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NCT01004861

Safety Study of PLX108-01 in Patients With Solid Tumors

Completed Phase 1 Results posted Last updated 4 January 2022
What this trial tests

Phase 1 trial testing PLX3397 in Solid Tumor in 132 participants. Completed in 25 October 2018.

Timeline
1 October 2009
Primary endpoint
31 January 2018
25 October 2018

Quick facts

Lead sponsorDaiichi Sankyo
PhasePhase 1
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment132
Start date1 October 2009
Primary completion31 January 2018
Estimated completion25 October 2018
Sites13 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Daiichi Sankyo — full company profile →

Who can join

18 and older, any sex, with Solid Tumor. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Escalation (Efficacy Evaluable Population) Primary · Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)

Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameter

Censored participants
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD0
Dose Escalation Cohort 2: 300 mg QD1
Dose Escalation Cohort 3: 400 mg QD2
Dose Escalation Cohort 4: 600 mg QD0
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)3
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)0
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)3
All Participants9
CR
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD0
Dose Escalation Cohort 2: 300 mg QD0
Dose Escalation Cohort 3: 400 mg QD0
Dose Escalation Cohort 4: 600 mg QD0
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)0
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)0
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)0
All Participants0
PR
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD0
Dose Escalation Cohort 2: 300 mg QD0
Dose Escalation Cohort 3: 400 mg QD0
Dose Escalation Cohort 4: 600 mg QD0
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)0
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)0
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)1
All Participants1
SD
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD0
Dose Escalation Cohort 2: 300 mg QD1
Dose Escalation Cohort 3: 400 mg QD0
Dose Escalation Cohort 4: 600 mg QD2
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)3
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)1
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)1
All Participants8
PD
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD3
Dose Escalation Cohort 2: 300 mg QD4
Dose Escalation Cohort 3: 400 mg QD3
Dose Escalation Cohort 4: 600 mg QD3
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)2
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)4
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)3
All Participants22
NE
GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD0
Dose Escalation Cohort 2: 300 mg QD0
Dose Escalation Cohort 3: 400 mg QD2
Dose Escalation Cohort 4: 600 mg QD0
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)1
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)0
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)1
All Participants4
Summary of Derived Best Tumor Response Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension (Efficacy Evaluable Population) Primary · Every 2 months beginning Cycle 3, Day 1 until disease progression (up to approximately 30 months postdose)

Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameter

CR
GroupValue95% CI
Dose Extension: MEC Cohort0
Dose Extension: PVNS Cohort2
Dose Extension: GIST Cohort0
Dose Extension: ATC Cohort0
Dose Extension: Malignant Effusion Cohort0
Dose Extension: Other Solid Tumor Type Cohort0
PR
GroupValue95% CI
Dose Extension: MEC Cohort0
Dose Extension: PVNS Cohort22
Dose Extension: GIST Cohort0
Dose Extension: ATC Cohort0
Dose Extension: Malignant Effusion Cohort0
Dose Extension: Other Solid Tumor Type Cohort1
SD
GroupValue95% CI
Dose Extension: MEC Cohort1
Dose Extension: PVNS Cohort8
Dose Extension: GIST Cohort4
Dose Extension: ATC Cohort0
Dose Extension: Malignant Effusion Cohort3
Dose Extension: Other Solid Tumor Type Cohort7
PD
GroupValue95% CI
Dose Extension: MEC Cohort1
Dose Extension: PVNS Cohort1
Dose Extension: GIST Cohort5
Dose Extension: ATC Cohort6
Dose Extension: Malignant Effusion Cohort2
Dose Extension: Other Solid Tumor Type Cohort6
NE
GroupValue95% CI
Dose Extension: MEC Cohort0
Dose Extension: PVNS Cohort4
Dose Extension: GIST Cohort0
Dose Extension: ATC Cohort0
Dose Extension: Malignant Effusion Cohort1
Dose Extension: Other Solid Tumor Type Cohort0
Overall response rate (CR or PR)
GroupValue95% CI
Dose Extension: MEC Cohort0
Dose Extension: PVNS Cohort24
Dose Extension: GIST Cohort0
Dose Extension: ATC Cohort0
Dose Extension: Malignant Effusion Cohort0
Dose Extension: Other Solid Tumor Type Cohort1
Duration of Response (Efficacy Evaluable Population) - Dose Extension Primary · From initial response until disease progression or death, up to approximately 30 months postdose

Duration of Response (DOR) is defined as the number of days from the date of initial response (CR or PR confirmed at least 28 days later) to the date of first documented disease progression/relapse or death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, DOR is censored as of the date of their last imaging exam of target or non-target lesions prior to post-surgery and/or off-treatment scans.

GroupValue95% CI
Dose Extension: PVNS CohortNA943 – NA
Dose Extension: Other Solid Tumor Type Cohort115NA – NA
Progression-free Survival (Efficacy Evaluable Population) - Dose Extension Primary · From Cycle 1 Day 1 to disease progression or death

Progression-Free Survival (PFS) is defined as the number of days from the first day of treatment to the first documented disease progression or date of death, whichever occurs first. If no disease progression or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, PFS is censored at the date of last evaluable tumor assessment.

GroupValue95% CI
Dose Extension: MEC CohortNA43 – NA
Dose Extension: PVNS CohortNA667 – NA
Dose Extension: GIST Cohort5440 – 164
Dose Extension: ATC Cohort5034 – 56
Dose Extension: Malignant Effusion Cohort7851 – NA
Dose Extension: Other Solid Tumor Type Cohort16154 – 504
Best Overall Tumor Response (PVNS Cohort) Per the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 - Dose Extension Primary · Every 2 months beginning Cycle 3, Day 1 until disease progression

Best overall tumor response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) is reported, including participants who were not evaluable (NE). RECIST v1.1 for target lesions are assessed by magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography and are summarized as: CR, Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm; PR, At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameter

CR
GroupValue95% CI
PVNS Cohort2
PR
GroupValue95% CI
PVNS Cohort22
SD
GroupValue95% CI
PVNS Cohort8
PD
GroupValue95% CI
PVNS Cohort1
NE
GroupValue95% CI
PVNS Cohort4
Overall response rate (CR or PR)
GroupValue95% CI
PVNS Cohort24
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Cmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation Primary · Cycle 1, Day 15

Cycle 1 Day 15 pharmacokinetic (PK) timepoints taken are: For once daily (QD) dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For twice a day (BID) dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.

GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD17301460 – 2900
Dose Escalation Cohort 2: 300 mg QD36301360 – 5300
Dose Escalation Cohort 3: 400 mg QD31602140 – 5210
Dose Escalation Cohort 4: 600 mg QD65704000 – 14300
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)62905520 – 10400
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)106005070 – 12500
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)63205920 – 10100
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Tmax, Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation Primary · Cycle 1, Day 15

Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.

GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD2.001.08 – 4.00
Dose Escalation Cohort 2: 300 mg QD1.970.58 – 2.03
Dose Escalation Cohort 3: 400 mg QD0.980.50 – 2.20
Dose Escalation Cohort 4: 600 mg QD1.040.50 – 2.03
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)2.000 – 2.03
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)1.051.00 – 4.17
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)2.030 – 6.95
Summary Statistics for Selected PLX3397 Pharmacokinetics Parameter Area Under the Curve (AUC0-24), Study Day Cycle 1 Day 15, Stratified by Cohort - Dose Escalation Primary · Cycle 1, Day 15 (QD dosing: predose [morning] and 0.5, 1, 2, 4, and 8 hours postdose; BID dosing: predose [morning] and 1, 2, 4, and 7 hours postdose)

Cycle 1 Day 15 PK timepoints taken are: For QD dosing, obtained predose (morning) and 0.5, 1, 2, 4, and 8 hours postdose. For BID dosing, predose (morning) and 1, 2, 4, and 7 hours postdose. The second dose will then be administered, and PK obtained 1 hour post the second dose (8 hours post the first dose). For BID dosing, no run-in is planned.

GroupValue95% CI
Dose Escalation Cohort 1: 200 mg QD2620013200 – 37100
Dose Escalation Cohort 2: 300 mg QD5040019500 – 83100
Dose Escalation Cohort 3: 400 mg QD4050029500 – 57300
Dose Escalation Cohort 4: 600 mg QD8100074300 – 166000
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)10700068400 – 139000
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)17300080200 – 190000
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)115000105000 – 226000
Numeric Rating Scale (NRS) for PVNS Symptoms Sum of Scores Through Cycle 2 (Efficacy Evaluable Population) - Dose Extension Primary · Baseline, Cycle 1 Day 15, Cycle 2, Cycle 3, Cycle 12, Cycle 24, Cycle 36, and Cycle 46 (each cycle was 28 days)

The NRS for PVNS Symptoms instrument is a 5-item self-administered questionnaire to assess the "worst" of each of the symptoms pain, swelling, stiffness, instability and limited motion in the last 24 hours. A 0 to 10 NRS is provided for each symptom. For pain, 0 indicates "no pain" and 10 indicates "pain as bad as you can imagine". For the other 4 symptoms, 0 indicates "no (symptom)" and 10 indicates "(symptom) worst imaginable", e.g., "swelling - worst imaginable." Higher scores indicated worse outcome.

Pain; Baseline
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population5.2± 2.1
Pain; Cycle 1 Day 15
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population3.5± 2.9
Pain; Cycle 2
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population3.6± 2.6
Pain; Cycle 3
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population2.3± 1.9
Pain; Cycle 12
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population1.3± 1.8
Pain; Cycle 24
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population1.5± 1.4
Pain; Cycle 36
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population2.0± 2.8
Pain; Cycle 46
GroupValue95% CI
NRS for PVNS Symptoms Evaluable Population1.8± 2.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events (and serious adverse events) were recorded from the time the participant received the first dose of study drug up to 30 days after the last dose, up to approximately 30 months postdose.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Dose Escalation Cohort 1: 200 mg QD
Serious: 0/3 (0%)
Deaths: 0/3
Dose Escalation Cohort 2: 300 mg QD
Serious: 1/6 (17%)
Deaths: 1/6
Dose Escalation Cohort 3: 400 mg QD
Serious: 0/6 (0%)
Deaths: 1/6
Dose Escalation Cohort 4: 600 mg QD
Serious: 0/6 (0%)
Deaths: 0/6
Dose Escalation Cohort 5: 900 mg/Day (500mg AM, 400mg PM)
Serious: 1/7 (14%)
Deaths: 0/7
Dose Escalation Cohort 6: 1200 mg/Day (600mg BID)
Serious: 1/6 (17%)
Deaths: 1/6
Dose Escalation Cohort 7: 1000 mg/Day (500mg BID)
Serious: 3/7 (43%)
Deaths: 0/7
MEC Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 2/4 (50%)
Deaths: 1/4
PVNS Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 5/39 (13%)
Deaths: 0/39
GIST Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 4/11 (36%)
Deaths: 3/11
ATC Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 1/9 (11%)
Deaths: 1/9
Malignant Effusion Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 2/8 (25%)
Deaths: 1/8
Other Solid Tumor Type Cohort 1000 mg/Day (600mg AM, 400mg PM)
Serious: 3/20 (15%)
Deaths: 1/20

Serious adverse events (29 terms)

ReactionSystemDose Escalation Cohort 1: …Dose Escalation Cohort 2: …Dose Escalation Cohort 3: …Dose Escalation Cohort 4: …Dose Escalation Cohort 5: …Dose Escalation Cohort 6: …Dose Escalation Cohort 7: …MEC Cohort 1000 mg/Day (60…PVNS Cohort 1000 mg/Day (6…GIST Cohort 1000 mg/Day (6…ATC Cohort 1000 mg/Day (60…Malignant Effusion Cohort …Other Solid Tumor Type Coh…
HyponatraemiaMetabolism and nutrition disorders
Neck painMusculoskeletal and connective tissue disorders
PneumoniaInfections and infestations
CellulitisInfections and infestations
Clostridium difficile colitisInfections and infestations
DehydrationMetabolism and nutrition disorders
HypoglycaemiaMetabolism and nutrition disorders
HypomagnesaemiaMetabolism and nutrition disorders
AscitesGastrointestinal disorders
HaematocheziaGastrointestinal disorders
Small intestinal obstructionGastrointestinal disorders
Acute respiratory failureRespiratory, thoracic and mediastinal disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
Pleural effusionRespiratory, thoracic and mediastinal disorders
CholecystitisHepatobiliary disorders
Hepatic haemorrhageHepatobiliary disorders
Febrile neutropeniaBlood and lymphatic system disorders
Transaminases increasedInvestigations
Renal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Cerebrovascular accidentNervous system disorders
Renal failure acuteRenal and urinary disorders
Mental status changesPsychiatric disorders
Deep vein thrombosisVascular disorders
SepsisInfections and infestations
DiarrhoeaGastrointestinal disorders
Other adverse events (284 terms — click to expand)

ReactionSystemDose Escalation Cohort 1: …Dose Escalation Cohort 2: …Dose Escalation Cohort 3: …Dose Escalation Cohort 4: …Dose Escalation Cohort 5: …Dose Escalation Cohort 6: …Dose Escalation Cohort 7: …MEC Cohort 1000 mg/Day (60…PVNS Cohort 1000 mg/Day (6…GIST Cohort 1000 mg/Day (6…ATC Cohort 1000 mg/Day (60…Malignant Effusion Cohort …Other Solid Tumor Type Coh…
FatigueGeneral disorders
Hair colour changesSkin and subcutaneous tissue disorders
NauseaGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
DysgeusiaNervous system disorders
Periorbital oedemaSkin and subcutaneous tissue disorders
Oedema peripheralGeneral disorders
VomitingGastrointestinal disorders
PruritusSkin and subcutaneous tissue disorders
HeadacheNervous system disorders
RashSkin and subcutaneous tissue disorders
HypophosphataemiaMetabolism and nutrition disorders
ConstipationGastrointestinal disorders
DizzinessNervous system disorders
Pain in extremityMusculoskeletal and connective tissue disorders
AnaemiaBlood and lymphatic system disorders
Decreased appetiteMetabolism and nutrition disorders
Alanine aminotransferase increasedInvestigations
Aspartate aminotransferase increasedInvestigations
ErythemaSkin and subcutaneous tissue disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
HypertensionVascular disorders
CoughRespiratory, thoracic and mediastinal disorders
InsomniaPsychiatric disorders
Skin hypopigmentationSkin and subcutaneous tissue disorders
Cognitive disorderNervous system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
Joint swellingMusculoskeletal and connective tissue disorders
Face oedemaGeneral disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
Upper respiratory tract infectionInfections and infestations
Vision blurredEye disorders
Weight increasedInvestigations
Mucosal inflammationGeneral disorders
Blood alkaline phosphatase increasedInvestigations
Dry skinSkin and subcutaneous tissue disorders
DyspepsiaGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders

Most-reported serious reactions: Hyponatraemia, Neck pain, Pneumonia, Cellulitis, Clostridium difficile colitis, Dehydration, Hypoglycaemia, Hypomagnesaemia.

Data from ClinicalTrials.gov NCT01004861 adverse events section.

Sponsor's own description

PLX3397 is a selective inhibitor of Fms, Kit, and oncogenic Flt3 activity. The primary objective of this study is to evaluate the safety and pharmacokinetics of orally administered PLX3397 in patients with advanced, incurable, solid tumors in which these target kinases are linked to disease pathophysiology. The secondary objective is to measure the pharmacodynamic activity of PLX3397 via blood, plasma and urine biomarkers of Fms activity.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Tumour-associated macrophages as treatment targets in oncology.
    Mantovani A, Marchesi F, Malesci A, Laghi L, et al · · 2017 · cited 3104× · PMID 28117416 · DOI 10.1038/nrclinonc.2016.217
  2. Macrophages and therapeutic resistance in cancer.
    Ruffell B, Coussens LM. · · 2015 · cited 1235× · PMID 25858805 · DOI 10.1016/j.ccell.2015.02.015
  3. Immune cell promotion of metastasis.
    Kitamura T, Qian BZ, Pollard JW. · · 2015 · cited 916× · PMID 25614318 · DOI 10.1038/nri3789
  4. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy.
    Cannarile MA, Weisser M, Jacob W, Jegg AM, et al · · 2017 · cited 796× · PMID 28716061 · DOI 10.1186/s40425-017-0257-y
  5. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.
    Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, et al · · 2015 · cited 439× · PMID 26222558 · DOI 10.1056/nejmoa1411366
  6. Targeting Macrophages in Cancer: From Bench to Bedside.
    Poh AR, Ernst M. · · 2018 · cited 378× · PMID 29594035 · DOI 10.3389/fonc.2018.00049
  7. Resistance Mechanisms to Anti-angiogenic Therapies in Cancer.
    Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, et al · · 2020 · cited 288× · PMID 32175278 · DOI 10.3389/fonc.2020.00221
  8. TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy.
    Shiao SL, Ruffell B, DeNardo DG, Faddegon BA, et al · · 2015 · cited 222× · PMID 25716473 · DOI 10.1158/2326-6066.cir-14-0232

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