Millikan IHO Week 2

Question 1

Human Oncology Trials: Phase 1 Goals

Answer 1

to define a dose (and schedule) tolerable for human patients and ‘optimized’ by some criteria for toxicity and/or efficacy

Question 2

Human Oncology Trials: Phase 2 Goals

Answer 2

to define an anti-cancer effect in some defined group of patients-a ‘disease state’ (hypothesis generating)

Question 3

Human Oncology Trials: Phase 3 Goals

Answer 3

to formally compare some ‘novel’ treatment (or therapeutic strategy) with an existing standard (hypothesis testing)

Question 4

how the body affects the drug

Answer 4

pharmacokinetics

Question 5

how the drug affects the body

Answer 5

pharmacodynamics

Question 6

Phase 1 Clinical Trials

Answer 6

aims to define ‘dose limiting toxicity’ for a particular schedule of 1 or more agents; typically less than 40 patients

Question 7

Toxicity of Events: Grade 1

Answer 7

No physiologic or clinical consquence

Question 8

Toxicity of Events: Grade 2

Answer 8

Physiologically Relevant

Question 9

Toxicity of Events: Grade 3

Answer 9

Events are potentially associated with major morbidity (hospitalization, intensive treatment, etc)

Question 10

Toxicity of Events: Grade 4

Answer 10

Events are life threatening

Question 11

Phase 2 Clinical Trials

Answer 11

Scientific and statistical goal is to define the rate of ‘benefit’ in a defined population; uses a quick response marker, 30-60 patients; includes available info about prognostic factors

Question 12

What do the following have in common: low albumin, high ferritin, high platelets, elevated crp, esr, elevated beta 2 microglubulin, elevated IL6, age, particular genetic lesions

Answer 12

Prognostic Factors

Question 13

Phase 3 Clinical Trials

Answer 13

scientific and statistical goal to formally compare 2 or more tx or strategies using a definitive end-point such as survival time; 300-1200 patients; needs to be pass ‘lucky you’ ethical test

Question 14

alkyator, nitrogen mustard; small molecule; breast cancer, lymphomas, immunosuppression, stem cell mobilization; $1,050

Answer 14

Cyclophosphamide

Question 15

alkyator, nitrogen mustard; small molecule; lymphomas; $10,300/month

Answer 15

Bendamustine

Question 16

alkyator, nitrogen mustard; small molecule; brain cancer

Answer 16

Temozolomide

Question 17

alkyator, nitrogen mustard; small molecule; germ cell tumors, bladder cancer

Answer 17

Cisplatin

Question 18

alkyator, nitrogen mustard; small molecule; epithelial malignancies, second-line treatment of lymphoma

Answer 18

Carboplatin

Question 19

single most important cytoxic drug ever discovered; acrolein metabolite (bladder cancer); good TI unforseen ALDH; ESPECIALLY 5q- (myelodysplasia)

Answer 19

Cyclophosphamide

Question 20

germ cell tumor tumors in pre-transplant salvage regimens for lymphoma and sarcoma; electrolyte wasting, CNS toxicity,

Answer 20

Ifosfamide

Question 21

MESNa

Answer 21

Mercapto-EthylSulphonic Acid, Na salt; protects bladder from acrolein

Question 22

3 Downsides of Cyclophosphamide

Answer 22

-hemorrhagic cystitis, bladder cancer, myelodysplasia

Question 23

Name the 3 Platinums

Answer 23

cisplatin (nephrotoxic), carboplatin(safe, less effective), oxaliplatin (safe, less effective)

Question 24

3 Consequences of DNA Adducts

Answer 24

-inhibition of transcription, inhibition of DNA replication, induction of apoptosis

Question 25

8 Resistance Mechanisms

Answer 25

reduced platium uptake, increased efflux, intracellular detox by glutathione, increased DNA repair, decreased mismatch repair, defective apoptosis, modulation of signaling pathways, presence of quiescent non-cycling cells

Question 26

germ cell tumors, NOT VERY MYELOSUPPRESSIVE, damage to the 8th nerve and long sensory nerves, kidney damage (irreversible), n/v

Answer 26

Cisplatin

Question 27

solid tumors and salvage lymphoma regimens, not as active as ciplatin except for = in lung, gyn and breast cancers, less neurotoxic/emetogenic and nephrotoxic, quite myelosuppressive, causing throbocytopenia

Answer 27

Carboplatin

Question 28

GI cancers, cold intolerance/neuropathy, uncommon for patients to tolerate more than about 8 cycles of tx including oxaliplatin

Answer 28

Oxiplatin

Question 29

important in sarcoma and hodgkin lymphoma; methylates N7 and O6 on GUANINE and N3 on adenine

Answer 29

Dacarbazine

Question 30

prodrug for MTIC, important in CNS tumors, expression of Methylguanine Methyltransferase predicts poor response

Answer 30

Temozolomide

Question 31

4 Clinically Important Facts about non-classical alkylators

Answer 31

1. used for gliomas 2. profound hematologic stem cell toxicity makes them useful for bone marrow transplant conditioning regimens 3. carbazines are vessicants, emetogenic & not used 4. dacarbazine-related prodrug for glioma: MGMT or MMR deficient-> methylation doesn't work

Question 32

Antimetabolite, anti-fol, small molecules, many cancers

Answer 32

Methotrexate

Question 33

Antimetabolite, pyrimidine analog, small molecules, GI cancers

Answer 33

5-Fluorouracil

Question 34

Antimetabolite, pyrimidine analog, small molecules, pancreas cancer, bladder cancer, widely used in second line setting

Answer 34

Gemcitabine

Question 35

Antimetabolite, pyrimidine analog, small molecules, AML, second-line lymphoma

Answer 35

Cytarabine

Question 36

blocks dihydrofolate reductase which impairs DNA synthesis by depleting Thymidine

Answer 36

Methotrexate

Question 37

Do NOT give methotrexate to patients with what

Answer 37

anasarca, ascites, large pleural effusions or impaired renal function b/c it is myelosuppressive

Question 38

Methotrexate antidote

Answer 38

reduced folates in the form of leucovorin

Question 39

dose limiting toxicity of methotrexate

Answer 39

stomatitis

Question 40

Most of the efficacy of methotrexate versus the toxicity

Answer 40

DNA dysfunction (effect) versus RNA dysfunction (toxicity)

Question 41

dose limiting toxicity of 5-FU

Answer 41

infusion is GI, stomatitis, diarrhea odynophage and hand/foot syndrome and actinic recall

Question 42

5 FU antidote

Answer 42

uridine tri-acetate

Question 43

broad spectrum, syndergistic with DNA damaging agents, self potentiating, interactive with platinum drugs/radiotherapy, SAFE IN RENAL PTS., rarely causes alopecia

Answer 43

Gemcitabine

Question 44

important for AML and various lymphomas, intrathecally

Answer 44

Ara-C

Question 45

remarkably active against hairy cell leukemia, some use in autoimmune ds, active in many other B cell malignancies

Answer 45

Cladribine (2-CdA)

Question 46

immunosuppressive class (used for cancer also)

Answer 46

purine analogs

Question 47

allowed for first successful kidney transplant

Answer 47

azathioprine