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H-11047: A Study of PS-341 Followed by Radical Prostatectomy for Patients With Adenocarcinoma of the Prostate (Spore #: 11-01-30-13)


Phase 2
18 Years
N/A
Open (Enrolling)
Male
Prostate Neoplasms

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Trial Information

H-11047: A Study of PS-341 Followed by Radical Prostatectomy for Patients With Adenocarcinoma of the Prostate (Spore #: 11-01-30-13)


In murine and human xenograft tumor models, administration of PS-341 weekly was associated
with significant antitumor activity. In primate studies using a schedule of twice weekly for
six weeks, the highest PS-341 dose not associated with severe irreversible toxicity was
0.067 mg/kg/dose or 0.80 mg/m2/dose. The PS-341 dose selected for this study, 1.6 mg/m2,
and the dose regimen of a 4-week treatment schedule (PS-341 once weekly for four weeks on
days 1, 8, 15 and 22) is supported by preclinical data and data collected in the completed
Phase I studies conducted in advanced solid tumors and hematologic malignancies. In the
Phase I dose escalation study conducted at the M.D. Anderson Cancer Center that is sponsored
by Millennium Pharmaceuticals, in patients with solid tumors in which PS-341 was
administered once per week for four weeks followed by a 14-day rest period (35-day cycle),
the observed MTD was 1.8 mg/m2.11,12 The LTs were observed at 2.0 mg/m2 and included
hypotension, diarrhea, and fatigue. Fifty-three patients were treated in this study and
received a maximum of 15 cycles. At the dose level 1.60 mg/m2, 70%-75% 20S proteasome
inhibition and peripheral blood was achieved at this dose. One false response, a major
radiographic response of retroperitoneal lymph nodes without PSA change was noted in a
prostate cancer patient and a second prostate patient had radiographic stabilization of a
retroperitoneal lymph node with an unchanged PSA. One partial response, a major
radiographic response of retroperitoneal lymph nodes without PSA change was noted in a
prostate cancer patient and a second prostate patient had radiographic stabilization of a
retroperitoneal lymph node with an unchanged PSA. One partial response, a major
radiographic response of retroperitoneal lymph nodes without PSA change was noted in a
prostate cancer patient and a second prostate patient had radiographic stabilization of a
retroperitoneal lymph node with an unchanged PSA. Further company-sponsored trial at
Memorial Sloan-Kettering Cancer Center is assessing twice weekly administration for two
weeks every three weeks. This trial is currently dosing at 1.65 mg/m2 and a proteasome
inhibition is in the range of 74-78%. One prostate cancer patient has had a significant
decrease in PSA levels. There have been no dose-limiting toxicities noted in either of the
studies to date, although drug associated toxicities have included fatigue, fever, nausea
and vomiting, anorexia, diarrhea and thrombocytopenia. The NCI is sponsoring three Phase I
trials of PS-341 administered IV twice weekly (days 1 and 4). One trial is assessing an
every other week administration of PS-341 in patients with solid tumors and non-Hodgkin's
lymphoma. A weekly times 4 every six weeks schedule is being evaluated in patients with
solid tumors and B cell lymphoproliferative disorders. A third trial is evaluating the same
administration schedule in patients with acute myeloid leukemias, myelodysplastic syndromes
and chronic myeloid leukemia in blast phase.14 These trials have all recently opened. Based
on these observations, PS-341 will be administered once a week for 4 weeks with a 24-72 hour
recovery period prior to radical prostatectomy.

We propose to study the in vivo effect of systemic treatment with PS-341 doing correlative
scientific markers assessing apoptosis, evaluation of protease protein targets, angiogenesis
markers. We do not anticipate any perioperative morbidity when prostatectomy is performed
24-72 hours following the last drug dose. A residual drug activity may impact transiently
on wound healing or on operative blood loss but this effect (if present) should dissipate
within a short period while proteasome activity recovers in all normal tissues. Long term
effects on the vesico-urethral anastomosis or the recovery of bladder and erectile functions
are not expected.

At the same time, obtaining the prostate within 72 hours (at most) following the last drug
dose should enable us to evaluate multiple protein markers while still influenced by
proteasome inhibition and to document biologic activity of the drug in the target organ.


Inclusion Criteria:



- Histologic proof of prostatic adenocarcinoma without evidence of regional and/or
distant metastasis, clinical stage T1, T2 or T3 with high grade disease (Gleason's
grade 7 or above).

- Recent (less than or equal to 6 weeks prior to study entry) negative bone scan and CT
scan of abdomen/pelvis.

- Appropriate surgical candidate for radical prostatectomy and a performance status of
less than or equal to 2 (Zubrod scale).

- Patients should have adequate bone marrow function defined as an absolute peripheral
granulocyte count greater than or equal to 1,500 and platelet count of greater than
or equal to 100,000, adequate hepatic function with a bilirubin less than or equal to
1.5 mg % and SGPT less than 2.5x the upper limits of normal, adequate renal function
defined as serum creatinine less than or equal to 2.0 mg %.

- Patients must have normal coagulation profile (PT, PTT) and no history of substantial
non-iatrogenic bleeding diatheses. Use of anticoagulants is limited to local use only
(for control of central line patency).

- Patients must sign an informed consent indicating that they are aware of the
investigational nature of the study, in keeping with the policies of the institution.

- Patients screened and found eligible for the study, but not wanting to participate
for any reason, will be followed along with the patients enrolled in the study in an
effort to obtain outcome information (as historical information for design of future
trials).

- No evidence of bifascicular block or active ischemia on EKG.

- Patients must have no history of congestive heart failure or previous MI.

Exclusion Criteria:

- Previous or current hormonal treatment, chemotherapy, radiation therapy,
immunotherapy or other investigational status drug.

- Unable to tolerate transrectal ultrasound.

- Patients who are not appropriate surgical candidates for radical prostatectomy based
on the evaluation of co-existent medical diseases and competing causes of death.
Patients with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric disorder
are not eligible.

- Patients who are HIV positive or have chronic hepatitis B or C infections are not
eligible.

- Patients on steroid medications are not eligible.

- Patients with uncontrolled and symptomatic orthostatic hypotension or uncontrolled
hypertension are not eligible.

- Patients with significant arteriosclerotic disease, as defined by a previous arterial
bypass, claudication limiting activity, or a history of cerebrovascular events within
the last year (including TIA) are not eligible.

- Patients with diabetes mellitus requiring insulin or oral hypoglycemics for more than
5 years are not eligible.

- Patient has greater than or equal to grade 1 peripheral neuropathy within 14 days
before enrollment.

- Hypersensitivity to boron, mannitol, or bortezomib.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The purpose of the present study is to assess the safety of PS-341 as a pretreatment in patients who are to undergo a radical prostatectomy. Poor wound healing and excessive bleeding, with historical rates of <1% and 10% respectively will be measured.

Outcome Time Frame:

Poor wound healing (dehiscence of fascia during the first postoperative week) and bleeding 24 hours after surgery

Safety Issue:

Yes

Principal Investigator

Teresa Hayes, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

H-11047

NCT ID:

NCT00425503

Start Date:

December 2001

Completion Date:

December 2013

Related Keywords:

  • Prostate Neoplasms
  • Prostate Cancer
  • Bortezomib
  • Radical Prostatectomy
  • Phase 2 Clinical Trial
  • Neoplasms
  • Prostatic Neoplasms

Name

Location

Scott Department of Urology, Baylor College of MedicineHouston, Texas  77030