calgb fall committee meeting october 2006 correlative science protocol development paula n....

CALGB Fall Committee Meeting October 2006

Correlative Science Protocol Development

Paula N. Friedman, PhDDirector, Biospecimen & Correlative Science

Operations


Where in the protocol should there be information about CS?

• Introduction• Objectives• Sample Submission• CS Methods*• Statistical Considerations• Model Consent Form


When in the process does CS need to be considered?

Right from the start!!


Things that should be included in the concept/protocol

• The biologic rationale for studying the proposed marker(s). – Why are the markers relevant to study and

how are they related to the therapy?• The specific hypotheses behind the proposed

correlative studies.– What is it you are expecting to find and why?


Things that should be included in the concept/protocol

• Preclinical data that supports the proposal to look at the markers*

• Preliminary data from other clinical trials that have looked at the markers*

• Statistical considerations• The proposed contributions that this study will

make to the field• Future plans for analysis of the markers if this

study accomplishes its goals*references should be provided


Things that should be included in the protocol

• A detailed description of the types of samples to be collected and the timepoints (Table).

• Any information about the stability of the marker under the collection conditions proposed

• A description of the assay method and the reason for selecting it.

• A summary table that includes assay type, sample type, key contact and institution


Correlative Science Table

Correlative Study Assay Sample Type Testing Investigator/

Institution

DNMT1 Expression and Protein Level Q RT-PCR Bone Marrow/

Peripheral Blood Blum, Marcucci/

OSUMC

Western blot

Bone Marrow/ Peripheral Blood

Blum, Marcucci/ OSUMC

DNA Demethylation as measured by HbF expression

HPLC Peripheral Blood Blum, Marcucci/

OSUMC

Global Hypomethylation HPLC/MS/MS Bone Marrow/

Peripheral Blood Blum, Marcucci, Chan/

OSUMC

Minimal Residual Disease Q PCR and/or “Genescan”



Re-expression of Epigenetically Silenced Genes – Ex-Vivo Studies

Q RT-PCR Bone Marrow/

Peripheral Blood Blum, Marcucci/

OSUMC

Bio-COBRA



Busulfan Pharmacokinetics HPLC/MS/MS Plasma Merril Egorin, UPCI


Submitting Institution

Frozen cores/Surgical Specimens + touch prep slide

Paraffin Cores/ Surgical Specimens and touch prep slide

20* Slides to UNC lab for: topoII/HER2 FISH Ki67 Feulgen Ploidy BCL2* HER2* FAK* p53* EGFR Cd34* Mcm2* Controls *whenever feasible markers will be combined as dual assays (p53/EGFR)

6 Slides to UPenn for: Cyclin D* Cyclin E* P21 P27 Controls *dual assay

UNC- Dressler Lab

5 slides to GMU

Petricoin/ Liotta Lab

for Proteomics

4 slides to UCSF

Haqq Lab for CDNA

arrays

Extract DNA

Extract RNA

UCSF- Chew/Haqq Lab

Immortalize DNA

DNA to Kathy Conway (UNC) for p53 sequencing

DNA to Gray Lab (UCSF/ LBNL) for CGH arrays

RNA sent to Chuck Perou (UNC) for Gene Expression Microarrays

HER2 by ELISA assay

Serum

CALGB PCO

UCSF- Park Lab


Things that should be included in the protocol

• The technical performance of the assay– Qualitative vs. quantitative– Accuracy (Sens, Spec, PPV, NPV)– Reproducibility (day and user)– Sources of variability and how variability will be minimized

• A description of the positive and negative controls to be used

• Method of scoring that will be used. • The certification of the testing lab

– CLIA and/or CAP– If not, how the QA/QC will be handled


Why is this so important?• If the sample collection is not accurately

described then the appropriate samples will not be collected.

– Example: CALGB 80101- The companion study, CALGB 150205, calls for analysis of IGF-1, IGF-2 and IGFBP-3 in serum but the protocol is not clear as to the collection of serum samples.

– We collected plasma at the bank from the blood tube designated for PET and some markers can be done on plasma but not all

• While going to all the trouble of collecting these valuable samples we need to make sure that they are being utilized fully.– We need to consider using the sample for proteomics (discovery)


Why is this all so important?

• If the protocol text is not clear then a patient may not be registered to the companion, samples may not be collected appropriately and sent to the bank and consent may not be obtained or correctly recorded.– Example: CALGB 60401 - PET companion to

CALGB 80303


The Reality

Patients accrued to the clinical trial 601Patients that consented to the companion and have a high quality sample banked 362Patients that consented to the companion and have a poor quality sample banked 13Patients that consented to the companion and have no sample banked 85Patients that did not consent to the companion and have a high quality sample banked 17Patients that did not consent to the companion and have no sample banked 124


What we are doing to make the system work better

• Summary tables in protocols • SOPs for sample collection• Standardized consent questions• “Real-time” monitoring of sample submission• Patient brochures on the importance of sample

donation• New committee - Biospecimen & CS Advisory• Reference labs that are CLIA/CAP certified


Contact Information

Paula N. Friedman, PhD

CALGB Central Office

(773)702-4694

[email protected]

calgb fall committee meeting october 2006 correlative science protocol development paula n....

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