A Phase I trial of KX2-391, a novel non-ATP A Phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC competitive substrate-pocket directed SRC

inhibitor, in patients with advanced inhibitor, in patients with advanced malignanciesmalignancies

A. A. Adjei, R. B. Cohen, R. Kurzrock, G. S. Gordon, D. Hangauer, A. A. Adjei, R. B. Cohen, R. Kurzrock, G. S. Gordon, D. Hangauer, L. Dyster, G. Fetterly, S. Barrientes, D. S. Hong, A. NaingL. Dyster, G. Fetterly, S. Barrientes, D. S. Hong, A. Naing

Roswell Park Cancer Inst, Buffalo, NY; Fox Chase Cancer Center, Roswell Park Cancer Inst, Buffalo, NY; Fox Chase Cancer Center, Philadelphia, PA; MD Anderson Cancer Center, Houston, TX; Philadelphia, PA; MD Anderson Cancer Center, Houston, TX;

Kinex Pharmaceuticals, Buffalo, NY Kinex Pharmaceuticals, Buffalo, NY

1FOX CHASECancer Center

Disclosure InformationDisclosure InformationASCO ANNUAL MEETING 2009ASCO ANNUAL MEETING 2009

Alex A. AdjeiAlex A. Adjei

I have no financial relationships to disclose.I have no financial relationships to disclose.

Src signaling in tumor cells

Yeatman, Nat Rev Cancer, 2004

Src Kinase in Cancer

• There are over 500 serine and tyrosine kinases in There are over 500 serine and tyrosine kinases in humans; Src is a member of the tyrosine kinase family humans; Src is a member of the tyrosine kinase family and the 1and the 1stst oncogene discovered oncogene discovered

• Src activity is high in a majority of primary tumors with Src activity is high in a majority of primary tumors with further increases during metastasisfurther increases during metastasis

• Since Src activity generally increases as cells progress Since Src activity generally increases as cells progress from benign to invasive to metastatic, Src inhibition may from benign to invasive to metastatic, Src inhibition may inhibit primary tumor growth as well as metastasisinhibit primary tumor growth as well as metastasis

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Src kinase Inhibitors in the clinicSrc kinase Inhibitors in the clinic

• Dasatinib (Sprycel):Dasatinib (Sprycel): (approved for resistant CML, Phase I-II in (approved for resistant CML, Phase I-II in solid tumors)solid tumors)

• Bosutinib (SKI-606):Bosutinib (SKI-606): (Phase III in resistant CML, Phase I-II in (Phase III in resistant CML, Phase I-II in solid tumors)solid tumors)

• AZD0530:AZD0530: (Phase I-II in solid tumors) (Phase I-II in solid tumors)

• XL228:XL228: (Phase 1 in resistant CML & solid tumors) (Phase 1 in resistant CML & solid tumors)

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KX2-391

Mechanism of actionMechanism of action

Non-ATP competitive Src signaling inhibitorNon-ATP competitive Src signaling inhibitor

22ndnd MOA (not a kinase) currently under investigation MOA (not a kinase) currently under investigation

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NH

O

N

ON

O

H

CH3SO O

O

KX2-391:MSA

Efficacy of KX2-391 in Solid Tumor Cell LinesEfficacy of KX2-391 in Solid Tumor Cell Lines

KX2-391 has very potent activity (<50 nM) against a broad range of solid tumor cell lines

Human Tumor Cell LineHuman Tumor Cell Line KX2-391 GI50 (nM)KX2-391 GI50 (nM)

HT29 (Colon)HT29 (Colon) 2525

SKOV-3 (Ovarian)SKOV-3 (Ovarian) 1010

PC3-MM2 (Prostate)PC3-MM2 (Prostate) 99

L3.6pl (Pancreas)L3.6pl (Pancreas) 2525

MDA-MB-231 (Breast)MDA-MB-231 (Breast) 2020

A549 (Lung)A549 (Lung) 99

HuH7 (liver)HuH7 (liver) 99

769-P (kidney) 45

KX2-391 Compared to Dasatinib in KX2-391 Compared to Dasatinib in Resistant Solid Tumor Cell LinesResistant Solid Tumor Cell Lines

Human Tumor Cell LineHuman Tumor Cell Line KX2-391 IC50--IC90 (nM)KX2-391 IC50--IC90 (nM) Dasatinib IC50--IC90 (nM)Dasatinib IC50--IC90 (nM)

H460 (NSCLC))H460 (NSCLC)) 51--16251--162 90--48,88090--48,880

H226 (NSCLC)H226 (NSCLC) 98--49098--490 163--34,340163--34,340

HCT116 (colon)HCT116 (colon) 31--19531--195 880--not reached880--not reached

SW620 (colon)SW620 (colon) 109--903109--903 2,418--2,9402,418--2,940

Literature reported Dasatinib resistant cell lines:1) Johnson et al, Clin. Cancer Res 2005; 11(19), 69242) Serrels et al, Mol Cancer Ther 2006; 5(12), 3014

Average IC50 = 72 nM Average IC50 = 888 nM

Dasatinib 10X less potentthan KX2-391 at IC50 and

ca. 100X less potent at IC90

KX2-391 Compared to Dasatinib in Leukemia KX2-391 Compared to Dasatinib in Leukemia and Multiple Myeloma Cell linesand Multiple Myeloma Cell lines

Human Liquid Tumor Cell Human Liquid Tumor Cell LineLine

KX2-391 GI50 (nM)KX2-391 GI50 (nM) Dasatinib GI50 (nM)Dasatinib GI50 (nM)

K562 (CML)K562 (CML) 1313 0.370.37

K562R (Gleevec resistant K562R (Gleevec resistant CML)CML)

0.640.64 0.810.81

Ba/F3 + T315IBa/F3 + T315I

(Gleevec & Dasatinib (Gleevec & Dasatinib Resistant CML)Resistant CML)

3535 InactiveInactive

CCRF-HSB-2 (ALL)CCRF-HSB-2 (ALL) 1212 InactiveInactive

KG-1 (AML)KG-1 (AML) 1616 InactiveInactive

RPMI8226 (Multiple RPMI8226 (Multiple Myeloma)Myeloma)

4040 InactiveInactive

KX2-391 has a second MOA beyond Src signaling inhibition that might provide broader activity than dasatinib

KX2-391 Pre-clinical ToxicologyKX2-391 Pre-clinical Toxicology

Oral continuous bid dosing 28-day toxicity studiesOral continuous bid dosing 28-day toxicity studies

RodentRodent

GI Toxicity is Dose-LimitingGI Toxicity is Dose-Limiting

No cardiotoxicityNo cardiotoxicity

No renal toxicityNo renal toxicity

Non-Rodent (Dog)Non-Rodent (Dog)

GI and Hematologic Toxicities are Dose-LimitingGI and Hematologic Toxicities are Dose-Limiting

No cardiotoxicityNo cardiotoxicity

No renal toxicityNo renal toxicity

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Objectives of Phase I TrialObjectives of Phase I Trial

Primary Objective:Primary Objective:• To define the maximum tolerated dose (MTD) of KX2-391 To define the maximum tolerated dose (MTD) of KX2-391

in patients with advanced refractory malignanciesin patients with advanced refractory malignancies

Secondary Objectives:Secondary Objectives:• To determine the safety and tolerability of KX2-391 given To determine the safety and tolerability of KX2-391 given

as single and multiple doses as an oral solution in patients as single and multiple doses as an oral solution in patients with advanced refractory malignancieswith advanced refractory malignancies

• To characterize the pharmacokinetic profile after single and To characterize the pharmacokinetic profile after single and multiple oral dosing of KX2-391multiple oral dosing of KX2-391

• To determine the biological effects of KX2-391To determine the biological effects of KX2-391• To evaluate antitumor activity of KX2-391To evaluate antitumor activity of KX2-391

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Trial DesignTrial Design

• Multi-center Phase 1 trialMulti-center Phase 1 trial• Standard ‘3+3’ dose escalation designStandard ‘3+3’ dose escalation design• DosingDosing

• Single oral dose, followed by one week evaluationSingle oral dose, followed by one week evaluation• Then BID oral dosing for 3 of 4 weeksThen BID oral dosing for 3 of 4 weeks

• Efficacy evaluation every 2 cycles (8 weeks)Efficacy evaluation every 2 cycles (8 weeks)• PK evaluation after single and multiple dosesPK evaluation after single and multiple doses

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Inclusion/Exclusion CriteriaInclusion/Exclusion Criteria• Adults over age 18 years of ageAdults over age 18 years of age• Confirmed advanced solid tumor or lymphoma for which standard Confirmed advanced solid tumor or lymphoma for which standard

curative or palliative measure do not exist or are no longer effectivecurative or palliative measure do not exist or are no longer effective• ECOG performance status of 0-2 ECOG performance status of 0-2 • Adequate bone marrow reserveAdequate bone marrow reserve• Adequate liver and renal function Adequate liver and renal function • No investigational agents within 28 days of first day of studyNo investigational agents within 28 days of first day of study• No recent hormone therapyNo recent hormone therapy• Not using moderate or strong P450 modulators (inducers or inhibitors) Not using moderate or strong P450 modulators (inducers or inhibitors)

within 2 weeks or 5 half-lives (whichever is shorter)within 2 weeks or 5 half-lives (whichever is shorter)• No major surgery within 4 weeksNo major surgery within 4 weeks• No major GI diseaseNo major GI disease• No signs or symptoms of other major diseases or toxicitiesNo signs or symptoms of other major diseases or toxicities

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Patient DemographicsPatient DemographicsCharacteristicsCharacteristics ResultsResults

Age Median (range)Age Median (range) 60 (32-80) years60 (32-80) years

SexSex 15 males/ 22 females15 males/ 22 females

Median # of previous chemotherapy Median # of previous chemotherapy regimensregimens

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Median # of previous XRT regimensMedian # of previous XRT regimens 22

Most common cancersMost common cancers Number of patientsNumber of patients

Colo-rectalColo-rectal 44

Head and NeckHead and Neck 44

PancreasPancreas 44

BreastBreast 33

NSCLCNSCLC 33

ThyroidThyroid 33

OtherOther 161614

Dose EscalationDose Escalation

Dose GroupDose Group # patients# patients # with DLTs# with DLTs # with SD# with SD> > 4 4 cyclescycles

2 mg BID2 mg BID 33 00 11

5 mg BID5 mg BID 44 00 11

10 mg BID10 mg BID 44 00 11

20 mg BID20 mg BID 44 00 11

40 mg BID40 mg BID 77 00 11

80 mg BID80 mg BID 55 22 22

60 mg BID60 mg BID 66 22 33

50 mg BID50 mg BID 44 22 11

TOTALTOTAL 3737 66 1111

MTDMTD

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Pharmacokinetics of KX2-391

Conclusions: KX2-391 PK is dose-dependent and linear with increasing dose. Terminal T1/2 is approximately 4 hr. T max – 1 hour

Treatment Related Adverse EventsTreatment Related Adverse Events Adverse EventAdverse Event Grade 1/2*Grade 1/2* Grade 3/4*Grade 3/4* TotalTotal

AST increased 7 3 10

ALT increased 4 3 7

Anorexia 5 5

Fatigue 4 4

Lymphopenia 3 1 4

Nausea 4 4

Anemia 2 1 3

Leukopenia 2 1 4

Alk phos increased 3 3

Pancytopenia 1 2 3

Febrile Neutropenia 2 2

Dizziness 2 2

Flatulence 2 2

Neutropenia 1 1 2

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Other Grade 3 or 4 events in one patient: Abdominal pain, bilirubin increased, edema, failure to thrive, hyponatremia, mucositis, rash, thrombocytopenia

* Number of patients

Dose Limiting ToxicitiesDose Limiting Toxicities• Dose Limiting Toxicities at 50, 60 and 80 mg BIDDose Limiting Toxicities at 50, 60 and 80 mg BID

• Grade 4 Neutropenia – 2 patients (60 mg and 80 mg dose)Grade 4 Neutropenia – 2 patients (60 mg and 80 mg dose)• Grade 3 elevated ALT/AST – 2 patients (50 and 60 mg dose)Grade 3 elevated ALT/AST – 2 patients (50 and 60 mg dose)• Grade 4 thrombocytopenia – 1 patient (50 mg dose)Grade 4 thrombocytopenia – 1 patient (50 mg dose)• Grade 3 ALT/AST/Failure to Thrive – 1 patient (80 mg dose)Grade 3 ALT/AST/Failure to Thrive – 1 patient (80 mg dose)

• Serious Adverse EventsSerious Adverse Events (possibly related, at any dose level) (possibly related, at any dose level)• Febrile Neutropenia, pancytopenia, hyponatremia – 1 patientFebrile Neutropenia, pancytopenia, hyponatremia – 1 patient• Febrile Neutropenia, pancytopenia, edema – 1 patientFebrile Neutropenia, pancytopenia, edema – 1 patient• Neutropenia and mucositis – 1 patientNeutropenia and mucositis – 1 patient• Rash – 1 patientRash – 1 patient• Failure to thrive – 1 patientFailure to thrive – 1 patient

• All DLTs and SAEs reversible within 7 daysAll DLTs and SAEs reversible within 7 days• No pulmonary edema or cardiotoxicity notedNo pulmonary edema or cardiotoxicity noted

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Efficacy Results (N = 37)Efficacy Results (N = 37)

• Treatment durationTreatment duration• Median 2 cycles (range 1 – 11) Median 2 cycles (range 1 – 11) • 11 pts treated for 4 or more cycles11 pts treated for 4 or more cycles• 6 pts treated for 6 or more cycles6 pts treated for 6 or more cycles

• Patients with suggestion of efficacyPatients with suggestion of efficacy• Prostate – PSA decline : 205 to 39, 6 cyclesProstate – PSA decline : 205 to 39, 6 cycles• Pancreas – CA19-9 decline : 38,838 to 267, 4 cyclesPancreas – CA19-9 decline : 38,838 to 267, 4 cycles• Ovary – CA-125 decline : 665 to 207, 4+ cyclesOvary – CA-125 decline : 665 to 207, 4+ cycles• Thyroid – 3 patients on for 8, 8, and 6+ cycles Thyroid – 3 patients on for 8, 8, and 6+ cycles • Appendiceal carcinoid – 11+ cyclesAppendiceal carcinoid – 11+ cycles• Melanoma – 6 cyclesMelanoma – 6 cycles• Merkel cell – mixed response at 2 cyclesMerkel cell – mixed response at 2 cycles

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Prostate Cancer Patient Change in PSA

050

100150200250300350400450

20

On Trial Off Trial

Pancreas Cancer Patient Change in CA19-9

21

On Trial Off Trial

Ovary Cancer PatientChange in CA125

22

On Trial

ConclusionsConclusions

• KX2-391 is well-tolerated at a dose of 40 mg po BID for 3 KX2-391 is well-tolerated at a dose of 40 mg po BID for 3 out of 4 weeksout of 4 weeks

• Pulmonary and cardiac toxicities have not been seenPulmonary and cardiac toxicities have not been seen• Linear and dose-dependent PK profileLinear and dose-dependent PK profile• Half-life of 4 hours supports BID dosingHalf-life of 4 hours supports BID dosing• Demonstrates preliminary evidence of antitumor activity Demonstrates preliminary evidence of antitumor activity • Should be further evaluated in Phase II trialsShould be further evaluated in Phase II trials• Future trials plannedFuture trials planned

• ProstateProstate• PancreasPancreas• BreastBreast• AMLAML 23

AcknowledgementsAcknowledgements• To the patients and their familiesTo the patients and their families• To the staff:To the staff:• MDAndersonMDAnderson

Saneese K Stephen PA , MPAS , MPASaneese K Stephen PA , MPAS , MPA

Chandtip  Chandhasin, PhD Chandtip  Chandhasin, PhD

Senait N  Fessahaye , Data CoordinatorSenait N  Fessahaye , Data Coordinator

• Roswell Park Cancer InstituteRoswell Park Cancer InstituteGrace Dy, MDGrace Dy, MD

Wen Wee Ma, MDWen Wee Ma, MD

Kathy Galus, Pharm DKathy Galus, Pharm D

Deborah Yoon, BSNDeborah Yoon, BSN

• Kinex PharmaceuticalsKinex PharmaceuticalsAllen Barnett, PhDAllen Barnett, PhD

Kristen Thomas, MSKristen Thomas, MS

Johnson Lau, MD, PhDJohnson Lau, MD, PhD

Jane Fang, MDJane Fang, MD

• Fox Chase Cancer CenterFox Chase Cancer CenterRanee Mehra, MD Ranee Mehra, MD

Holly Dushkin, MD Holly Dushkin, MD

Igor Astsaturov, MD, PhDIgor Astsaturov, MD, PhD

Elizabeth Zeidler, RNElizabeth Zeidler, RN

Christine MalizziaChristine Malizzia

• AHRM, IncAHRM, IncLaura DalfonsoLaura Dalfonso

Ben FinkelBen Finkel

Mary CaparoleMary Caparole

Amy HaywardAmy Hayward

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