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Biological and Molecular Targeted Therapies in Cancer Treatment

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Title: 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

3
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.

6
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

12
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
13
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
18
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)
19
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)
21
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)
22
GM-CSF Side Effects
  • Bone pain
  • Fever
  • Headache
  • Rigors
  • Myalgia
  • Flushing

Leukine (Berlex)
23
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)
24
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)
25
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)
26
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)
28
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)
29
Molecular Targeted Therapies
Tyrosine Kinase Inhibitors Proteasome
Inhibitors Monoclonal antibodies (MoAbs)
30
Actions of Some Targeted Therapies
31
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.

32
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)
34
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.

39
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

42
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

43
Types of Monoclonal Antibodies
Human -umab
Murine -momab
Chimeric -ximab
Humanized -zumab
44
Monoclonal Antibodies Unconjugated
45
Monoclonal Antibodies Conjugated
46
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
Small avascular tumor
Angiogenic inhibitors may reverse this process
Rapid tumor growth and metastasis
Somatic mutation
63
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.
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