Biological and Molecular Targeted Therapies in Cancer Treatment

1
Biological and Molecular Targeted Therapies in
Cancer Treatment

• Produced by Oncology Education Services
• for the Oncology Nursing Society
• Online Resource Area
• Supported by an educational grant from
• Genentech BioOncology

2
Objectives

• After reviewing this program, nurses should be
  able to
• Discuss the mechanisms of action of several
  biological and molecular targeted therapies
• Discuss the use of such therapies in a variety of
  cancers
• Discuss side effects expected with the use of
  biological and molecular targeted therapies
• Discuss future directions in biological and
  molecular targeted therapy

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What Is Biological Therapy?

• Biological therapy is the therapeutic use of
  agents derived from biologic sources and/or
  affecting biologic responses.
• Also called immunotherapy and biotherapy.
• Modifies the bodys biologic/immune response
  resulting in therapeutic effects.
• Another mode of cancer therapy with surgery,
  radiation, and cytotoxic chemotherapy and often
  used in conjunction with one or more of the other
  three.

Chemotherapy
Biological Therapy
Radiation
Surgery
4
Varieties of Biological Therapies

• Interferons
• Interleukins
• Hematopoietic Growth Factors
• Monoclonal Antibodies (MoAbs)

5
The Immune System

• Complex system of cells and creation of
  antibodies
• Can remember previous encounters with immunogens
  and mount responses on new challenges
• Differentiates between self and foreign
• In many cancers, may not recognize the cancer as
  foreign and/or the immune system does not act
  against it
• Some biological therapies stimulate the immune
  system to attack cancer.

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Hematopoietic Cascade
Stem cells also develop into myeloid stem cells,
which can become red blood cells, megakryocytes
(pre-platelets), and a variety of leukocytes
(white blood cells) including dendritic cells.
Together, all these cells constitute the immune
system.
7
Interferons Biological Activities

• Antiviral action
• Inhibition of oncogenes
• Regulation of tumor cell growth limitation of
  proliferation
• Immunomodulation

8
Interferons Cancer Therapy
Intron A, Schering Roferon-A, Roche
Laboratories
9
Interferons Dosage
Intron A sample regimens Hairy Cell Leukemia
2 million IU/m2 IM or SC 3x week for up to 6
months Malignant Melanoma Induction treatment
for 5 days for each of 4 weeks, IV, 20 million
IU/m2 followed by maintenance treatment 3 x week
for 48 weeks, SC, 10 million IU/m2 Lymphoma 5
million IU SC 3 x week for up to 18 months in
conjunction with anthracycline regimen
Roferon A sample regimens Hairy Cell Leukemia
Induction dose 3 MIU daily for 16-24 weeks, SC.
Maintenance dose 3 MIU 3 x week. Chronic
Myelogenous Leukemia 9 MIU daily SC, may be
gradually increased over first week to reach
target dose. Optimal duration not yet
known. AIDS-Related Kaposis Sarcoma 36 MIU
daily for 10-12 weeks, IM or SC. Maintenance dose
36 MIU 3 x week.
Intron A, Schering Roferon-A, Roche
Laboratories
10
Interferons Side Effects

• Flu-like symptoms (common)
• Fatigue
• Neurological effects
• Dermatological effects

• Gastrointestinal effects
• Hepatic effects
• Hematological effects
• Cardiovascular effects

Intron A, Schering Roferon-A, Roche
Laboratories
11
Interleukins Biological Activities

• Autocrine action (T helper cells)
• Monocyte/macrophage activation
• Promotion of cell division and release of
  mediators (T cells)
• Activation and promotion of cell division (B
  cells)
• Activation of Natural Killer (NK) cells

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Interleukin-2 Indications/ Administration
Standard regimen, Interleukin-2 600,000 IU/kg
(0.037 mg/kg) administered every 8 hours by a
15-minute IV infusion for a maximum of 14 doses.
Following 9 days of rest, schedule is repeated
for another 14 doses, for maximum of 28 doses per
course, as tolerated. During clinical trials,
doses were frequently withheld for toxicity.
Because of the possible severity of high-dose
side effects, administration of high-dose therapy
should take place in the hospital setting and not
in out-patient clinics.
Proleukin, Chiron
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Interleukin-2 Side Effects
Leukopenia Lymphocytosis Macular
erythemia Malaise Mental changes Nausea Peripheral
edema Pleural effusions Pulmonary
congestion Pulmonary edema Sinus
tachycardia Stomatitis Taste changes Thrombocytope
nia Vomiting Weight gain
Anemia Anuria Anorexia Blurred vision Cardiac
arrhythmia Chills Cholestasis Diarrhea Dizziness
Dry skin Edema Eosino philia Fever Hypotension Inf
ection Jaundice
The most common side effects are shown all are
graded as severe. Other serious side effects are
less common, although they can be quite severe,
as well
Proleukin, Chiron
14
Denileukin Diftitox Indications/Administration
Fusion protein that directs the cytotoxic action
of diphtheria toxin to cells that express the
IL-2 receptor. It interacts with the receptor on
the cell surface and inhibits cellular protein
synthesis, resulting in rapid cell
death. Clinical studies demonstrated a 30-38
overall response rate among patients with
recurrent or persistent CTCL that expressed CD25
on at least 20 of sampled cells. Recommended
dose is 9mcg/kg/day and 18mcg/kg/day for 5 days,
every 21 days.
Ontak (Seragen, Ligand)
15
Denileukin Diftitox Side Effects

• All patients experienced one or more adverse
  events, and 21 required hospitalization.
• Most serious Fever, vascular leak syndrome,
  dehydration resulting from gastrointestinal
  toxicity.
• Most common Chills and fever, nausea and
  vomiting, hypoalbuminemia, anorexia, asthenia,
  infection, pain, headache, rash, hypotension.
• Adverse events diminish in frequency after the
  first two courses of treatment.

Ontak (Seragen, Ligand)
16
Hematopoietic Growth Factors Biological Activity
Hematopoietic Growth Factors (HGFs) proteins
that interact with specific receptors to regulate
the production, maturation, and function of blood
cells. Usually used to ameliorate side effects
of chemotherapy, although some are under
investigation for anti-tumor properties.
17
Hematopoietic Growth Factors
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G-CSF Indications/Administration
Granulocyte Colony-Stimulating Factor

• FDA-approved
• Enhance neutrophil recovery in patients with
  nonmyeloid malignancies being treated by
  myelosuppresive chemotherapy
• Mobilize hematopoietic progenitor cells into the
  peripheral blood for collection by leukapheresis
• Enhance neutrophil recovery and reduce fever
  after induction or consolidation chemotherapy
  treatment for myeloid leukemia
• Reduce the duration of neutropenia and
  neutropenic clinical sequelae in patients
  receiving bone marrow transplants

• Administration SC, IV
• Sample regimen 5 mcg/kg/day x 14 days or until
  absolute neutrophil count (ANC) 10,000/mm3 after
  expected chemotherapy-induced nadir

Neupogen (Amgen)
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G-CSF Side Effects

• Bone pain
• Transient liver function alterations

Neupogen (Amgen)
20
Pegfilgrastim (NeulastaTM)

• Covalent conjugate of G-CSF and
  monomethoxypolyethylene glycol
• Same mechanism of action as G-CSF
• Reduces incidence of infection (febrile
  neutropenia) in patients receiving
  myelosuppressive chemotherapy
• Same side effect profile as G-CSF
• Administered as single SC injection of 6 mg once
  per chemotherapy cycle at least 14 days before
  and 24 hours after chemotherapy

Neulasta (Amgen)
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GM-CSF Indications/Administration
Granulocyte-Macrophage Colony-Stimulating Factor

• FDA-approved
• Accelerate bone marrow recovery
• After allogeneic/autologous bone marrow
  transplantation and peripheral blood progenitor
  cell transplantation
• In allogeneic bone marrow transplantation, when
  engraftment is delayed or has failed
• After induction therapy in acute myeloid leukemia
• Mobilize progenitor cells for peripheral blood
  progenitor cell transplantation

• Administration SC, IV over 2-4 hours
• Sample regimen 250 mcg/m2/day x 3 weeks or until
  ANC 1,500/mm3 for three consecutive days

Leukine (Berlex)
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GM-CSF Side Effects

• Bone pain
• Fever
• Headache
• Rigors
• Myalgia
• Flushing

Leukine (Berlex)
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Erythropoietin Alpha Indications/Administration
Epoetin Alfa- Epogen

• FDA-approved
• Anemia
• Cancer patients on chemotherapy
• Patients with chronic renal failure
• Patients who are HIV positive and receiving AZT
• Surgical patients (to reduce need for allogeneic
  blood transfusion)

• Administration SC, IV
• Sample regimen 150 µg/kg x 3 times per week for
  8 to 12 weeks

Procrit (OrthoBiotech) Epogen (Amgen)
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Erythropoietin alpha Side Effects

• Pain at injection site (common)

• Nausea (17)
• Vomiting (17)
• Diarrhea (21)
• Headache (rare)
• Edema (rare)
• Fever (rare)
• Hypertension (rare)

Procrit (OrthoBiotech) Epogen (Amgen)
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IL-11 Oprelvekin Indications/Administration
Neumega

• FDA-approved First platelet growth factor,
  interleukin-11
• Stimulates platelet development
• Prevents chemotherapy-induced thrombocytopenia

• Administration SC
• Sample regimen
• 50 µg/kg daily
• Start 6-24 hours after completion of chemotherapy
• Continue until patients postnadir platelet count
  is 50,000 cells/ µL or for a maximum of 21
  days.
• Stop 2 days before chemotherapy

Neumega (Wyeth-Ayerst)
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Oprelvekin Side Effects

• Peripheral edema (59)
• Dyspnea on exertion (48)
• Tachycardia (20)
• Conjunctival redness/blurry vision (19)

Uncommon side effects (fibrillation, palpitations, oral moniliasis, or
pleural effusions
Neumega (Wyeth-Ayerst)
27
Darbopoeitin Alfa Indications and Administraton
ARANESP

• For the treatment of anemia in patients with
  non-myeloid malignancies where anemia is due to
  the effect of concomitantly administered
  chemotherapy.
• Due to longer serum half-life, administer less
  frequently than epoetin alfa (i.e., if epoetin
  alfa 3 x wk, administer weekly).
• Should be administered under the supervision of a
  health care professional.
• The recommended starting dose for darbopoeitin
  alfa is 2.25 mcg/kg administered as a weekly SC
  injection. Thereafter, dosage should be adjusted
  to maintain optimal hemoglobin levels.
• In clinical trials, significantly reduced the
  need for transfusions.

ARANESP (Amgen)
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Darbopoeitin Alfa Adverse Events

• Common adverse events
• fatigue, edema, nausea, vomiting, diarrhea,
  fever, dyspnea
• Serious adverse events (grades 3-4)
• death (10), fever (4), pneumonia (3),
  dehydration (3), vomiting (2), and dyspnea
  (2)
• For most patients, incidence of adverse events
  similar to placebo and/or consistent with cancer
  and its chemotherapy

ARANESP (Amgen)
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Molecular Targeted Therapies
Tyrosine Kinase Inhibitors Proteasome
Inhibitors Monoclonal antibodies (MoAbs)
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Actions of Some Targeted Therapies
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Tyrosine Kinase Inhibitors (TKI)
Imatinib Mesylate (Gleevec), Novartis Gefitinib
(Iressa), AstraZeneca

• TKIs are enzymes within the cell that block the
  ability of the protein tyrosine kinase to
  function, limiting cancerous cell growth.
• Certain leukemias, as well as cancer of the
  breast, prostate, ovary, bladder, liver, and lung
  may be successfully treated with tyrosine kinase
  inhibitors.

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Imatinib Mesylate (Gleevec)

• Protein-tyrosine kinase inhibitor that inhibits
  the Bcr-Abl tyrosine kinase (TK), the abnormal TK
  created by the Philadelphia chromosome
  abnormality in chronic myeloid leukemia (CML)
• Inhibits proliferation and induces apoptosis in
  Bcr-Abl positive cell lines as well as fresh
  leukemic cells
• Inhibits proliferation and induces apoptosis in
  gastrointestinal stromal tumor (GIST) cells that
  express activating c-kit mutation

Gleevec (Novartis)
33
Imatinib Mesylate Administration

• Chronic CML 400 mg/day
• Accelerated phase or blast crisis 600 mg/day
• Unresectable and/or metastatic GIST 400 or 600
  mg/day
• Oral tablets available 100 mg or 400 mg
• Administration can continue as long as there is
  no disease progression or unacceptable toxicity.

Neumega (Wyeth-Ayerst)
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Imatinib Mesylate Adverse Events

• Most patients experience side effects, mostly
  mild to moderate. Most common edema, nausea and
  vomiting, muscle cramps, bone pain, diarrhea, and
  rash.
• Edema has been managed with diuretics and dose
  adjustments. Fluid retention problems are
  dose-related, more common in blast crisis, and
  more common among the elderly.

Neumega (Wyeth-Ayerst)
35
Gefitinib (IRESSA)

• An anilinoquinazoline Inhibits intracellular
  phosphorylation of tyrosine kinases associated
  with transmembrane cell surface receptors
  including epidermal growth factor receptor
  (EGFR-TK)
• Its actual mechanism of clinical anti-tumor
  action has not been determined.
• Approved for treatment of patients with advanced
  non-small cell lung cancer who have failed
  previous treatment with chemotherapy containing a
  platinum drug and docetaxel.

IRESSA (AstraZeneca)
36
Gefitinib Administration

• Recommended daily dose one 250 mg tablet, with
  or without food.
• Higher doses do not achieve better response and
  produce greater toxicity.

IRESSA (AstraZeneca)
37
Gefitinib Adverse Events

• Most side effects experienced with gefitinib have
  been mild to moderate more severe reactions have
  been quite rare.
• Common side effects Diarrhea, rash, acne, dry
  skin, and nausea and vomiting
• Poorly-controlled or ill-tolerated diarrhea or
  skin reactions may be managed by an interruption
  of therapy of up to 14 days.

IRESSA (AstraZeneca)
38
Proteasome Inhibitors

• Block activity of proteasomes, enzymes that help
  regulate cell function and growth
• Proteasomes are involved in the cell cycle,
  growth of new blood vessels (angiogenesis), cell
  adhesion, cytokine production, and apoptosis.
• Blockade can lead to cell death in cancers.

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Bortezomib (Velcade) Indications and Dosing

• Indicated for patients with Multiple Myeloma (MM)
  who have received 2 prior therapies and have
  shown disease progression since the last therapy
• IV injection 1.3 mg/m2 twice weekly for 2 weeks
• Administered on days 1,4, 8, and 11, with a 10
  day rest period before the next cycle.

Velcade (Millennium Pharmaceuticals, Inc.)
40
Bortezomib (Velcade) Adverse Events

• Most common adverse events (30)
• Nausea, fatigue, diarrhea, constipation,
  thrombocytopenia
• Fever
• Peripheral neuropathy (numbness and tingling and
  occasional pain in extremities)
• Vomiting
• Severe (grade 3 or 4) adverse events
• Thrombocytopenia (30), neutropenia (14),
  peripheral neuropathy (13), and fatigue (11)

Velcade (Millennium Pharmaceuticals, Inc.)
41
Monoclonal Antibodies

• MoAbs are artificially produced in the laboratory
  and are designed to bind to the antigens
  expressed on the surface of malignant cells
• Block the growth of the tumor and/or recruit the
  bodys immune system to attack the cancer cells
• Can be given as a monotherapy, in combination
  with chemotherapy, and with other targeted
  therapies under clinical trial

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Differences Between Chemotherapy and Monoclonal
Antibody Therapy

• Traditional Chemotherapy
• Injury to cancer cells and normal cells
• Side effects/toxicity can be cumulative and may
  lead to long term sequelae
• Multi-drug resistance

• Monoclonal Antibodies
• Specifically target tumor cells
• Fewer side effects to normal cells
• Less chance of drug resistance
• Fewer cumulative side effects
• Few dose-limiting side effects

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Types of Monoclonal Antibodies
Human -umab
Murine -momab
Chimeric -ximab
Humanized -zumab
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Monoclonal Antibodies Unconjugated
45
Monoclonal Antibodies Conjugated
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MoAbs FDA-Approved for Cancer Therapy
47
FDA-Approved Moabs (cont.)
48
Rituximab (Rituxan)

• Indications
• Relapsed refractory low-grade or follicular or
  B-cell non-Hodgkins lymphoma
• Also approved for
• Initial treatment of bulky NHL
• Re-treatment of low-grade or follicular NHL
• Treatment in elderly patients

Rituxan (Genentech)
49
Rituximab Mechanism of Action
B-Cell non-Hodgkins Lymphoma - Targets CD20
Antigen
Rituxan (Genentech)
50
Rituximab Administration

• Rituximab 375 mg/m2 as slow IV infusion, once per
  week for 4 or 8 doses
• NCCN (National Comprehensive Cancer Network)
  guidelines include CVP, CHOP fludarabine
  combination chemotherapy with or without
  rituximab as first-line therapy

Rituxan (Genentech)
51
Rituximab Infusion-Related Reactions
Rituxan (Genentech)
52
Rituximab Serious Adverse Events
Rituxan (Genentech)
53
Trastuzumab (Herceptin)

• Indications
• In combination first-line treatment combined
  with paclitaxel for metastatic breast cancer in
  patients with HER2 tumors
• Single agent second-line treatment of metastatic
  breast cancer in patients with HER2 tumors

Herceptin (Genentech)
54
Trastuzumab Potential Mechanisms of Action
Herceptin (Genentech)
55
Trastuzumab Administration

• Recommended loading dose 4 mg/kg as 90 min
  infusion
• Weekly maintenance dose 2 mg/kg administered as
  30 min infusion
• Do not administer as an IV push or bolus.
• Can be administered in the out-patient clinical
  setting.

Herceptin (Genentech)
56
Trastuzumab Adverse Events
Black box warnings Cardiomyopathy,
hypersensitivity reactions including anaphylaxis,
infusion reactions, and pulmonary events. All
such serious events are rare.

• Infusion reactions (40 of patients) including
  fever and chills and sometimes nausea, vomiting,
  tumor pain, headache, and/or dizziness, are
  usually mild to moderate. Symptoms can be
  managed with acetaminophen, diphenhydramine, and
  meperidine.
• Exacerbation of chemo-induced neutropenia was
  noted in patients receiving trastuzumab plus
  chemo vs. chemo alone.
• About 25 of patients have diarrhea.

Herceptin (Genentech)
57
Alemtuzumab (Campath) Indications

• Indicated for the treatment of B-cell chronic
  lymphocytic leukemia (B-CLL) in patients who have
  been treated with alkylating agents and who have
  failed fludarabine therapy
• Chimerized monoclonal antibody
• Targets the CD52 antigen expressed on the surface
  of essentially all B and T lymphocytes

Campath (Berlex)
58
Alemtuzumab Dosing

• Begin at 3 mg as 2 hour IV infusion, daily.
• Once this dose tolerated (reactions less than
  Grade 2), escalate to 10 mg.
• Once this dose tolerated, maintenance dose of 30
  mg may be begun, administered 3 x week on
  alternate days for up to 12 weeks.
• For most patients, escalation is achieved in 3-7
  days.

Campath (Berlex)
59
Alemtuzumab Adverse Events

• Most commonly reported infusion-related adverse
  events in the pivotal study of 93 patients were
  rigors (89), fever (83), nausea (47), vomiting
  (33), and hypotension (15).
• The majority of events were grade 1 or 2 in
  severity.

Alemtuzumab received FDA warnings on hematologic
toxicity, severe infusion reactions, and
infections.
Campath (Berlex)
60
Bevacizumab (Avastin) Targeting VEGF

• 93 human, 7 murine
• Binds to VEGF with high affinity
• Prevents VEGF from binding to its receptors,
  inhibits VEGF induced angiogenesis

Avastin (Genentech)
61
Angiogenesis
EGFR
VEGF
VEGF
Tumor Cell
Capillary Endothelium
62
Inhibition of VEGF Pathway
Tumor secretion of VEGF stimulates angiogenesis
Smallavascular tumor
Angiogenic inhibitors may reverse this process
Rapid tumor growth and metastasis
Somatic mutation
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Bevacizumab Indications and Efficacy

• Addition of bevacizumab to first-line
  chemotherapy with IV 5-FU chemotherapy for
  metastatic colorectal cancer results in
  statistically significant and clinically
  meaningful improvements in
• Survival
• Progression free survival
• Duration of survival
• Overall response rate

Avastin (Genentech)
64
Bevacizumab Dosing

• Recommended dose 5 mg/kg once every 14 days as
  IV infusion until disease progression.
• Administer as part of regimen including
  5-fluorouracil chemotherapy.
• Do not begin for at least 28 days following major
  surgery and suspend several weeks prior to
  elective surgery.
• Monitor blood pressure every 2-3 weeks monitor
  for proteinuria with serial urinalysis.

Avastin (Genentech)
65
Bevacizumab Dosing (cont.)

• First infusion over 90 mins if well tolerated,
  2nd infusion over 60 mins, 3d and later over 30
  mins.
• Never administer 5 days a week
• Never administer as IV push
• Dilute with 100 cc normal saline
• Discontinue in patients who develop major side
  effects.

Avastin (Genentech)
66
Bevacizumab Adverse Events/Warnings
Gastrointestinal Perforation/Wound Healing
Complications Hemorrhage received black box
warnings.

• Safety warnings include
• Gastrointestinal Perforation/Wound Healing
  Complications
• Hemorrhage
• Hypertension
• Proteinuria/nephrotic syndrome
• Congestive Heart Failure
• All of these have been rare among most patients
  treated with bevacizumab except hypertension.
  Hypertension may worsen over time monitor blood
  pressure every 2-3 weeks during therapy and for 4
  months post bevacizumab therapy.

Avastin (Genentech)
67
Cetuximab (Erbitux) Targeting EGFR
Approved for second-line therapy of metastatic
colorectal cancer with cytotoxic chemotherapy
Erbitux (Imclone/Bristol-Meyers Squibb)
68
Cetuximab Indications and Administration

• Approved for 2nd-line treatment of metastatic
  colorectal cancer in patients who progressed on
  or within 3 months of irinotecan-based
  chemotherapy
• Cetuximab with irinotecan produced higher
  response rates and longer times to progression
  than cetuximab alone.
• Cetuximab (400 mg/m2 1st infusion over 120 mins,
  then 250 mg/m2 (IV over 60 mins weekly)
• Premedicate with diphenhydramine.
• Irinotecan administered at same dose and schedule
  that patients received previously or were on when
  they progressed

Erbitux (Imclone/Bristol-Meyers Squibb)
69
Cetuximab Adverse Events Noted in Clinical Trials
Erbitux (Imclone/Bristol-Meyers Squibb)
70
Gemtuzumab Ozogamicin (Mylotarg)

• Conjugated with calicheamicin, an antibiotic that
  is cytotoxic to certain cancer cells.
• Indicated for acute myeloid leukemia in first
  relapse.
• Binding of CD33 antigen internalizes the
  calicheamicin into the cell lysosomes where it
  binds to DNA, resulting in DNA breaks and cell
  death.
• Gemtuzumab ozogamicin is cytotoxic to CD33-
  positive HL-60 human leukemia cell line.

Mylotarg (Wyeth-Ayerst)
71
Gemtuzumab Ozogamicin Administration

• 9 mg/m2 as 2-hour IV infusion 2 doses spaced 14
  days apart
• Vital signs must be monitored during infusion and
  for 4 hrs after infusion.
• Should be administered in facilities equipped to
  monitor and treat leukemia patients.

Mylotarg (Wyeth-Ayerst)
72
Gemtuzumab Ozogamicin Adverse Events

• All patients experience severe myelosuppression.
  Almost all (99) have thrombocytopenia, and 47
  have anemia. Monitoring is required.
• Hypersensitivity reactions including anaphylaxis,
  infusion reactions, and pulmonary events have
  also occurred.
• Liver toxicities have also occurred.
• Most other side effects have been mild to
  moderate chills, fever, nausea and vomiting,
  headache, or hypotension

Mylotarg (Wyeth-Ayerst)
73
Tositumomab (Bexxar)

• The BEXXAR therapeutic regimen combines the MoAb
  tositumomab and radiolabeled MoAb Iodine I 131
  tositumomab.
• Tositumomab is a murine MoAb that targets the CD
  20 antigen, often found on the surface of
  malignant B lymphocytes.
• Appears to induce apoptosis and to produce its
  own cytotoxicity. In addition, its ionizing
  radiation promotes cell death.
• Approved for the treatment of relapsed,
  refractory follicular B cell Non-Hodgkins
  lymphoma

Bexxar (Corixa GlaxoSmithKline)
74
Tositumomab Dosing and Administration

• For patients refractory to rituximab not
  indicated for initial treatment of NHL
• Intended as a single course of treatment
• Regimen 4 components administered in two steps
• Dosimetric 1. Tositumomab 450 mg IV over 60 mins
  2. Iodine I 131 tositumomab (5.0 mCi I-131 and 35
  mg tositumomab) IV over 20 mins
• Therapeutic 1. Tosistumomab 450 mg IV over 60
  mins. 2. Iodine I 131 tositumobab (calculated
  depending on patient platelet level and whole
  body distribution of dosimetric dose) over 20
  mins.

Bexxar (Corixa GlaxoSmithKline)
75
Tositumomab Dosing and Administration (cont.)

• Patients must receive additional medications as
  follows
• Thyroid protective agents potassium iodide
  solution, Lugols solution, or potassium iodide
  tablets daily. At least 24 hrs before Iodine I
  131 tositumomab dosimetric dose and continued for
  2 wks after therapeutic dose
• Acetaminophen and diphenhydramine
• Should be administered by physicians and health
  care professionals qualified in using therapeutic
  radionuclides. Physicians must be certified by
  Corixa Corporation in dose calculation and
  administration.

Bexxar (Corixa GlaxoSmithKline)
76
Tositumomab Adverse Events

• BEXXAR black box warnings
• Hypersensitivity reactions, including
  anaphylaxis. Dosage must be reduced or stopped if
  hypersensensitivity reactions occur.
• Prolonged and severe cytopenias. Most patients
  experience severe thrombocytopenia and
  neutropoenia.
• BEXXAR safety warnings include
• Secondary malignancies MDS or acute leukemia
  were reported in fewer than 10 of patients in
  clinical trials.
• Hypothyroidism all patients must receive
  blocking agents.

Bexxar (Corixa GlaxoSmithKline)
77
Ibritumomab Tiuxetan (Zevalin) Indications and
Dosing

• Ibritumomab tiuxetan is a monoclonal antibody
  linked to the radioactive isotopes yttrium-90
  (Y-90 ZEVALIN) and Indium-111 (In-111 ZEVALIN).
  It delivers cytotoxic radiation directly to
  malignant cells.
• Indicated for the treatment of relapsed
  refractory low grade follicular or transformed
  B-cell non-Hodgkin's lymphoma (NHL) refractory to
  Rituxan (rituximab).
• Ibritumomab tiuxetan has been approved as part of
  a therapeutic regimen including rituximab.
• Studies have shown response rates in the 70-80
  range, with complete responses ranging from
  15-30.

Zevalin (IDEC)
78
Ibritumomab Tiuxetan (Zevalin) Dosing and
Administration

• Ibritumomab is administered with rituximab.
  ZEVALIN is ibritumomab combined with Y-90 or
  I-111.
• Step 1 250 mg/m2 of rituximab followed within 4
  hours by 5.0 mCi of In-111 ZEVALIN as a 10 minute
  IV push.
• Step 2 After 7-9 days, 250 mg/m2 of rituximab
  followed within 4 hours by .4 mCi/kg of Y-90
  ZEVALIN as a 10 minute IV push.
• Care is required in handling, preparing, and
  administering the ZEVALIN regimen because of the
  radioactive content. Proper aseptic technique
  and precautions for radioactive materials should
  be employed, including appropriate labeling and
  shielding.

Zevalin (IDEC)
79
Ibritumomab Tiuxetan Adverse Events

• Most side effects have been mild to moderate
  except for cytopenias, which most patients
  experience.
• Delayed cytopenia seen 4-6 weeks post therapy
• Serious adverse reactions included infections,
  allergic reactions, and hemorrhage while
  thrombocytopenic. In addition, the development of
  myeloid malignancies and dysplasias have been
  reported.
• Boxed warnings include Fatal infusion reactions
  related to rituximab
• Prolonged and severe cytopenias

Zevalin (IDEC)
80
Biological and Molecular Targeted Therapies in
Clinical Testing

• Interferons
• Interleukins
• Hematopoietic Growth Factors
• Tyrosine Kinase Inhibitors
• Proteasome Inhibitors
• Monoclonal Antibodies

All the types of biological and molecular
targeted therapies reviewed as approved agents in
cancer therapy remain under investigation. Some
are being explored in combinations with other
agents some are being studied in different forms
of cancer entirely new varieties are being
introduced. A few examples follow.
81
Vaccines
Many vaccines against cancer are in clinical
trials. Unlike prophylactic vaccines designed to
prevent disease, cancer vaccines are intended to
halt cancer after it has arisen. Malignant
melanoma has seen perhaps the most active
development of vaccines, with many trials
continuing. However, trials are also underway of
vaccines targeted at renal cell carcinoma,
colorectal cancer, lung and breast cancer,
prostate cancer, and more.
82
Vaccines (cont.)
Most cancer vaccines are manufactured from tumor
cells and are intended to stimulate the bodys
immune system to attack the cancer. One category
of vaccines is made from dendritic cells drawn
from the body and sensitized to tumor cells in
the presence of GM-CSF. Some vaccines are based
on GM-CSF itself. Others are based on
bacterially-derived proteins The side-effects of
cancer vaccines tend to be very minor.
83
Vaccine Examples
KLH vaccine (THERATOPE) Metastatic breast
cancer To prevent recurrence after
chemotherapy Phase III Anti-p-53 gene
vaccine Advanced malignancy (colorectal,
ovarian, SCLC, and other) Showed longer than
expected progression free survival Phase I/II -
Administered with IL-2 and leukocytes. EGFR
ligand vaccine NSCLC Improved survival times
over five years of trials Phase II underway
84
Vaccine Examples (cont.)
Polyvalent vaccine (PV) administered with
BCG (CanvaxinTM ) Metastatic melanoma To test
enhancement of immunogenicity when given with
GM-CSF Phase II MGT MART-1 (27-35), gp100
(209-217, 210M) Metastatic melanoma E2696 
and Intergroup 1694  Phase II
85
Immunologic Mediators
Interferon Alfa with Nonoxynol-9 Exovir-HZ Gel,
Exovir Cervical or vulvar cancer Interferon
Gamma Immuneron, Biogen Renal cell
carcinoma Interleukin-1 Alpha IL-1a,
Immunex Treatment of immunosuppression Interleuk
in-1 Beta Epikine, Immunex Melanoma Interleukin-
1 Soluble Receptor Immunex Chronic myelogenous
leukemia
Interleukin-4 Schering cancer
immunomodulation Interleukin-6 Sigosix,
Novartis Breast, lung, renal, ovarian cancers
lymphoma Interleukin-12 Genetics
Institute/Roche Kidney cancer Liposome-Encapsulat
ed Interleukin-2 Otx-287, OncoTherapeutics Brain
, CNS tumors kidney renal pelvic
cancers Macrophage CSF Macrolin, Biogen
86
Erlotinib Tarceva Tyrosine Kinase Inhibitor

• Highly selective, potent and reversible inhibitor
  of HER1/EGFR-TK phosphorylation
• Blocks tumor cell proliferation and promotes
  apoptosis
• Inhibits EGFRvIII mutant
• At least additive antitumor effects when combined
  with cytotoxic agents with no increase in
  toxicity
• Produces stasis and regression in NSCLC and other
  human xenografts
• Orally available
• Well tolerated

Tarceva (Genentech)
87
Clinical Development of Erlotinib

• Phase I monotherapy studies defined dosage and
  tolerability
• Phase Ib combination studies ongoing studies to
  examine feasibility of using erlotinib in
  combination with various cytotoxic agents
• Phase II studies completed studies show
  antitumor activity with erlotinib monotherapy in
  NSCLC, ovarian, and head and neck cancer
• Phase III studies ongoing and planned studies
  to examine erlotinib as monotherapy and in
  combination with cytotoxic agents in various
  indications

Tarceva (Genentech)
88
Erlotinib Monotherapy Summary Adverse Events
NA not available Final data pending
Tarceva (Genentech)
89
Erlotinib Other Trials

• A randomized phase III trial in patients with
  pancreatic carcinoma will compare the efficacy of
  erlotinib plus gemcitabine vs gemcitabine alone.
  Expected to enroll approximately 500 patients
  primary endpoint is survival.
• A multicenter, randomized placebo-controlled
  study of erlotinib in patients with incurable
  stage IIIB/IV NSCLC after failure of standard
  therapy for metastatic disease.
• A randomized phase III study of erlotinib in
  combination with gemcitatine and cisplatin in
  patients with stage IIIB/IV NSCLC.

Tarceva (Genentech)
90
Other TKIs in Testing
GW572016 Inhibits both EGFR ErbB-2 Tested in
breast cancer, head and neck carcinoma, and
NSCLC Administered with chemotherapy Variable
responses SU11248 Oral, multi-targeted
Platelet-derived growth factor, VEGFR, KIT, and
FLT3 Tested in many solid tumor types CEP-7055
Targets several VEGFRs Tested in solid tumors
91
Proteasome Inhibitors

• Bortezomib (Velcade)
• Remains in active testing for a variety of
  cancers
• Renal cell carcinoma
• Hematologic malignancies
• Breast cancer
• Ovarian cancer
• Multiple-myeloma
• Non-small cell lung cancer
• Prostate cancer
• Indolent lymphoma
• No other studies of proteasome inhibitors have
  yet been reported.

92
Sample of Monoclonal Antibodies under
Investigation
93
Monoclonal Antibodies under Investigation(cont.)
94
MoAb Bevacizumab Continuing Trials

• Phase II trial (E4599) in non-small cell lung
  cancer (NSCLC).
• Phase I/II trial with erlotinib in NSCLC to
  determine maximum dose, safety, and toxicity.
  Secondary endpoints ORR, PK.
• Phase III trial (E2100) as first-line combination
  therapy in metastatic breast cancer (MBC).
  Paclitaxel with or without bevacizumab.
• Phase III trial of capecitabine with or without
  bevacizumab in refractory MBC.
• Renal Cell Cancer Phase II trial showed
  significant increase in progression-free survival.

Avastin (Genentech)
95
MoAb Trastuzumab New Combinations

• Vinorelbine
• Gemcitabine
• Platinum compunds

96
Angiogenesis
97
Conclusion
This review of biological and molecular targeted
therapies for cancer has stressed the
FDA-approved agents available now. It has looked
at various types of therapies, including
molecular agents, growth factors, monoclonal
antibodies, and more. In addition, it has given
a brief look at on-going research. Clearly,
exploring substances derived from or mimicing
naturally-occurring proteins (i.e., inhibitors,
receptors, cell types, enzymes) is a field of
cancer research yielding new, efficacious
therapies, many targeted at specific cancer cell
functions, that offer hope for cancer patients.