Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT)
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Transcript of Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor (IMT)
Targeting ALK Receptor Tyrosine Kinase Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor in Inflammatory Myofibroblastic Tumor
(IMT)(IMT)James E ButrynskiJames E Butrynski11, David R D’Adamo, David R D’Adamo22, Andrew Wolanski, Andrew Wolanski11, ,
Linda AhnLinda Ahn22, Laurie Chiambalero, Laurie Chiambalero11, Kristie Stolgitis, Kristie Stolgitis11, , Pasi A JannePasi A Janne11, Eunice L Kwak, Eunice L Kwak33, Jeffrey W Clark, Jeffrey W Clark33, ,
Keith WilnerKeith Wilner44, James Christensen, James Christensen44, George D Demetri, George D Demetri11, , Robert G MakiRobert G Maki22, Geoffrey I Shapiro, Geoffrey I Shapiro11
1 Dana-Farber Cancer Institute, Boston, MA 1 Dana-Farber Cancer Institute, Boston, MA 2 Memorial Sloan-Kettering Cancer Center, New York, NY2 Memorial Sloan-Kettering Cancer Center, New York, NY3 Massachusetts General Hospital, Boston, MA 3 Massachusetts General Hospital, Boston, MA 4 Pfizer Oncology, La Jolla, CA4 Pfizer Oncology, La Jolla, CA
IMT- What do we knowIMT- What do we know • Myofibroblastic spindle cells with an Myofibroblastic spindle cells with an
inflammatory infiltrateinflammatory infiltrate
• Predilection for children and adolescentsPredilection for children and adolescents
• Common sites mesentery, omentum and Common sites mesentery, omentum and lunglung
• Standard treatment-SurgeryStandard treatment-Surgery
• No established systemic therapyNo established systemic therapy
• Anaplastic Lymphoma Kinase (ALK) Anaplastic Lymphoma Kinase (ALK) expression and expression and ALKALK gene rearrangement gene rearrangement
Courtesy of Jason L. Hornick, M.D., Ph.D.
IMT- What do we knowIMT- What do we know
• ALKALK fusion partners in IMT fusion partners in IMT
–TPM3,4TPM3,4
–RAN-BP2RAN-BP2
–CARSCARS
–ATICATIC
–SEC31L1SEC31L1
Courtesy of Yael Mosse, CCR 2009
HypothesisHypothesis
• ALK inhibitors have a role in ALK inhibitors have a role in refractory IMTrefractory IMT
PF-02341066PF-02341066
Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants
ON
N
Cl
F
Cl
NN
N
Kinase IC50 (nM)
Mean Selectivity
Ratioα
c-Met 8 ---
ALK 20 2X
RON 248 31X
Axl 308 39X
Tie-2 448 56X
Trk A 580 73X
Trk B 399 50X
PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.
PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.
MET/HGFRMET/HGFR ALKALK
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
SEMA
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPPYYPPYYPP
YYPP
YYPP
TMTM
YYPP
YYPP
YYPP
YYPP
TMTMExtracellular
Intracellular
YYPP
YYPP
Kinase
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
KinaseYY
PP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
YYPP
Kinase
Cytoplasmic Fusion Variants of ALK
Cytoplasmic Fusion Variants of ALK
NPM-ALKNPM-ALK EML4-ALKEML4-ALK
A8081001: Study ObjectivesA8081001: 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.
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.
Dose EscalationDose Escalation
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).
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).
Cohort 4Cohort 4
Cohort 1Cohort 1
50 mg QD50 mg QD
Cohort 2Cohort 2
100 mg QD100 mg QDMDZ Sub-StudyMDZ Sub-Study
Cohort 3Cohort 3
200 mg QD200 mg QD
Cohort 4Cohort 4
200 mg BID200 mg BID
Cohort 5Cohort 5
300 mg BID300 mg BID
Cohort 6Cohort 6
250 mg BID250 mg BID
MDZ Sub-StudyMDZ Sub-Study
MTD/RP2DMTD/RP2D
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
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
Pfizer Confidential
Most Common Treatment-Related Adverse Events Most Common Treatment-Related Adverse Events (≥ 10%) Dose Escalation Cohorts (N=37)(≥ 10%) Dose Escalation Cohorts (N=37)
Adverse EventAdverse Event 50 mg QD (n=3)
100 mg QD (n=4)
200 mg QD (n=8)
200 mg BID (n=7)
300 mg BID (n=6)
250 mg BID(n=9)
Grade 1-2 1-2 1-2 3 1-2 1-2 3 1-2 3
Nausea 2 3 6 0 3 4 0 4 0
Vomiting 2 2 5 0 2 2 0 3 0
Diarrhea 3 0 1 0 2 0 0 2 0
Fatigue 2 2 0 0 0 0 2 1 1
Headache 0 2 1 0 1 0 0 0 0
Visual Disturbance 0 0 0 0 1 1 0 0 0
ALT Increased 0 0 0 1 1 0 0 0 0
AST Increased 0 0 0 0 1 0 0 0 0
DLTs
43 year old male 43 year old male ALK-ALK-rearranged IMTrearranged IMT• June 2007 Ex Lap-omentectomy, right hemicolectomy, June 2007 Ex Lap-omentectomy, right hemicolectomy,
tumor debulking, IOHC with CDDP, Doxorubicin, MMCtumor debulking, IOHC with CDDP, Doxorubicin, MMC• August 2007 to November 2007 AIM X 6August 2007 to November 2007 AIM X 6• November 2007 to February 2008 ImatinibNovember 2007 to February 2008 Imatinib• March 2008 PF-02341066 200mg BIDMarch 2008 PF-02341066 200mg BID• May 2008 unconfirmed PRMay 2008 unconfirmed PR• June 2008 confirmed PRJune 2008 confirmed PR• October 2008 continued PR but some growingOctober 2008 continued PR but some growing• November 2008 PF-02341066 250 mg BIDNovember 2008 PF-02341066 250 mg BID• Dec 2008 Ex lap debulkDec 2008 Ex lap debulk• Jan 2009 PF-02341066 250mg BID. Continues NEDJan 2009 PF-02341066 250mg BID. Continues NED
Courtesy of Jason L. Hornick, M.D., Ph.D.
ALK
Courtesy of Jason L. Hornick, M.D., Ph.D.
FISH
Courtesy of Jason L. Hornick, M.D., Ph.D.
40%
53%
58%57%
Radiographic Response
Response at 3 months in ALK-rearranged IMTPRE POST
21 year old male 21 year old male nonnon ALKALK-rearranged -rearranged IMTIMT
• December 2007 Ex Lap- debulking, partial December 2007 Ex Lap- debulking, partial gastrectomy, partial right colectomy and gastrectomy, partial right colectomy and splenectomysplenectomy
• February 2008 prednisone and ibuprofenFebruary 2008 prednisone and ibuprofen• July 2008 PF-02341066 250mg BIDJuly 2008 PF-02341066 250mg BID• August 2008 increasing Total BiliAugust 2008 increasing Total Bili• August 2008 Hold PF-02341066August 2008 Hold PF-02341066• August 2008 Repeat imaging increasing August 2008 Repeat imaging increasing
abdominal diseaseabdominal disease
ConclusionsConclusions
• Dramatic response to PF-02341066 Dramatic response to PF-02341066 in in ALKALK-rearranged IMT.-rearranged IMT.
• No benefit to PF-02341066 in No benefit to PF-02341066 in nonnon ALK-rearranged IMT ALK-rearranged IMT
Future DirectionFuture Direction
• Phase II in Phase II in ALKALK-rearranged IMT-rearranged IMT
• Clinical trials in other ALK driven Clinical trials in other ALK driven tumorstumors
• Mechanisms of resistance to ALK Mechanisms of resistance to ALK inhibitioninhibition
AcknowledgmentsAcknowledgments
James Christensen, Keith James Christensen, Keith WilnerWilner
The Patients The Patients
Research StaffResearch Staff
Massachusetts General HospitalMassachusetts General Hospital
Dana-Farber Cancer InstituteDana-Farber Cancer Institute Memorial Sloan-KetteringMemorial Sloan-Kettering
Geoffrey Shapiro, George Demetri, Pasi Janne, Jason Hornick, Paola Dal Cin, Monica Bertagnolli, Andrew Wolanski, Laurie Chimbalero, Kristie Stolgitis
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
Robert Maki, David D’Adamo, Paul Myers, Linda Ahn
John Iafrate, Jeffrey Clark, Eunice KwakJohn Iafrate, Jeffrey Clark, Eunice Kwak
PfizerPfizer