ProstaScint

Pharmacodynamics

Prostate Specific Membrane Antigen is expressed in many primary and metastatic prostate cancer lesions, and in vitro immunohistologic studies have shown 7E11-C5.3 to be reactive with > 95% of the prostate adenocarcinomas evaluated. In general, PSMA expression by prostate cancer cells is either unchanged or increased in patients treated with hormonal therapy (see PRECAUTIONS, Drug Interactions). The 7E11-C5.3 antibody is immunoreactive with normal and hypertrophic adult prostate tissue. In clinical studies of patients with prostate cancer, Indium In 111 ProstaScint® (capromab pendetide) localized to the prostate, and some known primary and metastatic tumor sites.

Non-antigen-dependent localization, suspected to be secondary to catabolism, has been observed in the liver, spleen, and bone marrow. Although there is variation among individuals, there may also be localization and imaging activity in the bowel, blood pool, kidneys, urinary bladder, and genitalia. Intracellular localization of 7E11-C5.3 has been observed in histochemically prepared tissue sections from normal adult skeletal and cardiac muscle, although primate studies revealed no specific localization to these tissues.

Pharmacokinetics

Based on data obtained from clinical studies, Indium In 111 ProstaScint® demonstrated a monoexponential elimination pattern with a terminal-phase half life of 67 ± 11 hours (mean ± SD). Approximately 10% of the administered radioisotope dose is excreted in the urine during the 72 hours following intravenous infusion. The pharmacokinetics of Indium In 111 ProstaScint® are characterized by slow serum clearance rate (42 ± 22 mL/hr) and small volume of distribution (4 ± 2.1 L).

Indium In 111 ProstaScint® (capromab pendetide) has been administered in single doses to over 600 patients in clinical studies, and in repeat administrations (2 to 4 infusions) to 61 patients. A 0.5 mg dose was determined to be the lowest effective dose. The imaging performance of Indium In 111 ProstaScint® (capromab pendetide) was evaluated in a phase 2 and a phase 3 trial in each of two clinical settings: (1) patients with clinically-localized prostate cancer who were at high risk for metastases and (2) patients with a high clinical suspicion for occult recurrent or residual prostate cancer.

Imaging Performance in Newly-Diagnosed Patients

In one of two open label, multi-center, uncontrolled pivotal phase 3 trials, 160 patients with a tissue diagnosis of prostate cancer who were considered at high risk for lymph node metastases underwent Indium In 111 ProstaScint® immunoscintigraphy prior to scheduled staging pelvic lymphadenectomy. High risk was defined as at least one of the following: (1) prostate specific antigen (PSA) ≥10x the upper limit of normal & Gleason score ≥7; (2) prostatic acid phosphatase above the upper limit of normal; (3) equivocal evidence of lymph node metastases on CT or ultrasound & PSA ≥8x the upper limit of normal; (4) Gleason score ≥8; or (5) clinical stage C & Gleason score ≥6. All patients had been evaluated for metastatic disease using standard non-invasive imaging techniques, and were considered to have clinically-localized prostate cancer. The Indium In 111 ProstaScint® images were interpreted on-site, and the reader had access to all clinical data. The interpretations were correlated with the results of surgical staging; however, a correlation of specific areas of Indium In 111 ProstaScint® uptake to specific sites of tumor involvement was not performed.

One hundred fifty-two patients had an interpretable scan and surgical staging. Forty scans were classified as true positive, 25 as false positive, 63 as true negative, and 24 as false negative. The results for immunoscintigraphy are summarized in TABLE 4.

Sixty-five patients (43%) had positive Indium In 111 ProstaScint® (capromab pendetide) images for pelvic lymph node metastases: Of these 38% (25 patients) did not have metastatic prostate cancer at surgery. Eighty-seven patients (57%) had negative Indium In 111 ProstaScint® images: Of these 28% (24 patients) did have metastatic prostate cancer at surgery. The overall accuracy of Indium In 111 ProstaScint® immunoscintigraphy, as measured against pelvic lymph node dissection, was 68% (103/152).

A retrospective subset analysis suggested that a positive Indium In 111 ProstaScint® scan in patients with a Gleason score ≥ 7 and a PSA ≥ 40 contained additional information regarding the likelihood that tumor metastases would be found at the scheduled staging pelvic lymphadenectomy.

Imaging Performance in Patients with Occult Recurrent or Residual Disease

In the second open label, multi-center, uncontrolled pivotal phase 3 trial, 183 patients with a high clinical suspicion of residual or recurrent prostate cancer following radical prostatectomy were evaluated. Patients with a rising PSA, a negative bone scan, and negative or equivocal standard diagnostic techniques, (e.g. transrectal ultrasound, CT scan, or MRI) underwent Indium In 111 ProstaScint® (capromab pendetide) immunoscintigraphy prior to biopsy of the prostatic fossa. The Indium In 111 ProstaScint® images were interpreted on-site, and the reader had access to all clinical data. The interpretations were correlated with the results of histopathologic analysis of the prostatic fossa biopsy specimens.

One hundred fifty-eight patients had an interpretable scan and prostatic fossa biopsy. Twenty-nine scans were classified as true positive, 29 as false positive, 70 as true negative, and 30 as false negative. The results are summarized in TABLE 5.

Fifty-eight patients (37%) had positive Indium In 111 ProstaScint® (capromab pendetide) images in the prostatic fossa: Of these 50% (29 patients) did not have recurrent prostate cancer on biopsy. One hundred patients (63%) had negative Indium In 111 ProstaScint® images: Of these 30% (30 patients) had recurrent prostate cancer on biopsy. The overall accuracy of Indium In 111 ProstaScint® immunoscintigraphy, as measured against prostatic fossa biopsy, was 63% (99/158).

Indium In 111 ProstaScint® localized to only the prostatic fossa in 29 (18%) patients, to prostatic fossa and extrafossa sites in 29 (18%) patients, and to only extrafossa sites in 39 (25%) patients. The study was not designed to evaluate extrafossa sites of uptake. Three extrafossa sites of uptake were biopsied, one of which was positive for metastatic prostate cancer.

ProstaScint® Results in Patients with Distant Metastases

Clinical trials have not specifically studied the ability of Indium In 111 ProstaScint® (capromab pendetide) to image distant (extra-pelvic) metastases, and a limited number of patients with distant (primarily bone) metastases were enrolled. Thirteen patients out of 16 (81%) with CT evidence of distant soft tissue disease had positive extrafossa Indium In 111 ProstaScint® scans. Thirty-five out of 61 patients (57%) with bone scan evidence of disease had positive Indium In 111 ProstaScint® skeletal uptake; however, Indium In 111 ProstaScint® imaging did not identify most sites of abnormal bone uptake on bone scan, nor did it demonstrate any new sites of metastasis that were not seen on bone scan. The Indium In 111 ProstaScint® scan did, however, demonstrate sites of bone marrow metastases that were not seen on bone scan in 2 of 43 patients in the phase 1 study.

Repeat Scans

Sixty-one patients received a total of 74 repeat infusions of Indium In 111 ProstaScint®. The incidence of adverse reactions upon repeat infusion (5%) was comparable to that observed after single infusion (4%). Human anti-mouse antibody (HAMA) levels were detected (at levels >8 ng/mL) by radioimmune assay (RIA) after single infusion in 8% (20/239) of patients while 1% of patients had levels greater than 100 ng/mL. Serum HAMA levels were detected by RIA after repeat infusion in 19% (5/27) of patients.

Biodistribution was unaltered on 65 of 70 (93%) evaluable repeat scans. The efficacy of repeat Indium In 111 ProstaScint® imaging was not evaluated.

Indium In 111 ProstaScint® (capromab pendetide) should not be used in patients who are hypersensitive to this or any other product of murine origin or to Indium In 111 chloride.

Patient management should not be based on Indium In 111 ProstaScint® (capromab pendetide) scan results without appropriate confirmatory studies since in the pivotal trials, there was a high rate of false positive and false negative image interpretations (See PRECAUTIONS).

Indium In 111 ProstaScint® images should be interpreted only by physicians who have had specific training in Indium In 111 ProstaScint® image interpretation (see PRECAUTIONS, Imaging Precautions).

Allergic reactions, including anaphylaxis, can occur in patients who receive murine antibodies. Although serious reactions of this type have not been observed in clinical trials after Indium In 111 ProstaScint® administration, medications for the treatment of hypersensitivity reactions should be available during administration of this agent.

Indium In 111 ProstaScint® may induce human anti-mouse antibodies which may interfere with some immunoassays, including those used to assay PSA and digoxin (see PRECAUTIONS, Drug/Laboratory Test Interactions).

ProstaScint® (capromab pendetide) was generally well tolerated in the clinical trials. After administration of 529 single doses of Indium In 111 ProstaScint®, adverse reactions were observed in 4% of patients. The most commonly reported adverse reactions were increases in bilirubin, hypotension, and hypertension, which occurred in 1% of patients. Elevated liver enzymes and injection site reactions occurred in slightly less than 1% of patients. Other adverse reactions, listed in order of decreasing frequency, were: pruritus, fever, rash, headache, myalgia, asthenia, burning sensation in thigh, shortness of breath, and alteration of taste. Most adverse reactions were mild and readily reversible. Data from repeat administration in 61 patients revealed a similar incidence of adverse reactions (5%). No deaths were attributable to Indium In 111 ProstaScint® administration.

Jazz Pharmaceuticals, Inc. Customer Service: 1-(800) 833-3533

Manufactured by Jazz Pharmaceuticals, Inc.
Palo Alto, CA 94304
U.S. License No. 1901

ProstaScint® is a registered trademark of
Jazz Pharmaceuticals, Inc.

Printed in USA   PROSp-14-01
Revised 12/2010