclax is described chemically as 4-(4-{[2-(4-chlorophenyl)-4,4­ 
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4­ 
ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) and has the 
following chemical structure: 

 
 
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Figure 4: Structure of Venetoclax:  a selective and orally bioavailable small-molecule inhibitor 
of BCL-2. 
 
 
Venetoclax tablets for oral administration are supplied as pale yellow or beige tablets that 
contain 10, 50, or 100 mg venetoclax as the active ingredient. Each tablet also contains the 
following inactive ingredients: copovidone, colloidal silicon dioxide, polysorbate 80, sodium 
stearyl fumarate, and calcium phosphate dibasic. In addition, the 10 mg and 100 mg coated 
tablets include the following: iron oxide yellow, polyvinyl alcohol, polyethylene glycol, talc, 
and titanium dioxide. The 50 mg coated tablets also include the following: iron oxide yellow, 
iron oxide red, iron oxide black, polyvinyl alcohol, talc, polyethylene glycol and titanium 
dioxide. 
 
5.2.2. Dosage and Administration. 
Venetoclax is an oral medication that is taken continuously once daily with food and water: 
patients should take tablets with a meal and water at approximately the same time each day. 
Tablets should be swallowed whole and not chewed, crushed, or broken prior to swallowing. 
Tablet may be split in half to allow for more accurate dosing.   It will be administered according 
to the following dose schedule (Table 2). Compliance will be verified by counting the tablets 
provided per day during clinic visits.  
 
Table 2: Venetoclax ramp-up dose schedule 
Dosing 
Day 1 
Day 2 
Day 3 and onward 
Adolescent or adult patients 
100 mg/day 
200 mg/day 
400 mg/day 
 
 
 
 
 
 
 
 

 
 
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Tables 3 and 4 provide recommendations for management and potential interactions with 
CYP3A and P-gp inhibitors and examples of drugs that interact with venetoclax. 
 
Concomitant use of venetoclax with strong CYP3A inhibitors and inducers at initiation and 
during the ramp-up phase is not recommended due to the potential for increased risk of 
tumor lysis syndrome (TLS). If use of a strong CYP3A inhibitor is deemed necessary, Venetoclax 
dose should be modified according to Table 3.  Concomitant use of venetoclax with strong or 
moderate CYP3A inducers is not recommended throughout the study period. Concomitant 
strong or moderate CYP3A or P-gp inhibitors must have reached steady state prior to 
venetoclax initiation and must also not be discontinued until after the initiation and ramp-up 
phase of venetoclax. If a concomitant strong or moderate CYP3A inhibitor or P-gp inhibitor is 
discontinued after the initiation and ramp-up phase, increase venetoclax to 400 mg/day 2 to 
3 days after discontinuation of the inhibitor. Reduce venetoclax once-daily dose by 50% for 
patients with severe hepatic impairment (Child-Pugh C); monitor these patients more closely 
for signs of toxicity. 
 
Table 3: Management of potential venetoclax interactions with CYP3A and P-gp inhibitors* 
Coadministered drug 
Initiation and ramp-up phase 
Steady daily dose(after ramp-up phase) 
Posaconazole 
Start at 10 mg on day 1,  followed by 
20 mg on day 2, 50 mg on day 3, and 
70 mg on day 4 
Reduce the venetoclax dose to 70 mg 
Other strong CYP3A inhibitor 
Start at 10 mg on day 1,  followed by 
20 mg on day 2, 50 mg on day 3, and 
100 mg on day 4 
Reduce the venetoclax dose to 100 mg 
Moderate CYP3A inhibitor 
Reduce the venetoclax dose by at least 50% 
P-gp inhibitor 
*Consider alternative medications or reduce the venetoclax dose as described in this table. 
CYP3A=cytochrome P450; P-gp=P-glycoprotein. 
 
Table 4 : Examples of CYP3A and P-gp inhibitors/inducers* 
Coadministered 
drug 
Name 
Other strong 
CYP3A inhibitor 
Clarithromycin, Conivaptan, Diltiazem, Indinavir, Itraconazole, Ketoconazole, 
Lopinavir, Ritonavir, Telaprevir, Voriconazole, Posaconazole 
Moderate CYP3A 
inhibitor 
Aprepitant, Cimetidine, Ciprofloxacin, Cyclosporine, Dronedarone, 
Erythromycin, Fluconazole, Isavuconazole, Verapamil 
P-gp inhibitor 
Amiodarone, Carvedilol, Clarithromycin, Cyclosporine, Dronedarone, 
Itraconazole, Ketoconazole, Quinidine, Ranolazine, Ritonavir, Verapamil, 
Posaconazole 
Strong CYP3A 
inducer 
Carbamazepine, Phenytoin, Rifampin, St. John’s wort 
Moderate CYP3A 
inducer 
Bosentan, Efavirenz, Etravirine, Modafinil 
*This is not an exhaustive list and is intended only to complement, not replace, clinical 
judgment during treatment of patients with venetoclax. Please refer to the FDA website for 
more examples. 
 
5.2.3. Risk Assessment and Prophylaxis for Tumor Lysis Syndrome (TLS) 
Venetoclax can cause rapid reduction in tumor and thus poses a risk for TLS in the initial ramp-
up phase. Changes in blood chemistries consistent with TLS that require prompt management 
can occur as early as 6 to 8 hours following the first dose of venetoclax and at each dose 
increase. 

 
 
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The risk of TLS is a continuum based on multiple factors, including tumor burden and 
comorbidities. Perform tumor burden assessments, including radiographic evaluation (e.g., CT 
scan), assess blood chemistry (potassium, uric acid, phosphorus, calcium, and creatinine) in 
all patients and correct pre-existing abnormalities prior to initiation of treatment with 
venetoclax. Reduced renal function (creatinine clearance [CrCl] <80 mL/min) further increases 
the risk. 
 
Patients with ALL at high risk of tumor lysis should be assessed rapidly for evidence of 
symptomatic hyperleukocytosis, tumor lysis syndrome, and coagulopathy. Suggested initial 
studies, obtained prior to initiating antileukemia therapy, may include a complete blood count 
(CBC), prothrombin (PT) and activated partial thromboplastin times (aPTT)and serum 
electrolytes, including creatinine, BUN, uric acid, phosphorus, and calcium. Continued 
monitoring of these studies should be carried out at suitable intervals until abnormalities have 
resolved or the risk has abated. 
 
Recommended TLS prophylaxis based on Tumor Burden from clinical trial data (consider all 
patient co-morbidities before final determination of prophylaxis and monitoring schedule) is 
shown in Table 5: 
 
Table 5: TLS Prophylaxis 
Tumor Burden 
Prophylaxis 
Hydration 
Anti-hyperuricemics 
Low 
Any LN <5cm AND ALC 
<25 x109/L 
Oral (1.5-2 L) 
Allopurinol 
Medium 
All LN >5cm to <10cm 
AND ALC ≥25 x109/L 
Oral (1.5-2 L) and consider 
additional intravenous  
Allopurinol 
High 
Any LN ≥10cm OR ALC 
≥25 x109/L AND any LN 
≥5cm 
Oral (1.5-2 L) and intravenous (150-
200 mL/hr as tolerated)  
Allopurinol: consider rasburicase 
if baseline uric acid is elevated  
ALC = absolute lymphocyte count; LN = lymph node. 
Administer intravenous hydration for any patient who cannot tolerate oral hydration. 
Start allopurinol or xanthine oxidase inhibitor 2 to 3 days prior to initiation of venetoclax. 
Evaluate blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine); review in real time. 
For patients at risk of TLS, monitor blood chemistries at 6 to 8 hours and 24 hours at each subsequent ramp-up 
dose. 
 
5.2.4. Drug Preparation, Storage and Handling. Detail drug preparation instructions are 
provided in the manufacturer's full prescribing information brochure. Unused portions of the 
study drug will be discarded properly as per the institutional policies. 
 
5.3. Intrathecal Dosage and Administration. 
Patients will receive intrathecal chemotherapy as per standard of care. Methotrexate, Cytarabine, 
hydrocortisone, or a combination of these is allowed on the study. The number of lumbar punctures 
with Intrathecal chemotherapies will depend on the age of the patient, clinical status, comorbidities, 
etc and will be determined by the PI.  
 
5.4. Venetoclax is commercially available. Commerical supply of each will be used. Detail product 
information may be found in the product prescribing information and available through the following 
links: 
5. 4.1. Venetoclax: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf 
 

 
 
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5.5. Patients with PR or stable disease (SD) after the reinduction cycle may continue the treatment 
with the combination of CB-103 and venetoclax for a maximum of three additional cycles or until 
disease progression or bone marrow transplantation, whicher comes first. 
 
6. DOSE MODIFICATIONS 
6.1. Recommended CB-103 Dose Modification. 
The follow-up evaluations for toxicities apply during or beyond cycle 1 of the study. 
 
The following sections outline the specific dose modifications for CB-103 for non-haematologic 
toxicities and should be followed by the Investigator accordingly. One dose level reduction indicated 
in case of moderate/severe non-haematological toxicities in the following Tables corresponds to a 
100mg reduction per dose of CB-103, e.g. from 500mg BID to 400 mg BID intermittent schedule.  
 
As CB-103 and venetoclax do not have overlapping toxicity, dose modification of venetoclax is 
independent of CB-103 dose modification: treatment modifications for venetoclax related toxicities 
will be performed as per Venetoclax Summaries of product characteristics (SmPC). 
 
6.1.1. Dose modification for renal toxicity (Table 7). 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be repeated at 
least twice a week until resolution to < CTCAE grade 1, to allow for initiation of re-treatment 
and then at least weekly until either resolution or until stabilisation. 
 
If proteinuria or haematuria > CTCAE grade 2 or serum creatinine > 2.0 x ULN has been 
demonstrated, a 24-hour urine collection must be obtained for total protein and total 
creatinine and must be repeated at least weekly until either resolution to baseline value to 
allow for initiation of re-treatment, or until stabilisation. Whenever a measured CrCl is 
obtained, a serum creatinine value should be obtained within < 72 hours of the urine 
collection. 
Table 7: Dose modifications for renal toxicities  
 
Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; LLN, 
lower limit of normal; ULN, upper limit of normal. 
Grading according to NCI-CTCAE v.5.0 guideline.  
 
6.1.2. Dose modification for liver toxicity (Table 8). 
If bilirubin or AST/ALT > CTCAE grade 2 has been demonstrated, these parameters must be 
repeated at least twice a week until resolution to < CTCAE grade 1, to allow for initiation of 
re-treatment and then at least weekly until either resolution or until stabilisation. 

 
 
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Patients with total bilirubin > ULN (any duration) should have fractionation of bilirubin into 
total/direct or indirect/direct components and any additional work-up as clinically indicated 
by these results. Follow-up of hyperbilirubinaemia should proceed as per the guidelines 
above, irrespective of the results of fractionation. 
 
Table 8: Dose modifications for hepatic toxicities  
 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil 
count; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse 
Events; LLN, lower limit of normal; PLT, platelets; ULN, upper limit of normal.  
Grading according to NCI-CTCAE v.5.0 guideline.  
 

 
 
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6.1.3. Dose modification for eye toxicity (Table 9). 
For toxicities related to visual symptoms related to CB-103, refer to the following table. In 
general, it is suggested that the patient avoids sudden exposure to bright sun light allowing 
time for possible delayed light accommodation. 
 
Table 9: Dose modifications for ocular/vision related toxicities  
 
Grading according to NCI-CTCAE v.5.0 guideline.  
 
6.1.4. Dose modification for gastro-intestinal toxicities (diarrhoea) (Tables 10-11) 
In non-clinical studies in different species (dog, rat, mouse), CB-103 administered at different 
doses and administration schedules did not show any gastro-intestinal toxicities, e.g. 
diarrhoea, weight loss. However, as other Notch inhibitors (GSIs, mABs) have shown diarrhoea 
as their major DLT, there might be a risk for CB-103 to also develop gastro-intestinal toxicities. 
In the event that diarrhoea is observed in clinical trial patients, the following algorithm for CB-
103 dose modifications should be followed. Furthermore, section 6.1.7. provides a 
management plan for the occurrence of diarrhoea with a description of measures and 
treatment suggestions. 
 
Table 10: NCI CTCAE version 5.0 grading of diarrhoea  
 
Grading  
0  
1  
2  
3  
4  
5 
Diarrhoea None 
Increase of < 4 
stools per day 
over baseline; 
mild increase in 
ostomy output 
compared to 
baseline  
Increase of 4 - 6 stools 
per day over baseline; 
moderate increase in 
ostomy output 
compared to baseline: 
limiting instrumental 
ADL  
Increase of ≥7 stools per day 
over baseline; incontinence; 
hospitalisation indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
ADL  
Life- threatening 
consequences; 
urgent 
intervention 
indicated  
Death 
 
Definition: A disorder characterized by an increase in frequency and/or loose or watery bowel 
movements. 
 
 
 
 
 
 
 

 
 
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Table 11: CB-103 Dose Modifications for Gastro-Intestinal Toxicity 
Dose Modifications of CB-103 for Gastro-Intestinal Toxicity 
Worst Toxicity 
CTCAE Grade unless otherwise 
specified (Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Grade 1 
Maintain dose level 
Grade 2 
(see section 6.1.7. for treatment 
algorithm) 
Omit dose administration until recovery to Grade 0 or baseline then 
continue at current dose level if grade 2 toxicity persisted for ≤ than 7 
days. 
If grade 2 toxicity persisted for more than 7 days decrease dose by 1 dose 
level after resolution to Grade 0 or baseline 
Grade 3 
(see section 6.1.7. for treatment 
algorithm) 
Omit dose administration until recovery to Grade 0 or baseline then 
decrease the next scheduled dose by 1 dose level 
Grade 4 
(see section 6.1.7. for treatment 
algorithm) 
Omit dose administration until recovery to Grade 0 or baseline then 
decrease the next scheduled dose by 1 dose level* 
In the event Grade 4 toxicity lasts > 24 hours despite maximal medical 
attention discontinue treatment. 
If grade 4 toxicity lasts < 24 hours reduce dose by 1 dose level at next cycle 
If toxicity recurs discontinue treatment. 
All grades 
At the first sign of abdominal cramping, loose stools, or onset of 
diarrhoea, the patient should be treated according to section 6.1.7. 
according to the recommended treatment algorithm. 
Omit dose administration of CB-103 for ≥ CTCAE grade 2 diarrhoea only if 
diarrhoea could not be controlled despite the use of optimal anti-
diarrhoea treatments. 
Grading according to NCI-CTCAE v.5.0 guideline. 
 
 
 
 
 
6.1.5. Dose modification for cardiac toxicity (Table 12) 
As in non-clinical studies with CB-103, QT prolongation was observed at higher doses and ECG 
changes in patients may be observed, therefore, intensive cardiac monitoring is implemented 
into this study with central management and review of multiple ECGs and Holter ECGs at 
selected timepoints. Furthermore ECHO/MUGA scans and cardiac markers will be assessed at 
selected time points. For toxicities related to QTc prolongation, refer to the table below. 
 
The study treatment should be halted for any patient who experiences grade 4 QT 
prolongation (torsades or other related event) unless a clear alternative cause for the event 
can be identified and the event completely reverses with correction of the underlying issue. 
 

 
 
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Table 12: Dose modifications for cardiac abnormalities  
Dose Modifications for CB-103 
Worst Toxicity 
CTCAE Grade unless otherwise specified 
(Value) 
At any time during a cycle of CB-103 
(including intended day of dosing) 
Cardiac - Prolonged QTcF interval2 
During Cycle 1:  
 
Absolute QTcF< 450 ms 
Maintain dose level and ECG monitoring as per visit 
schedule. 
QTcF ≥ 450 ms 
and < 480 ms 
Maintain dose level. ECG monitoring assessments should 
be increased as indicated (e.g. hourly until no QTcF ≥ 450 
ms). Consider discontinuation of concomitant QT 
prolonging agents. 
During any Cycle: 
 
Grade 3 or QTcF ≥ 480 ms as identified by 
the Investigator on the ECG. 
Omit dose administration and recommend discontinuation 
of concomitant QT prolonging agents. Monitor patient with 
frequent ECGs as indicated (e.g. hourly) until the QTcF has 
returned to ≤ 450 ms. Further monitoring as clinically 
indicated. Exclude other causes of QTc prolongation such 
has 
hypokalaemia, 
hypo-magnesaemia 
and 
blood 
oxygenation status. Once QTcF prolongation has resolved, 
and if the QTcF prolongation was confirmed by central 
reading, patients may be re-treated at one lower dose level 
at the Investigator’s discretion. 
ECG monitoring must continue throughout the treatment 
period as follows: 
• ECG monitoring assessments should be performed for 2 
additional cycles at higher frequency as clinically 
indicated 
• If the ECGs obtained in the first additional cycle after 
dose reduction are without any QTcF prolongation, then 
ECG monitoring in subsequent cycles will be continued 
as per the visit schedule. 
• If the patient had an absolute QTcF ≥ 450 ms and 
< 480 ms, then ECG monitoring at a higher frequency 
will be continued for all subsequent cycles. 
• Patients who experience absolute QTcF ≥ 480 ms after 
one dose reduction will be discontinued from study. 
Abbreviations: AE, adverse event; QTcF, corrected QT interval using Fridericia formula. 
Grading according to NCI-CTCAE v.5.0 guideline. 
2Exclude other causes of QTcF prolongation such has hypokalemia, hypomagnesemia and blood 
oxygenation status. Patients who develop hypokalemia or hypomagnesemia during the study 
should receive electrolyte replacement as soon as possible and should not receive further CB-103 
dosing until the respective electrolytes are documented to be within normal limits. 
 

 
 
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6.1.6. Dose modification for non-laboratory toxicities (Table 13) 
Patients who experience non-laboratory DLTs must be evaluated at least once a week 
following demonstration of the toxicity until resolution of the toxicity to allow for 
retreatment, stabilisation of the toxicity, or study treatment completion.  
 
Table 13: Dose modification for non-laboratory toxicities 
 
Grading according to NCI-CTCAE v.5.0 guideline. 
 
 
6.1.7. Diarrhoea and Nausea Management Plan 
Although no signs of gastro-intestinal toxicities (e.g., diarrhoea) were observed in the non-
clinical safety and toxicology studies in different species (dog, rat, mouse) treated with CB-
103 at different doses and administration schedules, the occurrence of diarrhoea cannot be 
excluded.  
 
6.1.7.1. General measures: 
• 
Stop all lactose-containing products, alcohol 
• 
Stop laxatives, bulk fibre (e.g., Metamucil®, Procter & Gamble), and stool 
softeners (docusate sodium; Colace, Roberts) 
• 
Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte® 
(Ross), Gatorade (Quaker), broth) 
• 
Eat frequent small meals (e.g., bananas, rice, apple sauce, Ensure®, toast) 
• 
Stop high-osmolar food supplements such as Ensure Plus and Jevity Plus (with 
fibre) 
 
It is recommended that patients be provided loperamide tablets. It is mandatory that 
patients are instructed on the use of loperamide at cycle 1 in order to manage signs 
or symptoms of diarrhoea at home. Patients should be instructed to start oral 
loperamide (initial administration of 4 mg, then 2 mg every 4 hours (maximum of 16 
mg/day) at the first sign of loose stool or symptoms of abdominal pain. These 
instructions should be provided at each cycle and the investigational site should 
ensure that the patient understood the instruction. At the beginning of each cycle, 
each patient should be specifically questioned regarding any experience of diarrhoea 
or diarrhoea related symptoms. If symptoms were experienced, then the 
investigational site should question the patient regarding the actions taken for these 
symptoms. 
 
 
 

 
 
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6.1.7.2. Treatment of Diarrhoea Grade 1 or 2 
Diarrhoea grade 1 or 2 will be treated with standard loperamide (initially at first 
administration 4 mg, then 2 mg every 4 hours [maximum of 16 mg/day] or after each 
unformed stool). 
 
12-24 hours later: 
 
Diarrhea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide after 12-hours diarrhoea-free interval 
 
Diarrhea unresolved 
Persisting diarrhoea grade 1 or 2 will be treated with addition of opium tincture, 
dihydrocodeine tartrate tablets/injections and start early on with corticosteroids 
which is the recommended treatment for the development of goblet cell metaplasia 
seen with other Notch inhibitors. Treatment should be accompanied by monitoring 
the patient's condition (to rule out dehydration, sepsis, ileus), medical check and 
selected workup. Observe patient for response to antidiarrheal treatment and may 
also consider treatment with high dose corticosteroids.  
Persisting diarrhoea grade 3 or 4 may be treated with high dose loperamide (initially 
4 mg, then 2 mg every 2 hours), addition of opium tincture or dihydrocodeine tartrate 
tablets/injections and with high dose corticosteroids to potentially inhibit the 
development of the goblet cell metaplasia seen with other Notch inhibitors. 
Furthermore, start of i.v. fluids, parenteral nutrition and antibiotics as needed with 
monitoring of patients' condition (to rule out dehydration, sepsis, ileus), medical 
check and workup (perform appropriate additional testing) should be started 
immediately. Observe patient for response. 
 
After 12-24 hours: 
 
Diarrhoea resolved 
• 
Continue instructions for dietary modification 
• 
Gradually add solid foods to diet 
• 
Discontinue loperamide and/or other treatment after 12-hours 
diarrhoea-free interval 
 
Diarrhoea unresolved 
• 
If diarrhoea still persisting (NCI CTC grades 1 and 2), after 2 x 24 hours 
with high dose loperamide, opiates and corticosteroids then admit to 
hospital and employ measures as for grade 3 and 4 until diarrhoea 
resolved. 
• 
If diarrhoea still persisting and progressed to NCI grades 3 and 4, 
employ measures described below. 
 
6.1.7.3. Treatment of Diarrhoea Grade 3 or 4 
Severe diarrhoea grade 3 or 4 may be treated with hospitalisation, high dose 
loperamide (initially 4 mg, then 2 mg every 2 hours, addition of opium tincture or 
dihydrocodeine tartrate tablets/injections as well as early start of administration of 
corticosteroids as being the recommended treatment for goblet cell metaplasia 

 
 
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observed in patients treated with other Notch inhibitors. Furthermore, start of i.v. 
fluids, parenteral nutrition and antibiotics as needed with monitoring of patients' 
condition (to rule out dehydration, sepsis, ileus), medical check and workup. Observe 
patient for response.  
 
After 12-24 hours: 
• 
If diarrhoea persisting administer high dose corticosteroids and 
consider subcutaneous (s.c.) Sandostatin/octreotide (100-500 μg 
three times daily [TID]) 
• 
Continue i.v. fluids, parenteral nutrition and antibiotics as needed 
• 
If diarrhoea grade 3 or 4 still persists patients should receive besides 
corticosteroids opium tincture or dihydrocodeine tartrate injections 
s.c. or intramuscular (i.m.) 
• 
If diarrhoea grade 3 or 4 is still persisting s.c. Sandostatin/octreotide 
(500-1000 μg TID) should be administered. 
• 
To control and/or resolve diarrhoea, next cycle of treatment should 
be delayed by 1 or 2 weeks. Treatment should be continued only 
when diarrhoea resolved. 
 
6.1.7.4. Diarrhea Workup 
Perform appropriate tests (American Gastroenterological Association [AGA] Technical 
Review on the Evaluation and Management of Chronic Diarrhoea; Fine and Schiller, 
1999). 
Spot stool analysis 
• 
Collect stool separating it from urine (special containers, analysis 
immediately, exceptionally freeze samples) 
• 
Blood 
• 
Faecal leukocytes (Wright's staining and microscopy) or 
• 
C. difficile toxin 
• 
Faecal cultures such as Shigella and pathogenic E. coli - 
enterotoxigenic, enterohaemorrhagic etc., possibly Aeromonas, 
Pleisiomonas (if suspected exposure to contaminated water) 
 

 
 
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6.2. Recommended Venetoclax Dose Modification. 
Interrupt dosing, reduce number of days, or reduce dose for toxicities. Treatment modifications for 
venetoclax related toxicities will be performed as per the respective summaries of product 
characteristics (SmPC). As CB-103 and venetoclax do not have overlapping toxicity, dose modification 
of CB-103 is independent of venetoclax dose modification: treatment modifications for CB-103 related 
are described in Section 6.1. 
 
See the following Tables 14a and 14b for dose modifications for hematologic and other toxicities 
related to venetoclax. For patients who have had a dosing interruption greater than 1 week reassess 
for risk of TLS to determine if reinitiation with a reduced dose is necessary. 
 
Table 14a: Recommended Dose Modifications of Venetoclax for Toxicitiesa 
Event 
Occurence Action 
Tumor Lysis Syndrome 
Blood 
chemistry 
changes or 
symptoms 
suggestive of 
TLS 
Any 
Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume 
at the same dose.  
For any blood chemistry changes requiring more than 48 hours to resolve, resume 
at a reduced dose.  
For any events of clinical TLSb, resume at a reduced dose following resolution.  
Non-Hematologic Toxicities 
Grade 3 or 4 
non- 
hematologic 
toxicities 
1st 
occurrence  
Interrupt venetoclax. 
Once the toxicity has resolved to Grade 1 or baseline level, VENCLEXTA therapy 
may be resumed at the same dose. No dose modification is required. Consider 
decreasing treatment days. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax. 
Follow dose reduction guidelines in Table 14b when resuming treatment with 
Venetoclax after resolution. Consider decreasing treatment days. A larger dose 
reduction may occur at the discretion of the physician. 
Hematologic Toxicities 
Grade 3 or 4 
neutropenia 
with 
infection or 
fever; or 
Grade 4 
hematologic 
toxicities 
(except 
lymphopenia) 
1st 
occurrence  
Interrupt venetoclax. 
To reduce the infection risks associated with neutropenia, granulocyte-colony 
stimulating factor (G-CSF) may be administered with Venetoclax if clinically 
indicated. Once the toxicity has resolved to Grade 1 or baseline level, Venetoclax 
therapy may be resumed at the same dose. Consider decreasing treatment days. 
2nd and 
subsequent 
occurrences 
Interrupt venetoclax. 
Consider using G-CSF as clinically indicated. Follow dose reduction guidelines in 
Table 14b when resuming treatment with Venetoclax after resolution. Consider 
decreasing treatment days. A larger dose reduction may occur at the discretion of 
the physician. 
Consider decreasing treatment days for those patients with toxicities. Treatment could be decreased from 28 
days to 21, 14 or 7 days, depending on the PI. Discontinue venetoclax for patients who require dose 
reductions to less than 25% of the scheduled dose for more than 2 weeks. 
aAdverse reactions were graded using NCI-CTCAE v.5.0 guideline. 
bClinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac 
arrhythmias, or sudden death and/or seizures. 
 
 
 
 
 
 

 
 
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Table 14b: Dose reduction for toxicity during Venetoclax treatment 
 
aDuring the ramp-up phase, continue the reduced dose for 1 week before increasing the dose. 
 
 
 
 
 
 
7. CONCOMITANT THERAPY 
Concomitant medication data will not be collected or entered into the case report form except for 
concomitant hydroxyurea and intrathecal chemotherapy; however, the subject's medication record 
will contain a list of concomitant medications. All supportive measures consistent with optimal patient 
care should be provided throughout the study according to the departmental standards. 
 
7.1. Allowed Concomitant Therapy: Prophylactic or therapeutic intrathecal therapy is allowed, if 
central nervous system leukemia involvement is diagnosed after enrollment in this clinical trial. The 
use of hematopoietic growth factors or transfusions is allowed. The use of hydroxyurea is permitted 
at any time during the study period for cytoreduction. Corticosteroids (e.g. for management of allergic 
reactions, prophylaxis, etc.) are also allowed.  Use of other immunosuppressive therapy, e.g. 
tacrolimus, may be allowed at the disgression of the clinical provider.  Other supportive care studies 
are allowed, even if under an IND. 
 
7.2. Prohibited Concomitant Therapy: Patients may not receive other investigational anti‐neoplastic 
therapy drugs, excluding therapy as described in previous Section "Allowed Concomitant Therapy".  
Patients may not receive radiotherapy during the study. 
 
The following medications should be strictly prohibited during the study treatment period, unless 
there are no signs of QTc prolongation in scheduled EKG: 
• 
Drugs with a known risk to induce Torsades de Pointes: All QT-prolonging drugs (see Table 1 in of 
Appendix 1) are prohibited for all patients until permanent discontinuation of study treatment. 
• 
Drugs with a conditional risk to induce Torsades de Pointes: Any QT prolonging medication with 
a conditional risk of inducing Torsades de Pointes listed in Table 2 of Appendix 1 are prohibited 
for all patients from screening through permanent discontinuation of study treatment, except for 
the assumptions described in Section 6.1.7. for the treatment of diarrhea and nausea. These 
exceptions must be discussed in advance with the Sponsor on a case-by-case basis. 
• 
Warfarin and Coumarin-type anticoagulants within 1 week prior first CB-103 dose. 
 

 
 
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8. Visit schedule and study assessments 
Written ICF for participation in the study must be obtained from the patient, signed and dated before 
performing any study procedure. Patients will be informed about the study drug and will receive 
pertinent information regarding the study objectives, possible benefits, and potential AEs. They will also 
receive information on the follow-up procedures and possible risks they will be exposed to. The ICF 
also informs patients about how biological samples will be obtained and collected and its legal 
implications. Patients are allowed to enter the study based on confirmation of the eligibility criteria 
(refer to inclusion and exclusion criteria in Section 3.1. and Section 3.2.) at screening/baseline. 
 
Assessments scheduled for days 1 of each cycle must be performed within 48 hours prior to study 
treatment administration, unless otherwise indicated in the schedule of assessments, in order to 
confirm to the patient if treatment can continue. All examinations listed below will be performed 
according to the Schedule of Assessments outlined in Table 16. 
 
All screening tests and evaluations must be completed and reviewed to confirm that patients meet  all 
eligibility criteria within 21 days prior to the first administration of study medication. Disease 
assessments, such as bone marrow samples (aspirate and/or biopsy), EKG and LVEF evaluation, such 
as ECHO/MUGA scan, available and performed as part of clinical practice prior to obtain the signature 
of the ICF, and within 21 days prior to treatment start, are accepted. Therefore,  such evaluations are 
not required to be repeated during the screening period. 
 
Patients should be admitted for Cycle 1 days 1-7 to monitor for any adverse events and for completion 
of study evaluations due on day 5.  Patients may be discharged after the completion of study 
evaluations at the discretion of the treating physician if drug combination is being tolerated without 
need for close monitoring for adverse events and patient is clinically stable for safe discharge.  
 
8.1. Medical History and Demographic Data: Medical history includes clinically significant diseases, 
surgeries, reproductive status, smoking history, use of alcohol and drugs of abuse, all medications 
(e.g., prescription drugs, over the counter drugs, herbal or homeopathic remedies, nutritional 
supplements) and physical/occupational/exercise. Demographic data will include year of birth, sex 
and self reported race/ethnicity (collecting this information is essential in order to be able to evaluate 
the results of this study, for example, in the case of PK outliers or important between-patient 
differences in terms of treatment effect). Evaluation of the inclusion and exclusion criteria will be 
performed at the screening visit. 
 
8.2. Disease History: The patients’ disease history from the time of diagnosis (including any biomarker 
information and details regarding anti-neoplastic treatments they have received in the past) will be 
collected at screening. The exact parameters to be collected will be outlined on the respective 
screening eCRF pages. Disease history will be taken at the screening visit. 
 
8.3. ECOG performance status: Performance status will be measured using the ECOG performance 
status scale (Table 15a). Patient’s performance status should preferentially be assessed by the same 
person throughout the study. 
Table 15a: ECOG performance status grading 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, i.e., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 

 
 
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3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: http://www.ecog.org/general/perf_stat.html 
Lansky scale may be used with adolescent of age ≤ 16 years (Table 14b). It is rated by parents based 
on their child's activity over the past week. Parents fill out the assessment based on the directions 
on the form, and the form is readministered over time to assess for changes in performance status.  
 
Table 15b: Lansky performance status grading 
Rating 
Description  
100  
Fully active, normal  
90  
Minor restrictions with strenuous physical activity  
80  
Active, but gets tired more quickly  
70  
Both greater restriction of, and less time spent in, active play  
60  
Up and around, but minimal active play; keeps busy with quieter activities  
50  
Lying around much of the day, but gets dressed; no active play; participates in all 
quiet play and activities  
40  
Mostly in bed; participates in quiet activities  
30  
Stuck in bed; needs help even for quiet play  
20  
Often sleeping; play is entirely limited to very passive activities  
10  
Does not play nor get out of bed  
0  
unresponsive  
 
 
8.4. Vital signs and physical exam: Oral body temperature, respiratory rate, sitting blood pressure, 
and sitting heart rate will be obtained while the patient is in a semi-supine/supine position after 
resting for approx. 5 minutes. Vital signs should be measured prior to blood draw or at least 10 
minutes after the last blood draw. Additional determinations include body height (only at Screening) 
and body weight. 
 
A complete physical examination should include an examination of head, eyes, ears, nose, and 
throat, as well as cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems. As part of the tumor assessment, physical exams should 
also include evaluation of presence and degree of increase of lymph nodes, hepatomegaly, and 
splenomegaly. 
 
Eye examinations will be performed by an ophthalmologist during screening, at EOT, and in case of 
abnormalities at the safety follow-up visit. An extended eye examination including invasive 
ophthalmologic assessments should be performed by an ophthalmologist during the treatment 
period, in case significant abnormalities are experienced by the patient or seen by the study doctor 
at the regular eye evaluation as part of the physical examinations. 
 
The following standard ophthalmological assessments performed by an ophthalmologist are 
recommended: 

 
 
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1. Visual acuity test 
2. Intraocular pressure test 
3. Slit-lamp test 
4. Dilated fundus test 
5. Colour-vision (Ishihara-plate) test 
 
Additional assessments or tests may be conducted by an ophthalmologist as clinically indicated. 
Invasive ophthalmologic assessments such as electroretinography (ERG) may be conducted if 
feasible, at the discretion of the site and may be conducted at the time when visual symptom(s) 
are reported (if any). 
 
For any significant abnormalities seen at the eye examination, all assessed parameters and findings 
should be documented in the respective eCRF pages and source documents. 
 
8.5. Pregnancy tests and assessment of fertility: Only female patients of childbearing potential 
must undergo serum and urine pregnancy tests 
 
8.6. Disease assessment: Disease assessment by bone marrow samples (aspirate and/or biopsy), 
cytogenetics and flow cytometry is done  at baseline screening and at completion of each treatment 
cycle. A bone marrow biopsy and/or aspirate will be obtained to assess bone marrow cellularity and 
to determine the percentage of leukemic blasts, including assessment of minimal residual disease 
(MRD) to confirm remission status.  
 
At the baseline assessment, bone marrow biopsy and/or aspirate is within 3 weeks and no less than 
1 day before the first drug dose. Then on each cycle, patients are assessed for disease response by 
bone marrow biopsy and/or aspirate on day 28. If the blasts in bone marrow are <5% but marrow is 
hypocellular (cellularity ≤15%) on day 28 (±3 days), then a repeat bone marrow biopsy and/or 
aspirate is obtained 1 week later to assess response; if residual leukemia is present, repeated bone 
marrow biopsy and/or aspirate will be obtained as medically indicated. 
 
Only for patients with extramedullary disease or as clinically indicated a PET-CT will be performed at 
baseline and if positive, also at end of the induction and of the reinduction cycles, and  thereafter as 
clinically indicated. A time window of ± 3 days is allowed for the tumor assessments. A wider time 
window is allowed only at baseline; however, assessments should be performed as close as possible 
to the 1st drug administration and if feasible, not later than 3 weeks prior to the 1st drug 
administration 
 
8.7. Cardiac Assessments 
8.7.1 12-lead ECG: 12-lead ECG monitoring will be performed within 14 days before the start of 
treatment, at Cycle 1 Day 1 and Cycle 1 Day 5, and then at day 1 of all reinduction cycles and EOT. 
• 
C1D1: pre-dose, 2-hours post-dose morning dose and 2-hours post-dose evening dose 
• 
C1D5: 2-hours post-dose morning dose and 2-hours post-dose evening dose 
 
8.7.2. Cardiac Imaging – ECHO or MUGA: monitoring will be performed within 14 days before the  
start of treatment, and then prior to day 1 of each subsequent cycle if clinically indicated based on 
the treating physician’s assessment. 
 
8.8. Pharmacokinetic Profile: Blood samples for determination of plasma concentrations of CB-103, 
will be collected as detailed below: 
• 
C1D1: pre-dose, 2-, 6-hours post-dose morning dose and  2- hours post-dose evening dose (± 5 
minutes)  

 
 
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• 
C1D5: pre-dose, 2-, 6-hours post-dose morning dose and  2- hours post-dose evening dose (± 5 
minutes)  
On the day of PK sampling the patient should be fasting: on that day, CB-103 will be taken together 
with the study staff with a glass of water. On Cycle 1 Day 1 food should be withheld for at least 3 hours 
after study drug intake. Water can be taken ad libitum. On Day 5 of Cycle 1, food consumption can be 
started after the second PK sample. 
 
8.9. Laboratory assessments: The following laboratory tests will be performed within 48 hours prior 
Day 1 of each cycle: they do not need to be repeated at Cycle 1, Day 1 if they were performed at 
screening within 48 hours prior to start of study treatment. They may be performed at a local 
laboratory. For table of assessment and schedule, see Table 16. 
 
Outside labs will be permitted and the PI/treating physician will review the labs for clinical 
significance, and sign/date the results. If patients present treatment-related toxicities, monitor 
blood counts and chemistries as clinically indicated. These tests should include: 
 
8.9.1. Hematology: Complete blood counts (CBC), white blood count (WBC) with 
differential, unless WBC <0.5 x109/L (in which case differential not needed), hemoglobin, 
platelet count). Hematology assessments will be performed at least 2 times weekly during 
the first treatment cycle and at least 1 time weekly during each successive treatment cycle.  
 
8.9.2. Coagulation: Prothrombin time (PTT) and activated partial thromboplastin time (aPTT) 
 
8.9.3. Biochemistry: Clinical Chemistry includes albumin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), 
carbon dioxide (CO2), uric acid, calcium, chloride, glucose, phosphorus, potassium, sodium, 
magnesium, total bilirubin, direct bilirubin (if total bilirubin is elevated above the upper limit 
normal), total protein, blood urea nitrogen (BUN) and creatinine. Clinical Chemistry will be 
performed at least 2 times weekly during the first treatment cycle and at least 1 time weekly 
during each successive treatment cycle. 
 
8.9.4. Pharmacodynamic/Biomarker Assessments: Serial blood, CSF, and bone marrow 
samples will be obtained if additional fluid is available to measure gene and protein 
expression levels of relevant pathways (e.g. NOTCH, BCL2) as well as for longitudinal 
monitoring of tumor evolution by NGS.  Results will not be limiting for patient enrollment. 
The samples will be analyzed by Cellestia and/or their designated laboratory  (ies) from the 
list below: 
 
- Cellestia R&D (Switzerland) 
- SGS (Switzerland) 
 
Blood and bone marrow samples are mandatory at baseline for local evaluation.  For all 
patients, repeated blood sampling and bone marrow biopsy will also be taken at completion 
of induction, reinduction cycles ± 3 days, and at time of progression. An additional blood 
sample to monitor target engagement (PD) will also be collected on C1D5 at one of the PK 
sampling timepoints and Day 26 of all cycles of treatment. Except for the baseline, blood 
samples must be taken on the last week-day of CB-103 intake before the 2 days off 
treatment. 
 
Details on sample collection requirements, preparation, processing, storage, and shipment 
will be provided in a separate laboratorymanual. 

 
 
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Changes to the sampling scheme may be implemented based on the emerging data. Any adjustment 
will be recorded in the study file and the total number of samples taken will not be exceeded.

 
 
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8. STUDY CALENDAR (28 day Cycle)  
Table 16: Study Calendar 
 
Screening 
Treatment Period 
End of Treatment 
Visit16 
Follow-
Up17 
 
 
Cycle 1 
Cycle 2 
From Cycle 3 
 
 
Day of cycle 
-21 to -1 
12 
5 
26 
28 
13 
26 
28 
13 
26 
28 
1 
 
Assessments1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics with body height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history (including number of prior 
therapy regimens for ALL) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
 
 
 
 
ID Panel 
X20 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X4 
X4 
 
 
 
X4 
 
 
X4 
 
 
X4 
 
Vital Signs and body measurements 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Weight (kg) 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Physical Exam 
X 
X 
 
X3 
 
X 
X3 
 
X 
X3 
 
X 
X 
Eye examination (see Section 8.4) 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Body Temperature 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Respiratory rate 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
Cardiac assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Pressure 
X 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
12‐Lead EKG 
X6 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
ECHO or MUGA 
X6 
X5 
 
 
 
X 
 
 
X 
 
 
X 
 
Standard Laboratory Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry7-8 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Hematology7-9 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Coagulation10 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Disease Assessment11 
X 
X5 
 
X 
 
X11 
X 
 
X11 
X 
 
 
X18 
Pharmacokinetic profile12 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Biomarker Assessments13 
 
X  
X 
X 
 
 
X 
 
 
X 
 
X 
 
Lumbar puncture & CSF sampling14 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
 
X 
X 
 
X15 
X15 
 
 
 
Adverse Events 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

 
 
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1. Assessments scheduled on days of dosing should be done prior to administration of study drug(s), unless otherwise specified. 
2. Screening assessments can be used as day 1 assessments of cycle 1 if done within the previous 72 hrs.   
3. End of previous cycle assessments (Day 26) can be used as day 1 assessments if done within Day 26-29. If subsequent cycle is delayed,  
hematology, chemistry, and coagulation labs and physical exam assessments should be repeated on Day 1 of cycle.  
4. For women of childbearing potential only. Serum pregnancy test must be performed within 24-48 hours before first study treatment. 
During the on-treatment period and at the EoT visit, urine pregnancy testing should be done as indicated in the table or whenever a 
pregnancy is suspected. Pregnancy and suspected pregnancy occurring while the patient is on study drug treatment or within 90 days 
after the last dose of CB-103 should be reported to the supporting company (Cellestia AG).  
5. Screening assessments can be used as day 1 assessments if done within the previous 14 days.  
6. EKG and LVEF assessment by ECHO or MUGA should be done within 14 days before first study treatment: these assessments may be 
repeated at the Investigator’s discretion in case of signs or symptoms of cardiotoxicity. See Sections 8.7.1 and 8.7.2. 
7. Tests will be performed at least 2 times weekly during the first treatment cycle and at least 1 time weekly during each successive 
treatment cycle. Outside labs will be permitted and the PI/treating physician will review the labs for clinical significance, and sign/date 
the results. If patients present treatment-related toxicities, monitor blood counts and chemistries as clinically indicated. This assessment 
does not need to be repeated at Cycle 1, Day 1 if it was performed at screening within 48 hours prior to start of study treatment.  
8. Laboratory tests to be performed locally, within 48 hours before study visit (Day 1 of each cycle, including Cycle 1, Day 1) include 
albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), carbon 
dioxide (CO2), uric acid, calcium, chloride, glucose, phosphorus, potassium, sodium, magnesium, total bilirubin, direct bilirubin (if total 
bilirubin is elevated above the upper limit normal), total protein, blood urea nitrogen (BUN) and creatinine. 
9. CBC (WBC with differential, unless WBC <0.5 x109/L in which case differential not needed, Hemoglobin, and Platelet count). 
10. Prothrombin time (PTT), activated partial thromboplastin time (aPTT), and fibrinogen. This assessment does not need to be repeated 
at Day 1 of cycles if it was performed within 3 days prior. 
11. Disease assessment:  
• 
Bone marrow samples (aspirate and/or biopsy), cytogenetics, and flow cytometry: screening assessment can be used as day 
1 assessment of the induction cycle if done within the previous 3 weeks; end of previous cycle assessment can be used as day 
1 assessment of the next cycle if done in +/- 3 days. 
• 
At the baseline assessment, bone marrow biopsy and/or aspirate is within 21 days and no less than 1 day before the first drug 
dose.  
• 
Patients are assessed for disease response by bone marrow biopsy and/or aspirate on day 28 (±3 days) induction and 
subsequent cycles. If the blasts in bone marrow are <5% but marrow is hypocellular (cellularity ≤15%) on day 26, then a 
repeat bone marrow biopsy and/or aspirate is obtained 1 week later to assess response; if no clear definition of response to 
therapy may be determined, repeated bone marrow biopsy and/or aspirate will be obtained as clinically indicated. 
• 
For patients with extramedullary disease a PET-CT will be performed at baseline and if positive, also at C1D26, and Day 26 of 
all subsequent cycles (±3 days).  Assessments should be performed as close as possible to the 1st drug administration and if 
feasible, a wider time window is allowed only at baseline, not later than 14 days prior to the 1st drug administration. 
12. PK time sampling: blood sampling will be collected as per the schedule and time window indicated below:     
• 
C1D1: pre-dose, 2-, 6-hour post-morning dose, 2- hour post evening dose (± 5 minutes) 
• 
C1D5: pre-dose, 2-, 6-hour post-morning dose, 2- hour post evening dose (± 5 minutes) 
PK Samples will be analyzed by a designated laboratory under Cellestia’s responsibility. 
13. Biomarker assessments:  Serial blood and bone marrow samples  will be obtained to measure gene and protein expression levels of 
relevant pathways (e.g. NOTCH, BCL2) as well as for longitudinal monitoring of tumor evolution by NGS if leftover sample is available. 
Baseline, at time of completion of induction (+/- 3 days), and reinduction cycles ± 3 days, and at time of progression. Additional blood 
samples will be collected on C1D5 and on Day 26 of all cycles for PD analysis by a designated laboratory under Cellestia’s 
responsibility.  
14. Lumbar puncture (T-ALL/T-LBL) for prophylactic intrathecal therapy: if prophylactic intrathecal therapy is foreseen by the treating 
physician, a lumbar puncture may be performed up to 3 days before the first dose of CB-103, and may be repeated at the discretion of 
the treating physician at the end of the first cycle and at the end of any subsequent cycles on or around day 28. If clinically feasible, one 
additional sample will be collected to determine the exposure of CB-103 in the CSF (this measurement will be done by a designated 
laboratory under Cellestia’s responsibility). 
15. For patients with PR or stable disease (SD) after the induction cycle(s) who may receive add-on selective therapy chosen by the 
investigator on the basis of the ongoing biomarker expression of the disease while continuing the treatment with the combination of 
CB-103 and venetoclax, the add-on therapy will be reported in details on the CRF. 
16. EoT visit is to be done 5 days after the last dose of any study treatment, unless the patient starts any subsequent antitumor 
therapy (in which case the EoT visit should be performed before the start of the new therapy, whenever possible).  
17 First follow-up visit will be 26 days after EoT (± 5 days), and every three months (± 14 days) thereafter, until EoS (i.e., death, patient’s 
refusal, lost to follow-up) or study termination, whichever occurs first. Survival status and information on posterior antitumor therapies 
will be collected, telephone contact being acceptable. 
18. If patient discontinued treatment without progression, tumor assessment will be done until progression or start of new antitumor 
treatment. 
19. In case of relevant related toxicities (i.e., Grade>1), every 4 weeks until resolution or stabilization: information collected by telephone 
contact is acceptable. 
20. Hepatitis B, C infection, and HIV will be obtained within 21 days of start of treatment.  
 
 
 
 
 
 

 
 
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8.10 Outside Physician Participation During Treatment 
1. MDACC Physician communications 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 a 
local physician agreement to supervise the patient's care. 
3. Protocol required evaluations outside MDACC will be documented by telephone, fax or email. The 
PI/treating physician must review the labs, determine clinical significance and sign and date the 
report. 
4. A copy of the informed consent,  treatment schema, and evaluation during treatment will be 
provided to the local physician. 
5. Documentation to be provided by the local physician will include progress notes, reports of protocol 
required laboratory and diagnostic studies, and documentation of any hospitalizations. 
6. The home physician will be requested to report to the MDACC physician investigator all life-
threatening events within 24 hours of documented occurrence. 
8. 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. 

 
 
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9. RESPONSE DEFINITIONS 
Because morphologic examination of the bone marrow during periods of hematopoietic recovery 
after intensive chemotherapy may be unreliable, a response will be based on blast percentage by flow 
cytometry. Flow cytometric assessment of response (MRD) should be performed at MDACC. Blast 
percentages determined by morphology can be  used in cases where the sample submitted for flow 
cytometry evaluation is limited or hemodiluted.   Patients will be considered evaluable for response if 
they have been administered greater than 50% of the dose of CB-103.  Patients will be evaluable for 
safety if they have been administered 1 dose of CB-103.   
 
9.1. Study Endpoints: 
9.1.1. Primary Efficacy Analysis: Clinical activity of CB-103 in combination with venetoclax will 
be assessed based on the overall response rate (NCCN Guidelines 2021) [30].  
 
9.1.2. Response Criteria T-ALL: 
9.1.2.1. CR (Complete Remission): Absolute neutrophil count > 1.0 x 109/L, platelets > 
100 x 109/L, red cell transfusion independence, and bone marrow with < 5% blasts. 
No evidence of extramedullary disease.  
 
9.1.2.2. CRi (CR with incomplete blood count recovery): Bone marrow with < 5% 
blasts, with peripheral neutrophils of ≤ 1.0 x 109/L or platelets ≤ 100 x 109/L. 
 
9.1.2.3. PR (Partial Remission): All of the hematologic values for a CR but with a 
decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow 
aspirate. No evidence of extramedullary disease. 
 
9.1.2.4. Relapse: Subsequent appearance, after achievement of CR, of ≥ 5% blasts in 
the bone marrow with confirmation by flow cytometry or the development of 
extramedullary disease after achievement of CR. 
 
9.1.3. Additional Response Criteria for T-LBL:  
In patients with extramedullary disase, radiographic tumor response assessments will be 
based on CT/MRI/PET-CT scans throughout the study and response determined by 
Investigator per the revised recommendations for response assessment of NHL per "The 
Lugano Classification", reported in Appendix 2 [31]. 
 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly measurable in two diameters. Nodes should 
preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, 
liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation.  
 
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal 
masses, and extranodal sites not selected as dominant or measurable or that do not meet the 
requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, 
abdominal masses, and other lesions that cannot be confirmed and followed by imaging. 
 
 
 

 
 
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9.1.4. Response Criteria for CNS Disease:  
9.1.4.1. CNS remission: achievement of CNS-1 status in a patient with CNS-2 or CNS-
3 status at diagnosis. 
 
9.1.4.2. CNS relapse: new development of CNS-3 status or clinical signs of CNS 
leukemia New development of CNS-2 status on 2 consecutive lumbar punctures 
(between 2–4 weeks apart) with confirmation by immunophenotyping or other 
molecular testing methods. 
 
9.1.5. Secondary efficacy endpoints:  
To assess whether the ORR to CB-103 in combination with Venetoclax is dependent on pre‐
treatment expression of Notch and/or BCL2 pathway, patients will be stratified according to 
the pre-treatment presence or absence of Notch and BLC2 expression. ORR will be evaluated 
in each of the four strata. 
 
For each subject, minimal residual disease (MRD, presence of leukemic cells below the 
threshold of detection by conventional morphologic methods), duration of response, event‐
free survival, and overall survival will be calculated. 
 
The depth of remission, i.e. detection of MRD, will be evaluated by PCR/NGS methods that 
can detect leukemic cells at a sensitivity threshold of at least 1x10-6 bone MNCs. Flow 
cytometry and/or molecular analysis with PCR methods that can detect leukemic cells at a 
sensitivity threshold of at least 1x10-4 bone marrow nuclear cells (MNCs) will also be 
performed. 
 
The duration of response is defined as the number of days from the date of initial response 
(PR or better) to the date of first documented disease progression/relapse or death, 
whichever occurs first. Event‐free survival is defined as the number of days from the date of 
treatment initiation (i.e., C1D1) to the date of documented treatment failure, relapses from 
CR, or death from any cause, whichever occurs first, and will be calculated for all patients. In 
the event that neither disease progression nor death is documented prior to study 
termination, analysis cutoff, or the start of confounding anticancer therapy, these endpoints 
will be censored at the date of last tumor assessment date. Overall survival is defined as the 
number of days from study enrollment to death due to any cause. 
 
9.1.6. Exploratory endpoints:  
9.1.6.1. CB-103 plasma concentrations, PK parameters (e.g., Cmax and AUC0-8) vs  
safety and/or efficacy  
9.1.6.2.  PD parameters, as for instance Notch and BCL2 expressionin pre- and post-
treatment marrow samples. 
9.1.6.3. the number and percentage of patients that are able to transition to HSCT in: 
9.1.6.3.1. Either in the patients achieving CR after the induction and 
reinduction cycles; 
9.1.6.3.2. Or in the patients with PR or stable disease (SD) after the induction 
and reinduction cycles. 
 
9.2. Primary Safety Endpoints:  
9.2.1. Primary Safety Analysis: The incidence rate, severity and relationship to CB-103 and/or 
venetoclax of adverse drug reactions and serious drug reactions according to common 
terminology criteria for adverse events (CTCAE) NCI CTCAE version 5.0. 
 

 
 
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The overall incidence and severity of all adverse events using Common Toxicity Criteria v 4.0. 
 
9.2.2. Safety Definitions: 
9.2.2.1. Adverse Event (AE):  
An Adverse Event is defined as any untoward medical occurrence in a patient 
regardless of its causal relationship to study treatment. An AE can be any unfavorable 
and unintended sign (including any clinically significant abnormal laboratory test 
result), symptom, or disease temporally associated with the use of the study 
treatment, whether or not it is considered to be study drug(s) related. Included in this 
definition are any newly occurring events and any previous condition that has 
increased in severity or frequency since the administration of the study. 
Attribution - the determination of whether an adverse event is related to a medical 
treatment or procedure.  
• 
Definite - the adverse event is clearly related to the investigational agent(s). 
• 
Probable - the adverse event is likely related to the investigational agent(s). 
• 
Possible - the adverse event may be related to the investigational agent(s). 
• 
Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
• 
Unrelated - The adverse event is clearly NOT related to the investigational 
agent(s) 
 
Medical conditions/diseases present before starting study drugs are only considered 
adverse events if they worsen after starting the study drug. Abnormal laboratory 
values or test results constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant or require therapy. 
 
The severity of the adverse events (AEs) -The severity of the adverse events (AEs) will 
be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE) V5.0.  Events not included in the NCI CTCAE will be 
scored as follows: 
General grading: 
• 
Grade 1: Mild: discomfort present with no disruption of daily activity, no 
treatment required beyond prophylaxis. 
• 
Grade 2: Moderate: discomfort present with some disruption of daily activity, 
require treatment. 
• 
Grade 3: Severe: discomfort that interrupts normal daily activity, not responding 
to first line treatment.  
• 
Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
RedCap will be used as the electronic Case Report Form (eCRF). The Investigator (or 
physician designee) is responsible for verifying and providing source documentation 
for all adverse events and assigning the attribution for all adverse events for subjects 
enrolled. 
 
Adverse events will be captured per the phase II recommended guidelines 
• 
Signs and symptoms relating to adverse event diagnoses will not be captured as 
individual events. (e.g. event of catheter related infection: redness, pain, swelling 

 
 
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at catheter site are signs and symptoms of the catheter related infection and thus 
will not be recorded as individual events). 
• 
The maximum grade of the adverse event (AE) will be captured per course or 
protocol defined visit date. The start date will be recorded as when the AE first 
began or worsened from baseline, regardless of when the event was at its highest 
grade. 
• 
An AE will be recorded as intermittent if the AE is not continuous but reoccurs at 
an irregular interval within a course. 
• 
Hematologic adverse events will not be recorded or reported for studies in 
patients with any type of leukemia and/or related disorders, except for: 
a. Prolonged myelosuppression as defined by marrow hypocellularity on 
day 42 or later (6 weeks) from start of therapy without evidence of 
leukemia (< 5% blasts).  
b. Hematologic events that result in dose modifications, interruptions or 
meets the protocol definition of DLT or SAE. 
• 
Abnormal laboratory values or test results will not be recorded or reported as 
adverse events unless it leads to therapeutic intervention, results in dose 
modification or interruption, or meets the protocol definition of a DLT or SAE. 
Only the following AEs from the Adverse Event Record will be reported in the CRF: 
• 
Any grade adverse event that is possibly, probably, or definitely related to the 
study drug(s). 
• 
All serious adverse events regardless of attribution to the study drug(s). 
• 
Any grade adverse event regardless of attribution to the study drug(s) that 
results in any dose modification. 
The investigator (or physician designee) is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for all 
adverse events for subjects enrolled.  For non-MD Anderson laboratory results, the 
principal investigator (or physician designee) will review laboratory results, and sign 
and date the results. 
 
Table 17: Recommended Adverse Event Recording Guidelines 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 

 
 
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Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
9.2.2.2. Serious Adverse Event or Serious Adverse reaction (SAE) Reporting 
Requirements for M D Anderson Sponsor IND:  
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 the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent.  
• 
Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
• 
All SAEs, expected or unexpected/ initial or follow up, must be reported to the 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 Sponsor 
within 24 hours of knowledge of the event  
• 
Additionally, any serious adverse events that occur after the 30-day time period 
that are related to the study treatment must be reported to the INDSponsor. This 
may include the development of a secondary malignancy. 
• 
The electronic SAE application (OnCore) will be utilized for safety reporting to the 
IND Sponsor and MD Anderson IRB.  

 
 
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• 
All events reported to the supporting company must also be reported to the 
INDSponsor. 
 
9.2.2.3. Reporting to Cellestia:  
The investigator has to report the SAE to the supporting company of the study, 
Cellestia, within 24hr after becoming aware of the event and regardless of the 
relationship. The Adverse Event Reporting Form must be completed and forwarded 
to HEMEX Pharmacovigilance. 
 
Contact details for HEMEX Pharmacovigilance are as follows: 
 
Email: safety@hemex.ch 
Phone number: +41 61 927 28 00 
 
 
Please note there are no AEs of Special Interest listed in the IB. 
 
 

 
 
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10. REGULATORY REQUIREMENTS 
10.1. Informed Consent: Before a subject's participation in the clinical study, the Investigator is 
responsible for obtaining written informed consent from the subject or legally acceptable 
representative after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol specific screening procedures or any investigational 
products are administered. A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the subject's 
participation in the clinical study. Consented subjects will be registered in the institutional database 
CORe.  
 
The acquisition of informed consent should be documented in the subject's medical records, and the 
informed consent form should be signed and personally dated by the subject or a legally acceptable 
representative and by the person who conducted the informed consent discussion. The original signed 
informed consent form should be retained in accordance with institutional policy, and a copy of the 
signed consent form should be provided to the subject or legally acceptable representative. 
 
Subjects must have signed and dated an IRB approved informed consent in accordance with regulatory 
and institutional guidelines. MD Anderson SOP 04 will be used to guide the consent process for any 
patients for whom English is not the preferred language. This written informed consent must be 
obtained before the performance of any protocol-related procedures that are not part of normal 
subject care. 
 
10.2. Independent Ethics Committee/Institutional Review Board: A copy of the protocol, proposed 
informed consent form, other written subject information, and any proposed advertising material 
must be submitted to the IRB for written approval. The Investigator must submit and, where 
necessary, obtain approval from the IRB for all subsequent protocol amendments and changes to the 
informed consent form. The Investigator should notify the IRB of deviations from the protocol or 
serious adverse events occurring at the site. The Investigator will be responsible for obtaining annual 
IRB approval/renewal throughout the duration of the study.  
 
10.3. Subject Confidentiality and Data Security: The Investigator must ensure that the subject's 
confidentiality is maintained. Additionally, this protocol is reviewed by the MD Anderson DSMC. 
Subjects should be identified by their study number only and should be kept in strict confidence by 
the Investigator. In compliance with ICH GCP Guidelines, it is required that the investigator and 
institution permit authorized representatives of the company, of the regulatory agency(s), and the IRB 
direct access to review the subject's original medical records for verification of study‐related 
procedures and data. Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study. The Investigator is obligated to 
inform and obtain the consent of the subject to permit named representatives to have access to 
his/her study‐related records without violating the confidentiality of the subject. 
 
Participant confidentiality and privacy is strictly held in trust by the participating investigator, their 
staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality 
is extended to the data being collected as part of this study. Data that could be used to identify a 
specific study participant will be held in strict confidence within the research team. No personally 
identifiable information from the study will be released to any unauthorized third party without prior 
written approval of the sponsor/funding agency, as applicable. 
 
All research activities will be conducted in as private a setting as possible. 
 

 
 
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10.3.1 Access to Study Records 
Study records may be accessed by IRB approved study personnel, or authorized inspectors. The study 
monitor, other authorized representatives of the sponsor or funding agency, representatives of the 
Institutional Review Board (IRB), regulatory agencies or representatives from companies or 
organizations supplying the product, may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) 
and pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
 
10.3.2 Methods of Storage of Study Records 
All data collected from MDACC sources will be maintained on a password protected server compliant 
with HIPAA. Study staff will have role based restricted access to directories and files on the server, 
according to project responsibilities. Only those with data entry permissions can add records. The PI 
or a delegate will review the conditions under which data will be released to recipient- investigators. 
Each application for use will need IRB approval and consents, if appropriate. The level of identifiability 
will determine the process for review and approval as well as the way information is shared. 
 
Any study data or records maintained in paper documents will be stored in the offices of the PI or 
other delegated study staff, in a locked cabinet or other comparable controlled environment, and will 
be accessible only to authorized study team members or authorized inspectors and will be available 
in the even of an audit/inspection.   
 
10.3.3 Duration of Study Record Storage 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for 
as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency 
requirements. 
 
10.3.4 Sharing of Study Records 
There are no plans to share study data with entities external to MD Anderson Cancer Center, aside 
from authorized inspectors as applicable (i.e. authorized representatives of the sponsor or funding 
agency, representatives of the Institutional Review Board (IRB), regulatory agencies or representatives 
from companies or organizations supplying the product).  If data will be shared, IRB approval will be 
sought, and applicable inter-institutional agreements executed, prior to data sharing.   
 
10.4. Data and Safety Monitoring Plan 
 
This monitoring plan will be used as a guideline for the review of protocols sponsored by The 
University of Texas M D Anderson Cancer Center. The purpose of the plan is to ensure that the rights 
and wellbeing of human subjects are protected; the conduct of the trial is in accordance with the 
protocol, regulatory requirements, and good clinical practices (GCP); and safety reporting to the 
Institutional Review Board (IRB) and Food and Drug Administration (FDA) is accurate and complete. 
 
10.4.1. Monitoring Visit Intervals 
• The Clinical Research Monitor (CRM) will notify the site in writing of planned visits and the 
purpose of the visit to ensure the availability of medical records, study personnel and 
regulatory documents (if they are scheduled for review). Subjects will be monitored 6 months 
from the time of consent or until 30 days after the last dose of study drug, whichever comes 
first. 
• The initial monitoring visit will occur after the first subject/preselected has completed the 
first cycle of treatment. 

 
 
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• Interim site monitoring visits will be conducted every 8-12 weeks during the enrollment 
phase of the study. In the case of slow/halted enrollment, monitoring visits may be extended 
to every 6 months (see section 12 below). 
• Additional monitoring visits may be conducted if: enrollment proceeds more rapidly than 
expected; data entry is not being completed in a timely manner, and/or; the site is not in 
compliance with the protocol, federal and state regulations, and GCP. 
 
10.4.2. Enrollment 
The research team will be responsible for screening and enrolling all subjects. During 
scheduled monitoring visits protocol eligibility will be reviewed for each pre-selected subject 
in order to verify all criteria were met, and the subject was eligible for study participation. 
 
10.4.3. Monitoring Requirements 
For this phase II trial 30% of the subjects enrolled for treatment will be monitored. 
Additional subjects may be monitored as needed and determined by the sponsor. 
When in-person visits are conducted, the Monitoring Visit Log will be signed and dated by the 
CRM and one representative from the research team. During remote monitoring visits, the 
Monitoring Visit Log will be signed and dated by the CRM and the attendance record from the 
query meetings (if a query meeting is necessary) will be saved. The signed log or attendance 
record will be maintained in the sponsor files. Any exceptions from above will be documented 
on the Monitoring Visit Log and clarified in the applicable monitoring visit report. 
 
a) Source Document Verification 
The Clinical Research Monitor will review source documentation to verify study 
procedures were conducted per protocol specifications. The medical record and other 
protocol-specific documentation will be routinely reviewed. 
 
b) Informed Consent Process 
It will be verified that the most current IRB-approved version of the informed consent 
document was used to obtain consent; and that all required signatures are present, 
and the signature dates precede the performance of any study-related procedures. 
 
c) Study Product Accountability/Administration 
The protocol treatment plan includes investigational products (CB-103 and 
Venetoclax) and standard of care intrathecal treatment. The CRM will only verify that 
the standard of care regimen was administered at the appropriate time point per 
protocol. Venetoxclax will be dispensed through commercial supply and only 
treatment compliance will be monitored. CB-103 will be dispensed through 
Investigational Pharmacy, and compliance and accountability will be reviewed during 
monitoring visits. The Investigational Pharmacy records pertaining to the CB-103 
shipping, receipt, storage, return, and destruction will also be periodically reviewed. 
The following investigational product documentation will be verified during 
scheduled monitoring 
visits: 
• Drug/product dosing and scheduling adheres to the protocol guidelines 
• Dose reductions, escalations, and/or delays were completed per protocol, and 
documented in the medical record 
• Drug/product compliance and accountability records are being maintained 
 
10.4.4. Adverse Event Reporting 

 
 
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The Clinical Research Monitor will verify adverse events are collected/reported per protocol 
guidelines, graded using NCI Common Toxicity Grading Criteria, and attribution is assigned by 
the PI or designee; and ensure serious adverse events are reported per IND and IRB guidelines, 
and per any agreements with supporting companies. 
 
10.4.5. Concomitant Medication 
Concomitant hydroxyurea and intrathecal chemotherapy will be entered into the REDCap case 
report form. 
 
10.4.6. Response 
It will be verified that response assessments are obtained and documented, and the 
corresponding treatment decisions are in compliance with the protocol guidelines. 
 
10.4.7. Data Recording 
The REDCap database and OnCore will be utilized as the electronic case report form (eCRF) 
for this study. During monitoring visits key eCRF entries will be reviewed and compared with 
source documentation. This limited data review will include the eligibility criteria, adverse 
events, protocol treatment, and off-study summary. The Principal Investigator and research 
team will be responsible for ensuring all other data is entered per the protocol specifications, 
and the needs of the investigator. 
 
10.4.8. Regulatory Document Review 
Periodically throughout the course of the trial the regulatory files will be reviewed to ensure 
that the documentation is current, accurate and complete. 
 
10.4.9. Queries/Findings 
When issues are identified during the monitoring visit, queries will be generated on the query 
form and provided to the research team for response/resolution. The Clinical Research 
Monitor will attempt to meet with the research nurse and/or study/data coordinators at each 
visit, document discussions, and note any outstanding issues in a Follow-up Memo to the 
investigator. Resolution of all open queries will be requested prior to the start of the next 
monitoring visit. 
 
10.4.10. Monitoring Reports/Follow Up Memo 
A Monitoring Reports will be completed and saved in the sponsor files. The report will include, 
but is not limited to: 
• Enrollment updates 
• Informed consent 
• Eligibility and supporting source documentation 
• Status of limited case report form data entry 
• Treatment and response 
• Toxicity assessment and reporting 
• SAE submissions 
• Protocol compliance/protocol deviations and violations 
• Compliance with all applicable regulations and GCP 
• Concerns/issues expressed by study site personnel 
 
Status of previously identified issues will be addressed in subsequent reports, including any 
actions or requests of the IND sponsor. 

 
 
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The research team will receive a Follow-up Memo to identify the issues noted during the 
monitoring visit (queries will be sent as an attachment as applicable) and state the plan for 
resolution of the open issues. 
 
10.4.11. Deviations/Violations 
The CRM will ensure that protocol deviations and violations are reported per the 
Investigator’s interpretation of IRB policy. Deviations and violations will be documented in the 
Monitoring Report. 
 
10.4.12. Monitoring Update Visits 
When all monitoring has completed as outlined in the Monitoring Plan, or during periods of 
slow enrollment, the protocol can be transitioned to Monitoring Update status. A Monitoring 
Update report will be completed every 6 months until the closeout process has concluded 
(see section 13), or enrollment resumes. The report will include, but is not limited to the 
following: 
• Enrollment status 
• Subjects on active treatment or in follow up 
• Protocol revisions since the last visit 
• Re-consents for preselected subjects (as applicable) 
• SAE submissions 
• Changes with key study personnel 
A Follow up Memo will be sent to the research team, which will include any outstanding issues 
noted during the Monitoring Update review. 
 
10.4.13. Study Closeout 
Once all subjects have been removed from the study a closeout visit will be conducted to 
ensure the regulatory documents are in order, and all closeout procedures are completed. 
Following an initial regulatory document review, the CRM will provide the research team with 
a summary of any outstanding items. Once all issues have been addressed and resolution 
verified, a Closeout Completion Memo will be provided to the investigator, and a Closeout 
Report will be completed for the sponsor files. 
 
10.5. Study Termination: The investigators reserve the right to terminate the study according to the 
study contract. The Investigator should notify the IRB in writing of the study's completion or early 
termination. Subjects may be eligible for continued treatment off protocol and determined by the 
Principal Investigator.  
 
11. TREATMENT DISCONTINUATION 
Treatment will continue until discontinuation due to unacceptable toxicity, lack of response, relapse 
or progressive disease. This includes any of the following: 
 
• 
Clinically significant progressive disease at any time. 
• 
Death 
• 
Possibility of undergoing allogeneic stem cell transplantation. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s), that are not manageable with dose adjustments and/or 
optimal medical management, or that, in the opinion of the Investigator, pose an 
unacceptable risk for the patient. 
• 
Patient decision for study withdrawal. 
• 
General or specific changes in the patient's condition that render the patient unacceptable 
for further treatment in the judgment of the Investigator, sponsor, or any regulatory body. 

 
 
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Patients who discontinue treatment due to unacceptable toxicity, lack of response, relapse or 
progressive disease, or bone marrow transplantation are considered to have completed the study 
treatment per protocol.  The patients need to complete End Of Treatment (EOT) visit. 
 
Once a patient has discontinued the study treatment and has completed the EOT visit, the patient 
shall be followed-up for survival up to two years from enrollment onto the study: data on survival 
status and any new anti-cancer therapy may be collected by phone every 3 months for up to 2 years 
after study enrollment. In case of relevant related toxicities (i.e., Grade>1) occurring during survival 
follow-up, the relevant information will be collected every 4 weeks until resolution or stabilization of 
the event: information collected bytelephone contact is acceptable. 
 
At disease progression or treatment discontinuation, the emergence of new neoplastic clones or 
further mutations during therapy with this combination shall be investigated by next generation 
sequencing (NGS) in peripheral blood mononuclear cells (PMBC) or, If available, bone marrow samples 
obtained from patients. 
 

 
 
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12. STATISTICAL CONSIDERATIONS 
This is a phase II open-label single arm and single institution clinical trial to evaluate the 
efficacy and safety of CB-103 in combination with venetoclax in adolescent and adult 
patients with T-ALL/T-LL in first or second bone marrow recurrence refractory to initial 
induction therapy or refractory to at least one reinduction attempt.  Up to 30 patients may 
be enrolled, without regard to Notch status; we anticipate that approximately 50% of these 
patients will be Notch positive. The primary efficacy endpoint of the study is overall 
response rate (ORR, including CR,CRi and PR rate) after the first two induction cycles, and 
the primary toxicity endpoint is the rate of toxic events, defined as  a grade ≥3 non-
haemtological AEs that are possibly or probably related to the study drugs (see Adverse 
Events (SAE) definition in section 9.2.2.1.) occurring during the 28 days of induction cycle. 
We simultaneously monitor efficacy and toxicity using the Bayesian optimal phase 2 (BOP2) 
design [32]. Specifically, let 𝑛𝑛 denote the interim sample size, and 𝑁𝑁 denote the maximum 
sample size. Let 𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒 and 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡 denote the binary efficacy and toxicity endpoints, with 𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒=
1 and 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1 indicating that patients experience efficacy and toxicity, respectively. We 
assume that the joint distribution of (𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡) follows a multinomial distribution with four 
elementary outcomes: (𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡) = (1, 1), (1, 0), (0, 1) and (0, 0). Let 𝐩𝐩= (𝑃𝑃11, 𝑃𝑃10, 𝑃𝑃01, 𝑃𝑃00) 
denote the probabilities of observing the four outcomes, and let 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 𝑃𝑃𝑃𝑃(𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒= 1), 
𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 𝑃𝑃𝑃𝑃(𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1) and 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 𝑃𝑃𝑃𝑃(𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒= 1, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1). When efficacy and toxicity 
endpoints are monitored separately, the joint distribution reduced to marginal distribution 
of efficacy and marginal distribution of toxicity, respectively. 
The treatment is deemed unacceptable if 𝒑𝒑𝒆𝒆𝒆𝒆𝒆𝒆≤𝟎𝟎. 𝟏𝟏𝟏𝟏 or 𝒑𝒑𝒕𝒕𝒕𝒕𝒕𝒕> 𝟎𝟎. 𝟐𝟐𝟐𝟐. Thus, we will stop enrolling 
patients and claim that the treatment is unacceptable if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒> 0.15|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼
, 
or 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡≤0.20|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼/3
, 
where 𝜆𝜆=0.57 and 𝛼𝛼=0.86 are design parameters optimized to maximize the study power, 
i.e., probability of correctly concluding an efficacious and safe treatment as acceptable 
when 𝒑𝒑𝒆𝒆𝒆𝒆𝒆𝒆= 𝟎𝟎. 𝟑𝟑, 𝒑𝒑𝒕𝒕𝒕𝒕𝒕𝒕= 𝟎𝟎. 𝟏𝟏𝟏𝟏 and 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 0.05, while controlling that the probability of 
incorrectly claiming an inefficacious and toxic treatment, i.e., type I error, with 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.15, 
𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 0.20 and 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 𝟎𝟎. 𝟎𝟎𝟎𝟎, to 8.3%. Note that in the safety stopping rule, the original 
publication of the design used the probability cutoff 𝜆𝜆(𝑛𝑛/𝑁𝑁)𝛼𝛼, here the attenuation factor 3 
is added (i.e., 𝛼𝛼/3) to obtain stricter interim stopping boundaries to enhance safety. 
This optimization is performed assuming a vague Dirichlet prior Dir(0.05,0.1,0.15,0.7) for p. The prior 
is chosen such that it corresponds to a prior effective sample size of 1 patient, and the prior 
estimates of p_eff and p_tox match the values specified when the treatment is unacceptable. The 
above decision rule leads to the following optimal stopping boundaries: 

 
 
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Table 18: Optimized stopping boundaries 
 
# patients treated Stop if # response <= OR # toxicity >= 
10 
0 
3 
20 
2 
5 
30 
5 
6 
When the total number of patients reaches the maximum sample size of 30, we conclude that the 
treatment is acceptable if the number of responses are greater than 5, and the number of toxicities 
are less than 6; otherwise we conclude that the treatment is unacceptable. The go/no-go criteria in 
Table 18 are non-binding. 
Below (Table 19) are the operating characteristics of the design based on 10000 simulations using 
the BOP2 web application (BOP2 V1.4.10.0), which is available at http://www.trialdesign.org. 
Table 19: Operating characteristics 
 
Scenario Pr(Eff) Pr(Tox) 
Pr(Eff & 
Tox) 
Early 
Stopping (%) 
Claim 
Acceptable (%) 
Average 
Sample Size 
1 
0.30 
0.2 
0.05 
48.77 
33.34 
21.7 
2 
0.15 
0.3 
0.05 
89.47 
1.56 
14.2 
3 
0.30 
0.1 
0.05 
14.26 
77.76 
27.6 
4 
0.15 
0.1 
0.05 
51.07 
20.83 
22.3 
5 
0.30 
0.2 
0.10 
49.39 
31.94 
21.6 
6 
0.15 
0.2 
0.05 
71.48 
8.34 
18.2 
7 
0.20 
0.1 
0.05 
31.75 
45.19 
25.1 
8 
0.15 
0.4 
0.06 
97.62 
0.19 
11.6 
9 
0.40 
0.1 
0.06 
9.74 
86.76 
28.3 
10 
0.40 
0.4 
0.16 
96.03 
0.50 
12.1 
Upon completion of the trial, efficacy (per ORR and toxicity rates will be summarized as proportions 
with corresponding 95% Agresti-Coull confidence intervals.  Given 30 patients, the following table 
(Table 20) provides rates and confidence intervals over a range of incidences: 
 
Table 20: Rates and Confidence Intervals  
 
Incidence 
Proportion (95% CI) 
0/30 
0 (0, 0.13) 
1/30 
0.03 (0, 0.18) 
2/30 
0.07 (0.01, 0.22) 
3/30 
0.1 (0.03, 0.26) 
4/30 
0.13 (0.05, 0.3) 
5/30 
0.17 (0.07, 0.34) 
6/30 
0.2 (0.09, 0.38) 
7/30 
0.23 (0.12, 0.41) 

 
 
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8/30 
0.27 (0.14, 0.45) 
9/30 
0.3 (0.17, 0.48) 
10/30 
0.33 (0.19, 0.51) 
11/30 
0.37 (0.22, 0.55) 
12/30 
0.4 (0.25, 0.58) 
13/30 
0.43 (0.27, 0.61) 
14/30 
0.47 (0.3, 0.64) 
15/30 
0.5 (0.33, 0.67) 
16/30 
0.53 (0.36, 0.7) 
17/30 
0.57 (0.39, 0.73) 
18/30 
0.6 (0.42, 0.75) 
19/30 
0.63 (0.45, 0.78) 
20/30 
0.67 (0.49, 0.81) 
21/30 
0.7 (0.52, 0.83) 
22/30 
0.73 (0.55, 0.86) 
23/30 
0.77 (0.59, 0.88) 
24/30 
0.8 (0.62, 0.91) 
25/30 
0.83 (0.66, 0.93) 
26/30 
0.87 (0.7, 0.95) 
27/30 
0.9 (0.74, 0.97) 
28/30 
0.93 (0.78, 0.99) 
29/30 
0.97 (0.82, 1) 
30/30 
1 (0.87, 1) 
 
 
In secondary analysis, ORR will be summarized separately by Notch status as proportions with 
corresponding 95% Agresti-Coull confidence intervals.  The difference in ORR between Notch groups 
will be assessed by Fisher’s exact test.   
 
Other measures of response (CR, Cri, PR, relapse, radiographic tumor response, CNS remission, CNS 
relapse) and minimal residual disease (MRD) will be summarized as proportions with corresponding 
95% Agresti-Coull confidence intervals. 
 
Duration of Response (DoR), Overall Survival (OS), and event-free Survival (EFS) will be summarized 
using Kaplan-Meier methods. 
 
In exploratory analyses, correlations between ORR and pharmacokinetic and pharmacodynamics 
markers will be summarized.  Rates of patients transitioning to Hematopoietic stem cell transplant 
(HSCT) will be summarized.  Endpoints may be further summarized separately by Notch status.   
 
Additional statistical methods may be used. 
 
The Investigator is responsible for completing an efficacy/safety summary reports and submitting it 
to the IND Office Medical Affairs and Safety Group, for review and approval. 
This should be submitted after the first 10 evaluable patients complete 1 cycle of study treatment, 
and every 10 evaluable patients, thereafter.  Efficacy summary will be submitted for every 10 
evaluable patients after they complete 2 cycles of therapy. 

 
 
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A copy of the safety summary report should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 1 QT Prolonging Drugs with Risk of Torsades de Pointes. 
 
Table 1 List of prohibited QT prolonging drugs with a known risk to induce Torsades 
de Pointes 
Drug 
QT risk (*) 
Comment 
Aclarubicin 
Known risk for TdP 
Not available in US 
Amiodarone 
Known risk for TdP 
Females >Males, TdP risk regarded as low 
Anagrelide 
Known risk for TdP 
 
Arsenic trioxide 
Known risk for TdP 
 
Astemizole  
Known risk for TdP 
Removed from US market 
Azithromycin 
Known risk for TdP  
Females>Males 
Bepridil 
Known risk for TdP 
Removed from US market; Females>Males 
Cesium chloride 
Known risk for TdP 
 
Chloroquine 
Known risk for TdP 
 
Chlorpromazine 
Known risk for TdP 
 
Chlorprotixene 
Known risk for TdP 
Not available in US 
Cilostazol 
Known risk for TdP 
 
Ciprofloxacin 
Known risk for TdP 
 
Cisapride 
Known risk for TdP 
Removed from US market; Females>Males 
Citalopram 
Known risk for TdP 
 
Clarithromycin 
Known risk for TdP 
 
Cocaine 
Known risk for TdP 
 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
 
Domperidone 
Known risk for TdP 
Not available in the US 
Donepezil 
Known risk for TdP 
 
Dronedarone 
Known risk for TdP 
 
Droperidol 
Known risk for TdP 
 
Erythromycin 
Known risk for TdP 
 
Escitalopram 
Known risk for TdP 
 
Flecainide 
Known risk for TdP 
 
Fluconazole 
Known risk for TdP 
 
Gatifloxacin 
Known risk for TdP 
Removed from US market 
Grepafloxacin 
Known risk for TdP 
Removed from US market 
Halofantrine 
Known risk for TdP 
Not available in US; Females>Males 
Haloperidol 
Known risk for TdP 
When given i.v. or at higher than 
recommended doses, risk of sudden death, 
QT prolongation and torsades increased 
Hydroquinidine 
Known risk for TdP 
Not available in US 
Hydroxychloroquin
e 
Known risk for TdP 
 
Ibogaine 
Known risk for TdP 
Not available in US 
Ibutilide 
Known risk for TdP 
Females>Males 
Levofloxacin 
Known risk for TdP 
 
Levomepromazine 
Known risk for TdP 
Not available in the US 
Levomethadyl 
acetate 
Known risk for TdP 
Removed from US market 

 
 
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Drug 
QT risk (*) 
Comment 
Levosulpiride 
Known risk for TdP 
Not available in US 
Meglumine 
antimoniate 
Known risk for TdP 
Not available in US 
Mesoridazine 
Known risk for TdP 
Removed from US market 
Methadone 
Known risk for TdP 
Females>Males 
Mobocertinib 
Known risk for TdP 
 
Moxifloxacin 
Known risk for TdP 
 
Nifekalant 
Known risk for TdP 
Not available in US 
Ondansetron 
Known risk for TdP 
 
Oxaliplatin 
Known risk for TdP 
 
Papaverine HCl 
Known risk for TdP 
Intracoronary 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
Removed from US market 
Procainamide 
Known risk for TdP 
 
Propofol 
Known risk for TdP 
 
Quinidine 
Known risk for TdP 
Females>Males 
Roxithromycin 
Known risk for TdP 
Not available in US 
Sertindole 
Known risk for TdP 
Not available in US 
Sevoflurane 
Known risk for TdP 
 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
Removed from US market 
Sulpiride 
Known risk for TdP 
Not available in US 
Sultopride 
Known risk for TdP 
Not available in US 
Terfenadine 
Known risk for TdP 
Removed from US market 
Terlipressin 
Known risk for TdP 
Not available in US 
Terodiline 
Known risk for TdP 
Not available in US 
Thioridazine 
Known risk for TdP 
 
Vandetanib 
Known risk for TdP 
 
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. Updated versions 
of medications which may prolong the QTc interval may be found at the following website: 
https://crediblemeds.org/index.php/?cID=328    
 
Table 2 List of QT prolonging drugs with a conditional risk to induce Torsades de 
Pointes 
Drug 
QT risk (*) 
Abiraterone 
Conditional risk for TdP 
Amantadine  
Conditional risk for TdP 
Amisulpride (not available in the US) 
Conditional risk for TdP 
Amitriptyline 
Conditional risk for TdP 
Amphotericin B 
Conditional risk for TdP 
Amsacrine (not available in the US) 
Conditional risk for TdP 
Atazanavir 
Conditional risk for TdP 
Bendroflumethiazide or bendrofluazide 
Conditional risk for TdP 
Chloral hydrate 
Conditional risk for TdP 

 
 
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Drug 
QT risk (*) 
Cimetidine 
Conditional risk for TdP 
Clofazimine 
Conditional risk for TdP 
Clomipramine 
Conditional risk for TdP 
Dilitazem 
Conditional risk for TdP 
Diphenhydramine 
Conditional risk for TdP 
Doxepin 
Conditional risk for TdP 
Eperisone (not available in the US) 
Conditional risk for TdP 
Esomeprazole 
Conditional risk for TdP 
Famotidine 
Conditional risk for TdP 
Fluoxetine 
Conditional risk for TdP 
Fluvoxamine 
Conditional risk for TdP 
Furosemide (frusemide) 
Conditional risk for TdP 
Galantamine 
Conditional risk for TdP 
Garenoxacin (not available in the US) 
Conditional risk for TdP 
Hydrochlorothiazide 
Conditional risk for TdP 
Hydroxyzine 
Conditional risk for TdP 
Indapamide 
Conditional risk for TdP 
Itraconazole 
Conditional risk for TdP 
Ivabradine 
Conditional risk for TdP 
Ketoconazole 
Conditional risk for TdP 
Lansoprazole 
Conditional risk for TdP 
Loperamide 
Conditional risk for TdP 
Metoclopramide 
Conditional risk for TdP 
Metolazone 
Conditional risk for TdP 
Metronidazole 
Conditional risk for TdP 
Nelfinavir 
Conditional risk for TdP 
Olanzapine 
Conditional risk for TdP 
Omeprazole 
Conditional risk for TdP 
Pantoprazole 
Conditional risk for TdP 
Paroxetine 
Conditional risk for TdP 
Piperacillin/Tazobactam 
Conditional risk for TdP 
Posaconazole 
Conditional risk for TdP 
Propafenone 
Conditional risk for TdP 
Quetiapine 
Conditional risk for TdP 
Quinine sulfate 
Conditional risk for TdP 
Ranolazine 
Conditional risk for TdP 
Risperidone 
Conditional risk for TdP 
Sertraline 
Conditional risk for TdP 
Solifenacin 
Conditional risk for TdP 
Telaprevir 
Conditional risk for TdP 
Torsemide (Torasemide) 
Conditional risk for TdP 
Trazodone 
Conditional risk for TdP 
Voriconazole 
Conditional risk for TdP 
Ziprasidone 
Conditional risk for TdP  
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. Updated versions 
of medications which may prolong the QTc interval may be found at the following website: 
https://crediblemeds.org/index.php/?cID=328   

 
 
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Table 3 List of QT prolonging drugs with a possible risk to induce Torsades de 
Pointes 
Drug 
QT risk (*) 
Abarelix (not available in the US) 
Possible risk for TdP 
Alfuzosin 
Possible risk for TdP  
Alimemazine (not available in the US) 
Possible risk for TdP 
Apalutamide 
Possible risk for TdP 
Apomorphine 
Possible risk for TdP 
Aripiprazole 
Possible risk for TdP 
Artemether/Lumefantrine 
Possible risk for TdP 
Artenimol+piperaquine (not available in the US) 
Possible risk for TdP 
Asenapine 
Possible risk for TdP 
Atomoxetine 
Possible risk for TdP 
Bedaquiline 
Possible risk for TdP 
Bendamustine 
Possible risk for TdP 
Betrixaban 
Possible risk for TdP 
Bicalutamide 
Possible risk for TdP 
Bortezomib 
Possible risk for TdP 
Bosutinib 
Possible risk for TdP 
Buprenorphine 
Possible risk for TdP 
Cabozantinib 
Possible risk for TdP 
Capecitabine 
Possible risk for TdP 
Carbetocin 
Possible risk for TdP 
Ceritinib 
Possible risk for TdP 
Clotiapine (not available in US) 
Possible risk for TdP 
Clozapine 
Possible risk for TdP 
Cobimetinib 
Possible risk for TdP 
Crizotinib 
Possible risk for TdP 
Cyamemazine (not available in the US) 
Possible risk for TdP 
Dabrafenib 
Possible risk for TdP 
Dasatinib 
Possible risk for TdP 
Degarelix 
Possible risk for TdP 
Delamanid (not available in the US) 
Possible risk for TdP 
Desipramine 
Possible risk for TdP 
Deutetrabenazine 
Possible risk for TdP 
Dexmedetomidine 
Possible risk for TdP 
Dextromethorphan/Quinidine 
Possible risk for TdP 
Dolasetron 
Possible risk for TdP 
Efavirenz 
Possible risk for TdP 
Eliglustat 
Possible risk for TdP 
Encorafenib 
Possible risk for TdP 
Entrectinib 
Possible risk for TdP 
Epirubicin 
Possible risk for TdP 
Eribulin mesylate 
Possible risk for TdP 
Ezogabine (Retigabine) 
Possible risk for TdP 
Felbamate 
Possible risk for TdP 
Fingolimod 
Possible risk for TdP 

 
 
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Drug 
QT risk (*) 
Fluorouracil (5-FU) 
Possible risk for TdP 
Flupentixol (not available in the US) 
Possible risk for TdP  
Gemifloxacin 
Possible risk for TdP 
Gilteritinib 
Possible risk for TdP 
Glasdegib 
Possible risk for TdP 
Granisetron 
Possible risk for TdP 
Hydrocodone - ER 
Possible risk for TdP 
Iloperidone 
Possible risk for TdP 
Imatinib 
Possible risk for TdP 
Imipramine (melipramine) 
Possible risk for TdP 
Inotuzumab ozogamicin 
Possible risk for TdP 
Isradipine 
Possible risk for TdP  
Ivosidenib 
Possible risk for TdP 
Ketanserin (not available in the US) 
Possible risk for TdP 
Lacidipine (not available in the US) 
Possible risk for TdP 
Lapatinib 
Possible risk for TdP 
Lefamulin 
Possible risk for TdP 
Lenvatinib 
Possible risk for TdP 
Leuprolide 
Possible risk for TdP 
Levetiracetam 
Possible risk for TdP 
Levoketoconazole 
 
Levomethadone (not available in the US) 
Possible risk for TdP 
Lithium 
Possible risk for TdP  
Lofexidine 
Possible risk for TdP 
Lopinavir/Ritonavir 
Possible risk for TdP 
Lumateperone 
Possible risk for TdP 
Lurasidone 
Possible risk for TdP 
Maprotiline 
Possible risk for TdP 
Melperone (not available in the US) 
Possible risk for TdP 
Mianserin (not available in the US) 
Possible risk for TdP 
Midostaurin 
Possible risk for TdP 
Mifepristone 
Possible risk for TdP 
Mirabegron 
Possible risk for TdP 
Mirtazapine 
Possible risk for TdP 
Necitumumab 
Possible risk for TdP 
Nicardipine 
Possible risk for TdP 
Nilotinib 
Possible risk for TdP 
Norfloxacin  
Possible risk for TdP 
Nortriptyline 
Possible risk for TdP 
Nusinersen 
Possible risk for TdP 
Ofloxacin 
Possible risk for TdP  
Oliceridine 
Possible risk for TdP 
Osilodrostat 
Possible risk for TdP 
Osimertinib 
Possible risk for TdP 
Oxytocin 
Possible risk for TdP  
Ozanimod 
Possible risk for TdP 
Paliperidone 
Possible risk for TdP 
Palonosetron 
Possible risk for TdP 

 
 
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Drug 
QT risk (*) 
Panobinostat 
Possible risk for TdP 
Pasireotide 
Possible risk for TdP 
Pazopanib 
Possible risk for TdP 
Perflutren lipid microspheres  
Possible risk for TdP 
Perphenazine 
Possible risk for TdP 
Pilsicainide (not available in the US) 
Possible risk for TdP 
Pimavanserin 
Possible risk for TdP 
Pipamperone (not available in the US) 
Possible risk for TdP 
Pilsicainide (not available in the US) 
Possible risk for TdP 
Pitolisant 
Possible risk for TdP 
Ponesimod 
Possible risk for TdP 
Pretomanid 
Possible risk for TdP 
Primaquine phosphate 
Possible risk for TdP 
Promethazine 
Possible risk for TdP 
Prothipendyl (not available in the US) 
Possible risk for TdP 
Relugolix 
Possible risk for TdP 
Remimazolam 
Possible risk for TdP 
Ribociclib 
Possible risk for TdP 
Rilpivirine 
Possible risk for TdP 
Romidepsin 
Possible risk for TdP 
Rucaparib 
Possible risk for TdP 
Saquinavir 
Possible risk for TdP 
Selpercatinib 
Possible risk for TdP 
Siponimod 
Possible risk for TdP 
Sorafenib 
Possible risk for TdP 
Sunitinib 
Possible risk for TdP 
Tacrolismus 
Possible risk for TdP 
Tamoxifen 
Possible risk for TdP 
Tazemetostat 
Possible risk for TdP 
Telavancin 
Possible risk for TdP 
Telithromycin 
Possible risk for TdP 
Tetrabenazine 
Possible risk for TdP 
Tiapride (not available in the US) 
Possible risk for TdP 
Tipiracil and Trifluridine 
Possible risk for TdP 
Tizanidine 
Possible risk for TdP 
Tolterodine 
Possible risk for TdP 
Toremifene 
Possible risk for TdP 
Tramadol 
Possible risk for TdP 
Trimipramine 
Possible risk for TdP 
Tropisetron (not available in the US) 
Possible risk for TdP 
Valbenazine 
Possible risk for TdP 
Vardenafil 
Possible risk for TdP 
Vemurafenib 
Possible risk for TdP 
Venlafaxine 
Possible risk for TdP  
Voclosporin 
Possible risk for TdP 
Vorinostat 
Possible risk for TdP 
Zotepine (not available in the US) 
Possible risk for TdP 
Zuclopenthixol, Zuclopentixol (not available in the US) 
Possible risk for TdP 

 
 
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Drug 
QT risk (*) 
Source: 
(*) Classification according to the Qtdrugs org advisory board of the Arizona CET. Updated versions of 
medications which may prolong the QTc interval may be found at the following website: 
https://crediblemeds.org/index.php/?cID=328  
 
 
Appendix 2 Revised Criteria for Response Assessment 
 
Response and 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Lymph nodes 
and extra-
lymphatic 
sites 
 
 
 
 
 
 
 
 
 
Non-
measured 
lesion 
Organ 
enlargement 
New lesions 
Bone marrow 
Complete metabolic response 
Score 1, 2, or 3 with or without 
a residual mass on 5PS† 
It is recognized that in 
Waldeyer’s ring or extranodal 
sites with high physiologic 
uptake or with activation within 
spleen or marrow (eg, with 
chemotherapy or myeloid 
colony-stimulating factors), 
uptake may be greater than 
normal mediastinum and/or 
liver. In this circumstance, 
complete metabolic response 
may be inferred if uptake at 
sites of initial involvement is no 
greater than surrounding 
normal tissue even if the tissue 
has high physiologic uptake 
Not applicable 
Not applicable 
None 
No evidence of FDG-avid 
disease in marrow 
Complete radiologic response (all 
of the following): 
Target nodes/nodal masses 
must regress to 1.5 cm in LDi 
No extralymphatic sites of 
disease 
 
 
 
 
 
 
 
 
Absent 
Regress to normal 
None 
Normal by morphology; if 
indeterminate, IHC negative 
Partial 
Lymph nodes 
and extra-
lymphatic 
sites 
 
 
 
Partial metabolic response 
Score 4 or 5† with reduced 
uptake compared with baseline 
and residual mass(es) of any 
size 
At interim, these findings 
suggest responding disease 
At end of treatment, these 
Partial remission (all of the 
following) 
> 50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites 
When a lesion is too small to 
measure on CT, assign 5 mm X 
5 mm as the default value 

 
 
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Non-
measured 
lesions 
Organ 
enlargement 
 
New lesions 
Bone marrow 
findings indicate residual 
disease 
 
 
Not applicable 
Not applicable 
 
None 
Residual uptake higher than 
uptake in normal marrow but 
reduced compared with 
baseline (diffuse uptake 
compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in 
the context of a nodal response, 
consideration should be given 
to further evaluation with MRI 
or biopsy or an interval scan 
When no longer visible, 0 X 0 
mm 
For a node > 5 mm X 5 mm, 
but smaller than normal, use 
actual measurement for 
calculation 
Absent/normal, regressed, but 
no increase 
Spleen must have regressed 
by > 50% in length beyond 
normal 
None 
Not applicable 
No response or 
stable disease 
Target 
nodes/nodal 
masses, 
extranodal 
lesions 
Nonmeasured 
lesion 
 Organ 
enlargement 
New lesions 
Bone marrow 
No metabolic response 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
 
 
Not applicable  
Not applicable 
None 
No change from baseline 
Stable disease 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria 
for progressive disease are 
met 
 
No increase consistent with 
progression 
No increase consistent with 
progression 
None 
Not applicable 
Progressive 
disease 
Individual 
target 
nodes/nodal 
masses 
 
Extranodal 
lesions 
 
Progressive metabolic disease 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment 
 
 
 
Progressive disease requires at 
least 1 of the following PPD 
progression: 
 
An individual node/lesion must 
be abnormal with: LDi > 1.5 cm 
and 
Increase by > 50% from PPD nadir 
and  
an increase in LDi or SDi from 

 
 
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Nonmeasured 
lesions 
 
New lesions 
 
 
 
 
 
 
Bone marrow 
 
 
 
 
 
 
 
None 
 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (eg, infection, 
inflammation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered 
 
 
 
New or recurrent FDG-avid foci 
nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, 
the splenic length must increase 
by > 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to 
> 16 cm). If no prior 
splenomegaly, must increase by 
at least 2 cm from baseline 
New or recurrent splenomegaly 
New or clear progression of 
preexisting non-measured lesions  
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in 
any axis; if <  
1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance 
imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular 
diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular 
diameters for multiple lesions. 
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured 
dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters. Nodes should preferably be from disparate 
regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-
nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous 
lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, 
dominant disease and truly assessable disease should be considered not measured. These sites 
include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that 
do not meet the requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal 
disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 

 
 
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Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater 
than in the mediastinum with complete metabolic response, but should be no higher than surrounding 
normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth 
factors). 
†PET 5-Point Scale (5PS): see next Table. 
Score 
18-FDG uptake 
1 
No uptake 
2 
≤ Mediastinal blood pool 
3 
>Mediastinum and ≤ liver  
4 
Moderately > liver at any site 
5 
Markedly1>liver at any site and/or new sites of disease 
X 
New areas of uptake unlikely to be related to lymphoma 

 
 
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