Zometa for Prostate Cancer Bone Metastases
Protocol 039
Amna Ibrahim, M.D.Oncology Drug Products
FDA
Critical Questions: Study 039
• Considering both the 4 mg and 8/4 mg arms, how convincing is the Prostate Cancer Trial (039)?
• Can data from other studies provide support?
Overview of Prostate Cancer Trial
• Study Results• Exploratory analysis • No baseline imbalances• No impact of early discontinuations on
primary endpoint• Summary of issues of trial
Proportions of Patients with SREs: Protocol defined Primary Endpoint
95% C.I. and P-value for the differenceProportionZol 4 mg Zol 8/4 mg
Placebo 92/20844%
-20.3%, -1.8%p=0.021
-15.1%, 3.6%p=0.222
4 mg 71/21433%
- (-3.7%, 14.3%),p=0.255
8/4 mg 85/22138%
- -
Time To First Event:FDA preferred Primary Endpoint
N Median TTE in days
(95% C.I.)
P-value (Log-rank)
Hazard Ratiovs placebo(95% C.I.)
Placebo 208 321(252, Not reached)
- -
Zol 4 mg 214 Not reached(383, Not reached)
0.009 0.66(0.48, 0.90)
Zol 8/4 mg 221 363(255, Not reached)
0.541 0.912(0.68, 1.23)
Time to to First SREHazard Ratios with 95% C.I.
Study 011
Study 039
4 mg
8 mg
4 mg
8 mg
HR = 1
Secondary Endpoints - 039
BPI scores
Analgesic scores
ECOG PS
FACT-G scores
TTP in bone
TTP
Overall survival
P value not significant for any endpoint at the end of 15 months
Exploratory analysis
Pooled analysis: Zometa vs. Placebo - 039exploratory analysis
Time to first SRE: Zometa 4 mg + 8/4 mg vs Placebo:p-value * = 0.06H.R. point estimate = 0.7895% C.I. = 0.60, 1.01Proportion of Patients with SRE: Zometa 4 mg + 8/4 mg vs Placebop-value * = 0.04Diff. In proportions = -0.0895% C.I. = -0.161, -0.001
* Should be interpreted with caution due to exploratory nature of the analysis. is not adjusted for multiple testing
Proportion of Patients with Individual SREs - 039
exploratory analysis
Prop. Of patients with path fractures 4 mg vs placebo significant (p=0.015)
23
13
5 42
24
15
85
3
29
22
7 73
0
5
10
15
20
25
30
35
Radiation tobone
All fractures Change ofantineoplastic
therapy
Spinal cordcompression
Surgery to bone
Perc
ent o
f pat
ient
s
ZOMETA 4 mgZOMETA 8/4 mgPlacebo
N214221208
Proportions (%) of Patients with any SRE in Blastic Metastasis in Solid Tumor Trial-011
exploratory analysis - support for prostate cancer study
05
101520253035404550
4 mg8/4 mgPlacebo
Patients with blastic metastasis at baseline of Study 011
N=133
42 patients 51 patients 40 patients
26%29%
35%N=11
N=15
N=14
Perc
ent o
f pat
ient
s
No Baseline ImbalancesMultivariate Cox Regression model - 4 mg arm vs. placebo p-value = 0.02 HR = 0.68 95% CI = 0.49, 0.94- 8 /4 mg vs. placebo p-value = 0.37 HR = 0.8795% CI = 0.67, 1.18
Early discontinuations were not the cause of inconsistency
Number of infusions and patients with SREs at 3 months of treatmentZol 4 mgN=213
Zol 8/4 mgN=219
PlaceboN=208
Discontinuations prior to15 months
62% 72% 69%
Infusions at 3 mos. 82% 81% 83%
SREs by 3 mos. 2512%
4822%
4723%
Summary of ResultsProstate Cancer Trial - 039
• Proportion of patients with SRE and Time to first SRE for 4 mg arm were significantly better than placebo
• Proportion of patients with SRE and Time to first SRE for 8/4 mg arm show no difference compared to placebo
FDA Guidance for IndustryProviding Clinical Evidence of Effectiveness for
Human Drug and Biological Products
“When considering whether to rely on a single multicenter trial, it is critical that the possibility of an incorrect outcome be considered and that all the available data be examined for their potential to
either support or undercut reliance on a single multicenter trial”
FDA Guidance for IndustryFDA approval of New Cancer Treatment Uses for
Marketed Drug and Biological Products
“If a product has already been shown to be safe and effective in the treatment of patients with a
given type of cancer, a single, adequate and well-controlled, multicenter study demonstrating
acceptable safety and effectiveness in another biologically similar pattern of responsiveness to
chemotherapy may support labeling for that additional form of cancer”
Summary of Issues
• Considering both the 4 mg and 8/4 mg arms, how convincing is Study 039?
• This is a first indication of a bisphosphonate for a predominantly osteoblastic disease. Can support be drawn from other trials?
• Is there substantial evidence to support efficacy of the 4 mg arm?
Zometa for Bone Metastases of Solid Tumors other than Breast
Cancer and Prostate CancerProtocol 011
Overview of the Solid Tumor Trial
• Study Results
• Heterogeneous population
• Response of bone metastases to chemotherapy
• Summary of issues
Proportions of Patients with SREs: Protocol defined Primary Endpoint
95% C.I. andP-value for the difference
Proportionof patients
4 mg 8/4 mgPlacebo 111/250
44%-15.2%,1.9%
p=0.127-18.2%,-1.4%
p=0.023
Zol 4 mg 97/25738%
- -11.4%,5.1%p=0.452
Zol 8/4 mg 92/26635%
- -
Time To First Event:FDA preferred Primary Endpoint
Treatmentarm
Median(days)
p value compared to placeboand 95% confidence limits
Placebo 163 -106-188 days
4 mg 230 0.026168 days - not reached
8/4 mg 219 0.035172 days - not reached
Pooled analysis: Zometa vs. Placebo - 011exploratory analysis
Time to first SRE Zometa: 4 mg + 8/4 mg vs Placebo:p-value * = 0.01H.R. point estimate = 0.7495% C.I. = 0.58, 0.935Proportion of Patients with SRE: Zometa 4 mg + 8/4 mg vs Placebop-value * = 0.03Diff. In proportions = -0.0895% C.I. = -0.15, -0.01
*Should be interpreted with caution due to exploratory nature of the analysis. is not adjusted for multiple testing
Heterogeneous Population
• Varying predilection of different tumors to
metastasize to bone.
• Variable tumor behavior in bone
• Potentially variable tumor response to Zometa in
diverse tumor types
Tumor Types in Solid Tumor TrialCancer type Placebo Zol 4 mgNSCLC 121 124Renal 19 26Small cell lung cancer 22 19Colorectal 16 19Unknown 14 17Bladder 16 11GI (other) 12 10Head and neck 4 6GU 6 6Malignant melanoma 4 5hepatobiliary 4 3Thyroid 4 2Other 2 3Sarcoma 3 3Neuroendocrine/carcinoid 3 2Mesothelioma 0 1
Response of bone metastases to chemotherapy
• Prior chemotherapy treatment not recorded
• The study was blinded and randomized, and
likely will not impact on study results.
Results Summary ‘Other Solid Tumor Trial’ - 011
• No statistical difference for 4 mg for protocol-specified endpoint
• Substantial evidence for 4 mg for Time to First SRE
• Substantial efficacy for 8 mg in both endpoints, i.e. Proportions of Patients with any SRE and for Time to First Event
Issues of ‘Other Solid Tumors’ Trial
• Heterogeneous population
• Is there substantial evidence to support efficacy of the 4 mg arm?
• If yes, should Zometa be approved for all solid tumors?
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