Seminal Papers Flashcards
In Bergman et al 2006 on xenogenic DNA vaccine:
What AE was encountered?
aural depigmentation with muGP75
foot pad vitiligo with muTyr
In Bergman et al 2006 on xenogenic DNA vaccine:
What was the MST for dogs with adequate locoregional control?
MST = 569d
In Bergman et al 2006 on xenogenic DNA vaccine:
Which xenogenic DNA had the longest MST?
Out of huTyr, muTyr, and muGP75
MST = 389 vs 224d and 153d
In Bergman et al 2006 on xenogenic DNA vaccine:
What kind of study is this?
a combination of Phase I and Phase II
In Bergman et al 2006 on xenogenic DNA vaccine:
How does DNA vaccine work?
The DNA is inserted into a bacterial plasmid that has promoter that is always “on” to produce the antigen of interest.
The vaccine is given IM for the antigen presenting cells, esp the dendritic cells, to pick and present to the immune system. The bacteria and plasmid itself will also act to help to stimulate the immune system
In Bailey et al 2009 for cat AUC GFR carbo:
What’s the study design?
Phase I, 3x3 cohort study
- dose escalate until there is at least 1 toxicity, then expand the same dose with 3 more cat, if >2 toxicities noted, reduce the dose by 0.25
- if no more AE, then continue with the dose escalation
- Max dose = <1 in 6 cats develop unacceptable AE
(non clinical grade IV neutropenia, clinical neutropenia, grade IV thrombocytopenia, >grade III GI, death)
In Bailey et al 2009 for cat AUC GFR carbo:
How was the GFR determined and what was the median GFR?
The GFR was determined by 99mTc-DTPA with serial blood draw and the plasma radioactivity measured by sodium iodide well counter
- the median GFR was 1.97
- healthy cats = 2.01; those with renal insufficiency = 1.04.
Interestingly, 34% cats have GFR <1.71 but only 19% of them have clinical azotemia
In Bailey et al 2009 for cat AUC GFR carbo:
What’s the final dose for carboplatin based on GFR?
AUC = 2.75
dose = 2.75 x 2.6 x BW x GFR
What are the potential problems with BSA dosing based on Price et al 1998?
the formula for BSA = k x BW*a
- the “k” may not be accurate
- the a (2/3), taken from volume calculation, but also not be accurate
- but changing those 2 still doesn’t resolve overdosing smaller dogs
- adding in length ends up underdosing smaller dogs
- BSA also doesn’t take into functional differences (ex. liver mets, renal tumours)
- would be great to have a better BSA, but may need to look into alternative dosing methods (ex. GFR)
When would BSA dosing be appropriate based on Frazier et al 1998?
- elimination intact via glomerular filtration
- or degraded nonenzymatically with GFR = rate limiting factor for excretion
Based on Frazier et al 1998:
What’s the issue with BSA dosing when examining the PK of chemoetherapy?
- Absorption. This is not dependent on metabolism (ex. carrier mediated, or passive diffusion)
- Distribution.
BSA independent processes include: carrier mediated transport, protein binding, issues with pathological states (ex. effusion and hydrophilic drugs), hypoalbuminemia, passive diffusion - Excretion.
- GFR will depend on protein binding of the drug
- metabolism may be the rate limiting factor, which may have species differences but not within species - Metabolism.
Not all functions associated with metabolism is due to BSA, may just have species variation
How are the following drugs eliminated:
- doxorubicin
- cisplatin
- mitoxantrone
- 5-FU
- vincristine
- vincristine
Biliary: doxorubicin, mitoxantrone, vincristine
Renal: cisplatin, 5-FU
In London et al 2009 on Palldia on recurrent MCT:
How does c-kit influence outcome with Palladia?
c-kit is associated RR but not TTP
In London et al 2009 on Palldia on recurrent MCT:
What were the causes of death in 2 dogs that could be due to Palladia?
pancreatitis
gastric ulcer
What’s the RR of the following chemo for canine MCT?
- lomustine
- vincristine/ vinblastine
- vinblastine with pred
- prednisone only
Lomustine = 42%
Vincas = 7039%
VINB + pred = 27-64%
Prednisone = 20-70%
but all of short duration
According to London et al 2009 on Palldia on recurrent MCT:
What’s the significance of the c-kit mutation in canine MCT
- c-kit mutation is more likely to be found in high grade tumour (grade 3 vs 2: 16.4% vs 31.6%)
- it is associated with improved RR (60% vs 31.3%)
- but no association with TTP or duration of resposne
In London et al 2009 on Palldia on recurrent MCT:
What’s the overall RR for Palladia in dogs with MCT?
42.8%
What type of study is London et al 2009 on Palldia on recurrent MCT?
Prospective, double blinded, centrally randomized, multi-centre sequential clinical trial with a blinded and open label phase
In Vail et al 2009 on Tanovea:
Duration of first remission:
B vs T cell
Naive vs relapsed
Overall median duration of first remission = 128d (4m)
B cell = 132d (4m)
T cell = 14d
Naive = 142d (~5m)
Pre-treatment = 99d (3m)
In Vail et al 2009 on Tanovea:
What were the DLT AE observed? Which groups had the most AE?
DLT = dermatologic, GI and neutropenia.
- mostly in the daily x 5d group
- no derm toxicity in the 21-day group
- Derm = superficial erythematous lesions, pruritic, mostly in the ear canal and/or small foci on the back or inguinal area
- resolved within 2-3 weeks with drug holiday
- 2 dogs had respiratory signs
What’s the MOA of Tanovea?
it’s a double pro-drug of PMEG.
- PMEG itself has poor permeability and nonspecific toxicity
- but has activity against leukemia and melanoma
- as a double pro-drug, it will be hydrolyzed in lymphocytes, and then deaminated to PMEG
- then phosphorylated to its active form, PMEG diphosphate
In Vail et al 2009 on Tanovea:
What’s the ORR and RR based on naive/ pre-treated and immunophenotype?
ORR = 79% (61% CR, 18% PR)
Naive: 100% (76% CR)
Pre-treated: 62% (48% CR)
B-cell = 86%
T-cell = 56%
According to the VCOG consensus on LN measurements (Vail et al 2015):
What’s the definition of target disease?
- a pathological lesion should be >10mm
- a target lesion should be >20mm
- record min 1, max 5
- if becomes non-palpable or WNL –> default to 5mm
According to the VCOG consensus on LN measurements (Vail et al 2015):
What’s a new lesion?
- any previously none documented lesion (ie. not a target lesion or non-target lesion)
- or if unsure, continue to monitor to see if it progresses
- if it’s a peripheral LN, it must be >15mm
