NONTECHNICAL RESEARCH PLAN

Objectives:

1.      Define the toxicity and maximal tolerated dose (MTD) of humanized monoclonal antibody (mAb) huJ591 in patients with prostate cancer who have recurrent and/or metastatic prostate cancer (Pca).

2.      Define the pharmacokinetics of huJ591.

3.      Define the human anti-humanized antibody (HAHA) response to huJ591.

4.      Define the preliminary efficacy (response rate) of huJ591.

Background:

                        Prostate cancer is the most commonly diagnosed and 2nd most common cause of cancer deaths in American males. In 1998, 185,000 new cases were diagnosed and 37,000 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, NEJM).

            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.  The median time to development of androgen-independence is 9-30 months from the time of initiating hormonal treatment (3).  Once this occurs, there is no effective standard therapy and the median duration of survival is 18-24 months (3).  Endocrine therapy is thus palliative, not curative.  Cytotoxic chemother­apy is poorly tolerated in this age group and generally considered ineffective and/or impractical. No chemotherapeutic regimen has been demonstrated a survival benefit.

Rationale:

            Monoclonal antibodies (mAbs) are undergoing investigation in many tumor types because of their ability to specifically target tumor sites while sparing normal tissues.  MAbs are now FDA-approved in several clinical settings: transplantation, cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, infectious disease and cancer. In the latter setting (cancer), mAbs are approved in Europe for the adjuvant treatment of colon cancer (and in multi-center pivotal trials in the U.S.) and approved in the U.S. for treatment of non-Hodgkins’ lymphoma and breast cancer. Two additional mAbs, a radiolabeled mAb for treatment of lymphoma and a drug-conjugated mAb for treatment of leukemia, are currently under review by the FDA for possible approval.

            In general, the attributes and strengths of mAbs are particularly well-suited to the demands of prostate cancer therapy:

            1)  mAbs can specifically and precisely target tumor sites while sparing normal tissues.  The ability to spare normal tissue and the resulting toxicity is particularly important in this generally elderly population.

            2) Prostate cancer metastases predominantly involve the bone marrow and lymph nodes--sites which receive very high levels of administered antibody. 

            3) cancers similar to Pca have been successfully treated with mAbs. (Lymphoma and breast cancer both have a predilection for bone marrow and lymph nodes.) 

            4) Individual tumor sites tend to be small volume sites, ideally suited for both antibody delivery and access. At the time of PSA relapse, patients have a very low disease burden, typically years from becoming manifest on imaging studies.

            5) the availability of clinical parameters such as serum prostate specific antigen (PSA) and pathological features of a patient's cancer such as stage, Gleason score, extracapsular, seminal vesicle or perineural invasion, positive margins, etc. provides the clinician with appropriate indications for mAb therapy in an adjuvant setting where such therapy is likely to be of the greatest benefit. 

            6) The ability to rapidly define biochemical response to treatment using PSA as a surrogate marker.

            Given the theoretical advantages of mAbs in this disease, it is compelling to evaluate this approach.

PSMA/ mAb anti-PSMA:

            Prostate specific membrane antigen (PSMA) is the single most well-established, highly restricted prostate epithelial cell membrane antigen (4-11).

The PSMA gene has been cloned, sequenced (5), and mapped to chromosome 11 (6). 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 (4,5,7,8), PSMA is expressed by virtually all PCa (9, 15), expression is further increased in higher grade cancers and in metastatic disease (9) and in hormone-refractory PCa (8-10).

            Initial validation of PSMA as an in vivo target has been borne out by imaging trials with mAb 7E11/CYT-356 (17-20), marketed as ProstaScintÒ. Molecular mapping, however, indicates that mAb 7E11/CYT-356/ ProstaScint targets a portion of the PSMA molecule that is in the cell’s interior and not exposed on the outer cell surface (21,22). In living cells, this interior binding site is not accessible to antibody (14,21,22). Successful imaging with ProstaScint relates to targeting of dead/dying cells within tumor sites (22-24). It has been noted (22-24) 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 (PSMA_ext; ref 24).

These antibodies to PSMA_ext demonstrate high affinity binding to PCa cells in tissue culture, on tissue sections and in animal models.  Furthermore, unlike ProstaScint, these mAbs can bind to viable cells (24) as the target binding site is present on the exterior of the cell.

Clinical grade mouse (murine) antibody was produced and began clinical trials at NYPH-WMC in October, 1998 (see below). In parallel, using genetic engineering techniques, these mouse antibodies have been “deimmunized” by replacing murine sequences with human sequences (25).  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 ADCC with human effector cells. Pre-clinical cell culture and animal studies with mAbs to PSMA_ext have demonstrated substantial anti-tumor effect ().

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 consecutive 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).

Exclusion Criteria:

1. Prior treatment with mouse mAb requires patient’s anti-huJ591 titer < 1/10.

2. Prior cytotoxic chemotherapy, corticosteroids, adrenal hormone inhibitors or radiation therapy

within 4 weeks of entry.

3.   Active CNS metastasis.

4.   WBC < 3,500/ mm³.

5.   Platelets < 100,000/mm³.

6.   Serum creatinine > 2.0

7.   SGOT > 2x normal

8.   Bilirubin (total) >1.5

9.  Serum calcium > 12.5

10. Active serious infection not controlled by antibiotics.

11. Active angina pectoris or NY Heart Association Class III-IV.

12. Karnofsky Performance Status < 60

13. Life expectancy < 6 months

14. Age < 21 y.o.

15. 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.

Procedures:

            Patients with Pca will undergo pre-study (screening) evaluation including:

1.  Medical history:

            including but not limited to:

date of Pca diagnosis

PSA history

Pca treatments since diagnosis

                        appetite

                        weight loss

                        bone pain

                        voiding symptoms

                                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

Biochemistry profile (electrolytes, glucose, BUN, creatinine, total protein, albumin, hepatic enzymes, alkaline phosphatase)

            Urinalysis

4.  Electrocardiogram (ECG)

5.  Radiographic studies

            Chest x-ray

            Computed Tomography-abdomen and pelvis (or MRI)

            Bone scan

Treatment Plan:

Patients will be treated in the Clinical Research Center (GCRC), either Outpatient or Inpatient Unit, and will receive 4 weekly doses of huJ591 as intravenous infusions. Dose levels are indicated in the Table below. The total dose of J591 will be escalated in cohorts of 3-6 patients at each dose level as indicated below.

Follow-up: Patients will be followed for a minimum of 8 weeks after completion of the huJ591 administration or, if their disease stabilizes or responds, until progression. A single treatment course (4 doses) is planned unless subsequent evaluation reveals evidence of a response (³50% PSA decline or ³25% shrinkage in bidimensional measurable disease; see Appendix for Response definitions).  Re-treatment will be at the discretion of the Principal Investigator and the option of the patient.  In order to be retreated, the patient must satisfy all initial Eligibility and Exclusion criteria and be HAHA-negative. Re-treatment will be at the identical dose level as that initially provided to the patient.

Follow-up on study consists of:

*week 0 is defined as the date of initial administration of huJ591

**selected patients with metastatic disease on CT, MRI and/or bone scan   

Pharmacokinetics:

Each dose will include 1% (by mass) ¹¹¹In-DOTA-huJ591 to allow pharmacokinetic determinations. In the case of patients whose conventional imaging studies demonstrate no apparent metastatic disease, 100 mCi ¹¹¹In  will be labeled to the huJ591-DOTA for serum pharmacokinetic determinations after each dose. In the alternate case of patients whose conventional imaging studies demonstrate presumed metastatic disease, 5 mCi ¹¹¹In will  be utilized to allow antibody imaging and biodistribution in addition to the pharmacokinetic determinations. In this latter group of patients, doses 2,3 and 4 will be at the 100mCi ¹¹¹In level purely for pharmacokinetic determinations. Following injection of ¹¹¹In-DOTA-huJ591, blood samples will be obtained at 10 min, 1, 2, 4, 24 hours and days 2,3,4 and just prior to the following dose. The percent injected dose (% I.D.) in blood will be determined by measuring an aliquot of blood along with a known ¹¹¹In standard.

Radiolabeling of huJ591 with ¹¹¹Indium (¹¹¹In):

A detailed procedure is provided in the Appendix.

¹¹¹In-huJ591 Imaging:

Patients admitted to this trial who are noted to have presumed metastatic disease on conventional imaging studies (CT, MRI and/or bone scan), will receive a higher dose of ¹¹¹In (5 mCi vs 0.1 mCi) in order to allow antibody imaging and a study of antibody bio-distribution.  Total body images will be obtained within 1 hour post-infusion (day 0) and on days 1, 3, and 5.  The gamma camera images will be obtained using a dual head ADAC gamma camera fitted with an appropriate collimator.  The percent injected dose (% i.d.) in major organs (heart, liver, spleen, kidneys, bone marrow, GI tract and bladder) will be estimated by drying regions of interest (ROI) and determining the relative counts in each organ and kinetics of wash out from each organ over 7 days. SPECT studies will be performed of the abdomen, pelvis and/or areas of suspected metastatic lesions.  Using known standards of ¹¹¹In, percent (i.d.) in tumor relations will be estimated per gram of tumor mass. 

Toxicity:

NCI CTEP Common Toxicity Criteria (CTC), version 2 (April, 1999) will be utilized. Since CTEP has standardized the CTC, the NCI does not require inclusion of the CTC within this document. All treatment areas will have access to a copy of the CTC version 2.0. A copy may also be downloaded from the CTEP web site (http://ctep.info.nih.gov/CTC3/ctc.htm). If no Grade III or IV toxicity is observed among the initial 3 patients at a given dose level, the dose may be escalated for the successive group of 3 or more patients.  If one instance of Grade III or IV toxicity is observed among the initial 3 patients placed on a given dose level, an additional 3 patients will be treated at that level.  If no further instances of Grade III or IV toxicity are observed, the dose may be escalated for the successive group of 3 or more patients.  If, at any time, 2 instances of Grade III or IV toxicity are observed at a given dose level, further entry at that dose level will be terminated.

Specific  interventions   solely  for the  purpose  of the study:  Other  than  the actual administration of huJ591 and related studies to define the pharmacokinetics and biodistribution of the mAb, the other interventions (labs, imaging studies, office visits) performed are standard procedures.  Some of the lab tests would not typically be done in the setting of prostate cancer (e.g., HAHA or complement levels). Others lab and radiographic procedures, although standard in the management of patients with prostate cancer, may be done at greater frequency than typical.

Criteria for therapeutic response:

Prostate cancer is manifest by rising PSA levels, new lesions on the bone scan, new disease-related symptoms and, most commonly, increasing size of a measurable soft tissue mass.  Response is commonly assessed either biochemically (PSA change) or by change in size of the measurable lesion.  PSA change will be determined by comparing the nadir PSA level after therapy to the baseline, pre-treatment PSA determined just prior to initiating therapy.  A decline of > 50% has been demonstrated by numerous investigators (references) to correlate with improved survival.  In addition, Scher and associates ( ref ) have demonstrated that a PSA which either declines or shows no change from baseline 12 weeks after initiating therapy correlates with improved survival compared to patients whose PSA rises despite therapy.

In patients with measurable disease: Complete response is defined as complete disappearance of all indicator lesions by physical examination or imaging studies with no appearance of new lesions.  Partial response: is defined as a 50% or greater reduction in the sum of the products of the longest perpendicular diameters of all indicator lesions.  There may be no new lesions.  Stable disease: patients who do not meet the criteria of partial response and who are without signs of progressive disease.  Progressive disease is defined as a greater than 255 increase in the sum of the products of the longest perpendicular diameters of the indicator lesions, the appearance of new lesions or a rise in prostate specific antigen. 

Duration of response: Typically, the first sign of progression will be a rise in serum PSA.  In this trial the duration of response will be the time interval from treatment initiation until progression is documented by either a rise in PSA, enlargement of the measurable lesion, new lesion(s) on bone scan.  The rising PSA must be confirmed by a second, serially rising PSA and the duration will be the time from initiation of treatment to the time of the first rising PSA.

References

1. NCI SEER data

2. NEJM

3. Eisenberger

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