Cancer IV Flashcards
molecular targeted therapy overview
- becoming possible to determine which defective molecules or pathways dirving malignant progression
- can take a rational approach to develop mechanism based cancer meds to target defective molecules/pathways
preclinical studies
- new drug is tested on normal and cancer cell lines in a lab setting
- animal testing for efficacy and tox
investigational new drug app
-new drug sponsor files an IND application with the FDA for clinical testing in humans
phase I
- determines safe and appropriate doses for subsequent studies
- determines toxic effects, preferred mode of admin, pharm behavior.
- usually 10-30 patients with different types of malignancies who have failed standard trt
- need life expectancy of 1-2 months with functioning organs capable of metabolism and excretion
- patients divided into cohorts of 3-6 and each treated with increasing dose
- if no serious side effects in first dose, second group goes until dose limiting tox
- highest dose with acceptable tox recommended for phase II
phase II
- determines effectiveness and side effects of new drug in one type of cancer
- up to 100 patients with same malignancy and no effective trt, 3 month life expectancy
- all usually given same dose and effectiveness evaluated, closely monitored
phase III
- it evaluates the effectiveness of new drug and compares it to best available standard trt
- large and long term trials involving 100 to 1000s of patients
- specific types of malignancy
- eligibility varies-stage, first time trt, status of prior trt, goals
- conducted at multiple centers, randomly assigned to a group
new drug app
- drug sponsor files this of biologics license application with FDA
- submit phase III data
FDA approval
- if satisfied with phase II results, FDA approves new drug, which can take about 1.5 years
- after approval can be marketed to public under a label, which includes dosage, safety, indications, and side effects
phase IV
-determine long term safety and effectiveness of new drug
CML
- clonal hematopoietic stem cell disorder
- 15-20% of all leukemias
- cytogenetic analysis- Ph chromosome in more than 90% of cases
- 9;22 translocation
- BCR-ABL- Tyrosine kinase
- chronic, accelerated, blast phases
- chronic is excess number of myeloid cell that differentiate normally but 4-6 years transforms to accelerated and blast-fatal
- used to be treated with hydroxyurea or interferon alpha and allogenic stem cell transplant
- late age disease so difficult to find donors, treatment sucked
new trt for CML
- imatinib/gleevec
- lead compound with selective activity agains abl tyrosine kinase
- BCR-ABL activates signaling pathways, but needs ATP to phosphorylate other proteins
- imatinib binds where ATP binds
preclinical studies with imatinib
- showed specific inhibition of BCR-ABL expressing cell in vitro and in animals
- showed acceptable animal tox profile
clinical studies with imatinib
- phase I- CML patients who failed INF-a
- at oral doses of 300 mg and higher 98% of patients displayed complete hematologic response within 3 weeks of therapy
- response was maintained in 96% with median duration of follow up of 3 weeks
- cytogenetic response were noted in 53% of patients with 13% displaying complete cytogenetic response
- minimal side effects of nausea, vomiting, fluid retention, muscle cramps and arthralgia
- myelosuppression in 29% of patients
pharmacokinetics of imatinib
-orally has relatively long half life of about 13-16 hours and good for daily dosing
-with oral admin of 400 mg peack Css was 2.3 micrograms/ ml, which is higher than needed
-metabolized by cyto p450 (3A4)
-
phase II imatinib
- more than 1000 patients at 27 centers in 6 countries
- confirmed phase I
phase III imatinib
- started to compare to INF+cytarabine
- imatinib was superior
- standard first line therapy
- 8 year follow up show effective and safe
intrinsic resistance of imatinib
- patients with persistent BCR-ABL kinase activity and could occur due to mutations in BCR-ABL or drug efflux or increased plasma protein binding
- relapse involves reactivation of BCR-ABL
- some patients have ABL mutations, less sensitive
- some who relapse show peristent inhibition on BCR-ABL, must be additional abnormal growth
second generation TKIs
-nilotinib- june 2010 FDA approved for newly diagnosed
-first approved in 07 for imatinib resistant
-300 mg twice daily oral
dasatinib- oct 2010 approved for newly diagnosed
-06 for imatinib resistant
-100 mg twice daily oral
GI stromal tumors
-most common mesenchymal malignancies of the GI tract
-accounts for 1% of all GI malignancies
-can be benign and malignant, although all may be potentially malignant
-stomach is most common site then small intestine, esophagus, color and rectum less freq
-generally do not involve lymph nodes
-predominantly to liver
-generally affect older adults, 50-65
-mostly present with abd pain and GI bleeding, 20-25% asymptomatic
-about 90% are CD117 (KIT) pos
-kit is a receptor tyrosine kinase
GISTs harbor activating mutations in genes that encode KIT and PDGFRA (another TK)
-75-85% KIT, 5-10% PDGFRA
-10-15% no mutations
management of GISTs
-complete surgical resection of primary tumor is approach of choice and is usually associated with 48-65% 5 year survival
-sometimes due to site/size complete resection not possible
-high chance of metastatic relapse to liver and peritoneal surface, and response to conventional chemo/ radiation is poor
-imatinib beneficial for these patients and approved by the FDA for trt of unresectable and metastatic GISTs
-400 mg/day, no added benefit at higher dose
some patients show primary resistance or develop secondary resistance
acute promyelocytic leukemia
-paradigm for differentiation therapy
-type of acute myeloid leukemia, M3
-7-10% of all AML cases
-up to 30% incidence in latin american countries
-distinct blockage of myeloid differentiation resulting in accumulation of immature promyelocytes in marrow and peripheral blood
-reciprocal translocation 15,17 occurs in 98% of all cases
-other rare translocations, but always involves 17 (RARa)
-fuses retinoic acid receptor a (RARa) with promyelocytic leukemia gene- PML-RARa
-oncoprotein responsible for transformation
PML on 15, RARa on 17
all trans retinoic acid trt for APL
- metabolite of vitamin A
- first used in china- complete remission of APL
- published results in 1988
- provided to a french group-also had remission
- published in 1990
- one of earliest examples of molecular targeted therapy, mechanism discovered later
mechanism of retinoic acid
- in APL the malignant immature promyelocutes continue to self renew and proliferate without differentiation
- retinoic acid induces terminal differentiation of the cells, which then undergo apoptosis
- acid binds to RARa, which in association with other similar receptors binds to DNA and induces the expression of gene involved in myeloid differentiation
- the abnormal RARa in APL associates with other proteins, and at physiologic levels of retinoic acid is unable to cause cells to differentiate
- drug causes RARa to turn on differentiation genes again
dosage of retinoic acid
- total dose of 25 mg/m^2 to 45 mg/m^2 per day in two oral doses
- complete remission can be induced in more than 80-90% of previously untreated cases
- since all cases invariably relapse if retinoic acid is monotherapy, administered concurrrently with anthracycline based meds
- maintenence trt with retinoic acid in combo with low dose chemo is mostly recommended to reduce incidence of relapse
- current general practice is to start with retinoic acid plus anthracycline based regimens as induction trt
- gived two courses of anthra based for consolidation
- then maintenence is retinoic plus low dose chemo for 2 years
- such trt can achieve complete remission in more than 90% and relapse is less than 10% by year 2
pharmacokinetics of retinoic acid
- reaches circulation via portal vein
- peak plasma levels in 1-2 hours following ingestion
- plasma t1/2 is 1 hr
- binds to albumin and transported as a complex
- metabolites and glucuronic acid conjugates are mostly secreted into bile and excreted in urine and stools
tox of retinoic acid
- if used alone, 1/3 of pts develop increase in white blood count- leukocyte activation syndrome or retinoic acid syndrom
- fever, resp distress, weight gain, pleural or pericardial effusion and occasionally renal failure
- concurrent use of chemo plus acid plus corticosteroids have shown to block the syndrome
- dryness of skin and lips, nausea, headache, arthralgias, bone pain
mechanism of relapse/resistance to RA
- induction of cytochrome p450 that enhance RA catabolism and reduces Cp
- alterations in level of cytosolic RA binding protein II (CRBP II) that could affect transport
EGFR family
- ErbB1
- ErbB2
- ErbB3
- ErbB4
- cell surface proteins with extracellular domain, transmembrane segment and intracellular tyrosine kinase domain (except B3)
- receptors activated by ligands
- activation involves dimerization between two identical or two different dimers
- ligand binding induces dimerization, so can high receptor density
- following dimerization, receptors are auto phosphorylated on tyrosine residues and transduce proliferative and survival signals inside the cells
- overexpression in cancer cells results in hyperproliferation and enhanced cell survival
- good targets for anticancer therapy
ErbB2
- her 2/neu
- no ligand
- forms heterodimers with all other receptors
- believed to function as a master coordinator that shares the ErbB ligands
- overexpressed in breast, ovarian, gastric
ErbB1
- EGFR or Her1
- bound by EGF and TGFa
- overexpressed in different cancers
- gastric, breast, prostate, bladder, ovarian, colorectal, non small cell lung and glioblastomas
ErbB3/4
HER3/4
-bound by neuregulin
anti-ErbB2 monoclonal antibodies
- trastuzumab is humanized monoclonal antibody against ErbB2 (HER2/neu) GF receptor
- overexpressed in about 25-30% of advanced breast cancers and is predictive of worse prognosis
- approved in 1998 for trt of HER2 pos cancers
dosage of trastuzumab
- loading dose of 4 mg/kg as a 90 min iv infusion
- maintenance dose of 2 mg/kg per week as a 30 min iv infusion
- usually give in combination with taxanes
pharmacokinetics of trastuzumab
- plasma concentration varies from patient to patient due to presence of circulating extracellular domain of ErbB2 shed receptor
- in general, Cp is about 10-25 ug/ml
- half life is 8.3 +/- 5 days
tox of trastuzumab
- hypersensitivity- can still occur even with humanized version
- ventricular dysfunction and CHF
- can enhance cardiac tox of doxorubicin
mechanism of trastuzumab
- not known exactly
- appears to prevent the transduction of proliferation and survival signals
- induces cytostatic growth inhibitory effects agains HER2/neu overexpressing cells, which could occur due to antibody induced downregulation of the receptor and subsequent degradation
- antibody probably disrupts proliferative signals from other receptors
- monotherapy only modest response
- better if combined with paclitaxel or doxorubicin, the antibody enhances cytotoxic effects of these drugs
anti ErbB1 antibodies
- cetuximab
- competes for binding with ligands
- inhibits tyrosine kinase activity and growth signals
- redicted to work better in combination with cisplatin and other chemo
- 2004- FDA accelerated approval for combo with irinotecan for trt of metastatic colorectal carcinomas that express EGFR and are refractory to irinotecan based chemo
- approved for single use in pts who can’t tolerate irinotecan
- 2006- approved in combo with radiation therapy for sp cell carcinoma of head and neck and as single agent in ppl treated previously with platinum
- 2012- approved for use with irinotecan, 5FU, and leucovorin as 1st line management for patients with Kras wild type EGFR expressing metastatic colorectal cancer
dosage of cetuximab
- supplied as single dose vials of 50ml containing 100g (2mg/ml)
- recommended dose as a single agent of in combo with irinotecan
- 400mg/m^2 as initial loading dose administered as a 120 min IV infusion
- weekly maintenance is 250 mg/m^2
FOLFIRI
- FOL-folinic acid-leucovorin
- F-5FU
- IRI-irinotecan
- cetuximab is 400 mg/m^2 IV infusion in 120 min initial dose followed by 250 mg/m^2 over 30 min weekly in combo with FOLFIRI
- cetuximab completed 1 hr before FOLFIRI
non-hodgkins lymphoma
- lymphoid neoplasms
- include more than 20 distinct entities affecting B or T cells
- 6th most common cause of cancer related deaths in the US
follicular lymphoma
- type of NHL
- involves mature B cells
- 75-80% of indolent B cell lymphomas are follicular lymphomas
- mostly affects older adults
- classified into grade 1,2,3
- t14:18 present in about 95% of grade 1 and II and smaller portion of III
- about 40% transform into diffuse large b cell lymphomas
- transformed into diffuse are aggressive with worse prognosis
standard trt for follicular lymphoma
- only about 15 % of grade 1 and 2 diagnosed at early stage- can use radiation therapy for these
- majority of grade 1 and 2 have advanced disease
- conservative-no initial trt, single agent, CHOP and/or radiation as needed
- aggressive-initial CHOP plus radiation
- meaningful response lasts up to 2 years
- grade 3 represents about 10% of follicular lymphomas, aggressive form, trt is CHOP based
trt with rituximab
- for FL
- chimeric monoclonal antibody with variable region of mice igG but constant region and Fc from humans
- effective in many relapsed or refractory follicular lymphomas
- 375 mg. m2 weekly for 4 weeks
- binds to CD20, which is a transmembrane protein in all B cells
- eliminates CD20 pos by activating apoptosis, complement, and cell mediated cytotox
melanoma
- highly aggressive
- melanocytes
- cutaneous, acral, mucosal, uveal
- cutaneous most commone
- acral-skin of palsm, soles, and underneath nails
- uveal-other organs-iris of eye
- in 2013, 76,690 people and 9,480 die
types of cutaneous melanoma
- superficial spreading-70%
- nodular- 15%, common in males and older
- acral lentigious-about 5%, more common in darker skin
- lentigo maligna- 10%, middle aged to older
BRAF mutations and melanoma
- found in 45-50% of cutaneous melanomas
- more freq in melanomas not associated with sun induced damage
- less common in acral, mucosal, uveal
- serine threonin kinase
- BRAF v600e mutation in kinase activation domain-leads to constitutive activation of kinase
- v600k second most common
management of melanoma
- surgical excision with or without lymphadenectomy
- metastatic managed medically by dacarbazine-only FDA approved for metastatic melanoma
vemurafenib
- BRAF inhibitor, binds to oncogenic kinase
- clinical trials- see notes
- led to 63 % reduction in risk of death and 74% reduction in risk of tumor progression in previously untreated patients
- 13.2 months vs 9.9 on dacarbazine
- improvement in overall survival and progression free survival
previously trted patients
- response rate of 53%, 6% complete remission
- median duration of response 6.5 months, 1.4 months to response
- manageable side effects
current status of vemurafenib
- effective and well tolerated
- approved in 2011 for unresectable stage III and IV or metastatic melanomas that harbor BRAF v600 mutations
- approved in europe in 2012
- 906 mg BID orally
- until disease progression or unacceptable side effects
side effects of vemurafenib
- arthralgia, fatigue, photosensitivity, alopecia, nausea, diarrhea
- cutaneous sq cell, keratoacanthoma, or both
- QT prolongation, inc risk for arrhythmias
- new primary cutaneous melanoma
contraindications of vemurafenib
- not for melanomas with WT BRAF
- electrolyte anomalies
- long QT syndrome
- patients on drugs that will cause long QT interval
Dabrafenib
- approved in 2013 for BRAF pos unresectable or met melanomas
- next gen agent
- 150 mg BID + dacarbazine at 1000 mg/m2 IV every three weeks
- acceptable safety profile, improvement in PFS and ORR
side effects of darbrafenib
- higher risk to develo cutaneous sq cell, keratoacanthoma, and melanoma
- serious febrile drug reactions- fever or fever associated with hypotension, rigors, chills, dehydration, kidney failure
- uveitis and iritis
- hyperglycemia
- hyperkeratosis
- may inhibit fertility in males
trametinib
-approved in may 2013 for BRAF mutated melanoma
-inhibits MEK- extracellular signal regulated kinase
-2 mg orally once daily
side effects:
-cardiomyopathy
-retinal pigment epithelial detachment
-retinal vein occlusion
-interstitial lung disease
-serious skin tox- rash, dermatitis, acneiform rash, palmar/plantar erythrodysesthesia syndrome/ erythema
-rash, diarrhea, lymphedema, dermtitis, stomatitis, hypertension, abd pain, hemorrhage, dry skin, pruritus, paronychia
-male infertility
-not for wt BRAF or pts previously trted with BRAF inhibitors
immunotherapy for melanoma
-ipilimumab- cytotoxic T cell Antigen 4 inhibitor
-CTLA4 is a receptor on T cells to down regulate immune system- without this, immune system stimulation
IL2
-increases immune response
-10-20% response rate, 4-6% complete remission
