Phase I clinical study of intratumoral injection of ......008-029 Sepsis Grade 4 Cohort 6 008-029...
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1 UT M. D. Anderson Cancer Center, Houston, TX 77030, USA; 2 Memorial Sloan-Kettering Cancer Center, New York, NY 10022, USA; 3 WUSOM Siteman Cancer Center, St. Louis, MO; 4 Cleveland Clinic, Cleveland, OH; 5 BioMed Valley Discoveries Inc., Kansas City, MO 64111, USA; 6 Atlas Venture, Boston, MA 02139, USA Filip Janku 1 , Ravi Murthy 1 , Andrea Wang-Gillam 3 , Dale Shepard 4 , Thorunn Helgason 1 , Tashane Henry 2 , Charles Rudin 2 , Steven Y. Huang 1 , Divya Sakamuri 1 , Stephen B Solomon 2 , Amanda Collins 5 , Brent Kreider 5 , Maria Miller 5 , Saurabh Saha 5,6 , David Tung 5 , Mary Varterasian 5 , Linping Zhang 5 , Halle H Zhang 5 , Mrinal M. Gounder 2 Phase I clinical study of intratumoral injection of oncolytic Clostridium novyi-NT spores in patients with advanced cancers BACKGROUND Intratumoral injection of Clostridium novyi-NT (C. novyi-NT), an attenuated strain of Clostridium, induced a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model, in companion dogs bearing spontaneous solid tumors, and in the first patient treated on a Phase 1 human clinical trial (Roberts et al, Sci Transl Med. 2014) 1 . C. novyi- NT spores germinate in hypoxic tumor environment and lyse malignant cells by secreting lipases, proteases, other hydrolytic enzymes, and recruiting inflammatory cells to tumors eliciting anti-tumor immune responses in animals 2 . Furthermore, intratumoral injection can plausibly induce an immune mediated abscopal effect in non-injected tumor sites. METHODS Study Design Objectives • To determine the maximum tolerated dose (MTD), and dose-limiting toxicities (DLT) of a single intratumoral injection of C. novyi- NT using the standard 3+3 dose escalation schedule • To document preliminary anti-tumor activity of both the injected tumor and an overall response • To study the presence of circulating C. novyi- NT spores • To measure the host immune and inflammatory response to C. novyi- NT administered as a single IT injection in humans with treatment- refractory solid tumor malignancies Major eligibility criteria • Adult patients with advanced solid tumor malignancy • Targeted tumor has a longest diameter ≥ 1 cm and < 12 cm and is amenable to percutaneous injection of C. novyi-NT spores. • The target tumor must not be located in either the thoracic, abdominal, pelvic cavities or in the brain. • ECOG 0-2 • ANC ≥ 1,000/uL • Hemoglobin ≥ 9 g/dL • Platelets ≥ 100,000/uL • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) • ALT/AST ≤ 2.5 x ULN • INR ≥ 1.3 • No primary brain malignancies or brain metastases • No active infection or treatment with antibiotics Intratumoral Injection 1 Roberts, N, Zhang, L, et al. (2014). Intratumoral injection of Clostridium novyi -NT spores induces antitumor responses. Sci Transl Med. 6(249):249ra111 2 Agrawal N, Bettegowda C, et al. (2004) Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc Natl Acad Sci U S A 101:15172-7 RESULTS Dose Escalation Patients Characteristics (n=21) Best Response Toxicity Data Summary Tumor-specific T-cell Response CONCLUSION Dose Level Dose of Intratumoral C. Novyi-NT Spores Number of patients Enrolled Dose-limiting toxicities (DLT) 1 1 x 10 4 3 None 2 3 x 10 4 3 None 3 10 x 10 4 4 None 4 30 x 10 4 6 1 (sepsis) 5 100 x 10 4 3 Planned cohort expansion to 6 patients to determine MTD None 6 300 x 10 4 2 2 (sepsis, gas gangrene) Median age – years (range) 55 (29-75) Male/Female 11/10 The Type, Location, Size, and Response of Injected Tumors Green Fill: C. novyi-NT germination/tumor destruction * SAE • Anti-cancer activity was observed in 10 out of 21 (48%) patients in whom C. novyi-NT germination resulted in extensive, in some cases, complete central necrosis of the injected tumor. • Two patients had 22-24% shrinkage in the injected tumor at Month 1-2 based on RECIST assessment. One patient has 14% shrinkage in the injected tumor at Month 4. • Out of the 10 patients who were evaluated at Month 2, 8 patients had an overall response of stable disease; 2 patients had progressive disease. One patient had stable disease at Month 4. • Three out of 21 patients had no visible signs of C. novyi-NT germination but experienced dramatic clinical improvement at Month 1 (Patient 008-013) or slowed tumor growth at Month 2 as compared with tumor growth before C. novyi-NT injection (Patient 011-028, 008-026). Baseline Day 7 Patient 008-029: 65-year-old male with a 8.5 x7 cm metastatic right anterior hip leiomyosarcoma. Patient was treated at Dose Level 6 (300x10 4 spores) Baseline Day 4 Patient 011-019: 75-year-ol male with a 3 cm liposarcoma in the right inguinal node. Patient was treated at Dose Level 4 (30x10 4 spores). • A single dose of intratumoral injection of Clostridium novyi-NT is feasible and has led to significant destruction of injected tumor masses. • Stabilization/slow down in tumor growth in non-injected masses has been observed in two patients. • The tolerable dose has been exceeded, and expansion of cohort 5 is planned to define MTD and RP2D. • A Phase I study of a PD1 antibody with C. novyi- NT has been designed. Patient 011-001: 53-year-old female with a 7.6 cm leiomyosarcoma in the right shoulder with adjacent humerus involvement. Patient was treated at Dose Level 1 (1x10 4 spores). 1 Day 4 Baseline Baseline: contrast enhancing mass involving soft tissue and possibly adjacent bone. Lesion measures about 7.2cm AP x 7.4cm transverse in the axial dimensions. Day 4: markedly diminished contrast enhancement within the tumor mass of soft tissue and possibly adjacent bone component Day 29: non-enhancing tumor mass becomes more homogeneous consistent with ongoing necrosis Bay 29 To assess tumor-specific T-cell responses in patients treated with C. novyi-NT injection, circulating CD4 and CD8 cells were isolated from patient’s blood and stimulated with patient’s own dendritic cells which were pulsed with tumor antigens. Release of T-cell cytokines and effector molecules such as IFN- γ , granzyme-B, and TNF- α were quantified by Enzyme-linked Immune Absorbent Spot (ELISPOT) assays. Most common adverse events (AEs) are hyperthermia/fever and tumor inflammation. Fever is expected due to the nature of the therapy and has been observed in half of treated patients. Tumor inflammation and abscess events are generally considered desired mechanisms of C. novyi-NT treatment. Related Grade 3 and Above AEs and Serious Adverse Events (SAEs) Patient ID Adverse Event Severity Cohort Dose 011-001 Respiratory Insufficiency Grade 3 Cohort 1 011-001 Pathologic Fracture of Right Humerus Grade 3 Cohort 1 008-018 Sepsis Grade 4 Cohort 4 011-019 Genital Swelling Grade 2 Cohort 4 011-023 Pain Grade 3 Cohort 4 011-023 Swelling Grade 3 Cohort 4 011-023 Possible Skin Infection Grade 3 Cohort 4 011-027 Abscess Grade 3 Cohort 5 008-029 Sepsis Grade 4 Cohort 6 008-029 Soft Tissue Infection Grade 3 Cohort 6 008-030 Gas Gangrene Right Upper Extremity Grade 4 Cohort 6 Green Fill: SAEs P284 C. novyi-NT spores are injected with a needle or alternate injection device, which may be carried out under radiographic guidance. The injection can be redirected to multiple distinct sites in the tumor to achieve adequate dispersal of spores throughout the tumor. Patient Cohort Tumor Type Location Size (cm) 011-001 1 Leiomyosarcoma Peri- humerus Soft Tissue (right) 7.6* 011-002 1 Chondrosarcoma SQ Chest Wall (Left) 2.7 011-003 1 Leiomyosarcoma SQ Abdominal Wall (Left) 2.6 011-004 2 Mullerian Carcinoma SQ left flank 10.5 008-006 2 Angiosarcoma SQ neck lymph node 2.8 011-007 2 Papillary thyroid Carcinoma SQ Scapular Lesion 3 006-010 3 Breast cancer Skin Lesion 3 (Ductal Carcinoma) 008-012 3 Serous Ovarian Axillary Mass 5 Cystadenocarcinoma 008-013 3 Oropharyngeal Cancer (HPV-related Squamous Cell Carcinoma) Pre- auricular Lymph Node 2 011-014 3 Breast Cancer Left Chest Wall 3 (Triple Negative adenocarcinoma) Superficial Lesion 011-016 4 leiomyosarcoma Right Abdominal Wall 5 008-018 4 Metastatic Osteosarcoma Right Leg Amputation Site 8* 011-019 4 Liposarcoma Right Groin 3* 011-021 4 Endometrial Carcinoma Abdominal Wall 3 003-022 4 Sarcoma Left Lateral Abd ominal Wall 3.7 011-023 4 Adenocarcinoma Axilla 10 008-026 5 Chordoma Chest Wall (Left Posterior) 2.8 011-027 5 Spindle Cell Sarcoma Right Arm 4.5* 011-028 5 NRAS- mutated Melanoma Abdominal Wall 2.5 008-029 6 Leiomyosarcoma Right Anterior Hip 8.5* 008-030 6 Myxofibrosarcoma Bicep 10*
Transcript of Phase I clinical study of intratumoral injection of ......008-029 Sepsis Grade 4 Cohort 6 008-029...
RESEARCH POSTER PRESENTATION DESIGN © 2015
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1 UTM.D.AndersonCancerCenter,Houston,TX77030,USA;2MemorialSloan-KetteringCancerCenter,NewYork, NY 10022,USA;3 WUSOMSitemanCancerCenter,St.Louis,MO;4 ClevelandClinic,Cleveland,OH;5BioMedValleyDiscoveriesInc.,KansasCity,MO64111,USA;6AtlasVenture,Boston,MA02139,USA
FilipJanku1,RaviMurthy1,AndreaWang-Gillam3,DaleShepard4,ThorunnHelgason1,TashaneHenry2,CharlesRudin2,StevenY.Huang1,DivyaSakamuri1,StephenBSolomon2,AmandaCollins5,BrentKreider5,MariaMiller5,SaurabhSaha5,6,DavidTung5,MaryVarterasian5,LinpingZhang5,HalleHZhang5,MrinalM.Gounder2
PhaseIclinicalstudyofintratumoralinjectionofoncolyticClostridiumnovyi-NTsporesinpatientswithadvancedcancers
BACKGROUNDIntratumoralinjectionofClostridiumnovyi-NT(C.novyi-NT),anattenuatedstrainofClostridium,inducedamicroscopicallyprecise,tumor-localizedresponseinaratorthotopicbraintumormodel,incompaniondogsbearingspontaneoussolidtumors,andinthefirstpatienttreatedonaPhase1humanclinicaltrial(Robertsetal,SciTranslMed.2014) 1.C.novyi-NTsporesgerminateinhypoxictumorenvironmentandlysemalignantcellsbysecretinglipases,proteases,otherhydrolyticenzymes,andrecruitinginflammatorycellstotumorselicitinganti-tumorimmuneresponsesinanimals2.Furthermore,intratumoralinjectioncanplausiblyinduceanimmunemediatedabscopaleffectinnon-injectedtumorsites.
METHODS
Study Design
Objectives• Todeterminethemaximumtolerateddose(MTD),anddose-limiting
toxicities(DLT)ofasingleintratumoral injectionofC.novyi-NTusingthestandard3+3doseescalationschedule
• Todocumentpreliminaryanti-tumoractivityofboththeinjectedtumorandanoverallresponse
• TostudythepresenceofcirculatingC.novyi-NTspores• TomeasurethehostimmuneandinflammatoryresponsetoC.novyi-
NTadministeredasasingleITinjectioninhumanswithtreatment-refractorysolidtumormalignancies
Majoreligibilitycriteria• Adultpatientswithadvancedsolidtumormalignancy• Targetedtumorhasalongestdiameter≥1cmand< 12cmandis
amenabletopercutaneousinjectionofC.novyi-NTspores.• Thetargettumormustnotbelocatedineitherthethoracic,
abdominal,pelviccavitiesorinthebrain.• ECOG0-2• ANC≥1,000/uL• Hemoglobin≥9g/dL• Platelets≥100,000/uL• Totalbilirubin≤1.5xupperlimitofnormal(ULN)• ALT/AST≤2.5xULN• INR≥1.3• Noprimarybrainmalignanciesorbrainmetastases• Noactiveinfectionortreatmentwithantibiotics
Intratumoral Injection
1Roberts,N,Zhang,L,etal.(2014).IntratumoralinjectionofClostridiumnovyi-NTsporesinducesantitumorresponses.SciTranslMed.6(249):249ra1112AgrawalN,BettegowdaC,etal.(2004)Bacteriolytictherapycangenerateapotentimmune responseagainstexperimentaltumors.ProcNatlAcadSciUSA101:15172-7
RESULTSDose Escalation
Patients Characteristics (n=21)
Best Response
Toxicity Data Summary
Tumor-specificT-cellResponse
CONCLUSION
DoseLevel
DoseofIntratumoralC.Novyi-NT
Spores
NumberofpatientsEnrolled Dose-limitingtoxicities(DLT)
1 1x104 3 None2 3x104 3 None3 10x104 4 None4 30x104 6 1(sepsis)
5 100x1043
Plannedcohortexpansionto6patientstodetermineMTD
None
6 300x104 22
(sepsis,gasgangrene)
Medianage– years(range) 55(29-75)
Male/Female 11/10
The Type, Location, Size, and Response of Injected Tumors
GreenFill:C.novyi-NT germination/tumordestruction*SAE
• Anti-canceractivitywasobservedin10outof21(48%)patientsinwhomC.novyi-NTgerminationresultedinextensive,insomecases,completecentralnecrosisoftheinjectedtumor.
• Twopatientshad22-24%shrinkageintheinjectedtumoratMonth1-2basedonRECISTassessment.Onepatienthas14%shrinkageintheinjectedtumoratMonth4.
• Outof the10patientswhowereevaluatedatMonth2,8patientshadanoverallresponseofstabledisease;2patientshadprogressivedisease.OnepatienthadstablediseaseatMonth4.
• Threeoutof21patientshadnovisiblesignsofC.novyi-NTgerminationbutexperienceddramaticclinicalimprovementatMonth1(Patient008-013)orslowedtumorgrowthatMonth2ascomparedwithtumorgrowthbeforeC. novyi-NTinjection(Patient011-028,008-026).
Baseline Day7
Patient008-029:65-year-oldmalewitha8.5x7cmmetastaticrightanteriorhipleiomyosarcoma.PatientwastreatedatDoseLevel6
(300x104 spores)
Baseline Day4
Patient011-019:75-year-olmalewitha3cmliposarcomaintherightinguinalnode.PatientwastreatedatDoseLevel4(30x104 spores).
• A singledoseofintratumoralinjectionofClostridiumnovyi-NTisfeasibleandhasledtosignificantdestructionofinjectedtumormasses.
• Stabilization/slowdownintumorgrowth innon-injectedmasseshasbeenobservedintwopatients.
• Thetolerabledosehasbeenexceeded,andexpansionofcohort5isplannedtodefineMTDandRP2D.
• APhaseIstudyofaPD1antibodywithC.novyi-NThasbeendesigned.
Patient011-001:53-year-oldfemalewitha7.6cmleiomyosarcoma intherightshoulderwithadjacenthumerus involvement.Patientwastreated
atDoseLevel1(1x104 spores).1
Day 4Baseline
Baseline:contrastenhancingmassinvolvingsofttissueandpossiblyadjacentbone.Lesionmeasuresabout7.2cmAPx7.4cmtransverseintheaxialdimensions.
Day4:markedlydiminishedcontrastenhancementwithinthetumormassofsofttissueandpossiblyadjacentbonecomponent
Day29:non-enhancingtumormassbecomesmorehomogeneousconsistentwithongoingnecrosis
Bay 29
Toassesstumor-specificT-cellresponsesinpatientstreatedwithC.novyi-NT injection,circulatingCD4andCD8cellswereisolatedfrompatient’sbloodandstimulatedwithpatient’sowndendriticcellswhichwerepulsedwithtumorantigens.ReleaseofT-cellcytokinesandeffectormoleculessuchasIFN-γ,granzyme-B,andTNF-α werequantifiedbyEnzyme-linkedImmuneAbsorbentSpot(ELISPOT)assays.
Most common adverse events (AEs) are hyperthermia/fever and tumorinflammation. Fever is expected due to the nature of the therapy andhas been observed in half of treated patients. Tumor inflammation andabscess events are generally considered desired mechanisms of C.novyi-NT treatment.
RelatedGrade3andAboveAEsandSeriousAdverseEvents(SAEs)
PatientID AdverseEvent Severity CohortDose
011-001 RespiratoryInsufficiency Grade3 Cohort1
011-001 PathologicFractureofRightHumerus Grade3 Cohort1
008-018 Sepsis Grade4 Cohort4
011-019 GenitalSwelling Grade2 Cohort4
011-023 Pain Grade3 Cohort4
011-023 Swelling Grade3 Cohort4
011-023 PossibleSkinInfection Grade3 Cohort4
011-027 Abscess Grade3 Cohort5
008-029 Sepsis Grade4 Cohort6
008-029 SoftTissueInfection Grade3 Cohort6
008-030 GasGangreneRightUpperExtremity Grade4 Cohort6
GreenFill:SAEs
P284
C.novyi-NT sporesareinjectedwithaneedleoralternateinjectiondevice,whichmaybe carriedoutunderradiographicguidance.Theinjectioncanberedirectedtomultipledistinctsitesinthetumortoachieveadequatedispersalofsporesthroughoutthetumor.
Patient Cohort TumorType Location Size(cm)
011-001 1 LeiomyosarcomaPeri-humerusSoftTissue(right)
7.6*
011-002 1 Chondrosarcoma SQChestWall(Left) 2.7
011-003 1 Leiomyosarcoma SQAbdominalWall(Left) 2.6
011-004 2 MullerianCarcinoma SQleftflank 10.5
008-006 2 Angiosarcoma SQnecklymphnode 2.8
011-007 2 PapillarythyroidCarcinoma SQScapularLesion 3
006-010 3 Breastcancer SkinLesion 3(DuctalCarcinoma)
008-012 3Serous Ovarian
AxillaryMass 5Cystadenocarcinoma
008-013 3OropharyngealCancer(HPV-relatedSquamous
CellCarcinoma)
Pre-auricularLymphNode 2
011-014 3BreastCancer LeftChestWall
3(TripleNegativeadenocarcinoma)
SuperficialLesion
011-016 4 leiomyosarcoma RightAbdominalWall 5
008-018 4 MetastaticOsteosarcoma RightLegAmputationSite 8*
011-019 4 Liposarcoma RightGroin 3*011-021 4 EndometrialCarcinoma AbdominalWall 3
003-022 4 Sarcoma Left Lateral AbdominalWall 3.7
011-023 4 Adenocarcinoma Axilla 10
008-026 5 Chordoma ChestWall(LeftPosterior) 2.8
011-027 5 SpindleCellSarcoma RightArm 4.5*011-028 5 NRAS-mutatedMelanoma AbdominalWall 2.5
008-029 6 Leiomyosarcoma RightAnteriorHip 8.5*
008-030 6 Myxofibrosarcoma Bicep 10*
