ASCO 2006 Supportive Care

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ASCO 2006Supportive Care

• John Glaspy, MD
• Sanders Chair in Cancer Research
• Jonsson Comprehensive Cancer Center
• Professor of Medicine
• UCLA School of Medicine

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Supportive Care Overview

• Integrative Medicine (diet, exercise, etc.)
• Fresh Start
• HBEX
• Yoga
• Bone health
• Focusing zoledronic acid rx
• Denosumab
• Aromatase inhibitors and bone loss (511)
• Hematopoietic growth factors
• Thrombocytopenia
• Anemia

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Supportive Care Overview (2)

• GI Toxicities
• Octreotide ineffective for pelvic RT (8506)
• Chlorhexidine or cryotherapy for prevention of
  chemotherapy mucositis
• Cachexia/Inanition/Depression
• Etanercept (TNF inhibitor) is ineffective for the
  treatment of cancer cachexia (8534)
• Pain, depression and fatigue do not cluster in
  advanced cancer (8522)
• Depressive symptoms are a strong predictor of
  short survival in lung cancer (8511)
• Depression is common in older men with prostate
  cancer (8510)

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Supportive Care Overview (3)

• Chemotherapy-induced nausea and vomiting (CINV)
• Severity of nausea and not presence of vomiting
  is the main driver of QOL in CINV (8514)
• Neurokinin-1 (NK-1 RA) receptor antagonists

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Fresh Start (8503)

• Prostate or breast cancer
• RCT of tailored, iteratively customized print
  materials vs. standardized materials
• N 270/group, 2 years of follow up
• Excluded
• Disabled
• Contraindication to fruits and vegetables or
  exercise
• Already exercising 150 min/w or low fat high F
  V diet

Demark-Wahnefried, et. al.
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Results
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HBEX (8504)

• Prostate or breast cancer undergoing RT
• RCT of home-based exercise (HBEX), aerobic
  resistance vs. standard of care
• N 38, endpoints FACT-F, aerobic capacity (AC)
  and strength (S)
• HBEX decreased fatigue and increased AC, standard
  care was associated with increased fatigue and
  decline in AC (p lt .05). Strength declined less
  with HBEX
• Some of the fatigue and functional impairment in
  that we treat with EPO may preventable

Mustian, et. al.
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Yoga (8505)

• Breast cancer undergoing RT
• RCT of Yoga (2X/wk X 6 weeks) vs. wait list
• N 71, endpoints SF36, depression, fatigue,
  sleep, impact of events, perceived benefit
• Yoga well tolerated, viewed as beneficial
• Yoga associated with improvements in SF36, PSQI
  (sleep) and fatigue

Cohen, et. al.
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Yoga Results

• Change from baseline at one week follow up
• Preliminary, but change scores compare favorably
  to ESAs, the major QOL/fatigue treatment
  administered in oncology

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Predictors of Benefit from Bisphosphonates
(8529)

• Retrospective review of 3 large, RCT
• Stratified on the of bone mets at baseline
• Greater of bone mets associated with higher
  risk of SRE and greater benefit from therapy

Shirina et. al.
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Denosumab

• RANK-ligand, acting through RANK on osteoclast
  progenitors is the primary regulator of
  osteoclast formation and survival

• Ratio of RANKL to decoy receptor (osteoprogerin)
  determines the level of osteoclastogenesis
• Denosumab (AMG 162) is a human monoclonal
  antibody to RANKL

Roodman NEJM 3501655, 2004
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Active-Control RCT of Denosumab in
Bisphosphonate-Naïve Breast Cancer (512)

• Endpoints Changes in urinary N-telopeptide
  (uNTx) and skeletal-related events (SRE) at week
  16

Lipton, et al
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Results

• Safety profiles excellent (no ONJ)
• Dose chosen for phase III is 120 mg SQ q 4w

Lipton, et al
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TPO is the Primary Regulator of Platelet
Production

• Levels correlate inversely with platelet count in
  humans
• Regulated primarily though clearance by platelets
  and precursors
• Knockout results in severe thrombocytopenia

Kaushansky Blood 86(2) 419, 1995
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AMG 531 TPO-R Agonist Peptibody

• A peptide TPO-R binding domain that has no
  sequence homology to endogenous thrombopoietin
• An antibody Fc domain that increases serum half
  life

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Eltrombopag Small Molecule TPO-R Agonist

• Small molecule TPO-R agonist (mw442)
• Interacts with TPO-R differently than endogenous
  TPO
• Stimulates megakaryocyte proliferation and
  differentiation
• Orally bioavailable
• Does not prime platelets for activation

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Rationale for TPO-R Agonists in ITP

• Endogenous TPO levels relatively low in ITP
• Platelet production is reduced or normal in 2/3
  of ITP patients (based upon I125 labeling
  studies)
• Auto-antibodies bind and induce apoptosis of
  platelet precursors

Nichol J, Stem Cells 16(suppl2)165-175, 1998
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Future Applications

• Both drugs are safe and raise platelet counts in
  ITP

Bussel, 8602

• Likely to find a role in chemotherapy-induced
  thrombocytopenia
• Incidence is not trivial and increasing (see
  Kuderer, 8616)
• Results in dose delays and reductions, as well as
  txns and bleeding

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Parenteral Iron and Darbepoetin in CIA (8612)

• Darbepoetin, 50 mcg q3w /- parenteral iron
• Parenteral iron was given at a dose of 200 mg
  every 3 weeks held for ferritin gt 1,000 ng/mL
• N 196 of planned 400, interim analysis

Vandebroek, et. al.
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Iron/Darbepoetin Outcomes, Interim Analysis
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Epoetin q2w (8624)

• Open-label, randomized trial of epoetin alfa
  40,000U/week vs. 80,000/2 weeks for CIA
• No dose escalation in q2w group crossover
  allowed for hb decline in q2w group
• Duration 12 weeks, endpoint hb change from
  baseline, N 198
• No difference in toxicity or clinically relevant
  TVE

Henry, et. al.
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Epoetin q2w (8624) Results
Primary Endpoint
Transfusions
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AMG 114 for CIA (8626)

• Hyperglycosylated rhuEPO 10 aa difference, 4
  additional carbohydrate chains
• Efficacy q3w, no antibodies reported

Österborg , et. al.
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Chlorhexidine or Cryotherapy for Chemotherapy
Mucositis (8508)

• Patients with GI cancer undergoing FULV
  chemotherapy
• RCT of chlorhexidine mouthwash vs. cryotherapy
  (crushed ice in mouth 10 min before to 35 min
  after chemotherapy) vs. placebo mouthwash
• N 206, endpoint self-reporting questionnaire

Sorensen, et. al.
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Results (8508)
Grading of Mucositis
Incidence of Mucositis
Duration of Mucositis
Sorensen, et. al.
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NK-1 RA (8512)

• RCT of ondansetron dex /- casopitant for CINV
  due to moderately emetogenic chemotherapy 6
  arms, N719
• Casopitant groups better than control (p lt .05).
  Single day dosing of particular interest.

Arpornwirat et. al.
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NK-1 RA (8513)

• RCT of ondansetron dex /- casopitant for CINV
  due to highly emetogenic chemotherapy 6 arms,
  N493
• Casopitant groups better than control (p lt .05).
  Single day dosing of particular interest.

Rolski et. al.
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Olanzapine (Zyprexa) for CINV (8608)

• A thienobenzodiazepine anti-psychotic useful in
  bipolar disorders and schizophrenia
• Phase II trial of olanzapine palonosetron
• Olanzapine, 10 mg PO day 1-4
• Palonosetron, .25 mg IV day 1
• Dexamethasone, d1, 20 mg (HEC) or 8 mg (MEC)
• N40, well tolerated

Navari et. al.