Quality Control Efforts in a Large-scale, Preclinical ...€¦ · Rhabdomyosarcoma, NOS. 2;...
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Osteosarcoma Quality Control Efforts in a Large-scale, Preclinical Trial of Rare Cancer PDXs by The National Cancer Institute’s Patient-Derived Models Repository (PDMR) Y A Evrard 1 , B Das 2 , SY Alcoser 3 , S Borgel 1 , D Breen 1 , J Carter 1 , T Chase 1 , A Chen 4 , L Chen 2 , K Cooley 1 , E Delaney 1 , R Divelbiss 1 , L. Dutko 2 , T Forbes 2 , K Georgius 1 , MM Gottholm-Ahalt 3 , T Grinnage-Pulley 3 , S Hoffman 1 , C Karlovich 2 , S. Jiwani 2 , J. Mills 1 , M Morris 1 , M Mullendore 1 , D Newton 1 , R Patidar 2 , G Rivera 2 , H Stotler 1 , J Stottlemyer 1 , S Styers 1 , D Trail 1 , S Uzelac 1 , T Vilimas 2 , A Walke 1 , T Walsh 1 , NE Walters 1 , P Wang 2 , PM Williams 2 , MG Hollingshead 3 , JH Doroshow 4 1 Applied Development and Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; 2 Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; 3 Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD 21702; 4 Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20892 Overview The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https ://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with 39 PDX models of rare cancers (table below) treated with 56 novel therapeutic combinations in an exploratory, n-of-4 arm, study to identify novel therapeutic combinations for these underserved cancers. Combinations that show regression or durable inhibition of tumor growth are repeated along with the single agents to determine if the response is driven by the combination or one of the agents. To do this in a timely manner, the PDX tumors are serially passaged and each passage is treated with a set of 8 combinations plus relevant vehicle control(s); in parallel sufficient PDXs are retained to be expanded for the next passage and drug set. Every serial passage undergoes several quality control assessments that serve as go/no-go criteria, including pathology assessment, human:mouse DNA content assessment, and low pass whole genome sequencing to determine the average fraction of genome changed compared to the original donor material. If there is a QC failure, the PDX model is restarted from early passage cryo-material (passage 1- 2). We also bookend the combination studies with the first set of agents to see if tumor response is similar across passages, a reflection of the inherent heterogeneity of the models. To date, most of the models have demonstrated a high degree of genomic, histopathologic, and response stability, though a couple of models have moved toward murine content and have been restarted from early passage. DNA and RNA are retained from all passages so a full NGS evaluation can be performed. Single agent studies of drug combinations that demonstrated a response in 30%- 50% of the models conducted are also underway to determine which combinations have a more than additive effect compared to the single agents. Promising combinations will be evaluated in clinical trials at the NCI in patients with these rare cancers. Active combinations are repeated against each single agent; examples are shown below. Single agents and the combination are tested to determine if response is driven by one agent or an additive or synergistic effect. Low-Pass Whole Genome Sequencing (LP-WGS) and Percent Human Tumor Content (%Hu) Assessment Summary • Due to the large study size, a visual assessment of depth and durability of response was used to fast-track drug combinations for single-agent follow-up studies. • Bookend studies indicate some variability in consistency of response across passages. Further analysis including increased numbers of drug studies with bookends and NGS of tumor material from the studies will be performed to identify any underlying factors. • Overall genome heterogeneity of models across passages is consistent with the intra-model heterogeneity observed at baseline by low-pass whole genome sequence assessment. • Single agent studies are beginning to identify drug combinations with increased efficacy over single agents. Combinations where this holds in a larger percentage of all models, or within a specific rare disease type, will be moved forward to full efficacy and biomarker studies. Compare Single Agent to Combination Bookend Drug Response Comparison This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. These studies were conducted on an Institutional Animal Care and Use Committee approved protocol. In addition to genomic and histopathologic QC assessments, a QC metric for response across passages was also implemented. Once all drug combinations have been tested, the first set of drugs tested are repeated (average: +8 passages) to determine if a higher passage tumor has an altered response compared to the initial study. These bookend studies are underway for several models. As seen below in the first bookend studies to be completed, most therapeutic combinations have a very consistent response across passages while specific model/therapeutic combinations (red arrows) have an altered response (growth delay vs progressive growth). More studies will be needed to determine if there is a pattern between altered response across passages and genomic characteristics, mechanism of action of the therapeutics, patient clinical history, and/or histology. Visual Assessment of Response to Fast-Track Single-Agent Follow-up Studies Original Study Bin 1 CR Achieved, >1 timepoint (<60mm 3 ) Bin 2 Tumor regressed ~30%, durable response (~1 cy) Bin 3 Tumor regressed ~30% >1 timepoint, regrew at drug removal Bin 4 Tumor stasis, durable response (~1 cy) Bin 5 Tumor stasis, regrew at drug removal Bin 6 Slowed, but Progressive Growth Bin 7 Grew at Same Rate as Control 1. Where in vivo data for NSG hosts was not available, toxicity testing for single and combination agents was performed 2. Test novel therapeutic combinations (n-of-4) with vehicle controls (n-of-12). Monitor until tumor is ≥1000 mm 3 • 39 models x 56 combinations = 2184 unique data sets • Serial passaging required • QC of material at every passage by Low Pass WGS, pathology review, STR profiling, and %human DNA by qRT-PCR • Body weight monitored throughout for toxicity 3. If a response is observed with the combination in several models, repeat the study and include single agent arms to determine if response is driven by a single agent or possible additive/synergistic effect 4. For combinations that have additive/synergistic affects, perform a full efficacy study with planned sampling for biomarker exploration and PK Overall Study Design DONORs Pn+1 Pn+2 Pn+3 Pn+4 Pn+5 REF Material QC QC QC QC Bookend: Repeat First Drug Set Set-up for Each Passage 100 NSG hosts Implanted 40 for Drug Study (Randomized) 5-10 PDXs For Passage QC 10 Donors (Randomized) For Next Passage PDX Growth to ~200mm 3 Qualitative Visual Assessment •Tumor volume curves are visually assessed while drug study is on-going to determine trend of response •Binning of visual assessment is used to categorize response. Combinations that are active in 30%-50% of the models are prioritized for single-agent testing •Pie charts represent visual response assessment of all models treated with therapeutic combinations, irrespective of histology • All studies maintained until subcutaneous tumor burden is ≥1000 mm 3 at which point quantitative response assessment will be performed TKi + EGFRi (n=9) VEGFi + EGFRi (n=37) TKi + Cytotoxic (n=37) CDK5/6i + Cytotoxic (n=19) AKTi + MEKi (n=33) Combination better than single agents Single agent driving response Rare Cancer PDX Models in Study Diagnoses Number of Models Carcinosarcoma of the uterus 3 Ewing sarcoma/Peripheral PNET 3 Liposarcoma 3 Malig. periph. nerve sheath tum. 3 Merkel cell tumor 3 Neuroendocrine cancer, NOS 3 Osteosarcoma 3 Salivary gland cancer 3 Synovial sarcoma 3 Gastrointestinal stromal tumor 2 Mesothelioma 2 Rhabdomyosarcoma, NOS 2 Adenocarcinoma - anal 1 Adenocarcinoma - small intest. 1 Alveolar soft part sarcoma 1 Hurthle cell neoplasm (thyroid) 1 Penile squamous car.(epidermoid) 1 Small Cell Lung Cancer 1 Fraction of genome changed between two samples is defined as the fraction of altered genomic regions with relative copy number changes >0.4 (log2 ratio, 1.32 ploidy). Baseline distribution is determined by the average and standard deviation of fraction of genome changed from intra-model pairwise comparison of REF Material samples. For QC material, fraction of genome changed is assessed at each passage versus REF Material samples. Table represents average QC metrics for all passages where at least 4 serial passages had been assessed versus baseline REF material. Overall genome heterogeneity of models across passages is consistent with the intra-model heterogeneity observed at baseline (REF Material Only) by LP-WGS assessment. • RT-PCR performed as described in Alcoser et al. (Biotechnology, 2011. PMID: 22176647) • Low Pass WGS: Mouse read removal, BBSplit; Copy Number detection, CNVkit, 1 Mbp bin size Diagnosis REF Material Passage * Highest Passage On-Study* Avg %Hu (RT-PCR) STDEV #QC Sets Assessed Avg, %Genome Changed vs REF Material (LP-WGS) STDEV #QC Sets Assessed Avg, %Genome Changed REF Material Only (LP-WGS) STDEV Synovial sarcoma 2 6 83.70 6.38 5 0.00 0.000 2 0.00 0.000 Ewing sarcoma/Peripheral PNET 2 7 92.34 4.69 5 0.10 0.001 2 0.00 0.000 Carcinosarcoma of the uterus 2 10 82.21 10.52 9 0.15 0.001 6 0.00 0.000 Merkel cell tumor 2 7 88.52 11.30 6 0.32 0.002 3 0.50 0.006 Mesothelioma 2 6 70.68 12.07 5 0.75 0.006 2 0.29 0.002 Ewing sarcoma/Peripheral PNET 2 11 94.72 3.64 10 1.00 0.008 5 0.50 0.005 Merkel cell tumor 2 6 92.84 5.84 5 1.04 0.003 2 1.23 0.011 Mesothelioma 2 6 85.42 6.33 5 1.36 0.005 2 0.98 0.009 Liposarcoma 2 10 49.92 20.38 9 1.39 0.010 5 0.56 0.005 Rhabdomyosarcoma, NOS 2 10 80.49 9.46 9 1.50 0.005 5 1.23 0.010 Hurthle cell neoplasm (thyroid) 2 9 46.79 12.02 8 1.69 0.009 4 1.10 0.010 Osteosarcoma 1.5 8.5 76.43 13.79 7 1.84 0.017 5 0.14 0.002 Neuroendocrine cancer, NOS 2 6 87.02 8.21 5 2.04 0.009 2 2.65 Adenocarcinoma - small intest. 2.5 9.5 61.54 13.42 8 3.66 0.028 5 2.74 0.017 Osteosarcoma † 2 10 49.68 10.16 13 † 4.73 0.012 10 † 5.30 0.023 Malig. periph. nerve sheath tum. 2 7 66.77 15.10 6 7.07 0.011 3 6.00 0.017 Rhabdomyosarcoma, NOS 2 6 52.40 13.86 5 8.28 0.001 2 8.21 0.040 Penile SCC (epidermoid) 2 6 57.75 4.47 4 9.54 0.015 2 Pending Neuroendocrine cancer, NOS 2 6 84.82 9.11 5 16.07 0.055 2 19.97 0.060 Average 73.85 3.18 2.76 *Passages determined from initial implant material. If a passage 1 and passage 2 vial were used for initial implantation and then mice were randomized for the drug study, the average passage of the study is 1.5. † Model restarted from cryomaterial due to human DNA content of <20% in Passage 11 QC material; excluded from analysis above. Variability of Model Avg, %Genome Changed vs REF Material (LP-WGS) Heterogeneous > 5% Intermediate Heterogeneity 1.5% ~ 5% Homogeneous < 1.5% Merkel Cell Carcinoma Nucleoside analog A + HDACi Nucleoside analog A HDACi Carcinosarcoma of the Uterus Cytotoxic PARPi + cytotoxic PARPi Perform Single Agent Studies No Further Studies at this Time Additional Studies Needed Book-end Study IAPi + cytotoxic HDACi + PARPi Nucleoside Analog A , HDACi Nucleoside Analog A + Nucleoside Analog B Vehicle Control VEGFi + EGFRi HDACi + PARPi Nucleoside Analog A , HDACi Nucleoside Analog A + Nucleoside Analog B Vehicle Control TKi + cytotoxic HDACi + PARPi Nucleoside Analog A , HDACi Nucleoside Analog A + Nucleoside Analog B Vehicle Control Median Tumor Volume (mm 3 , Min/Max) Study Day Rhabdomyosarcoma Carcinosarcoma of the Uterus Study Day Study Day Median Tumor Volume (mm 3 , Min/Max) Median Tumor Volume (mm 3 , Min/Max) P2 P10 P2 P10 P2 P10 Median Tumor Volume (mm 3 , Min/Max) Study Day Study Day Median Tumor Volume (mm 3 , Min/Max) Ewing’s Sarcoma Nucleoside analog A + HDACi HDACi Nucleoside analog A Rhabdomyosarcoma Cytotoxic CDK4/6i + cytotoxic CDK4/6i Poster #5056 Study Day Study Day
Transcript of Quality Control Efforts in a Large-scale, Preclinical ...€¦ · Rhabdomyosarcoma, NOS. 2;...
Osteosarcoma
Quality Control Efforts in a Large-scale, Preclinical Trial of Rare Cancer PDXs by The National Cancer Institute’s Patient-Derived Models Repository (PDMR)
Y A Evrard1, B Das2, SY Alcoser3, S Borgel1, D Breen1, J Carter1, T Chase1, A Chen4, L Chen2, K Cooley1, E Delaney1, R Divelbiss1, L. Dutko2, T Forbes2, K Georgius1, MM Gottholm-Ahalt3, T Grinnage-Pulley3, S Hoffman1, C Karlovich2, S. Jiwani2, J. Mills1, M Morris1, M Mullendore1, D Newton1, R Patidar2, G Rivera2, H Stotler1, J Stottlemyer1, S Styers1, D Trail1, S Uzelac1, T Vilimas2, A Walke1, T Walsh1, NE Walters1, P Wang2, PM Williams2, MG Hollingshead3, JH Doroshow4
1 Applied Development and Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; 2Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; 3Biological Testing Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, MD 21702; 4Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD 20892
OverviewThe National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR;https://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with39 PDX models of rare cancers (table below) treated with 56 novel therapeuticcombinations in an exploratory, n-of-4 arm, study to identify novel therapeuticcombinations for these underserved cancers. Combinations that show regression ordurable inhibition of tumor growth are repeated along with the single agents todetermine if the response is driven by the combination or one of the agents. To dothis in a timely manner, the PDX tumors are serially passaged and each passage istreated with a set of 8 combinations plus relevant vehicle control(s); in parallelsufficient PDXs are retained to be expanded for the next passage and drug set.Every serial passage undergoes several quality control assessments that serve asgo/no-go criteria, including pathology assessment, human:mouse DNA contentassessment, and low pass whole genome sequencing to determine the averagefraction of genome changed compared to the original donor material. If there is aQC failure, the PDX model is restarted from early passage cryo-material (passage 1-2). We also bookend the combination studies with the first set of agents to see iftumor response is similar across passages, a reflection of the inherent heterogeneityof the models. To date, most of the models have demonstrated a high degree ofgenomic, histopathologic, and response stability, though a couple of models havemoved toward murine content and have been restarted from early passage. DNAand RNA are retained from all passages so a full NGS evaluation can be performed.Single agent studies of drug combinations that demonstrated a response in 30%-50% of the models conducted are also underway to determine which combinationshave a more than additive effect compared to the single agents. Promisingcombinations will be evaluated in clinical trials at the NCI in patients with these rarecancers.
Active combinations are repeated against each single agent; examples are shown below. Single agents and the combination are tested to determine if response is driven by one agent or an additive or synergistic effect.
Low-Pass Whole Genome Sequencing (LP-WGS) and Percent Human Tumor Content (%Hu) Assessment
Summary
• Due to the large study size, a visual assessment of depth anddurability of response was used to fast-track drug combinations forsingle-agent follow-up studies.
• Bookend studies indicate some variability in consistency of responseacross passages. Further analysis including increased numbers ofdrug studies with bookends and NGS of tumor material from thestudies will be performed to identify any underlying factors.
• Overall genome heterogeneity of models across passages isconsistent with the intra-model heterogeneity observed at baseline bylow-pass whole genome sequence assessment.
• Single agent studies are beginning to identify drug combinations withincreased efficacy over single agents. Combinations where this holdsin a larger percentage of all models, or within a specific rare diseasetype, will be moved forward to full efficacy and biomarker studies.
Compare Single Agent to CombinationBookend Drug Response Comparison
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. These studies were conducted on an Institutional Animal Care and Use Committee approved protocol.
In addition to genomic and histopathologic QC assessments, a QC metric for response across passages was also implemented. Once all drug combinations have been tested, the first set of drugs tested are repeated (average: +8 passages) to determine if a higher passage tumor has an altered response compared to the initial study. These bookend studies are underway for several models. As seen below in the first bookend studies to be completed, most therapeutic combinations have a very consistent response acrosspassages while specific model/therapeutic combinations (red arrows) have an altered response (growth delay vs progressive growth). More studies will be needed to determine if there is a pattern between altered response across passages and genomic characteristics, mechanism of action of the therapeutics, patient clinical history, and/or histology.
Visual Assessment of Response to Fast-Track Single-Agent Follow-up Studies
Orig
inal
Stu
dy
Bin 1 CR Achieved, >1 timepoint (<60mm3)Bin 2 Tumor regressed ~30%, durable response (~1 cy)Bin 3 Tumor regressed ~30% >1 timepoint, regrew at drug removalBin 4 Tumor stasis, durable response (~1 cy)Bin 5 Tumor stasis, regrew at drug removal Bin 6 Slowed, but Progressive GrowthBin 7 Grew at Same Rate as Control
1. Where in vivo data for NSG hosts was not available, toxicitytesting for single and combination agents was performed
2. Test novel therapeutic combinations (n-of-4) with vehicle controls(n-of-12). Monitor until tumor is ≥1000 mm3
• 39 models x 56 combinations = 2184 unique data sets• Serial passaging required• QC of material at every passage by Low Pass WGS,
pathology review, STR profiling, and %human DNA byqRT-PCR
• Body weight monitored throughout for toxicity3. If a response is observed with the combination in several models,
repeat the study and include single agent arms to determine ifresponse is driven by a single agent or possibleadditive/synergistic effect
4. For combinations that have additive/synergistic affects, perform afull efficacy study with planned sampling for biomarkerexploration and PK
Overall Study Design
DONORsPn+1
Pn+2
Pn+3
Pn+4
Pn+5
REFMaterial
QC
QC
QC
QC
Bookend: Repeat First Drug Set
Set-up for Each Passage
100 NSG hostsImplanted
40 for Drug Study(Randomized)
5-10 PDXsFor Passage QC
10 Donors (Randomized)For Next Passage
PDX Growthto ~200mm3
Qualitative Visual Assessment
•Tumor volume curves are visually assessed while drug study is on-going to determine trend of response•Binning of visual assessment is used to categorize response. Combinations that are active in 30%-50% ofthe models are prioritized for single-agent testing
•Pie charts represent visual response assessment of all models treated with therapeutic combinations,irrespective of histology
•All studies maintained until subcutaneous tumor burden is ≥1000 mm3 at which point quantitative responseassessment will be performed
TKi + EGFRi(n=9)
VEGFi + EGFRi(n=37)
TKi + Cytotoxic(n=37)
CDK5/6i + Cytotoxic(n=19)
AKTi + MEKi(n=33)
Combination better than single agents Single agent driving response
Rare Cancer PDX Models in Study
Diagnoses Number of ModelsCarcinosarcoma of the uterus 3Ewing sarcoma/Peripheral PNET 3Liposarcoma 3Malig. periph. nerve sheath tum. 3Merkel cell tumor 3Neuroendocrine cancer, NOS 3Osteosarcoma 3Salivary gland cancer 3Synovial sarcoma 3Gastrointestinal stromal tumor 2Mesothelioma 2Rhabdomyosarcoma, NOS 2Adenocarcinoma - anal 1Adenocarcinoma - small intest. 1Alveolar soft part sarcoma 1Hurthle cell neoplasm (thyroid) 1Penile squamous car.(epidermoid) 1Small Cell Lung Cancer 1
Fraction of genome changed between two samples is defined as the fraction of altered genomic regions with relative copy number changes >0.4 (log2 ratio, 1.32 ploidy). Baseline distribution is determined by the average and standard deviation of fraction of genome changed from intra-model pairwise comparison of REF Material samples. For QC material, fraction of genome changed is assessed at each passage versus REF Material samples. Table represents average QC metrics for all passages where at least 4 serial passages had been assessed versus baseline REF material. Overall genome heterogeneity of models across passages is consistent with the intra-model heterogeneity observed at baseline (REF Material Only) by LP-WGS assessment.• RT-PCR performed as described in Alcoser et al. (Biotechnology, 2011. PMID: 22176647)• Low Pass WGS: Mouse read removal, BBSplit; Copy Number detection, CNVkit, 1 Mbp bin size
DiagnosisREF Material
Passage *Highest Passage
On-Study*Avg %Hu (RT-PCR) STDEV
#QC Sets Assessed
Avg, %Genome Changed vs REF Material
(LP-WGS) STDEV#QC Sets Assessed
Avg, %Genome Changed REF Material Only
(LP-WGS) STDEV Synovial sarcoma 2 6 83.70 6.38 5 0.00 0.000 2 0.00 0.000Ewing sarcoma/Peripheral PNET 2 7 92.34 4.69 5 0.10 0.001 2 0.00 0.000Carcinosarcoma of the uterus 2 10 82.21 10.52 9 0.15 0.001 6 0.00 0.000Merkel cell tumor 2 7 88.52 11.30 6 0.32 0.002 3 0.50 0.006Mesothelioma 2 6 70.68 12.07 5 0.75 0.006 2 0.29 0.002Ewing sarcoma/Peripheral PNET 2 11 94.72 3.64 10 1.00 0.008 5 0.50 0.005Merkel cell tumor 2 6 92.84 5.84 5 1.04 0.003 2 1.23 0.011Mesothelioma 2 6 85.42 6.33 5 1.36 0.005 2 0.98 0.009Liposarcoma 2 10 49.92 20.38 9 1.39 0.010 5 0.56 0.005Rhabdomyosarcoma, NOS 2 10 80.49 9.46 9 1.50 0.005 5 1.23 0.010Hurthle cell neoplasm (thyroid) 2 9 46.79 12.02 8 1.69 0.009 4 1.10 0.010Osteosarcoma 1.5 8.5 76.43 13.79 7 1.84 0.017 5 0.14 0.002Neuroendocrine cancer, NOS 2 6 87.02 8.21 5 2.04 0.009 2 2.65Adenocarcinoma - small intest. 2.5 9.5 61.54 13.42 8 3.66 0.028 5 2.74 0.017Osteosarcoma† 2 10 49.68 10.16 13† 4.73 0.012 10† 5.30 0.023Malig. periph. nerve sheath tum. 2 7 66.77 15.10 6 7.07 0.011 3 6.00 0.017Rhabdomyosarcoma, NOS 2 6 52.40 13.86 5 8.28 0.001 2 8.21 0.040Penile SCC (epidermoid) 2 6 57.75 4.47 4 9.54 0.015 2 PendingNeuroendocrine cancer, NOS 2 6 84.82 9.11 5 16.07 0.055 2 19.97 0.060Average 73.85 3.18 2.76*Passages determined from initial implant material. If a passage 1 and passage 2 vial were used for initial implantation and then mice were randomized for the drug study, the average passage of the study is 1.5.†Model restarted from cryomaterial due to human DNA content of <20% in Passage 11 QC material; excluded from analysis above.
Variability of Model
Avg, %Genome Changed vs REF
Material(LP-WGS)
Heterogeneous > 5%Intermediate
Heterogeneity 1.5% ~ 5%
Homogeneous < 1.5%
Merkel Cell CarcinomaNucleoside analog A + HDACi
Nucleoside analog AHDACi
Carcinosarcoma of the UterusCytotoxicPARPi + cytotoxic
PARPi
Perform Single Agent Studies No Further Studies at this Time Additional Studies Needed
Book
-end
Stu
dy
IAPi + cytotoxic HDACi + PARPiNucleoside Analog A , HDACiNucleoside Analog A + Nucleoside Analog BVehicle Control
VEGFi + EGFRiHDACi + PARPiNucleoside Analog A , HDACiNucleoside Analog A + Nucleoside Analog BVehicle Control
TKi + cytotoxicHDACi + PARPiNucleoside Analog A , HDACiNucleoside Analog A + Nucleoside Analog BVehicle Control
Med
ian
Tum
or V
olum
e (m
m3 ,
Min
/Max
)
Study Day
Rhabdomyosarcoma Carcinosarcoma of the Uterus
Study Day Study Day
Med
ian
Tum
or V
olum
e (m
m3 ,
Min
/Max
)
Med
ian
Tum
or V
olum
e (m
m3 ,
Min
/Max
)
P2
P10
P2
P10
P2
P10
Med
ian
Tum
or V
olum
e (m
m3 ,
Min
/Max
)
Study Day Study Day
Med
ian
Tum
or V
olum
e (m
m3 ,
Min
/Max
)
Ewing’s SarcomaNucleoside analog A + HDACi
HDACiNucleoside analog A
RhabdomyosarcomaCytotoxicCDK4/6i + cytotoxic
CDK4/6i
Poster #5056
Study Day Study Day
