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Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT)

Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT). James E Butrynski 1 , David R D’Adamo 2 , Andrew Wolanski 1 , Linda Ahn 2 , Laurie Chiambalero 1 , Kristie Stolgitis 1 , Pasi A Janne 1 , Eunice L Kwak 3 , Jeffrey W Clark 3 ,

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Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT)

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  1. Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT) James E Butrynski1, David R D’Adamo2, Andrew Wolanski1, Linda Ahn2, Laurie Chiambalero1, Kristie Stolgitis1, Pasi A Janne1, Eunice L Kwak3, Jeffrey W Clark3, Keith Wilner4, James Christensen4, George D Demetri1, Robert G Maki2, Geoffrey I Shapiro1 1 Dana-Farber Cancer Institute, Boston, MA 2 Memorial Sloan-Kettering Cancer Center, New York, NY 3 Massachusetts General Hospital, Boston, MA 4 Pfizer Oncology, La Jolla, CA

  2. IMT- What do we know • Myofibroblastic spindle cells with an inflammatory infiltrate • Predilection for children and adolescents • Common sites mesentery, omentum and lung • Standard treatment-Surgery • No established systemic therapy • Anaplastic Lymphoma Kinase (ALK) expression and ALK gene rearrangement

  3. Courtesy of Jason L. Hornick, M.D., Ph.D.

  4. IMT- What do we know • ALK fusion partners in IMT • TPM3,4 • RAN-BP2 • CARS • ATIC • SEC31L1

  5. Courtesy of Yael Mosse, CCR 2009

  6. Hypothesis • ALK inhibitors have a role in refractory IMT

  7. PF-02341066 Extracellular TM TM TM TM P P P P P P P P Y Y Y Y Y Y Y Y Kinase Kinase Intracellular P P P P P P P P Y Y Y Y Y Y Y Y P P P P P P P P P P P P Y Y Y Y Y Y Y Y Y Y Y Y Kinase P P P P P P P P P P P P Y Y Y Y Y Y Y Y Y Y Y Y P P P P Y Y Y Y P P P P Y Y Y Y Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants Cytoplasmic Fusion Variants of ALK MET/HGFR ALK ba SEMA Extracellular TM TM TM TM Intracellular PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases. P P P P Kinase Y Y Y Y P P P P Y Y Y Y NPM-ALK EML4-ALK Y Y P P P P Y Y P P P P Y Y Y Y P P P P Y Y Y Y P P P P Y Y Y Y

  8. A8081001: Study Objectives PF-02341066 dosing schedule: Day minus 7 lead-in, then continuous oral administration for 28 days per cycle. 1. Dose-Escalation • Determine the safety profile of PF-02341066. • Determine recommended phase 2 dose (RP2D) of PF-02341066. • Determine the PK profile of PF-02341066 after oral dosing. 2. Recommended Phase 2 Dose Cohort (RP2D) • Explore anti-tumor activity in an enriched molecular cohort (ALK fusion or MET mutation/amplification). • Promising clinical activity seen in ALK fusion patients.

  9. Dose Escalation Key Eligibility • Advanced malignancy (excluding leukemias) • Age ≥ 18 years • Refractory to or no standard care • ECOG PS 0 or 1 • Adequate organ function • Stable brain metastases Cohort 5 300 mg BID MDZ Sub-Study Cohort 6 250 mg BID Cohort 4 Cohort 4 MTD/RP2D 200 mg BID Cohort 3 200 mg QD Cohort 2 MTD = Maximum Tolerated Dose RP2D = Recommended Phase 2 Dose MDZ = Midazolam (In-vitro data indicated that PF-02341066 is a major substrate and inhibitor of CYP3A activity). 100 mg QD MDZ Sub-Study Cohort 1 50 mg QD

  10. Most Common Treatment-Related Adverse Events (≥ 10%) Dose Escalation Cohorts (N=37) DLTs

  11. 43 year old male ALK-rearranged IMT • June 2007 Ex Lap-omentectomy, right hemicolectomy, tumor debulking, IOHC with CDDP, Doxorubicin, MMC • August 2007 to November 2007 AIM X 6 • November 2007 to February 2008 Imatinib • March 2008 PF-02341066 200mg BID • May 2008 unconfirmed PR • June 2008 confirmed PR • October 2008 continued PR but some growing • November 2008 PF-02341066 250 mg BID • Dec 2008 Ex lap debulk • Jan 2009 PF-02341066 250mg BID. Continues NED

  12. Courtesy of Jason L. Hornick, M.D., Ph.D.

  13. ALK Courtesy of Jason L. Hornick, M.D., Ph.D.

  14. FISH Courtesy of Jason L. Hornick, M.D., Ph.D.

  15. Radiographic Response 40% 53% 57% 58%

  16. Response at 3 months in ALK-rearranged IMT PRE POST

  17. 21 year old male nonALK-rearranged IMT • December 2007 Ex Lap- debulking, partial gastrectomy, partial right colectomy and splenectomy • February 2008 prednisone and ibuprofen • July 2008 PF-02341066 250mg BID • August 2008 increasing Total Bili • August 2008 Hold PF-02341066 • August 2008 Repeat imaging increasing abdominal disease

  18. Conclusions • Dramatic response to PF-02341066 in ALK-rearranged IMT. • No benefit to PF-02341066 in non ALK-rearranged IMT

  19. Future Direction • Phase II in ALK-rearranged IMT • Clinical trials in other ALK driven tumors • Mechanisms of resistance to ALK inhibition

  20. Acknowledgments The Patients Research Staff Dana-Farber Cancer Institute Memorial Sloan-Kettering Geoffrey Shapiro, George Demetri, Pasi Janne, Jason Hornick, Paola Dal Cin, Monica Bertagnolli, Andrew Wolanski, Laurie Chimbalero, Kristie Stolgitis Robert Maki, David D’Adamo, Paul Myers, Linda Ahn Pfizer Massachusetts General Hospital James Christensen, Keith Wilner John Iafrate, Jeffrey Clark, Eunice Kwak

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