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TheraSphere Phase II trial results SIR

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TheraSphere Phase II trial results SIR Powered By Docstoc
					                              SIR ABSTRACT #1
Safety, Response and Survival Outcomes of Y90
    Microsphere Radioembolization for Liver
     Metastases: Results from a 151 Patient
    Investigational Device Exemption Multi-
               Institutional Study
•   Study Chair
     – Dr. Al Benson III, Northwestern Memorial Hospital
•   Principle Investigators
     –   Dr. Gary Siskin, Albany Medical Center
     –   Dr. Jeff Geschwind, Johns Hopkins University Hospital
     –   Dr. Gregory Wiseman, Mayo Clinic Rochester
     –   Dr. William Rilling, Medical College of Wisconsin
     –   Dr. Mary Mulcahy, Dr. Riad Salem, Northwestern Memorial Hospital
                                TheraSphere
• Y-90 integral constituent of the
  insoluble, biocompatible glass
  microspheres
• Mean sphere diameter : 20-30 m
• 22,000 to 73,000 spheres / mg
                                                                Comparison of a Human Hair
• 6 dose sizes (3, 5, 7, 10, 15, 20 GBq)                        with TheraSphere (500x)


• Dose by selected target volume
   Activity = [Desired Dose (Gy)] [Mass of Liver Target (kg)]
                       50

• Arterial administration preferentially
  delivers microspheres to tumor;
  spares normal parenchyma
                                                                  TheraSphere Y-90 Glass
                                                                  microspheres Radiation
                    Study Overview
Design
• Single-arm prospective, open-label
• Investigational Device Exemption (Nordion)
• Independent contract research organization
• Patients with Liver Metastases:
    – Primary Colorectal Cancer (CRC)
    – Neuroendocrine (NE)
    – Non-Colorectal/Non-Neuroendocrine (Non-CRC/Non-NE)
Objectives
• Evaluate safety of TheraSphere at doses of 120 ± 10% Gy
• Evaluate Imaging Outcomes (RECIST v1.0)
    – Response Rate (RR)
    – Progression Free Survival (PFS)
    – Independent central review
•   Evaluate Overall Survival (OS)
        Main Inclusion Criteria
• ≥ 18 years of age
• Metastatic disease refractory to, or inappropriate for
  other systemic or liver-directed therapies
• Unresectable tumors
• Measurable disease
• Tumor replacement  50% by liver volume
• ECOG PS 0-2
• ≥ 30 day from prior cancer therapy
• Signed informed consent
           Main Exclusion Criteria
• Risk of hepatic or renal failure
   – Serum creatinine >2.0 mg/dL, unless on dialysis
   – Serum bilirubin  2.0 mg/dL
   – Albumin < 2.0 g/dL
   – History of hepatic encephalopathy
• Pulmonary insufficiency, clinically evident COPD
• Contraindication to TheraSphere or radiology procedures
• Cirrhosis or portal hypertension
• Prior Y90 microspheres or EBRT to the liver
• Intervention for, or compromise of the Ampulla of Vater
• Clinically evident ascites
• Co-morbidities or unresolved adverse events
• Positive serum pregnancy test
          Trial Treatment Schedule
• Pre-Treatment Procedures (< 28 days prior to Day 0)
   – Screening for eligibility, informed consent; medical history; labs;
     CT/MRI; 99TcMAA scan and hepatic angiography (coil embolization)
   – Develop treatment plan: determine target volume; activity to treat
     target volume; account for decay; schedule treatment, order dose
     vial
• Day 0 - Treatment first lobe: position catheter, infuse
  microspheres
• Week 2 – Telephone follow-up (safety)
• Week 5 – Assess safety & response, treat 2nd lobe
• Months 3, 6, 9, 12 then every 6 months – Assess safety &
  progression
                    Study Enrollment
                       CRC           NE        Non CRC / Non NE   All Patients
   Study Center        N=61         N = 44          N = 46          N = 151
                       N (%)        N (%)           N (%)            N (%)

  Albany Medical     17 ( 27.9)    5 ( 11.4)      10 ( 21.7)      32 ( 21.2)
      Center
   Johns Hopkins     12 ( 19.7)   11 ( 25.0)       4 ( 8.7)       27 ( 17.9)

    Mayo Clinic      4 ( 6.6)     10 ( 22.7)       8 ( 17.4)      22 ( 14.6)
      Medical        8 ( 13.1)     8 ( 18.2)       6 ( 13.0)      22 ( 14.6)
      College
     Wisconsin
   Northwestern      20 ( 32.8)   10 ( 22.7)      18 ( 39.1)      48 ( 31.8)
    University

• First patient enrolled: January 2007
• Last patient enrolled: October 2009
• Last patient visit: by March 1, 2011
        Results – Patient Population
•   Mean age 63.7 years
•   55.6 % male
•   91.4 % Caucasian
•   95.4 % ECOG 0-1
•   68.9% bilobar disease
•   Mean 2.5 years from initial diagnosis
•   Medical history consistent with age/disease:
    – > 50% patients with histories in GI, Musculoskeletal, General Cardiac,
      Dermatology, Allergy/immunology & Endocrine body systems
• Non CRC/Non NE included: cholangiocarcinoma, breast, ovarian,
  renal cell/bladder, esophageal/gastric, lung, pancreas
         Results – Prior Treatments

                                          Non CRC/
                         CRC      NE       Non-NE    All Patients
     Prior Therapy      N = 61   N = 44    N = 46      N = 151
2 or fewer therapies     43%      93%       59%         62%
3 or more therapies     57 %      7%        41%         38%
Systemic Chemotherapy   100%      30%       70%         70%
Hormone Therapy          0%       50%       20%         20%
Other                    30%      10%       20%         20%
              Results – Dosing
• 243 lobar treatments per protocol
• Average 1.6 treatments per patient
• All patients received 120 Gy +/– 20%
   – No USNRC reportable medical events
• Median cumulative lung exposure <10 Gy
• 2% of patients received > 30 Gy to lung without
  clinical sequelae
        Results – Total Liver Dosing (Gy)
                                                                  Non CRC/ Non-
                              CRC                 NE                   NE            All Patients
                             N = 61              N = 44              N = 46            N = 151
         Mean (SD)      115.3 ( 7.62)         116.4 ( 7.79)       116.3 ( 7.11)      116.0 ( 7.48)
       Median (IQR)     114.3 ( 11.4)          115.0 ( 9.3)        116.1 ( 9.0)      115.0 ( 10.3)

          Min, Max          100, 134            103, 138            97, 133            97, 138



               Site 1             Site 2              Site 3            Site 4            Site 5
Mean        112.2 ( 5.93)      116.3 ( 5.39)      117.3 ( 5.48)      120.2 ( 8.39)    111.7 ( 5.92)
(SD)
Median       111.7 ( 7.1)      117.4 ( 6.7)        116.7 ( 8.3)      119.6 ( 11.1)     110.7 ( 7.9)
(IQR)
Min,          102, 124          105, 126            108, 126           97, 138          104, 130
Max
    Study Analysis Populations
• Safety and OS populations
    • all patients receiving TheraSphere (N = 151)


• RR (CR+PR+SD)
    • patients with completed independent image review
      (N = 130)

• PFS populations
    • CRC patients (N = 56), NE patients (N = 31) with
      complete independent image review
1
2
3
4&5
         Response by RECIST v1.0

Response by      CRC          NE         Non CRC/Non-NE   All Patients
  RECIST        N = 56       N = 31           N = 43        N = 130
                 n (%)        n (%)           n (%)          n (%)

    CR         0 ( 0.0)     0 ( 0.0)        0 ( 0.0)        0 ( 0.0)

    PR         5 ( 8.9)     4 ( 12.9)       3 ( 7.0)      12 ( 9.2)

    SD         30 ( 53.6)   24 ( 77.4)     24 ( 55.8)     78 ( 60.0)

    PD         21 ( 37.5)   3 ( 9.7)       16 ( 37.2)     40 ( 30.8)

CR + PR + SD   35 (62.5)    28 (90.3)       27 (62.8)      90 (69.2)
           Survival Estimates
• CRC
  – Median PFS 2.8 months [95% CI: 1.2 - 3.1]
  – Median OS 9.4 months [95% CI: 6.6 - 11.9]


• Neuroendocrine
  – Median PFS 14.6 months [95% CI: 9.0 - 18.4]
  – Median OS 24.0 months [95% CI: 17.5 - 36.3]
         K-M Estimate of Hepatic or Extra-Hepatic PFS Probability




MONTHS
                                                               Kaplan-Meier Progression-Free Survival
         K-M Estimate of Survival Probability




MONTHS
                                                Kaplan-Meier Overall Survival
                     Conclusions
• TheraSphere demonstrated excellent tolerability and safety
  profile in patients with advanced metastatic liver disease

• Highly reliable delivery of planned radiation dose

• Prospective, multicenter confirmation of anti-tumor effect in
  patients without alternative therapeutic options

• Results were reproducible among all centers; set the stage
  for international, multicenter phase 3 RCTs