Crizotinib in addition to Radiotherapy and TMZ in newly diagnosed GBM - Juan M Sepúlveda Sánchez Unidad Multidisciplinar de Neurooncología ...

Crizotinib in addition to Radiotherapy
and TMZ in newly diagnosed GBM
              Juan M Sepúlveda Sánchez
       Unidad Multidisciplinar de Neurooncología
                Hospital 12 de Octubre
                        Madrid

GEINO 1402.
 Phase Ib, open-label, multicenter, dose-escalation study
  followed by an extension phase to evaluate the safety and
  activity of the combination of crizotinib with temozolomide and
  radiotherapy in patients with newly diagnosed glioblastoma

 Coordinators
   Dr. María Martínez. Hospital del Mar
   Dr. Juan M Sepúlveda. Hospital Universitario 12 Octubre
 Dose-scalation phase  MTD
 Extension Phase
 4 GEINO Centers: Hospital del Mar, Hospital Clinic, ICO Bellvitge,
  H 12 Octubre

Crizotinib (Xalkori ®)

 Protein kinase inhibitor by competitive binding with
  the ATP-binding pocket
 On August 2011, FDA approved Crizotinib to treat
  metastatic NSCLC with abnormal ALK gene
 Kinases inhibited:
   ALK (and its fusion proteins)
   ROS1 (and its fusion proteins)
   C-MET/Hepatocyte growth factor receptor (HGFR)

MET signaling in GBM.

      C-MET amplification in 5% GBM

Chi AS, et al. JCO, Vol 30, No 3

(January 20), 2012: pp e30-e33

C-Met expression and function is associated with Cancer Stem Cell in GBM

•   GBMs contains stem-like cells (GSC)

     •   Unlimited growth

     •   Self-renewal potential

     •   Multilineage differentiation

     •   Tumor recurrence

     •   Responsible for tumor progression and resistance to radiotherapy and chemotherapy

•   MET activation

     •   Activates properties attributed to GSC

C-Met expression and function is associated with Cancer Stem Cell in GBM (in vitro

                                                               models)

•   Met signaling can shift the heterogeneous composition of glioblastoma-derived neurosphere cells

Ly Y. c-Met signaling induces a reprogramming network and supports the

glioblastoma stem-like phenotype. PNAS June 2011

Rationale. ROS1 in GBM

                  30 GBM treated with
                  the Stupp regimen

                 Dorta M, et al. ASCO 2014

Rationale. ALK-MIDKINE Axis
MIDKINE (MDK; MK;NEGF-2)

Midkine Receptors and signaling

Identification of MDK as a factor of
 resistance to anticancer therapies

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Lorente M et al, Cell Death Diff 2011.

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Blockade of MDK/ALK axis sensitizes Glioma Stem
    Cells to treatment with anticancer agents

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Slide Courtesy of Dr
Guillermo Velasco (UCM)

Slide Courtesy of Dr
Guillermo Velasco (UCM)

The role of the growth factor midquine (MDK) in
    the resistance of glioma cells to anticancer
    agents
• Midquine (MDK) is a factor of bad prognosis in GBM
  • high expression of this protein is associated with lower survival of glioma
                                                                             (Lorente et al. Cell Death Differ. 18:959-

         973; 2011)

•   Mdk promotes the resistance of glioma cells to anticancer agents

     •   This effect relies on the stimulation of ALK receptor

•   "in vivo" silencing of Mdk or pharmacological inhibition of ALK sensitized these tumors to the

    treatment with TMZ

Hypothesis

•   Crizotinib is a rational therapeutic agent. Mechanisms of action:
     • Blocking MET signalling
         • Decrease tumor cell proliferation, survival and migration
         • Of special interest in the 5% of patients with MET amplification
    •   Targeting GSCs
         • Cells related with chemo and radioresistance
         • blocking MET and Mdk are of special interest for GSC activation
    •   Reverting temozolomide resistance induced by high levels of
        Mdk
         • Mdk is a recently discovered ALK ligand
    •   ROS1 inhibition

Study Design

               23

STUDY DESIGN
• Escalation Phase
    Standard “3+3” dose escalation
    N~12 (based on currently estimated 4 cohorts x 3 patients)
      Crizotinib will be administered under fasting conditions initially QD, on a
      continuous schedule in successive dose-escalating cohorts at doses
  ranging from 200 QD to 250 mg BID (1st level- 200 QD; 2nd level- 250 QD, 3rd level- 200 BID and 4th
    level- 250 BID)

•   Expansion Phase

       Crizotinib+RT+TMZ at RPTD

       N~12

       Time to complete enrollment: 1 year (7 centers)

DOSE ESCALATION PHASE (N=12, Sites=4)

 Primary Objective
   To determine the safety profile including the MTD, of
    escalating doses of crizotinib administered with TMZ during
    and after RT in patients with newly diagnosed GBM.

 Secondary Objectives
   To determine the recommended phase II dose (RPTD) and
    schedule for crizotinib plus TMZ-RT.
   To describe the preliminary anti-tumor activity of the
    combination therapy through PFS (6 months PFS rate) and
    the response rate in patients with measurable disease.
   To analyze OS.

EXPANSION PHASE (N=12 , and 2 aditional sites)

    • Primary objectives:
     To describe the safety profile of crizotinib administered with TMZ during
      and after RT.
     To determine the RPTD and schedule for crizotinib plus TMZ-RT
     To assess PFS (PFS rate at 6 months)

     Secondary objectives:

     To assess anti-tumor response according to RANO criteria.
     To assess changes in glucocorticoid use.
     To assess changes in neurological status.

PATIENTS
                                        MAIN EXCLUSION:
 MAIN INCLUSION:
                                          Extracraneal metastatic
   Newly diagnosed GBM
                                           disease
    confirmed by biopsy or resection
                                          EIADs
    no > 4 weeks before registration
                                          GI abdnormalities, inability to
   15 unstained slides or tissue
                                           take oral medication
    block
                                          Significant cardiovascular
   KPS ≥60%
                                           disease
   Adequate hematologic,
                                          Leptomeningeal
    liver and renal function               disemination

TREATMENT PLAN

 4-6 weeks after surgery
 RT: 1,8-2 Gy/d, 5d/week, total dose 58-60Gy
 Concomitant TMZ 75 mg/m2, for max of 42 d, + Crizotinib
  (after RT continue)
 4 weeks after RT: TMZ maintenance: 150 mg/m2 5d/28d,
  and after 200 mg/m2, total of 6 cycles.
 Additional Crizotinib beyond 6 cycles will be allowed.

STATISTICAL CONSIDERATIONS

The primary objective of this trial is to find the RPTD of crizotinib in combination
with radiotherapy and temozolomide

A 6-month PFS rate between 50 and 70% will be considered of desirable interest
for a further phase II clinical trial. The 6 months PFS rate in the Stupp trial was
54% in those patients treated with RT and TMZ.

DDI : TMZ and Crizotinib

 No pharmacological interactions are expected with TMZ and
  crizotinib. Plasma clearance of temozolomide is independent
  of age, renal function, liver function or tobacco use.
  Temozolomide is eliminated primarily in the urine.
  Temozolomide does not appear to affect the metabolism
  of drugs by CYP450.

Biomarker Study

 ROS1, ALK and c-MET alterations
   Frequency
   Association with response and Survival

 MK tissue expression
 MK Blood levels

 Thank you for your attention