ASCO 2006Supportive Care

John Glaspy, MDSanders Chair in Cancer ResearchJonsson Comprehensive Cancer CenterProfessor of MedicineUCLA School of Medicine

UCLA

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

UCLA

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)

UCLA

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

UCLA

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 dietDemark-Wahnefried, et. al.

UCLA

Results

UCLA

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 < .05). Strength declined less with HBEX

• Some of the fatigue and functional impairment in that we treat with EPO may preventable

Mustian, et. al.

UCLA

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.

UCLA

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

UCLA

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.

UCLA

Denosumab

• Ratio of RANKL to decoy receptor (osteoprogerin) determines the level of osteoclastogenesis

• Denosumab (AMG 162) is a human monoclonal antibody to RANKL

Roodman: NEJM 350:1655, 2004

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

UCLA

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

UCLA

Results

• Safety profiles excellent (no ONJ)

• Dose chosen for phase III is 120 mg SQ q 4w

Lipton, et al

UCLA

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

UCLA

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

UCLA

Eltrombopag: Small Molecule TPO-R Agonist

• Small molecule TPO-R agonist (mw=442)

• Interacts with TPO-R differently than endogenous TPO

• Stimulates megakaryocyte proliferation and differentiation

• Orally bioavailable

• Does not prime platelets for activation

UCLA

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

UCLA

Future Applications

• Both drugs are safe and raise platelet counts in ITP

• 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

Bussel, #8602

UCLA

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 > 1,000 ng/mL• N = 196 of planned 400, interim analysis

Vandebroek, et. al.

UCLA

Iron/Darbepoetin: Outcomes, Interim Analysis

UCLA

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.

UCLA

Epoetin q2w (#8624): Results

Primary Endpoint

Transfusions

UCLA

AMG 114 for CIA (#8626)

• Hyperglycosylated rhuEPO; 10 aa difference, 4 additional carbohydrate chains

• Efficacy q3w, no antibodies reported

Österborg , et. al.

UCLA

Chlorhexidine or Cryotherapy for Chemotherapy Mucositis (#8508)

• Patients with GI cancer undergoing FU+LV 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.

UCLA

Results (#8508)

Sorensen, et. al.

Duration of Mucositis

Incidence of Mucositis

Grading of Mucositis

UCLA

NK-1 RA (#8512)

• RCT of ondansetron + dex +/- casopitant for CINV due to moderately emetogenic chemotherapy; 6 arms, N=719

• Casopitant groups better than control (p < .05). Single day dosing of particular interest.

OND 8 mg BID

d 1-3

8 mg BID

d 1-3

8 mg BID

d 1-3

8 mg BID

d 1-3

8 mg BID

d 1-3

16 mg/d

d 1-3

DEX 8 mg BID

d 1

8 mg BID

d 1

8 mg BID

d 1

8 mg BID

d 1

8 mg BID

d 1

8 mg BID

d 1

CAS - 50 mg/d

d 1-3

100 mg/d

d 1-3

150 mg/d

d 1-3

150 mg/d

d 1

150 mg/d

d 1-3

CR120 h

70% 81% 79% 85% 80% 84%

Arpornwirat et. al.

UCLA

NK-1 RA (#8513)

• RCT of ondansetron + dex +/- casopitant for CINV due to highly emetogenic chemotherapy; 6 arms, N=493

• Casopitant groups better than control (p < .05). Single day dosing of particular interest.

OND 32 mg IV

d 1

32 mg IV

d 1

32 mg IV

d 1

32 mg IV

d 1

32 mg IV

d 1

32 mg IV

d 1

DEX PO

d1-14

PO

d1-14

PO

d1-14

PO

d1-14

PO

d1-14

PO

d1-14

CAS placebo 50 mg/d

d 1-3

100 mg/d

d 1-3

150 mg/d

d 1-3

150 mg/d

d 1

Aprepitant

125 mg d1, 80 mg d 2-3

CR120 h

60% 76% 86% 77% 75% 72%

Rolski et. al.

UCLA

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)

• N=40, well tolerated

Navari et. al.

CR Rates Acute (d1) Delayed (d2-5)

HEC 100% 97%

MEC 75% 75%