4. Alkylating Agents-Bendamustine
• Approved in year 2008 for
– CLL- efficacy to first line drugs?
– NHL- progressed during or within 6 months of
t/t with rituximab or rituximab with CHOP
03/07/13 4
5. • Not a true ‘-mustine’( carmustine)
03/07/13 5
7. • Unique properties
– Cross-link repair slow
– Lacks resistance to other alkylators
– Significant activity CLL & other lymphoma
• Formulation
– Powder 100mg vial , reconstitution,
– iv infusion
03/07/13 7
8. • Dose regimen
CLL NHL
100 mg/m2 I.V. over 120 mg/m2 I.V. over
30 min on day 1, 2 60 min on day 1, 2
on 28 days cycle on 21 days cycle
upto 6 cycles upto 8 cycles
03/07/13 8
11. Pralatrexate
PRALATREXAT
Purine Synthesis
E
03/07/13 11
12. • Formulation & Dose
– Sol for iv admin
– Dose- 30 mg/m2 iv bolus once weekly for 6
weeks in 7 weeks cycles
– Vitamin supplementation
Folic acid 1mg – initiate 10 days prior
Vit B12 im- 10 weeks prior & every 10 weeks
03/07/13 12
14. Natural Products
S.No. Name of Drug Approved for Year
1. VinCRIStine sulphate Ph- ALL Aug2012
liposomal injection
2 Paclitaxel protein-bound Non small cell lung Oct 2012
particles cancer
3 Cabazitaxel Prostate cancer June2010
4 Eribulin Metastatic breast Nov 2010
cancer
5 L-Asparaginase erwinia ALL Nov 2011
chrysanthemi
6 Ingenol Actinic Keratosis Jan2012
03/07/13 14
15. VinCRIStine Sulphate liposomal Inj
• Approved for
– Adults with Ph- ALL in second or greater
relapse or whose disease has progressed
following > 2 anti-leukemic drugs
• Why liposomal preparation?
– “Liposome makes it adult”
03/07/13 15
16. • MOA
– Cell cycle specific(v/s alkylating agents)
– Polymerization of microtubules
• Formulation & Dose
– Solution for iv injection
– Initial dose 2.25 mg/m2 iv over one hour
weekly
03/07/13 16
18. Paclitaxel protein-bound particle
• Approved for
– First line t/t of locally advanced or metastatic
non-small cell lung cancer, in combination
with carboplatin, in pt who are not candidates
for curative surgery or radiation therapy
03/07/13 18
19. • Why nab- preparation of paclitaxel?
– To overcome limitations of conventional prep
Poor acqueous solubility
vehicle 50%ethanol + 50% polyethoxylated castor
oil ( cremophor)
• Advantage of nab-paclitaxel
– No hypersensitivity
– Less time in infusion
03/07/13 19
20. • MOA
– Promotes polymerization of microtubules
– Binds to beta tubulin
03/07/13 20
21. • Formulation & dose
– Solution for iv infusion
– Dose- 100mg/m2 as iv infusion over 30min on
day 1, 8 and 15 of each 21days cycle
– With carboplatin
• ADR
– Neutropenia
– Neuropathy- more
– Hypersensitivity- less
– Fatigue
03/07/13
21
22. Cabazitaxel
• Approved for
– t/t of hormone refractory prostate cancer pt
– In combination with prednisone who have
previously treated with docetaxel
• MOA- same as paclitaxel
03/07/13 22
23. • Formulation & Dose
– Sol for iv use
– 25 mg/m2 over every 3weeks
– Oral prednisolone 10mg
– Premedicate –antihistaminics, corticosterids
• ADRs
– N/V/D
– Hematological Rxn
– Hypersensitivity Rxn
– Anorexia, Fatigue
03/07/13 23
24. Eribulin
• Approved for
– t/t of metastatic breast cancer pt who have
previously received atleast two
chemotherapeutic regimens
• Isolated from Helichondria okadai
• MOA
– Not well known
– Acts on microtubules
– Affects growth phase
–
03/07/13 No affect on shortening phase 24
25. • Formulation & dose
– Solution for iv inj
– 1.4mg/m2 iv over 2-5 min on day 1 & 8 of 21
days cycle
• ADR
– N/V/D
– Hematological rxn
– Hypersensitivity rxn
– Anorexia, Fatigue
•
03/07/13 25
26. Asparaginase Erwinia
chrysanthemi
• Approved for
– As a component of multi-agent chemotherapy
for t/t of ALL who have developed
hypersensitivity to E.coli derived
asparaginase
o Why aspaginase Erwinia chrysanthemi?
Hypersensitivity Rxn 5-20%
Gram negative rod bacteria
03/07/13 26
27. • MOA
– Asparagine imp for protein synthesis
– Lyphocytic leukemic cells lack asparagine
synthetase
– Degrades into metabolites
03/07/13 27
28. • Formulation & dose
– Solution for im use
– 25000 IU three times a week for 8 weeks
• ADRs
– Hypersensitivity
– Inhibition of protein synthesis
Hyperglycemia
Hypertriglyceridemia, Pancreatitis
Thrombosis
Hypoalbuminemia 28
29. Ingenol
Approved For Source- Euphorbia
Actinic Keratosis
Formulation & Dose MOA ADR
0.015% or 0.05% gel for topical Inducer of -Local skin Rxn
Face, Scalp- once daily for 3 apoptosis & cell -Pain
consecutive days 0.015% death -Pruritis
Trunk, Extremities- once daily for -unknown MOA -Infection
2consecutive days 0.05%
03/07/13 29
30. Hormones & its antagonists
S.No. Name of Drug Approved MOA Year
For
1 Enzalutamide Androgen 2012
receptor
Metastatic inhibitor
castration
2 Degarelix GnRH 2008
resistant
analogue
prostate
cancer
3 Abiraterone Steroid 2011
synthesis
inhibitor
03/07/13 30
31. • Hormone therapy in prostate cancer
• Androgen Deprivation Therapy
– Surgical
– Medical
GnRH agonist- high dose/ continuous
GnRH antagonist
Androgen Receptor inhibitor
03/07/13 31
39. Tyrosine Kinase Inhibitor
S.No. Name of Drug Approved for Year
1 Bosutinb Ph+ CML 2012
2 Crizotinb ALK + Non small 2011
cell lung cancer
3 Vandetanib Metastatic MCT 2011
4 Cabontanib Metastatic MCT 2012
03/07/13 39
40. Bosutinib
• Congener of Imatinib
• Approved for
– Ph+ CML with resistance to prior therapies
03/07/13 40
48. Formulation & Dose
Cap 80mg, 20 mg
Dose 140 mg, without
food
ADRs
GI distress
Hair color changes
Hypertension
03/07/13 48
49. Inhibitors of Angiogenesis
S. Name of Approved for Year
No. Drug
1 Sunitinib Pancreatic NET 2011
2 Axitinib Advanced RCC 2012
3 Pazopanib Advanced RCC 2009
Advanced Soft tissue 2012
sarcoma
4 Bevacizum Metastatic RCC in 2009
ab combination with iFN-
alpha
5 Ziv- Metastatic CRC with 2012
afilabercept FOLFIRI 51
50. MOA
• Role of angiogenic factors
– VEGF, PDGF, TGF-b, FGF
• VEGF-most studied
• Angiogenesis inhibitors
– Binding of angiogenesis facors to its receptor
activate the intracellular TK activity --
mitogenic and antiapoptotic pathway within
endothelial cells-- cell proliferation
03/07/13 52
56. Everolimus
• Approved by FDA for
– Advanced RCC after failure of
Suniti-/Sorafenib- 2009
– Progressive Pancratic NET with unresectable
or metastatic disease- 2011
– Renal Angiomyolipoma associated with
tuberous sclerosis- 2012
– Hormone receptor +, her2 - Ca Breast after
failure of t/t with letrozole ,anastrozole- 2012
03/07/13 58
58. • Formulation & Dose
– 5mg, 10 mg tablet
– Dose-
10 mg once daily
Can be increased by 5 mg( max dose 20 mg)
03/07/13 60
59. • ADR
– Common ( 30-50%)
Maculopapuar rash
Mucositis
Anemia
Fatigue
– Less common
Leucopenia,Thrombocytopenia
Hyper-glycemia, -triglyceridemia
Pulmonary infilterates
03/07/13 61
60. Immunomodulators
S.N Name of Drug Year
o.
1 Peg-interferon alpha- 2011
2b
2 Plerixafor 2008
3 Pomalidomide Feb
08,2013
4 Sipuleuceucel-T 2010
( Provenge)
5 Recombinant HPV 2009
Type 16, 18 Vaccine
(Cervarix)
62
61. Peginterferon alpha 2b
• Approved for
– Adjuvant t/t of melanoma with nodal
involvemont within 84 days of definitive
surgical resection( + lymphadenectomy)
• Why PEGylation?
03/07/13 63
62. • MOA
– Pleiotropic cytokine
• Formulation
– Powder for reconstitution, sc
• Dose
– Initial-6mcg/kg/week eight doses
– Then 3mcg/kg/week upto 5 years
– Premedicate with PCM
03/07/13 64
64. Plerixafor
• Approved for
– In combination with G-CSF to mobilize
hematopoietic stem cells to the peripheral
blood for collection and subsequent
autologous transplantation in pt with NHL &
MM
03/07/13 66
65. • Transplantation of hematopoitic stem cells
• Indication
• Source
– BM
– Peripheral blood
• Role of interaction of CXCR4 & SDF-1
• MOA of Plerixafor
– Hematopoietic stem cells are mobilized in
peripheral blood
03/07/13 67
66. • Formulation
– Solution for sc
• Dose
– Given sc after 4 days of G-CSF t/t
– Dose 0.24mg/kg
• ADRs
– Injection site reactions
– GI distress
– Fatigue, headache, dizziness
03/07/13 68
67. Pomalidomide
• Approved for
– Pt with MM who have received atleast 2 prior
therapies including lenalidomide & bortezomib
and have demonstrated disease progression
within 60 days of last therapy
03/07/13 69
69. • Formulation
– Capsule for oral administration
• Dose
– 4 mg once daily without food on day 1-21 of
repeated 28 days cycles untill disease
progression
03/07/13 71
70. • ADRs
– No sedation
– Less constipation
– No sensory neuropathy
– Myelosuppression
Anemia
Neutropenia
– Fatigue, asthenia
03/07/13 72
71. Sipuleucel- T
• Autologus immunotherapy
– Against PAP
• Approved for
– Asymptomatic or minimally symptomatic
metastatic hormone refractory prostate cancer
03/07/13 73
73. • Formulation & Dose
– IV infusion 50 million autologous CD54+ cells
activated with PAP, GM-CSF designed
– 3 completed doses at 2 weeks interval
• ADRs
– Flu like
Chills, headache, fever
03/07/13 75
74. Recombinant Bivalent HPV
Vaccine
• Recombinant vaccine that contains L1
protein, major antigenic protein of HPV
type 16 & type18
• Approved for
– Prevention of the CIN & cervical cancer
• Formulation & Dose
– Suspension for im inj
– 3 doses, 0.5 ml, at 0,1 , 6 months
03/07/13 76
77. Monoclonal Antibodies
S.No. Name of Drug Approved for Year
1. Trastuzumab Gastric cancer Oct 2010
2. Ado- trastuzumab Metastatic breast Feb 22, 2013
cancer
3. Ofatumumab CLL Oct 2009
4. Pertuzumab Her+ metastatic June 2012
breast cancer
5. Denosumab Prevention of Nov 2010
metastatic skeletal
related events
6. Ipilimumab Metastaic melanoma March 2011
7. Brentuximab HL, anaplastic large August 2011
03/07/13 79
cell lymphoma
78. Trastuzumab
• Approved for
– t/t of her+ overexpressing metastatic gastric
or gastroesophageal adenocarcinoma in
combination with cisplatin & capecitabine or
5-FU who have not received prior t/t for it
03/07/13 80
80. • Formulation & Dose
– Sol for iv dose
– 8mg/kg 90 min iv infusion
– Followed by 6 mg/kg over 30-90 min in every
3 weeks untill disease progression
03/07/13 82
85. • ADRs
– Immunosuppresion
Reactivation of viral infections
Not with hepatitis B infection
URTI, pneumonia
– Myelosuppresion
– Hypersensitivity
03/07/13 87
86. Pertuzumab
• Approved for
– t/t of her+ metastatic breast cancer (+
trastuzumab and docetaxel)
• MOA
– Similar to trastuzumab
03/07/13 88
87. • Formulation & Dose
– 420 mg/ 14 ml vial iv infusion
– Initial Dose-840 mg administered as 60 min iv
infusion
• Maintenance dose- 420 mg administered
in 30-60min
• ADRs
– GI Distress
– Neutropenia
– Neuropathy
– Rashes
03/07/13 89
88. Denosumab
• Approved for
– prevention of skeletal related events in pt with
bone metastasis
• Tumor with common bone metastasis
– In adults
– In children
• MOA
– Binds to RANKL
– RANK present on osteoclast
03/07/13 90
90. Ipillitumumab
• Approved for
– t/t of metastatic melanoma
• MOA
– Blockade of CTLA-4
– CTLA-4 suppresses immune response
03/07/13 92
91. • Formulation & Dose
– Sol for iv
– 3mg/ kg iv over 90 mins every 3 weeks total 4
doses
• ADRs
– Fatigue
– Diarrhea
– Rash, Pruritus
– Colitis
03/07/13 93
92. Brentuximab
• Approved for
– HL
After failure of autologous stem cell transplant, or,
After failure of atleast 2 prior multiagent
chemotherapy regimen
– Systemic anaplastic large cell lymphoma
After failure of one prior multiagent chemotherapy
regimen
03/07/13 94
94. • Formulation & Dose
– Sol for iv infusion
– Dose 1.8 mg/kg over 30 min
• ADRs
– GI Distress
– Myelosupression
– Neuropathy
03/07/13 96
95. Others
S.No. Name of Drug Approved For Year
1 Carfilzomib MM 2012
2 Romidepsin Cutaneous T-cell 2009
lymphoma
3 Vismodegib BCC 2012
4 Omacetaxine CML 2012
5 Vemurafenib Melanoma 2011
03/07/13 97
96. Carfilzomib
• Approved for
– t/t of MM in pt who have received atleast 2
prior therapies (+ bortezomib &
immunomodulators) & have demonstrated
disease progression within 60 days of
completion of last therapy
03/07/13 98
98. • Formulation & Dose
– 28 days t/t cycle
– For 3 weeks, given on 2 consecutive days in
each week followed by rest
– Cycle 1- dose 20mg/m2---- 27mg/m2
03/07/13 100
102. • Formulation & Dose
– Sol for iv
– 14 mg/m2 over 4 hour period on day 1, 8and
15 of a 28 day cycles
– Cycle repeated till relief or toxicity
03/07/13 104
104. Vismodegib
• Approved for
– t/t of adults with metastatic or locally
advanced BCC that has recurred following
surgery or who are not candidates for surgery
or radiation
03/07/13 106
106. • Formulation & Dose
– Tablets for oral admin
– 150 mg once daily untill disease progression
of toxicity
• ADRs
– GI distress- N/V/ D/ C, appetite, wt loss
– Dysguesia, Aguesia
– Muscle spasm, Arthralgia, Fatigue
03/07/13 108
107. Omacetaxine
• Approved for
– t/t of adults with CML with resistance to
atleast 2 TKI
• MOA
– Protein synthesis inhibitor
– Binds to A-site of peptidyl transferase
03/07/13 109
108. • Formulation & Dose
– Solution for sc
Induction Scedule Maintenance dose
1.25 mg/m2 s.c. 1.25 mg/m2 s.c.
Twice daily Twice daily
14 consecutive days 07 consecutive days
In 28 days cycle In 28 days cycle
03/07/13 110
Total anti-neoplastic agents approved in last 5 years r 43 . They can b classified broadle into 2 groups –first is cytotoxic drugs which act non-selectively and kill tumor cells as well as normal cells . Second group is targeted therapy which r relatively more selective act upon only its target. This target may b some gene muation, sum antigen and any signal transduction molecule. It is obvious that cytotoxic drugs act non-selectively so produce more ADRs than targeted therapy. Considering this, new and new drugs r cuming in this group.Out of 43 drugs, 32 r in targeted therapy while only 9 r in cytotoxic group
Bendamustine is nitrogen mustard which is bifunctional – have 2 functional group and so they are more potent than other alkylating agent that one functional group. It has benzimidazole or purine backbone.
Intermediate is ethyleneimonium ion that acts in 2 steps. Major site of alkylation is N7 position of guanine. Other sites include N1 , N3 positions of adenine, N3 of cytosine, O6 of Guanine and phosphate and proteins associted with DNA. Apart from cross-linking other MOA of bendamustine- mispairing of guanine sothat it can bind thymine inspite of cytosine, and may be opening of imidazole ring.
It has purine like structure thatwhy it has sum unique properties.
Alkylating agents are highly toxic to rapidly dividing cells and these cells are present in BM, hair follicle, germinal organs n intestinal wall. So their ADR are more related to these structures. Nausea , vomiting are more common in nitrogen mustard group.
First 4 drugs act upon microtubules that are formed in metaphase of M- phase of cell cylcle. Vincristine sulphate is a member of vinca alkaloids and congener of vinblastine n vinorelbine. Paclitaxel protein bound paticles, cabazitaxel are fm taxane group which has other congener.Cabazitaxel is non- hormonal anti-neoplastic approved for prostate cancer. L-asparaginase is an enzyme that is found more in leukemic cells. Ingenol is active agent in sap of australian plant Euphorbia.
Conventional vincristine is toc along with glucocorticoids to induce remission in pediatric ALL. Used dose is 2mg/m2 i.v. but in adults it is used as dose of 1.4mg/m2 . At that level too, it is less tolerated in adults than children who develop severe, progressive neurological toxicity. To make the vincristine more tolerated it is encapsulated in sphinomyelin/ cholesterol liposome. Which increases its efficacy and reduces its toxicity. Liposome has the same structure as of cell membrane. It has bilyaer of phospholipid in which hydrophic head is outside and i/s and hydrophobic tail is facing towards to each other.
It binds selectively to beta tubulin and blocks its polymerization to alpha tubulin in microtubules. So there is no intact microtubules are left in the cell so movement of duplicated chromosomes is restricted n they cant align along the division plate. So cell division comes to a halt and cell death occurs.
It has less ADR than conventional vincristine.
Non- small cell lung cancer makes up around 75% of all cases of lung cancer n includes squ cell ca, adenocat n large cell ca. when it is diagnosed in advanced form, prognosis is very poor. Surgery n radiotherapy are tried along with chemotherapy. In chemotherapy – “ platinum doublets” is used. In platinum compound cisplatin or carboplatin are chosen. In companion drug frequently paclitaxel is found efffective.