Clinical trial NCT05116683
Conditions: Leiomyosarcoma Liposarcoma
Keywords: LMS LPS ATX-101
Sponsor: Benjamin Izar
Start date: 2022-01-11; Completion date: 2022-10-27
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effectiveness of a new investigational drug, ATX-101, for the treatment of dedifferentiated liposarcoma (LPS) and leiomyosarcoma (LMS). ATX-101 is an intravenous (IV) drug which blocks the interaction of a protein called PCNA with a number of "stress response" proteins. These interactions are thought to be important for cancer cell survival and growth. ATX-101 may disrupt these interactions and therefore help treat the cancer. In this study, all patients will receive the same treatment. Most of the exams, tests, and procedures are part of the usual approach to medical care for this condition. However, some additional tests or procedures may be performed, and other tests may be performed more frequently than usual.

Detailed description:
ATX-101 is a small molecule peptide comprised of a novel human proliferating cell nuclear antigen (PCNA) interacting motif termed APIM coupled to cellular and nuclear delivery domains. PCNA interacts with many cellular proteins and exerts pleiotropic effects in the cancer cell. Proteins that bind to PCNA via APIM are especially important in the cellular stress and DNA damage responses, as well as intracellular signaling, apoptosis, metabolism and anti-tumor immunity. In preclinical studies, ATX-101 demonstrated single-agent activity and potentiated other cytotoxic and targeted agents across multiple cancer models in vitro and in vivo, including LMS and LPS. ATX-101 is currently being evaluated in a phase 1 safety and pharmacokinetic study in solid tumors using a 3 + 3 dose escalation design. As of 10/29/2020, ATX-101 has been evaluated across dose levels of 20 mg/m2 - 60 mg/m2 IV weekly. Although no maximum tolerated dose (MTD) was reached, after review of the available safety data, the RP2D was determined to be 60 mg/m2 IV weekly, with no plans to dose escalate further. ATX-101 has been well tolerated, with no grade 3 or higher adverse events (AEs) observed during the phase 1 study. Common AEs include grade 1/2 infusion related reactions (which have been easily managed with supportive care), mild fatigue and diarrhea. In this study, ATX-101 demonstrated encouraging activity as prolonged disease stabilization in patients with progressive, heavily pre-treated malignancies.

Arms: arm 1: Patients will be treated with ATX-101 60 mg/m2 IV weekly in continuous 21 day cycles. Patients will receive premedication prior to the ATX-101 infusion to reduce the risk of infusion-related reactions.
Interventions: intervention 1: ATX-101
Intervention descriptions: intervention 1: Patients will be given ATX-101 at 60 mg/m2 IV weekly in continuous 21 day cycles.

Protocol documents:
Prot_SAP_000.pdf: 
Herbert Irving Comprehensive Cancer Center Protocol 
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10 
ATX-101 in Sarcoma Phase II 
 
 
For the first stage of enrollment, among the 10 patients enrolled, 5 
patients will have LMS, and 5 patients will have LPS. If the study 
proceeds to the second stage, among the 24 patients subsequently 
enrolled, 12 patients will have LMS and 12 patients will have LPS. 


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1. INTRODUCTION AND RATIONALE 
 
This document is a protocol for a human research study. This study is to be conducted according 
to US and International standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures. 
 
1.1 
Disease Background 
 
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1.2 
ATX-101, a peptide drug targeting PCNA 
 
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1.3 
Rationale for the use of ATX-101 in cancer 
 
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1.4 
Rationale for Selection of Subtypes 
 
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1.5 
Preclinical Experience with ATX-101 
 
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19 
ATX-101 in Sarcoma Phase II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. ATX-101 inhibits phosphorylation of ERK1/2 in liposarcoma and leiomyosarcoma. Western Blot of 
p-RB (Ser780), p-ERK1/2 (Thr202/Tyr204), p-AKT (Ser473) and LC3I/II and cleaved PARP is shown. 
GAPDH was used as a loading control. Cells were treated with 10µM ATX-101 for 72 hours. Briefly, 
leiomyosarcoma cell lines (SK-LMS, SK-UT1 and SK-UT1b) and liposarcoma cell lines (LS141, DDLS, 
CDK4/6 Res.DDLS) were treated and lysates were collected in RIPA buffer. Protein concentrations were 
determined and 20μg of protein were loaded onto an SDS/PAGE gradient gel and immunoblotted using 
indicated antibodies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. ATX-101 treatment affects the cell cycle in liposarcoma cell lines. Increase of G2 phase of the cell 
cycle in DDLS and induction of subG1 in Res. DDLS was observed with treatment. Briefly, propidium iodide 
DNA staining was performed on liposarcoma cell lines (DDLS and Res. DDLS) cells after 24 hours of 10µM 
ATX-101 treatment. Cells were fixed in 70% ethanol and stored at –20° C. Cells were then labeled with MPM-2 
antibody (mitotic marker) and followed by a secondary antibody anti-mouse Alex-488. Bi-parameter flow 
cytometry was performed on a Becton Dickinson LSRII flow cytometer. Data analysis was done using FCS 
Express 7 software. 


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Event (Preferred Term) 
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5.2 
Exclusion Criteria 
 
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6. REGISTRATION PROCEDURES 
 
6.1 
CUMC Research Participant Registration 
 
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All participants must be centrally registered through the Central Registration Office 
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treatment. 
 
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TREATMENT PLAN 
 
7.1 
Agent Administration 
 
REGIMEN DESCRIPTION 
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Infusion Rate Table 
 
Infusion 
Rate 
(mg/hr) 
Infusion 
Time (min) 
Cumulative 
Infusion 
Time 
(min) 
Dose Infused for 
timepoint (mg) 
Cumulative 
Dose infused 
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7.2 
General Concomitant Medication and Supportive Care Guidelines 
 
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7.3 
Duration of Therapy 
 
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7.4 
Duration of Follow Up 
 
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7.5 
Approach to COVID-19 Related Treatment Interruptions 


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8. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
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8.1 
Dose Levels 


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Dose Level 
ATX-101 Dose 
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8.2 
Management Guidelines for Non-Hematologic Adverse Events 
 
Management of Infusion-Related Reactions 
 
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Grade 
Modifications of AXT-101 
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Management of Other Non-Hematologic Toxicity 
 
All Other Non- 
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Management/Next Dose for ATX-101 
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Treatment delay 
Dose Modification 
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8.3 
Management Options for Hematologic Adverse Events 
 
Neutropenia 
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9. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
9.1 
Adverse events 
 
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Treatment related treatment emergent adverse events observed in study AM ATX101-01 (31 October 
2020) 
 
 
Event (Preferred Term) 
Cohort 1 
20 mg/m² 
(n=8) 
Cohort 2 
30 mg/m² 
(n=3) 
Cohort 3 
45 mg/m² 
(n=4) 
Cohort 4 
60 mg/m² 
(n=6) 
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Treatment related treatment emergent adverse events observed at least twice in study AM ATX101- 
01 (31 October 2020) 
 
Event (Preferred Term) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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9.2 
Definitions 
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9.3 
Recording of Adverse Events 
 
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9.4 
Reporting of Serious Adverse Events 
 
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9.5 
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10. 
PHARMACEUTICAL INFORMATION 
 
10.1 
Investigational Product 
 
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Receipt of Investigational Product 
 
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10.7 
Destruction and Return of Investigational Product 
 
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11. 
STUDY CALENDAR 
 
 
 
 
 
 
 
Procedure 
 
 
Screening 
(1) 
 
Cycle 1(8)  
Cycle 2 (8)  
Cycle 3 + (8) 
End of 
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MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
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12.2 
Disease Parameters 
 
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12.3 
Methods for Evaluation of Measurable Disease 


51 
ATX-101 in Sarcoma Phase II 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ³ 10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 


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12.9 
Stopping Rules 
 
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13. CORRELATIVE STUDIES 
 
13.1 
Tissue procurement and Handling 
 
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Data Collection 
 
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14.3 
Data and Safety Monitoring Committee 
 
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14.4 
Quality Control and Quality Assurance 
 
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14.5 
Confidentiality 
 
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14.6 
Source Documents 
 
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14.7 
Case Report Forms 
 
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14.8 
Records Retention 
 
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15. 
STATISTICAL PLAN 
 
15.1 
Primary Endpoint 
 
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15.2 
Size/Accrual Rate 
 
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15.3 
Stratification Factors 
 
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15.4 
Analysis of Secondary Endpoints 
 
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15.5 
Analysis of Correlative Science Endpoints 
 
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15.6 
Reporting and Exclusions 
 
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16. 
PROTECTION OF HUMAN SUBJECTS 
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17. STUDY FINANCES 
 
17.1 
Conflict of Interest 
 
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17.2 
Subject Stipends or Payments 
 
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18. PUBLICATION PLAN 
 
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19. CITED REFERENCES 
 
 
 
'HPHWUL*'HWDOEfficacy and Safety of Trabectedin or Dacarbazine for Metastatic 
Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results 
of a Phase III Randomized Multicenter Clinical Trial. -&OLQ2QFRO34S

 
6FKRIIVNL3HWDOEribulin versus dacarbazine in previously treated patients with 
advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 
3 trial. /DQFHW387S
 
SEER Cancer Stat Facts: Soft Tissue Cancer. >FLWHG@$YDLODEOHIURP
KWWSVVHHUFDQFHUJRYVWDWIDFWVKWPOVRIWKWPO
 
0DNL5*HWDORandomized phase II study of gemcitabine and docetaxel compared 
with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of 
sarcoma alliance for research through collaboration study 002 [corrected]. -&OLQ2QFRO
25S
 
YDQGHU*UDDI:7$HWDOPazopanib for metastatic soft-tissue sarcoma (PALETTE): 
a randomised, double-blind, placebo-controlled phase 3 trial. 7KH/DQFHW
379S
 
6FK|IIVNL3HWDOEribulin versus dacarbazine in previously treated patients with 
advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 
3 trial. 7KH/DQFHW387S
 
.ULVKQD765HWDOCrystal structure of the eukaryotic DNA polymerase processivity 
factor PCNA. &HOO79S
 
:\PDQ&DQG0%RWFKDQDNA Replication: A familiar ring to DNA polymerase 
processivity. &XUUHQW%LRORJ\5S
 
0DLODQG1,*LEEV6H\PRXUDQG6%HNNHU-HQVHQRegulation of PCNA-protein 
interactions for genome stability. 1DW5HY0RO&HOO%LRO14S
10. 
0ROGRYDQ*/%3IDQGHUDQG6-HQWVFKPCNA, the maestro of the replication fork. 
&HOO129S
 
1DU\]KQ\61DQG+/HHProliferating cell nuclear antigen in the cytoplasm interacts 
with components of glycolysis and cancer. )(%6/HWW584S
 
2ODLVHQ&HWDOPCNA-interacting peptides reduce Akt phosphorylation and TLR- 
mediated cytokine secretion suggesting a role of PCNA in cellular signaling. &HOO6LJQDO
27S
 
5RVHQWDO%HWDOProliferating cell nuclear antigen is a novel inhibitory ligand for the 
natural cytotoxicity receptor NKp44. -,PPXQRO187S
 
:LWNR6DUVDW9HWDOProliferating cell nuclear antigen acts as a cytoplasmic platform 
controlling human neutrophil survival. -([S0HG207S
 
:DUEULFN(PCNA binding through a conserved motif. %LR(VVD\V20S

 
*LOOMDP.0HWDOIdentification of a novel, widespread, and functionally important 
PCNA-binding motif. -&HOO%LRO186S
 
%DFTXLQ$HWDOThe helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)- 
mediated proteolysis in human cells. 1XFOHLF$FLGV5HV41S


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&LFFLD$HWDOPolyubiquitinated PCNA recruits the ZRANB3 translocase to maintain 
genomic integrity after replication stress. 0RO&HOO47S
 
)DWWDK)-HWDOThe transcription factor TFII-I promotes DNA translesion synthesis 
and genomic stability. 3/R6*HQHW10SH
 
*LOOMDP.0HWDONucleotide excision repair is associated with the replisome and its 
efficiency depends on a direct interaction between XPA and PCNA. 3/R62QH
7SH
 
$DV3$HWDOHuman and bacterial oxidative demethylases repair alkylation damage 
in both RNA and DNA. 1DWXUH421S
 
*HGHUDDV2$HWDOIncreased Anticancer Efficacy of Intravesical Mitomycin C 
Therapy when Combined with a PCNA Targeting Peptide. 7UDQVO2QFRO7S

 
6RJDDUG&.HWDOAPIM-peptide targeting PCNA improves the efficacy of docetaxel 
treatment in the TRAMP mouse model of prostate cancer. 2QFRWDUJHW9S

 
6RJDDUG&.HWDOTargeting the non-canonical roles of PCNA modifies and increases 
the response to targeted anti-cancer therapy. 2QFRWDUJHW10S
 
5DHGHU6%HWDOAPIM-Mediated REV3L(-)PCNA Interaction Important for Error 
Free TLS Over UV-Induced DNA Lesions in Human Cells. ,QW-0RO6FL20
 
0XOOHU5HWDOTargeting proliferating cell nuclear antigen and its protein interactions 
induces apoptosis in multiple myeloma cells. 3/R62QH8SH
 
2]D-HWDOHomologous recombination repair deficiency as a therapeutic target in 
sarcoma. 6HPLQ2QFRO47S
 
9DQ*ODEEHNH0HWDOProgression-free rate as the principal end-point for phase II 
trials in soft-tissue sarcomas. (XURSHDQ-RXUQDORI&DQFHU38S
 
'LFNVRQ0$HWDOPhase 2 study of the CDK4 inhibitor abemaciclib in 
dedifferentiated liposarcoma. -RXUQDORI&OLQLFDO2QFRORJ\37BVXSSOS

 
'LFNVRQ0$HWDOProgression-Free Survival Among Patients With Well- 
Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor 
Palbociclib: A Phase 2 Clinical Trial. -$0$2QFRO2S
 
'LFNVRQ0$HWDOPhase II trial of the CDK4 inhibitor PD0332991 in patients with 
advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. -&OLQ
2QFRO31S
 
6OHLMIHU6HWDOPazopanib, a multikinase angiogenesis inhibitor, in patients with 
relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European 
organisation for research and treatment of cancer-soft tissue and bone sarcoma group 
(EORTC study 62043). -&OLQ2QFRO27S
 
6LPRQ5Optimal two-stage designs for phase II clinical trials. &RQWURO&OLQ7ULDOV
10S