This seminar presentation on recent antineoplastic agents.

1. Anti-Neoplastic Agents Approved
by FDA in Last Five Years
(2008-till now)
Dr Nitin Kothari
03/07/13 1

2. Antineoplastic Agents in Last Five
Years
03/07/13 Total Drugs= 43 2

3. Cytotoxic Agents
– Alkylating Agents
– Antimetabolites
– Natural Products
– Hormones & its antagonists
03/07/13 3

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

6. MOA
03/07/13 6

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

9. • ADR
– BM toxicity
– Mucosal toxicity-
 stomatitis,
 intestinal denudation
– Reproduction
– Alopecia
– Nausea, vomiting
03/07/13 9

10. Anti-metabolites-Pralatrexate
• Approved for
– t/t of pt with relapsed or refractory peripheral
T-cell lymphoma
• Congener of Mtx
03/07/13 10

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

13. Pralatrexate
• ADRs
– BM - Myelosuppression
 Anemia
– Infection
– Haemorrhage
– Intestine
– Nausea, Constipation
03/07/13 13

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

17. • ADR
– GI distress
 Bulk forming laxative as prophylaxis
 Diarrohea
– Peripheral neuropathy
– Anemia
– Febrile neutropenia
– Pyrexia
03/07/13 17

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

32. DEGARELIX
ABIRATERONE
ENZALUTAMIDE
03/07/13 32

33. • Degarelix
– Avoids “flare” phenomenon of GnRH agonist
– Precursor – Abarelix
• Enzalutamide
– Potency & libido maintained
– Precursor- Flutamide, Bicalutamide
03/07/13 33

34. • Abiraterone
– Non-gonadal source of androgen
 Adrenal gland
 Prostate cancer cells
– Block CYP-17 ( 17 α hydroxylase)
– Congener- Ketoconazole
03/07/13 34

35. S. Name of Formulation Dose
No. Drug Available
1 Degarelix Powder for Initial- 240mg
reconstitution 120mg, Maintenance-
sc 80 mg /month
2 Abiraterone Tablet 1000mg
3 Enzalutamide Oral Capsule 40 mg 4 capsules
once
03/07/13 35

36. • ADRs of ADTs( Degarelix & Abiraterone)
– Hot flushes - Hypertension
– Loss of libido - UTI
– Impotence - Diarrohea( Abiraterone)
– Gynecomastia
– Anemia
– Weight gain
– ↓ insulin sensitivity
– Altered lipid profile
– Osteoporosis, fracture, loss of muscle mass 36
03/07/13

37. • ADRs of Enzalutamide
– Asthenia(>5%)
– Fatigue
– Arthralgia
– Musculosketal pain
– Headache
– Dizziness
– LRTI
– Spinal cord compression
03/07/13 37

38. Targeted Therapeutic Agents
• TK inhibitors
• mTOR inhibitors
• Inhibitors of angiogenesis
• Immunomodulators
• Monoclonal antibodies
• Others
03/07/13 38

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

41. 03/07/13 41

42. • Formulation & Dose
– Tablet for oral admn
– Dose 500 mg once daily
03/07/13 42

43. • Drug interaction
• Protease inhibitors
• Azoles antifunguals Common to
D, I, N
• Antiepileptics
• PPI
Common
• Antacid to
Dasatinib
03/07/13 43

44. • ADRs ( common with congeners)
– GI distress
– Myelosuppression
– Liver problems
– Fluid retention
– Others
 Rash No QT
prolongation
 Pyrexia
( Nilotinib)
 Fatigue
03/07/13 44

45. Crizotinib
• MOA
– Dual inhibitor
 C-Met-GF
 ALK-TK
• Formulation & Dose
– Tablet for oral admn
– 250 mg twice daily
• ADRs
– GI Distress-N/V/D/C
– Vision disorders
03/07/13 45

46. Vandetanib
• MOA
– TK R inhibitors
 VEGF
 EGF
• Formulation & Dose
– Tablet for oral admn
 300 mg once daily
• ADRs
– GI distress
– Headache, fatigue
03/07/13 46

47. Cabozantinib
• MOA
– Pan-tyrosine kinase inhibitor
 RET,MET,KIT
 VEGFR-1,2,3
 TRKB, FLT-3,AXL, TIE-2
03/07/13 47

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

51. • Sunitinb- VEGF-R, PDGF-R
• Axitinib- VEGF-R 1, 2 ,3
• Pazopanib- VEGF-R 1, 2 ,3
• Ziv-afilabercept- VEGF, Placental GF
• Bevacizumab- Antibody against VEGF
03/07/13 53

52. ADRs common to angiogenesis
Inhibitors
• Potential for vessel injury & bleeding
– Pulmonary haemorrhage<2%
– C/I
 Bleeding diathesis
 Hemoptysis
 Brain metastasis
– Operation should be avoided
03/07/13 54

53. • Hypertension
– Reason- decreased eNO
– Antihypertensive drugs
– Complications
 Reversible posterior leucoencepalopathy
 CCF
03/07/13 55

54. • Sunitinib ( pan TK-I)
– Fatigue- 50-70%
– Hypothyroid- 40%
– Severe neutropenia- 10%
• Recommendations
– Regular blood examination
– Thyroid test
– ECG
03/07/13 56

55. • Axitinib
– GI distress
– Palmer planter keratosis
• Pazopanib
– Dysguesia, Dyspnoea
– Skin hypopigmentation, hair color change
• Ziv-aflibercept
– Liver
– Kidney
03/07/13 57

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

57. Everolimus: MOA
Raf
03/07/13 59

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

63. • ADRs
– Flu like symptoms
 Fever, chills, headache
 Fatigue, myalgia
– Liver
03/07/13 65

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

68. Pomalidomide
03/07/13 70

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

72. Sipuleucel-T
(Provenge)
03/07/13 74

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

75. • ADRs
– Local reactions
 Pain, redness, swelling
– Fatigue, headache, myalgia
03/07/13 77

76. • Formulation & Dose
– Tablet for oral admn- 240 mg
• Dose-
– 4 tablets twice daily atleast gap of 12 hours
• ADRs
– Skin menifestation
 rash, skin papilloma, pruritis, photosensitivity
03/07/13 78

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

79. MOA
03/07/13 81

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

81. • ADRs
– Immunogenic
 Fever, chills, rashes
 Premedication
– Cardiac Toxicity
 Most serious, Fatal, 1%
 Baseline ECG, Cardiac ejection fraction
 careful follow-up- signs of CCF
•
03/07/13 83

82. Ado- trastuzumab
• Approved for her2+ metastatic breast
cancer
• MOA
– DM1 interferes cell growth
• ADRs
– Nausea,constipation,
– Headache, myalgia, fatigue Liver Toxicity, Heart Toxicity
Birth defects
– Raised liver enzymes
03/07/13 84

83. Ofatumumab
• Approved for
– t/t of pt with CLL refractory to fludarabine and
alemtuzumab
03/07/13 85

84. • Formulation- 20mg/ml
• Regimen- 12 dose
– Ist dose-300mg 1st
week
– Dose 2-8-2gm/week
– Dose 9-12-2gm/4
weeks
• Infusion rate
– Dose 1-3.6mg/hr
– Dose 2-24mg/hr
– Dose3-12-50mg/hr
03/07/13 86

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

89. • Formulation & Dose
– sc preparation
– 120 mg every 4 weeks
• ADRs
– Fatigue
– Hypophoshatemia
– Nausea
03/07/13 91

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

93. • MOA
– Antibody-drug conjugate
03/07/13 95

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

97. MOA
• NF-KB – cell survival & proliferation
• IkB is degraded by proteasome- NF-KB
promotes cell proliferation
CARFILZOMIB
β 5
03/07/13 99

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

99. • ADRs
– Fatigue
– Thrombocytopenia
– Anemia
– Diarrhoea
– Pyrexia
– No peripheral neuropathy
– No Hypotension
03/07/13 101

100. Romidepsin
• Approved for
– Cutaneous T-cell lymphoma who have
received atleast one prior systemic therapy
03/07/13 102

101. Acetylation---- transcription
increases
Deacetylation----
transcription decreases
Romidepsin Increases
Transcription
03/07/13 103

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

103. • ADRs
– GIT distress
 N/V/ D
– Anorexia
– Fatigue
– Pyrexia
03/07/13 105

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

105. Vismodegib
• MOA
– Inhibitor of Hedgehog signaling pathway
03/07/13 107

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

109. • ADRs
– Myelosuppression
 Anemia
 Neutropenia
 Thrombocytopenia
– Fatigue
– Asthenia
– Pyrexia
03/07/13 111

110. Vemurafenib
• Approved for
– Unresectable or metastatic metastatic
melanoma with BRAF V600E mutation
03/07/13 112

111. Vemurafenib
Raf
03/07/13 113

112. Drugs Approved for MM
Peg-interferon
03/07/13 114

113. THANK YOU
03/07/13 115