Satraplatin (JM-216)
10/31/07: GPC Biotech announced that the Phase 3
SPARC (Satraplatin) trial did not meet its primary efficacy endpoint.
The overall survival data did not achieve statistical significance. They
will no longer pursue the development of Satraplatin for HRPC.
Their website has the following:
"GPC Biotech AG and Pharmion
Corporation (NASDAQ: PHRM) announced topline overall survival results
for the double-blinded, randomized satraplatin Phase 3 registrational
trial, the SPARC trial (Satraplatin and Prednisone Against Refractory
Cancer). The trial evaluated satraplatin plus prednisone versus placebo
plus prednisone as a second-line treatment in 950 patients with
hormone-refractory prostate cancer (HRPC). The companies reported that
the trial did not achieve the endpoint of overall survival (p=0.80,
stratified log rank analysis). The median was 61.3 weeks for the
satraplatin arm compared to 61.4 weeks for the control group and the
hazard ratio was 0.97 (95% CI: 0.83, 1.13). The companies are currently
conducting pre-specified subset analyses."
The official name of
Satraplatin is ORPLATNA
An Investigational Drug for 2nd Line Chemotherapy
in HRPC Patients
Approval Process Status
In a press release dated 15 May
2007, GPC Biotech announced "...that the Company has been informed by
the U.S. Food and Drug Administration (FDA) that the New Drug
Application (NDA) for satraplatin for patients with hormone-refractory
prostate cancer (HRPC) whose prior chemotherapy has failed will be
reviewed by the Oncologic Drugs Advisory Committee (ODAC) on July 24,
2007. Advisory committees provide the FDA with independent advice
from outside experts on issues related to human drugs and other
regulated areas. Although the committees provide advice to the agency,
final decisions are made by the FDA. Earlier, the FDA had accepted for
filing the Company's NDA and had granted the NDA priority review status.
An action from the FDA on the application is expected in August of
this year."
Update July 24,2007: ODAC
voted 12-0 to recommend that the FDA should wait for the final survival
analysis before deciding on approving Satraplatin for HRPC as a 2nd line
chemo. The manufacturer reports that the death rate of patients in the
SPARC trial has slowed, so final overall survival results might take
longer than this fall.
Update July 30, 2007: GPC
Biotech withdraws NDA and will resubmit in 2008 after overall survival
results from SPARC become available and are analyzed (estimated to be
six month, but this is an extrapolation from death rates in the trial
and might change.)
See the PCRI's page on this meeting at
http://www.prostate-cancer.org/advocacy/SatraplatinFDA_Review.html
Net: We might see this drug on the
market in late 2007 IF the FDA bases its decision on PFS without
awaiting the final survival data.
Introduction
Satraplatin is a member of the
platinum family of compounds. Carboplatin, cisplatin, oxaliplatin are other
examples of chemotherapies in the platinum drug family and they both
require
intravenous administration. Satraplatin, however, is a
third-generation, orally bioavailable compound given as capsules that can be taken at home.
(1st generation = cisplatin; 2nd
generation = carboplatin).
Satraplatin is being developed as a second-line chemotherapy for HRPC
patients. Please see the news release from 23 February 2007, entitled, "Satraplatin
Shown to Significantly Reduce Risk of Disease Progression in Advanced
Hormone-Refractory Prostate Cancer Patients." The Prostate
Cancer Research Institute also
has information on an
Expanded Access program for Satraplatin
(SPERA) for US patients that is being offered by GPC-Biotech until
Satraplatin is approved for marketing. U.S. U.S. physicians interested
in receiving more information about SPERA can
contact 1-800-349-8086.
Definitions/Acronyms
SPARC - Satraplatin and Prednisone
Against Refractory Cancer.
PFS - Progression-Free Survival and the SPARC
trial's primary end point. PFS is sometimes called TTP or Time to
Progression. PFS is defined as the time from randomization to
first report of disease progression.
For the SPARC clinical trial, the PFS is a
composite measurement based on the first occurrence of either tumor
progression (radiological evidence), a skeletal event (fractures, bone
surgery, radiation, start of bisphosphonate therapy), or symptomatic
disease progression (pain, weight loss or decrease in performance status)
or death from any cause. Secondary endpoints are overall survival and TTP for
pain.
PSA Response (%) - A decrease of 50% or more in PSA.
At the ASCO 2007 meeting, a 30% reduction for TAX 327 was indicative of
lengthened survival. If 30% were used for SPARC, one wonders what
the PSA RR might be.
Hazard Ratio (HR) - Broadly equivalent to relative
risk (RR); useful when the risk is not constant with respect to time. It
uses information collected at different times. The term is typically
used in the context of survival over time. If the HR is 0.5 then the
relative risk of dying in one group is half the risk of dying in the
other group (from BMJ Clinical Evidence
Prednisone
In the SPARC trial, Satraplatin was
compared to prednisone. Prednisone has anti-HRPC properties by itself.
From Table 1 reference (4) we find the following 3 studies with prednisone
for HRPC patients.
| Reference |
Prednisone Treatment/dose |
No. Patients |
% PSA Response |
Median Duration of Response (mos.) |
| Fossa et al(a) |
5mg, 4 times/day |
101 |
21 |
Not Available |
| Sartor et al (b) |
10mg, 2 times/day |
29 |
34 |
2.0 |
| Tannock et al (c) |
7.5 - 10mg per day |
81 |
22 |
4.0 |
| Sternberg CN et al (1) |
5mg 2 times/day |
225 |
12 (28 of 225) |
- |
a. Foss SD, et al, Flutamide versus
prednisone in patients with prostate cancer symptomatically progressing
after androgen-ablative therapy: a phase III study of the European
organization for research and treatment of cancer genitourinary group,
J. Clin. Oncol. 2001 Jan 1;19(1):62-71.
b. Sartor O, et al, Effect of prednisone on
prostate-specific antigen in patients with
hormone-refractory prostate cancer.Urology. 1998 Aug;52(2):252-6.
c. Tannock IF, et al, Chemotherapy with mitoxantrone plus
prednisone or prednisone alone for symptomatic hormone-resistant
prostate cancer: a Canadian randomized trial with palliative end points,
J. Clin. Oncol. 1996 Jun;14(6):1756-64.
The study by Tannock uses the same dose as used in the SPARC satraplatin
trial -- PSA RR 22% and a median duration of response of 4.0 months.
Thus, some of the response seen in the SPARC trial may have been related
to the use of prednisone. Prednisone was also used with taxotere
in comparing taxotere/prednisone to mitoxantrone/prednisone so there is
some precedence in using this combination (TAX 327 phase III trial).
Since prednisone is common between the two arms of SPARC, any difference
in response rates, etc should only be due to the presence or absence of
Satraplatin.
Satraplatin plus Prednisone
The most recent publication on
Satraplatin was the paper presented at the June 2007 ASCO Annual Meeting
(1) which reviewed results from a randomized phase III clinical trial
comparing Satraplatin/prednisone to prednisone/placebo - the SPARC
trial. See also references (2) and (3). Table 7 of the page for
chemo-other summarizes an earlier trial.
Satraplatin: 80mg/m2/day x 5 every 5 weeks orally.
Prednisone: 5mg twice a day, days 1-35.
Patients receiving satraplatin also received
granisetron(Kytril), 1mg twice daily as an anti-emetic on days 1-5.
Patients had to have failed only one prior
chemotherapy (so this trial is for use of Satraplatin as a second-line
chemotherapy -- 51% of the patients had failed prior docetaxel.)
Number of patients: 950
Results
Satraplatin/Prednisone, median of 4 courses (range
of 1-28 courses).
Prednisone, median of 2 courses (range of 1-16).
802 of 950 patients met the PFS criteria of which
80% experienced radiologic progression, pain progression or death.
| |
Risk of PFS events |
Risk of Pain Progression |
Median Duration of Pain Response |
| Satraplatin/Prednisone vs Prednisone |
33% Less with S/P |
36% Less with S/P |
39.1 wks. |
| |
HR=.67 |
HR=.64 |
24.1 wks. |
| |
PSA RR |
Objective RR |
Pain Response Rate |
| Satraplatin/Prednisone |
25.4% |
6.5% |
24.2% |
| Prednisone |
12.4% |
0.6% |
13.8% |
Side Effects
Most frequent: myelosuppression,
with 4.1% grade 4 neutropenia, 1 patient with grade 4 thrombocytopenia
(grade 3/4 platelets was 21.1% for S vs 1.3% for P.) Also grade
3/4 Hgb was 9.4% for S vs 3.2% for P.
Grade 3 or 4 non-hematologic side
effects: infection (4%), vomiting
(1.6%), diarrhea (2.1%), and fatigue/asthenia (4.9%
for S vs 2.6% for P.) Notably, grade 3/4 neuropathy was .3% for S and
.3% for P.
Satraplatin was discontinued in 25%
vs. .6% for placebo.
Conclusions
Satraplatin plus prednisone
provides better palliation than prednisone alone, but prednisone alone
is not the standard of care for men who are fit enough to receive second
line chemotherapy.
For example, taxotere might be used
as a second-line chemotherapy for those who did not receive it as a
first-line treatment or mitoxantrone could be used as a 2nd-line
treatment. See Mitoxantrone for second-line
chemotherapy. See also the paper on Xeloda. Would these be better than satraplatin/prednisone?
Nevertheless, approval of
Satraplatin will provide another option for men with HRPC progressing
after 1st line chemotherapy.
References
1. C. N. Sternberg, D. Petrylak, F.
Witjes, J. Ferrero, J. Eymard, S. Falcon, K. Chatta, D. Vaughn, W.
Berry, O. Sartor, Satraplatin (S) demonstrates significant clinical
benefits for the treatment of patients with HRPC: Results of a
randomized phase III trial, Journal of Clinical Oncology, 2007 ASCO
Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement),
2007: 5019.
2. O. Sartor, et al, Satraplatin Significantly
Improves Progression Free Survival (PFS) and Pain Control in Patients
with Advanced Hormone-Refractory Prostate Cancer (HRPC): Preliminary
Results from the Phase III SPARC Trial, AUA May 2007, Abstract # 1014.
3. Sternberg CN, Satraplatin in the
treatment of hormone-refractory prostate cancer, BJU Int, 2005;
96:990–994. Erratum states: "
The drug Prednisone was incorrectly
changed to Prednisolone throughout the paper. We apologise for this
error. The
full text of this paper is free on-line.
4. John S. Lam et al, Secondary Hormonal Therapy
for Advanced Prostate Cancer, The Journal of Urology, Vol 175, 27-34,
January 2006.
Author: Howard Hansen
Date: 7/04/2007
Note: I have attempted to be accurate in the above
paper, but inevitably errors can and do creep in. I have used
information from abstracts, press releases and talks. Until a
final paper is written on Satraplatin for the SPARC trial, there remains
a certain amount of uncertainty in the results. The data presented to
the FDA July 24 may also provide an update on these results.
Appendix
Background on Satraplatin can be found in reference
(5) for studies in cell lines and in reference (6) for information on an
earlier phase III trial. Reference (7) has more detail on that
earlier trial. Reference (3) above has an overview of earlier
studies on Satraplatin and introduces the SPARC trial. It has
many, many references and the paper is available free on-line.
5. Wosikowski K, Rattel B, Caligiuri M, Unteregger G, Rozencweig M.
Cytotoxic activity of satraplatin (JM216) and its metabolites in human
prostate carcinoma cell lines. Program and abstracts of the 95th Annual
Meeting of the American Association for Cancer Research; March 27-31,
2004; Orlando, Florida. Abstract 4614.
6. Sternberg CN, Hetherington J, Paluchowska B, et al. Randomized phase
III trial of a new oral platinum, satraplatin (JM-216) plus prednisone
or prednisone alone in patients with hormone refractory prostate cancer.
Program and abstracts of the 39th Annual Meeting of the American Society
of Clinical Oncology; May 31 - June 3, 2003; Chicago, Illinois. Abstract
1586.
7. Sternberg CN, Whelan P, Hetherington J, et al. Phase III trial of
satraplatin, an oral platinum plus prednisone vs. prednisone alone in
patients with hormone-refractory prostate cancer. Oncology. 2005;68:2-9.
