mTOR Inhibition in Sarcoma

1
mTOR Inhibition in Sarcoma

• Richard Walgren, M.D., Ph.D.
• March 14th, 2008

2
Sarcoma

• Malignancy of tissues of mesenchymal origin
• Bone or Soft Tissue
• Average overall survival rate 60-70
• depending on sarcoma type, grade, stage
• Rare
• 1 of Adult Cancers
• 15-20 of Pediatric Cancers

3
Common Histologies of Soft Tissue Sarcomas
From Demetri Antman Atlas of Diagnostic
Oncology 3rd ed.
4
Genetics of Sarcoma

• Sarcomas with chaotic karyotypes ? copy number
  changes
• Leiomyosarcoma (LMS)
• Malignant fibrous histiocytoma (MFH)
• Sarcomas with tumor-specific translocations
• Alveolar rhabdomyosarcoma (RMS)
• t(213) in 50 Fusion of EWSR1 FLI1
• Ewings , pNET, Askin tumor
• t(1122) in 80 PAX3 DNA binding domain fused to
  gene of unknown function
• Synovial
• t(X18) Unknown

5
Signaling in Sarcoma

• Common Abnormalities
• retinoblastoma (RB),
• p53 (TP53),
• growth-factor signaling pathways
• IGF-1R pathway is the most commonly activated
  pathway
• leading to activation of PI3K, AKT, mTOR

6
mTOR

• 289-kD serine/threonine kinase
• product of FRAP1 (FK506 binding
• protein 12-rapamycin associated protein 1)
• Interfaces between
• RTK signaling via PI3K
• energy sensing pathways via serine threonine
  kinase 11 (LKB1)
• Participates in 2 complexes
• mTORC1 (raptor)- rapamycin sensitive,
• mTORC2 (rictor)- rapamycin resistant

7
Aberrant mTOR Signaling
Wan, X. et al. Oncologist 2007121007-1018
8

• Does inhibition of mTOR signaling alter the
  course of malignancy and in particular sarcoma?

9
mTOR Inhibitors

• Rapamycin (sirolimus)
• Isolated from Steptomyces hygroscopicus from
  Easter Island (Rapa Nui)
• Macrolide antibiotic
• Discovered in 1970s, FDA approval for
  immunosuppresion in 1990s
• Forms complex with FKBP12, complex binds mTOR and
  inhibits function of mTOR in mTORC1.
• NCI screening program demonstrated rapamycin has
  inhibitory activity against several human cell
  lines in vitro and in vivo but pharmaceutics
  (i.e. poorly soluble) limited development.
• Development of analogs

10
mTOR inhibitors in development
Wan, X. et al. Oncologist 2007121007-1018
11
Evidence of mTOR inhibitor activity in Sarcoma
12
Evidence of mTOR inhibitor activity in
SarcomaDeforolimus (AP23573)
13
Abstract No 10076 Journal of Clinical Oncology,
2007 ASCO Annual Meeting Proceedings Part I. Vol
25, No. 18S (June 20 Supplement), 2007 10076

• Survival results with AP23573, a novel mTOR
  inhibitor, in patients (pts) with advanced soft
  tissue or bone sarcomas Update of phase II
  trial.
• S. P. Chawla, A. W. Tolcher, A. P. Staddon, S.
  Schuetze, G. Z. D'Amato, J. Y. Blay, J. Loewy, R.
  Kan, G. D. Demetri
• Pts with advanced sarcomas, no restrictions on
  prior therapies
• Enrolled into 4 cohorts based on histological
  subtype
• AP23573 12.5 mg IV daily 5 days every 2 wks
• Efficacy assessed using RECIST, with
• CBR (clinical benefit response) defined as a
  CRPRSD 16 wks duration.
• OS was defined as the time from the first dose of
  AP23573 to the date of death from any cause.

14
Abstract No 10076

• 212 pts (105 M/107 F), median age 50.6 yrs
  (17-79 yrs)
• 79 had received 2 prior treatments, 40 having
  received gt 4 prior treatments
• Over 90 of pts had disease progression at time
  of enrollment.
• Only 10 subjects began the trial without
  metastases
• The overall CBR rate was 29, including 5 PRs
• (4 bone sarcoma, 1 MFH).
• The median OS was 40.1 wks for the entire study
  population.
• In the subset of patients achieving CBRs the
  median OS was 67.6 wks,
• suggesting that achievement of CBR, which is a
  measure of tumor control, correlates with
  extending OS.

15
Abstract No 10076

• EORTC historical controls
• inactive agents had PFS of 8 at 6 months and
  median PFS of 7 wks,
• active agents had PFS of 14 at 6 months and
  median PFS of 8 wks

16
Evaluating Response
Imaging from 23 yo male with osteosarcoma From
Chawla SP, Sankhala KK, Mida MM et al. AP23573 A
review of recentresults. Available at
http//www.liddyshriversarcomainitiative.org/Newsl
etters/V02N04/AP23573/ap23573.htm.
17
(No Transcript)
18
SUCCEED

• Sarcoma Multi-Center Clinical Evaluation of the
  Efficacy of Deforolimus trial
• Study Design
• Multicenter, international, randomized, Phase 3,
  double-blind, placebo-controlled study.
• Approximately 650 patients will be randomized
  (11) to oral deforolimus or placebo at
  approximately 125 sites, worldwide.
• Subjects with metastatic sarcomas who have
  demonstrated a favorable response to chemotherapy
  will be randomized to deforolimus or placebo.
• Study Objectives
• Primary To determine the rate of
  progression-free survival (PFS) for patients
  treated with deforolimus.
• Secondary To assess overall survival (OS), best
  target lesion response, improvement in symptoms,
  and safety and tolerability with deforolimus.

19
SUCCEED

• Key Eligibility Criteria
• Confirmed diagnosis of metastatic soft-tissue or
  bone sarcoma
• Ongoing favorable outcome after a minimum of 4
  cycles of prior chemotherapy for treatment of
  metastatic disease in sarcoma patients
• ECOG performance status of 0 or 1
• Age 13 years
• Adequate organ and bone marrow function
• Completed prior chemotherapy with last dose
  received at least 3 and up to 8 weeks prior to
  randomization
• Study Duration
• Enrollment is projected to be complete within
  approximately 2 years of the first patient being
  enrolled
• Patients will be followed for survival
  information for at least 2 years and up to 5
  years following randomization
• In total, trial is expected to continue for
  approximately 42 months

20
Closing Thoughts

• While the incidence of soft tissue sarcomas is
  low, the number of soft tissue sarcomas occurring
  as secondary malignancies is increasing as more
  curative regimens are introduced for other
  primary malignancies.
• Though there are a wide variety of histological
  subtypes included within soft tissue sarcomas,
  common molecular abnormalities are observed
  frequently within many of these histological
  groups.
• New therapies should be able to selectively take
  advantage of these abnormalities.