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A Phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies A. A. Adjei, R.

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Presentation on theme: "A Phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies A. A. Adjei, R."— Presentation transcript:

1 A Phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies A. A. Adjei, R. B. Cohen, R. Kurzrock, G. S. Gordon, D. Hangauer, L. Dyster, G. Fetterly, S. Barrientes, D. S. Hong, A. Naing Roswell Park Cancer Inst, Buffalo, NY; Fox Chase Cancer Center, Philadelphia, PA; MD Anderson Cancer Center, Houston, TX; Kinex Pharmaceuticals, Buffalo, NY 1 FOX CHASE Cancer Center

2 Disclosure Information ASCO ANNUAL MEETING 2009 Alex A. Adjei I have no financial relationships to disclose. I have no financial relationships to disclose.

3 Src signaling in tumor cells Yeatman, Nat Rev Cancer, 2004

4 Src Kinase in Cancer There are over 500 serine and tyrosine kinases in humans; Src is a member of the tyrosine kinase family and the 1 st oncogene discoveredThere are over 500 serine and tyrosine kinases in humans; Src is a member of the tyrosine kinase family and the 1 st oncogene discovered Src activity is high in a majority of primary tumors with further increases during metastasisSrc activity is high in a majority of primary tumors with further increases during metastasis Since Src activity generally increases as cells progress from benign to invasive to metastatic, Src inhibition may inhibit primary tumor growth as well as metastasisSince Src activity generally increases as cells progress from benign to invasive to metastatic, Src inhibition may inhibit primary tumor growth as well as metastasis 4

5 Src kinase Inhibitors in the clinic Dasatinib (Sprycel): (approved for resistant CML, Phase I-II in solid tumors)Dasatinib (Sprycel): (approved for resistant CML, Phase I-II in solid tumors) Bosutinib (SKI-606): (Phase III in resistant CML, Phase I-II in solid tumors)Bosutinib (SKI-606): (Phase III in resistant CML, Phase I-II in solid tumors) AZD0530: (Phase I-II in solid tumors)AZD0530: (Phase I-II in solid tumors) XL228: (Phase 1 in resistant CML & solid tumors)XL228: (Phase 1 in resistant CML & solid tumors) 5

6 KX2-391 Mechanism of action Non-ATP competitive Src signaling inhibitor 2 nd MOA (not a kinase) currently under investigation 6

7 Efficacy 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 Line KX2-391 GI50 (nM) HT29 (Colon) 25 SKOV-3 (Ovarian) 10 PC3-MM2 (Prostate) 9 L3.6pl (Pancreas) 25 MDA-MB-231 (Breast) 20 A549 (Lung) 9 HuH7 (liver) P (kidney)45

8 KX2-391 Compared to Dasatinib in Resistant Solid Tumor Cell Lines Human Tumor Cell Line KX2-391 IC50--IC90 (nM) Dasatinib IC50--IC90 (nM) H460 (NSCLC)) ,880 H226 (NSCLC) ,340 HCT116 (colon) not reached SW620 (colon) ,418--2,940 Literature reported Dasatinib resistant cell lines: 1)Johnson et al, Clin. Cancer Res 2005; 11(19), )Serrels et al, Mol Cancer Ther 2006; 5(12), 3014 Average IC50 = 72 nMAverage IC50 = 888 nM Dasatinib 10X less potent than KX2-391 at IC50 and ca. 100X less potent at IC90

9 KX2-391 Compared to Dasatinib in Leukemia and Multiple Myeloma Cell lines Human Liquid Tumor Cell Line KX2-391 GI50 (nM) Dasatinib GI50 (nM) K562 (CML) K562R (Gleevec resistant CML) Ba/F3 + T315I (Gleevec & Dasatinib Resistant CML) 35Inactive CCRF-HSB-2 (ALL) 12Inactive KG-1 (AML) 16Inactive RPMI8226 (Multiple Myeloma) 40Inactive KX2-391 has a second MOA beyond Src signaling inhibition that might provide broader activity than dasatinib

10 KX2-391 Pre-clinical Toxicology  Oral continuous bid dosing 28-day toxicity studies Rodent GI Toxicity is Dose-Limiting No cardiotoxicity No renal toxicity Non-Rodent (Dog) GI and Hematologic Toxicities are Dose-Limiting No cardiotoxicity No renal toxicity 10

11 Objectives of Phase I Trial Primary Objective: To define the maximum tolerated dose (MTD) of KX2-391 in patients with advanced refractory malignanciesTo define the maximum tolerated dose (MTD) of KX2-391 in patients with advanced refractory malignancies Secondary Objectives: To determine the safety and tolerability of KX2-391 given as single and multiple doses as an oral solution in patients with advanced refractory malignanciesTo determine the safety and tolerability of KX2-391 given as single and multiple doses as an oral solution in patients with advanced refractory malignancies To characterize the pharmacokinetic profile after single and multiple oral dosing of KX2-391To characterize the pharmacokinetic profile after single and multiple 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 KX

12 Trial 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 12

13 Inclusion/Exclusion Criteria Adults over age 18 years of ageAdults over age 18 years of age Confirmed advanced solid tumor or lymphoma for which standard curative or palliative measure do not exist or are no longer effectiveConfirmed advanced solid tumor or lymphoma for which standard curative or palliative measure do not exist or are no longer effective ECOG performance status of 0-2ECOG performance status of 0-2 Adequate bone marrow reserveAdequate bone marrow reserve Adequate liver and renal functionAdequate 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) within 2 weeks or 5 half-lives (whichever is shorter)Not using moderate or strong P450 modulators (inducers or inhibitors) 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 13

14 Patient Demographics CharacteristicsResults Age Median (range) 60 (32-80) years Sex 15 males/ 22 females Median # of previous chemotherapy regimens 3 Median # of previous XRT regimens 2 Most common cancers Number of patients Colo-rectal4 Head and Neck 4 Pancreas4 Breast3 NSCLC3 Thyroid3 Other16 14

15 Dose Escalation Dose Group # patients # with DLTs # with SD> 4 cycles 2 mg BID mg BID mg BID mg BID mg BID mg BID mg BID mg BID 421 TOTAL37611 MTD 15

16 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

17 Treatment Related Adverse Events Adverse Event Grade 1/2* Grade 3/4* Total AST increased7310 ALT increased437 Anorexia55 Fatigue44 Lymphopenia314 Nausea44 Anemia213 Leukopenia214 Alk phos increased33 Pancytopenia123 Febrile Neutropenia22 Dizziness22 Flatulence22 Neutropenia Other Grade 3 or 4 events in one patient: Abdominal pain, bilirubin increased, edema, failure to thrive, hyponatremia, mucositis, rash, thrombocytopenia * Number of patients

18 Dose 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 Events (possibly related, at any dose level)Serious Adverse Events (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 18

19 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+ cyclesThyroid – 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 19

20 Prostate Cancer Patient Change in PSA 20 On TrialOff Trial

21 Pancreas Cancer Patient Change in CA On TrialOff Trial

22 Ovary Cancer Patient Change in CA On Trial

23 Conclusions KX2-391 is well-tolerated at a dose of 40 mg po BID for 3 out of 4 weeksKX2-391 is well-tolerated at a dose of 40 mg po BID for 3 out 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 activityDemonstrates 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

24 Acknowledgements To the patients and their familiesTo the patients and their families To the staff:To the staff: MDAndersonMDAnderson Saneese K Stephen PA, MPAS, MPA Chandtip Chandhasin, PhD Senait N Fessahaye, Data Coordinator Roswell Park Cancer InstituteRoswell Park Cancer Institute Grace Dy, MD Wen Wee Ma, MD Kathy Galus, Pharm D Deborah Yoon, BSN Kinex PharmaceuticalsKinex Pharmaceuticals Allen Barnett, PhD Kristen Thomas, MS Johnson Lau, MD, PhD Jane Fang, MD Fox Chase Cancer CenterFox Chase Cancer Center Ranee Mehra, MD Holly Dushkin, MD Igor Astsaturov, MD, PhD Elizabeth Zeidler, RN Christine Malizzia AHRM, IncAHRM, Inc Laura Dalfonso Ben Finkel Mary Caparole Amy Hayward 24


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