Phase II Study of the Safety and Efficacy of Vicriviroc VCV in HIV TreatmentExperienced Subjects

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Phase II Study of the Safety and Efficacy of
Vicriviroc (VCV) in HIV Treatment-Experienced
Subjects
ACTG 5211

• Roy Gulick, MD
• Cornell University
• for the A5211 Protocol Team

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A5211 Study Objectives

• Primary Objective
• To evaluate the virologic activity of 3 doses of
  vicriviroc (VCV) at 14 days
• Main Secondary Objectives
• At weeks 24 and 48
• To assess safety/tolerability of VCV
• To evaluate virologic and immunologic activity
  (VCV with optimized ART)
• To assess co-receptor switching

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A5211 Study Population

• ART-experienced adults
• HIV RNA gt5000 copies/ml on a ritonavir
  (RTV)-containing regimen
• R5-only phenotype (Monogram co-receptor tropism
  assay)
• Stratified by
• enfuvirtide use
• Baseline CD4 lt or gt50 cells/µL

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A5211 Study Design
Placebo
VCV 5 mg qd
SCREENING genotype, phenotype, tropism
VCV 10 mg qd
VCV 15 mg qd
DAY 14
WEEK 24
WEEK 48
STUDY ENTRY
All regimens include 100-800 mg RTV Study powered
to detect gt0.7 log HIV RNA difference at day
14 Cross-over options (Step 2) following
virologic failure (after wk 16)
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A5211 Baseline Characteristics

• 118 subjects enrolled
• median age 46
• 92 men, 8 women
• 20 black, 12 Hispanic, 66 white, 2 other
• Median HIV RNA 36380 cps/ml
• Median CD4 cell count 146 cells/µL
• 33 were ENF-experienced
• 100 had R5-tropic virus at screening

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A5211 Study Monitoring Committee (SMC) Review

• 10/6/05 VCV 5 mg dose recommended to be
  stopped (and ? to 15 mg) because of
• trend for increased co-receptor switches
• trend for suboptimal virologic responses
• decision to stop lowest-dose VCV arm on
  Schering-sponsored rx-naïve study

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A5211 Mean Change in HIV RNA (log10 cps/ml 14
days, ITT)
lt50 cps/ml at week 24
placebo
2 (7)
PBO
VCV 5 mg
6 (26)
5 mg
VCV 15 mg
8 (27)
15 mg
VCV 10 mg
12 (40)
10 mg
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A5211 Mean Change in HIV RNA (log10 cps/ml 24
weeks, ITT)
placebo
VCV 5 mg
VCV 15 mg
VCV 10 mg
OBR
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A5211 Wk-24 Virologic Responses
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A5211 Mean Change in CD4 Cell Count (24
weeks, ITT)
VCV 15 mg
VCV 10 mg
VCV 5 mg
placebo
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A5211 Tropism

• At screening 118 (100) R5-only
• At study entry 102 (86) R5-only, 12 (10)
  dual/mixed, 4 (4) missing
• On initial study rx (n106), 13 subjects changed
  tropism 1 placebo, 7 VCV 5 mg, 3 VCV 10 mg, 2
  VCV 15 mg
• Virologic response (HIV RNA log cps/ml at week
  24 VCV 10 VCV 15 mg arms)
• R5-tropic at entry (n71) -1.83
• Dual/mixed tropic at entry (n10) -0.77
  (p.01)

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A5211 Adverse Events (1)

• No significant difference for grade 3 or 4
  adverse events among 4 arms (pairwise
  comparisons, pgt0.6)
• No seizures reported

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A5211 Adverse Events (2)

• 5 subjects randomized to VCV developed
  malignancies
• 1 on VCV 15 mg with a hx of Hodgkins disease
  (HD) developed non-Hodgkins lymphoma (NHL)
• 1 on VCV 10 mg with a hx of HD developed
  recurrent HD
• 1 on VCV 15 mg developed gastric adenocarcinoma
• 1 on VCV 5 mg developed NHL
• 1 on VCV 5 mg developed HD

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A5211 Adverse Events (3)

• 2 subjects randomized to PBO developed
  malignancies
• 1 subject on PBO developed multiple cutaneous
  squamous cell carcinomas
• 1 subject on PBO X 7 months, who then took VCV 10
  mg X 3 months, discontinued VCV for lack of
  response, and 1 month later developed localized
  perianal squamous cell carcinoma

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A5211 Conclusions

• In rx-experienced pts
• VCV (5, 10, 15 mg with RTV) demonstrated potent
  14-day virologic suppression
• Following optimization of background ART, VCV
  (10, 15 mg with RTV) demonstrated sustained
  antiretroviral activity over gt24 weeks.
• Subjects with dual/mixed-tropism had a reduced
  virologic response.
• VCV was generally well tolerated.
• The relationship of VCV to malignancy is
  uncertain.

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A5211 Acknowledgments (1)

• A5211 Protocol Team
• Co-chairs Daniel Kuritzkes, MD Charles
  Flexner, MD
• Immunologist Paul Skolnik, MD
• Statisticians Zhaohui Su, PhD
• Michael Hughes, PhD
• DAIDS Katy Godfrey, MD Carla
  Pettinelli, MD
• Team Investigators David Clifford, MD Robert
  Gross, MD Scott Hammer, MD Martin Hirsch, MD
  Timothy Wilkin,MD Andrew Zolopa, MD

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A5211 Acknowledgments (2)

• Clinical Trials Specialist Beatrice Kallungal,
  BS
• Data Manager Susan Owens, RN, MS
• Lab Data Coordinator Mary Dobson, BS
• DAIDS Pharmacist Ana Martinez, RPh
• Field Representative Valery Hughes, NP
• Laboratory Tech Antoine Simmons
• Community Rep Jim Smith

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A5211 Acknowledgments (3)

• Pharmaceutical Supporters
• Wayne Greaves, MD and Lisa Dunkle, MD
  (Schering-Plough Research Institute)
• Eoin Coakley, MD (Monogram Biosciences)
• Division of AIDS, NIAID, NIH

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A5211 Acknowledgments (4)

• ACTG study sites
• Harvard-BMC, Stanford, Rochester,
  Pitt-Georgetown, Cornell, NYU, Emory, U
  Washington, Vanderbilt, U Colorado, Case Western,
  UCLA, Wash U, Ohio State, Rush, Beth Israel,
  Miriam/RI, UNC, UCSF, U Iowa, U Texas/Galveston,
  UCSD, Wishard/Indiana, U Hawaii, Penn
• And the study participants!