|
|
|
|
|
Section A. NONTECHNICAL RESEARCH PLAN |
|
|
|
Objectives: |
|
1.
Define the toxicity and maximum tolerated dose (MTD)
of humanized monoclonal antibody (mAb) huJ591-DOTA-90Yttrium
(90Y) in patients with prostate cancer who have recurrent
and/or metastatic prostate cancer (Pca). |
|
2.
Define the pharmacokinetics of huJ591-DOTA-90Y. |
|
3.
Define the human anti-humanized antibody (HAHA)
response to huJ591-DOTA-90Y. |
|
4.
Define the preliminary efficacy (response rate)
of huJ591-DOTA-90Y. |
|
Background: |
|
Prostate cancer is the most commonly diagnosed and 2nd most
common cause of cancer deaths in American males. In 1999, approximately
185,000 new cases were diagnosed and 37,500 died of this disease (1). It
accounts for 40% of all cancers diagnosed in men. A male born in the
U.S. in 1990 has approximately a 1 in 8 likelihood of being diagnosed
with clinically apparent prostate cancer in his lifetime. Even prior to
the recent increase in incidence, prostate cancer was the most prevalent
cancer in men (2). |
|
There is currently no curative treatment for prostate cancer once
it has metastasized (spread beyond the prostate). Currently, systemic
therapy is limited to various forms of androgen (male hormone)
deprivation. While most patients will demonstrate initial clinical
improvement, virtually inevitably, androgen-independent cells develop.
Endocrine therapy is thus palliative, not curative. In a recently published study of 1387 patients with image
(e.g., bone or CT scan) -detectable metastatic disease, the median time
to objective disease progression (excluding biochemical/PSA progression)
after initiation of hormonal therapy (i.e., development of
androgen-independence) was 16-48 months (3). Median overall survival in
these patients was 28-52 months from the onset of hormonal treatment
(3). Subsequent to developing androgen-independence, there is no
effective standard therapy and the median duration of survival is 9-12
months (4-9). Cytotoxic chemotherapy is poorly tolerated in this age
group and generally considered ineffective and/or impractical. No
chemotherapeutic regimen has demonstrated a survival benefit. |
|
PSMA/
mAb anti-PSMA: |
|
Prostate specific membrane antigen (PSMA) is the single most well-established, highly restricted prostate epithelial cell membrane antigen (10-17). |
|
The PSMA gene has been
cloned, sequenced (18), and mapped to chromosome 11 (19). In contrast to
other highly restricted prostate-related antigens such as prostate
specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate
secretory protein (PSP), all of which are secretory proteins, PSMA is
anchored to the cell membrane. Among reasons for significant interest in
PSMA is that it is ideal for in
vivo prostate-specific targeting strategies.
In addition to its prostate specificity (5-9,11,12,15), PSMA is
expressed by virtually all PCa (13,15,21), expression is further
increased in higher grade cancers and in metastatic disease (15) and in
hormone-refractory PCa (14-16). |
|
Initial validation of PSMA as an in
vivo target has been borne out by imaging trials with mAb
7E11/CYT-356 (23-26), marketed as ProstaScintÒ. Molecular
mapping, however, indicates that mAb 7E11/CYT-356/ ProstaScint targets a
portion of the PSMA molecule that is within the cell’s interior and not
exposed on the outer cell surface (27,28). In living cells, this
internal binding site is not accessible to antibody (20,27,28).
Successful imaging with ProstaScint relates to targeting of dead/dying
cells within tumor sites (28-30). It has been noted (28-30) that a mAb
to the extracellular domain of PSMA would provide benefits including
improved localization in patients and enhanced imaging and therapy. At
Weill Medical College, Liu et al have reported the development of 4 IgG
mAbs to the external domain of PSMA (PSMAext;
ref 30). |
|
These antibodies to PSMAext
demonstrate high affinity binding to PCa cells in tissue culture, on
tissue sections and in animal models in
vivo. Furthermore,
unlike ProstaScint, these mAbs can bind to viable cells (30) as the
target binding site is present on the exterior of the cell. In
in vitro and in vivo
animal models, 90Y-DOTA-huJ591 has demonstrated substantial
anti-tumor activity. In these studies, immunodeficient ‘nude’ mice
are implanted intramuscularly with PSMA-expressing human prostate cancer
cells (LNCaP). In some studies, the same animals are simultaneously
implanted in the opposite thigh with a PSMA-absent human Pca line (PC3).
Cancers are allowed to ‘establish’ for a period of approximately 2
weeks during which time the cancer develops a blood supply allowing
further growth. At the time of treatment initiation, the cancer implants
average 1.0 cm in diameter (or approximately 5% of the animals body
weight. Results demonstrate that 90Y-DOTA-huJ591 induces an
average of >90% tumor reduction compared to control-treated mice
(saline or non-radioactive antibody or 90Y-DOTA-irrelevant
antibody). A portion of the animals have complete disappearance of
tumor. These studies also confirm significant improvement in survival of
the 90Y-DOTA-huJ591 treated animals. The PSMA-absent cancers
do not respond to treatment demonstrating the specificity of the
treatment. |
|
Clinical grade mouse (murine)
muJ591 antibody was produced and began clinical trials at NYPH-WMC in
October, 1998 (see below). In parallel, using genetic engineering
techniques, the mouse (muJ591) antibody has been “deimmunized” by
replacing murine protein sequences with human sequences (31).
This results in a non-immunogenic antibody, which can be
administered to patients on multiple occasions over long time periods
without inducing an immune response. Furthermore, the deimmunized mAb
additionally has been engineered to possess the additional effect of
inducing antibody dependent cellular cytotoxicty (ADCC) with human
immune effector cells. |
|
Eligibility
Criteria: |
|
1.
Histologic diagnosis (recent or remote) of
prostate adenocarcinoma. |
|
2.
Metastatic or recurrent carcinoma of the prostate
defined by: |
|
abnormal CT or MRI and/or |
|
abnormal bone scan and/or |
|
rising PSA |
|
3.
Rising PSA on 3 serial determinations over a period of ³ 2 weeks. |
|
4.
PSA ³
1.0 at the time of entry. |
|
5.
If patient is being treated with an LHRH analog,
the drug: |
|
a. must be maintained for the duration of this study or |
|
b. must be terminated ³ 10 weeks prior to entry (for 28 day depot preparations) or 24 weeks
(for 3 month depot preparations). |
|
6.
Platelet count > 150,000/mm3. |
|
7. Absolute neutrophil count (ANC) ≥ 2,000/mm3 |
|
8. Normal coagulation profile (PT, PTT) |
|
9.
Unilateral posterior iliac crest bone marrow
biopsy demonstrating < 10% or bilateral posterior iliac crest
bone marrow biopsies demonstrating a mean of <25% of the intra-trabecular
marrow space involved by cancer. |
|
10. Patients of child
bearing potential must agree to use an effective method of contraception. |
|
Exclusion
Criteria: |
|
1.
Prior treatment with mouse mAb requires patient’s
anti-huJ591 titer < 1/10. |
|
2.
Prior aspirin and/or non-steroidal anti-inflammatory
agents within 2 weeks of entry. |
|
3.
Prior corticosteroids and/or adrenal hormone inhibitors
within 4 weeks of entry. |
|
4.
Prior cytotoxic chemotherapy and/or radiation therapy
within 6 weeks of entry. |
|
5.
Prior radiation therapy encompassing >25% of expected
red marrow distribution. |
|
6.
Prior treatment with 89Strontium (Metastron®)
or 153Samarium (Quadramet®). |
|
7.
CNS metastasis. |
|
8.
History of seizure and/or stroke |
|
9.
History of HIV |
|
10.
Serum creatinine > 2.0 |
|
11.
SGOT > 2x ULN |
|
12.
Bilirubin (total) >1.5x ULN |
|
13.
Serum calcium > 12.5 |
|
14. Active
serious infection not controlled by antibiotics. |
|
15.
Active angina pectoris or NY Heart Association Class III-IV. |
|
16.
Karnofsky Performance Status < 60; ECOG Performance Status >
2. |
|
17.
Life expectancy < 6 months |
|
18.
Age < 21 y.o. |
|
19.
Other serious illness(es) involving the cardiac, respiratory, CNS,
renal, hepatic or hematological organ systems which might preclude
completion of this study or interfere with determination of causality of
any adverse effects experienced in this study. |
|
|
|
|
|
Screening
Procedures: |
|
Patients with Pca will undergo pre-study (screening) evaluation
including: |
|
1.
Medical history: |
|
including but not limited to: |
|
a. date of Pca diagnosis |
|
b. PSA history |
|
c. Pca treatments since
diagnosis (surgery, radiation, cryosurgery, hormonal or non-hormonal
chemotherapy, etc.) |
|
d. appetite |
|
e. weight loss |
|
f.
bone pain (site/s) |
|
g. voiding symptoms |
|
h.
current
medications (including analgesics, hormonal and/or cytotoxic agents) |
|
2.
Physical examination |
|
including
but not limited to: |
|
vital signs |
|
digital
rectal examination (DRE) |
|
weight |
|
3.
Laboratory studies: |
|
Prostate Specific Antigen (PSA) |
|
Prostatic Acid Phosphatase (PAP) |
|
Testosterone (T) |
|
Hemoglobin (Hb) /Hematocrit (Hct) |
|
White Blood Count (WBC) with differential |
|
Platelet count |
|
Electrolytes |
|
glucose |
|
BUN, creatinine |
|
total protein, albumin |
|
Biliruibin (total, direct) |
|
Gamma-glutamyl transpeptidase (GGT) |
|
SGOT (AST) |
|
SGPT (ALT) |
|
LDH |
|
alkaline phosphatase |
|
Protime, partial thromboplastin time |
|
Urinalysis |
|
4.
Electrocardiogram (ECG) |
|
5.
Bone marrow biopsy (within 6 weeks of entry) |
|
6.
Radiographic studies |
|
Chest
x-ray- (within 6 weeks of entry) |
|
Computed Tomography-abdomen and pelvis (or MRI)- (within 4 weeks of entry) |
|
CT or MRI
of brain (within 8 weeks of entry) |
|
Bone scan- (within 4 weeks of entry) |
|
Treatment
Plan: |
|
Patients will be treated in the New York Presbyterian Hospital General Clinical Research Center (GCRC). Antibody administration will be given in 2 steps: firstly, patients will receive an initial dose of huJ591-DOTA-111Indium (111In) for pharmacokinetic and biodistribution determinations. Secondly, 1 week later, a therapy dose of huJ591-DOTA-90Y will be administered. The 90Y dose (in mCi/m2) will be escalated in cohorts of 3-6 patients at each dose level . All administrations will be by intravenous infusion. |
|
|
|
Follow-up:
Patients will be followed for a minimum of 12 weeks after the huJ591-DOTA-90Y
administration. If the patient receives further huJ591-DOTA-90Y
doses, he will be followed for a minimum of 12 weeks after the last dose.
If the patient’s disease is stable or responding at 12 weeks after his
last dose, he will be followed until progression. |
|
|
Follow-up on study consists
of: |
|
|
Medical history |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,6,8,12 &
q12 wks until progression |
|
Physical exam (focused) |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,6,8,12 &
q12 wks until progression |
|
Performance status |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
PSA, PAP, alkaline
phosphatase |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
Testosterone |
post-Rx week 4, q 6 mos
until progression |
|
Human anti-humanized Ab |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
CBC, differential, platelet
count |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,2.5,3,3.5,4,4.5,5,5.5,6,>8,q4wks until
stable then q12 wks until progression. Monitor qod if ANC <1000 and/or
platelets <50,000 |
|
Electrolytes, BUN,
creatinine |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8, q4wks until stable then q12 wks until
progression |
|
Total protein, albumin,
bilirubin, GGTP, AST, ALT, LDH |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8, q4wks until stable then q12 wks until
progression |
|
Urinalysis |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4, then q4wks unless normal or baseline
|
|
CT or MRI |
Post-Rx week 12 and q12
weeks (if measurable or evaluable disease present at entry and/or if
patient classified as a “responder”) |
|
Bone scan |
Post-Rx week 12 and q12
weeks (if evaluable disease present at entry and/or if patient classified
as a “responder”) |
|
CXR
|
Post-Rx wk 12 and q 12 wks
(if disease present at entry) |
|
Weight |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
Appetite |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
Bone pain |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
Analgesic intake |
day of huJ591-DOTA-90Y
Rx, post-Rx week 1,2,4,8,12 &
q12 wks until progression |
|
References |
|
|
|
1.
NCI SEER data |
|
|
|
2.
Feldman, A.R., Kessler, L., Myers, M.H. and
Naughton, M.D.: The prevalence of cancer: estimates based on the
Connecticut tumor registry. NEJM 315:1394-7, 1986. |
|
|
|
3.
Eisenberger M.A., Blumenstein B.A., Crawford E.D.,
Miller G., McLeod D.G., Loehrer P.J., Wilding G., Sears K., Culkin D.J.,
Thompson I.M., Bueschen A.J. and Lowe B.A.:
Bilateral orchiectomy with or without flutamide for metastatic
prostate cancer. NEJM
339:1036-42, 1998. |
|
4.
Vollmer, R.T., Kantoff, P.W., Dawson, N.A., and Vogelzang, N.J.: A
prognostic score for homone-refractorey prostate cancer: analysis of two
cancer and leukemia group B studies.
Clin Can Res 5: 831-7, 1999. |
|
|
|
5.
Hudes G., Roth B., Loehrer P., Ramsey J., Sprandio M., Entmacher
M., et al: Phase III trial of
vinblastine versus vinblastine plus estramustine phosphate for metastatic
hormone refractory prostate cancer (HRPC) Proc Am Soc Clin Oncol 16:316a (abstact),
1997. |
|
|
|
6.
Pienta K.J., Redman B., Hussain M., Cummings G., Esper P.S., Appel
C., et al.: Phase II
evaluation of oral estramustine and oral etoposide in hormone-refractory
adenocarcinoma of the prostate. J
Clin Oncol 12(10):2005-12, 1994. |
|
|
|
7.
Pienta K.J., Redman B.G., Bandekar R., Strawderman M., Cease K.,
Esper P.S., et al.: A phase II trial of oral estramustine and oral
etoposide in hormone refractory prostate cancer.
Urology 50:401-7, 1997. |
|
|
|
8.
Tannock I.F., Osoba D., Stockler M., Ernest D.S., Neville A.J.,
Moore M.J., et al.: Chemotherapy with mitoxantrone plus prednisone or
prednisone alone of symptomatic hormone-resistant prostate cancer. A canadian randomized trial with palliative endpoints.
J Clin Oncol 14:1756-65, 1996. |
|
|
|
9.
Kantoff P.W., Conaway M., Winer E., Picus J., Vogelzang N.J.:
Hydrocortisone (HC) with or without mitoxantrone (M) in patients (pts)
with hormone refractory prostate cancer (HRPC): preliminary results from a
prospective randomized cancer and leukemia group B studt (9182) comparing
chemotherapy to best supportive care (addendum).
J Clin Oncol 15(Suppl):25, 1996 |
|
10. Zhang, S., Zhang, H.S., Reuter, V.E., Slovin, S.F., Scher, H.I., andLivingston, P.O.: Expression of potential target antigens for immunotherapyon primary and metastatic prostate cancers. Clin Cancer Res 4:295-302,1998. |
|
|
|
11 Lopes, D., Davis, Wendy L., Rosenstraus, M.J., Uveges, A.J. and Gilman, S.C.: Immunohistochemical and pharmacokinetic characterization of the site-specific immunoconjugate CYT-356 derived from antiprostate monoclonal antibody 7E11-C5. Cancer Res 50: 6423-6429, 1990. |
|
|
|
|
|
13.
Wright, G.L. Jr., Haley, C., Beckett, M.L. and Schellhammer,
P.F.:Expression of prostate-specific membrane antigen in normal, benign,
and malignant prostate tissues. Urol.
Oncol 1: 18-28, 1995. |
|
|
|
|
|
15. Wright, G.L, Jr., Grob, B.M., Haley, C., Grossman, K., Newhall, K., Moriarty, R.: Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology 48:326-334, 1996. |
|
|
|
|
|
17.
Sokoloff, R.L., Norton, K.C., Gasior, C.L., Marker, K.M., and Grauer,
L.S.Quantification of prostate specific membrane antigen (PSMA) in human
tissues and subcellular fractions. Proc
of the Am Assoc Cancer Res 39(abst #1811), 1998. |
|
|
|
18. Israeli, R.S., Powell, C.T., Fair, W.R. and Heston, W.D.W.: Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res 53: 227-230, 1993. |
|
|
|
19. Rinker-Schaeffer, C.W., Hawkins, A.L., Su, S.L., Israeli, R.S., Griffin, C.A., Isaacs, J.T. and Heston, W.D.W.: Localization and physical mapping of the prostate-specific membrane antigen (PSM) gene to human chromosome 11. Genomics 30:105-108, 1995. |
|
20. Horoszewicz, J.S., Kawinski, E. and Murphy G.P.: Monoclonal antibodies to a new antigenic marker in epithelial cells and serum of prostatic cancer patients. Anticancer Res 7: 927-936, 1987. |
|
21. Bostwick, D.G., Pacelli, A., Blute, M., Roche, P., Murphy, G.P.: Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma. Cancer 82:2256-2261, 1998. |
|
|
|
22. Diamond, S.M., Fair, W.R. and Heston, W.D.W.: Modulation of prostate specific membrane antigen (PSM) expression in vitro by cytokines and growth factors. Proc Am Assoc Cancer Res 36: 643 (abstract 3826), 1995. |
|
|
|
23. Babaian, R.J., Sayer, J., Podoloff, D.A., Steelhammer, L.C., Bhadkamkar, V.A. and Gulfo, J.V. (1994) Radioimmunoscintigraphy of pelvic lymph nodes with 111indium –labeled monoclonal antibody CYT-356. J Urol 152, 1952-1955. |
|
|
|
24. Kahn, D., Williams, R.D., Seldin, D.W., Libertino, J.A., Hirschhorn, M., Dreicer, R., Weiner, G.J., Bushnell, D. and Gulfo, J. (1994) Radioimmunoscintigraphy with 11indium-labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 152, 1490-1495. |
|
25. Kahn, D., Williams, R.D., Manyak, M.J., Hasenman, M.K., Seldin, D. W., Libertino, J.A., Maguire, R.T. (1998) 111Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. J Urol 159, 2041-6. |
|
|
|
26.
Kahn D., Williams R.D., Haseman M.K., Reed N.L., Miller S.J., and
Gerstbrein J.: Radioimmunoscintigraphy
with In-111-labeled capromab pendetide predicts prostate cancer response
to salvage radiotherapy after failed radical prostatectomy.
J Clin Oncol 16(1): 284-289, 1998. |
|
|
|
27. Troyer, J.K., Feng, Q., Beckett, M.L. and Wright, G.L., Jr.: Biochemical characterization and mapping of the 7E11-C5.3 epitope of the prostate-specific membrane antigen. Urol Oncol 1: 29-37, 1995. |
|
|
|
|
|
|
|
|
|
31.
Hamilton A., King S., Liu H., Moy P., Bander N., and Carr F.:
A novel humanized antibody against prostate specific membrane
antigen (PSMA) for in vivo targeting and
therapy. Proc Am Assoc for
Cancer Research 39:440(#2998) abstract, 1998. |
|
|
|
32.
Petrylak, D.P., Scher, H.I., Li Z., et al.: Prognostic factors for
survival of patients with bidemensionally measurable metastatic
hormone-refractory prostate cancer treated with single-agent chemotherapy.
Cancer 70:2870-78, 1992.
|
|
|
|
33.
. Kelly W.K., Scher H.I., Mazumdar M., et al: Prostate-specific
antigen as a measure of disease outcome in metastatic hormone-refractory
prostate cancer. J Clin Oncol
11: 607-15, 1993. |
|
|
|
34.
Kantoff P.W., Halabi S., Conaway M., Picus J., Kirshner J., Hors V.,
Trump D.,Winer E.P., and Vogelzang N.J.: Hydrocortisone with or without
mitoxantrone in men with hormone-refractory prostate cancer: results of
the cancer and leukemia group B 9182 study.
J Clin Oncol 17:2506-13, 1999. |
|
|
|
35.
Smith, D.C., Dunn R.L., Strawderman M.S., Pienta K.J.: Change in serum
prostate-specific antigen as a marker of response to cytotoxic therapy for
hormone-refractory prostate cancer. J
Clin Oncol 16:1835-43, 1998. |
|
|
|
36. Scher H.I., Kelly W.M.K., Zhang Z-F., Ouyang P., Sun M., Schwartz M., Ding C., Wang W., Horak I.D., Kremer A.B.: Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer. JNCI 91:244-51, 1999. |
|
|
