Download ACRIN 6671 Update

GOG 0233/ACRIN 6671
UPDATE & CHALLENGES
UTILITY OF PET/CT & USPIO MRI IN
DETECTION OF LYMPHADENOPATHY
IN LOCOREGINALLY ADVANCED
CERVIX CANCER
ACRIN 2008 FALL MEETING
ACRIN GYNECOLOGY COMMITTEE
SCHEMA
Locoregionally advanced, histologically confirmed invasive
cervical cancer
(Stages IB2, IIA ≥4cm, Stages IIB-IVA)
Pre-operative USPIO MRI (One MRIs will be performed 24-36
hours after injection of COMBIDEX) and
PET/CT Scan of the abdomen and pelvis and chest
No evidence of disease outside of the
pelvis or abdominal nodal region
amenable to biopsy or sampling (i.e.
intrahepatic, pulmonary, or thoracic
or supraclavicular lymphadenopathy
on PET/CT)
Evidence of disease outside of the
pelvis or abdominal nodal region
amenable to biopsy or sampling
(i.e. intrahepatic, pulmonary, or
thoracic or supraclavicular
lymphadenopathy on PET/CT)
Advanced
Lymph
adenopathy
not
amenable to
surgery
No evidence of disease outside of the
pelvis or abdominal nodal region on
PET/CT
Evidence of disease outside of
the pelvis or abdominal nodal
region on PET/CT
Advanced
Lymph
adenopathy
not
amenable to
surgery
Biopsy of metastatic
disease outside of the
Extra-peritoneal or laparoscopic
abdominal & pelvic lymph node Bx (-) pelvis or abdominal nodal
region by FNA, core biopsy,
sampling
or surgical biopsy
Bx (+)
Chemo-Radiation Therapy
to start within four weeks
of enrollment into the
study
Lymphadenectomy
abandoned, Chemotherapy
Protocol for Advanced
/Recurrent Disease
OBJECTIVES
PRIMARY
 Accuracy of CT/PET to detect
abdominal lymph node metastasis
 Accuracy of USPIO MRI to detect
abdominal lymph node metastasis
EXTRA-PERITONEAL/LAPAROSCOPIC
LYMPHADENECTOMY
 Separate regional lymphadenectomy
 Rt. & Lt. Obturator
 Rt. & Lt. External Iliac
 Rt. & Lt. Common Iliac
 Para-caval & Lt. Para-aortic
 Independent confirmation of ±
disease/region
 Intra-operative frozen section/biopsy for
grossly positive LNs
 Lymphadenectomy for negative LNs
SAMPLE SIZE AND INTERIM
ANALYSIS
 Sample size: 325 patients in 36 months
CENTRAL READER STUDY
AT ACRIN/Reader’s Institution
 7 Readers for PET/CT & 7 Readers for USPIO MRI
 60 positive and 60 negative patients
 Blinded independent review
 Initial PET review followed by PET/CT
 Initial USPIO insensitive review followed by USPIO MRI
IMAGE QUALITY REVIEW
According to Protocol
 First 3 MRI cases from each
participating center will be reviewed
 Random sample of MRI cases to be
reviewed
 The same QA for PET/CT at the
headquarter
PROTOCOL CHANGE
PRE & POST COMBIDEX MRI
 Study Population (N=40)
 Pre Combidex injection MRI
 Day of PET/CT
 Post Combidex MRI
 24 – 36 hours
 Separate analysis during central reader
study
HISTORY
 Initial CTEP approval: April 2007
 Activation date: September 2007
 Amendment # 4 approval: September
2008
 Accrued patients: N = 20
STUDY CHALLENGES
 Administrative
 Site issues
 20 sites have shown interest
 11 IRB approved
 7 sites “ready” to accrue
 4 sites have accrued (N = 20)
 Oklahoma: 17 patients accrued
 MSH in NY: 1 patient accrued
 Providence, RI: 1 patient accrued
 Brown: 1 patient accrued
SITES OPENED TRIAL
 UCLA: July 2008 (Oct 2008)
 Transportation, Uninsured patients,
PET/CT approval
 Montefiore Medical Center: March 2008
 Received ECLS certification Sept. 2008
 Brown University Jan. 2008 (Sept. 2008)
 Did not have access to Combidex
STUDY CHALLENGES
 Administrative
 Site issues
 20 sites have shown interest
 18 or 11 IRB approved
 7 sites “ready” to accrue
 4 sites have accrued
 Imaging issues
IMAGING ISSUES
QA: First 3 cases & Random
 COMBIDEX MRI
 T2*
 Use of Glucagon
 Coverage
 PET/CT
 Use of separate PET & CT machines
 Lack of contrast
IMAGING ISSUES
QA: First 3 cases & Random
 COMBIDEX MRI
 T2*
 Use of Glucagon
 Coverage
 PET/CT
 Use of separate PET & CT machines
 Lack of contrast
LESSONS LEARNED
 We are doing an efficacy study
 Any deviation from standard require
close monitoring
 Evaluation of innovation
 Any deviation from surgical guidelines
 Establish a true date for trial opening at
a site
STUDY
OPPORTUNITIES
 First ACRIN study involving an IND agent
 First ACRIN study involving FDA
 First ACRIN study requiring SAE reporting
 First ACRIN /GOG full cooperative study
ACRIN / RTOG Concept:
Pre-treatment tumor parameters and intratherapy tumor response as measured by FDGPET/CT and DCE-MRI
 Evaluates 2 functional imaging methods (targeting
metabolism and perfusion) for characterizing
primary tumor regarding susceptibility to RT
 Intra-therapy FDG-PET/CT or DCE-MRI at 3 weeks
predicts patient-specific response to treatment, as
indicated by 3-month post-treatment FDG-PET/CT
 Perfusion parameters determined by DCE-MRI can
be used as biomarkers for response to antiangiogenic chemotherapy
STUDY RESPONSIBILITIES
ACRIN
Registration
Data Collection &
Management & Analysis
Data Management
Training
Imaging Training
Pathology
GOG
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STUDY RESPONSIBILITIES
ACRIN
AE reporting
Imaging Adverse Event
Collection
Surgery Adverse Event
Collection
Publication
GOG
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INSTITUTIONAL MRI TRAINING




Site MRI PIs invited
One day course at ACRIN headquarter
MH, MG, MA presentations
Review of cases on individual
workstations
 Test cases on workstations
LYMPH NODE SAMPLING
 Lymph nodes < 1cm to be bisected from its hilum
 Lymph nodes > 1cm to be sliced in 5 mm sections
from the periphery
 Size of the largest focus of cancer in a lymph node
for each region (mm)
 Short axis of the largest positive lymph node (mm)
 The 120 cases for central reader study will be
reviewed for pathology in a central review
SUBMISSION TO FDA/CTEP
 March 2006:
Submission to FDA/CTEP
 April 2006:
Response from FDA/CTEP
 June 2006:
Response to FDA/CTEP
 Last correspondence: August
awaiting final approval
PROTOCOL CHANGE
 Addition of USPIO insensitive MRI review
 Termination of Combidex injection
 Anaphylaxis, systolic blood pressure <80 mmHg,
O2 saturation lower than 80%
 Evidence of hypersensitivity defined as
generalized rash, urticaria, or pruritis
 Central review is allowed at the reader’s
institution
IMAGE QUALITY REVIEW
 First 3 MRI cases from each
participating center will be reviewed by
Dr Harisinghani (MGH)
 Random sample of MRI cases to be
reviewed by MA and JB
 The same QA for PET/CT at the
headquarter
COMBIDEX & FDA SUBMISSION
 The FDA stated that it was willing to
work with Advanced Magnetics on how
to address the issues raised in the
approvable letter.
HISTORY
 2003 – 2004
GOG approved PET study became
ACRIN approved ACRIN 6671 USPIO
MRI and PET/CT
 Dec 2004
GOG organizes final protocol
development and submission to CTEP
COMBIDEX & FDA SUBMISSION
 March 24, 2005: Advanced Magnetics,
Inc. announced today that the
Company received an approvable letter
from (FDA) regarding Combidex, FDA
requested additional data to
demonstrate the efficacy of Combidex.
The FDA suggested that the data be
limited to a well defined population of
specific cancer types.
OBJECTIVES
SECONDARY (IMAGING)
 Accuracy of PET/CT to detect pelvic
and abdomen & pelvic combined LNM
 Accuracy of USPIO MRI to detect pelvic
and abdomen & pelvic combined LNM
OBJECTIVES
SECONDARY (IMAGING)
 To compare the accuracy of PET/CT and USPIO
MRI for abdomen, pelvic, A&P combined LNM
 To determine the added value of PET/CT
to PET alone
 To determine the added value of USPIO MRI
to USPIO insensitive MRI
OBJECTIVES
SECONDARY (NON-IMAGING)
 To determine complications associated
with laparoscopic or extra-peritoneal
lymphadenectomy including delay or
interruption of treatment
 To determine the adverse effects of
USPIO
HISTORY
 2003 – 2004
GOG approved PET study became
ACRIN approved ACRIN 6671 USPIO
MRI and PET/CT
 Dec 2004
GOG organizes final development and
submission to CTEP
 June 2005
GOG asked ACRIN to take over FDA
and CTEP submission
SUBGROUP OF ENTIRE
COHORT
LITERATURE REVIEW
PET & CERVIX CANCER
 PET meta-analysis (15 published series) p
 Pelvic LNs
 Sensitivity: 79% (95% CI 65%-90%)
 Specificity: 99% (95% CI 96%-99%)
 Para-aortic LNs
 Sensitivity: 84% (95% CI 68%-94%)
 Specificity: 95% (95% CI 89%-98%)
 PET/CT: Pelvis & Para-aortic (N=47) pp
 Sensitivity: 73%
 Specificity: 97%
P Havrilesky LJ, Gynecol Oncol 2005
pp Sironi S, Radiology 2006
LITERATURE REVIEW
MRI COMBIDEX & CERVIX CANCER
 Prostate cancer (N=80) P
 Pelvic LN
 Sensitivity: 100%
 Specificity: 96%
 Gynecology cancer: Pelvis & Paraaortic (N=44) pp
 Sensitivity: 95%
 Specificity: 91%
P Harisinghani MG, N Engl J Med 2003
pp Rockall AG, Journal of Clinical Oncology, 2005
STUDY RESPONSIBILITIES
ACRIN
Registration
Data Collection &
Management & Analysis
Pathology
+
+
+
AE reporting
Imaging Training
GOG
+
+
STUDY RESPONSIBILITIES
ACRIN
Data Management
Training
Imaging Adverse Event
Collection
Surgery Adverse Event
Collection
Publication
GOG
+
+
+
+
+
PATIENT ACCRUAL
N = 21
 Study opened: Sept. 2007
 First patient accrued at Oklahoma Univ.
 Oklahoma: 17 patients accrued
 MSH in NY: 2 patients accrued
 Brown: 1 patient accrued
SAMPLE SIZE AND INTERIM
ANALYSIS
 Sample size: 325 patients in 36 months
 Interim analysis
 30 positive cases & 30 negative cases
 At 20th month
 AMAG agrees to “Go ahead” with
Sensitivity > 60%
RATIONAL FOR A CLINICAL TRIAL
 Limited data for PET/CT For Para-aortic LNs
 Almost no data for Combidex MRI for Paraaortic LNs
 Published Study Methodology
 Single center
 Node/node correlation