Anthony Delacruz

Phase I Trial of 17-Allylamino-17-Demethoxygeldanamycin in Patients with Advanced Cancer

Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m2 daily for 5 days with cycles repeated every 21 days. Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily × 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m2 on the daily × 5 schedule; 112 mg/m2 on the daily × 3 schedule; and 220 mg/m2 on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily × 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies.

Phase I Trial of the Prostate-Specific Membrane Antigen–Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer

PURPOSE MLN2704 is an immunoconjugate designed to deliver the maytansinoid antimicrotubule agent drug maytansinoid-1 directly to prostate-specific membrane antigen (PSMA)-expressing cells via the PSMA-targeted monoclonal antibody MLN591. This novel immunoconjugate has shown cytotoxic anti-prostate cancer activity. This study investigated the safety profile, pharmacokinetics, immunogenicity, and preliminary antitumor activity of MLN2704. PATIENTS AND METHODS Patients with progressive, metastatic, castration-resistant prostate cancer received MLN2704 intravenously over 2.5 hours. Dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics, immunogenicity, and antitumor activity were assessed. RESULTS Twenty-three patients received MLN2704 at doses of 18 to 343 mg/m(2). Eighteen of these patients received >or= three doses at 4-week intervals. Pharmacokinetics of conjugate levels were dose proportional. There was no correlation between clearance and body-surface area. MLN2704 was nonimmunogenic. Study drug-related grade 3 toxicities occurred in three (13%) of 23 patients, including uncomplicated febrile neutropenia (the only DLT) in one patient, reversible elevations in hepatic transaminases, leukopenia, and lymphopenia. No grade 4 toxicities were observed. The most frequent grade 1 or 2 toxicities included fatigue, nausea, and diarrhea. Neuropathy occurred in eight (35%) of 23 patients, including five of six patients treated at 343 mg/m(2). Two (22%) of the nine patients treated at 264 or 343 mg/m(2) had sustained a more than 50% decrease in prostate-specific antigen versus baseline, accompanied by measurable tumor regression in the patient treated at 264 mg/m(2). CONCLUSION Therapeutic doses of MLN2704 can be administered safely on a repetitive basis. An MTD was not defined. MLN2704 is being administered at more frequent intervals in ongoing trials to determine an optimal dosing schedule.

Pilot Trial of Unlabeled and Indium-111–Labeled Anti–Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer

Background: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein primarily expressed on benign and malignant prostatic epithelial cells. J591 is an IgG1 monoclonal antibody that targets the external domain of the PSMA. The relationship among dose, safety, pharmacokinetics, and antibody-dependent cellular cytotoxicity (ADCC) activation for unlabeled J591 has not been explored. Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N′,N″,N‴-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed. Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline. Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.

Phase I Study of Samarium-153 Lexidronam With Docetaxel in Castration-Resistant Metastatic Prostate Cancer

PURPOSE Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ((153)Sm) lexidronam. PATIENTS AND METHODS Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m(2) and (153)Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and (153)Sm-EDTMP was administered on day -1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. RESULTS Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of (153)Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 (153)Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. CONCLUSION Docetaxel and (153)Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.

Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer.

BACKGROUND Growth of selected castration-resistant prostate cancer (CRPC) cell lines and animal models can be repressed by reexposure to androgens. Low doses of androgens, however, can stimulate tumor growth. OBJECTIVE We performed a phase 1 clinical trial to determine the safety of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer (CRMPC). DESIGN, SETTING, AND PARTICIPANTS Patients with progressive CRMPC who had been castrate for at least 1 yr received three times the standard replacement dose of transdermal testosterone. INTERVENTION Cohorts of 3-6 patients received testosterone for 1 wk, 1 mo, or until disease progression. MEASUREMENTS Toxicities, androgen levels, prostate-specific antigen (PSA) assays, computed tomography (CT) scans, bone scintigraphy, positron emission tomography (PET) scans, and metastatic tumor biopsy androgen receptor levels were assessed. RESULTS AND LIMITATIONS Twelve patients were treated-three in cohorts 1 and 2 and six in cohort 3. No pain flares were noted. One patient came off study because of epidural disease, which was treated with radiation. Average testosterone levels were within normal limits, although dihydrotestosterone (DHT) levels on average were supraphysiologic in cohort 3. One patient achieved a PSA decline of >50% from baseline. No objective responses were seen. For cohort 3, median time on treatment was 84 d (range: 23-247 d). CONCLUSIONS We have demonstrated that patients with CRMPC can be safely treated in clinical trials using high-dose exogenous testosterone. Patients did not, on average, achieve sustained supraphysiologic serum testosterone levels. Future studies should employ strategies to maximize testosterone serum levels, use contemporary methods of identifying patients with androgen receptor overexpression, and utilize PSA Working Group II Consensus Criteria clinical trial end points. TRIAL REGISTRATION ClinicalTrials.gov; NCT00006044.

High‐dose calcitriol, zoledronate, and dexamethasone for the treatment of progressive prostate carcinoma

Preclinical and clinical data have suggested that high‐dose calcitriol (1,25‐dihydroxycholecalciferol) has activity against prostate carcinoma. Pulse‐dosed calcitriol and dexamethasone may maximize tolerability and efficacy. The authors examined the toxicity of pulse‐dosed calcitriol with zoledronate and with the addition of dexamethasone at the time of disease progression.

Phase I trial of MLN2704 in patients with castrate-metastatic prostate cancer (CMPC)

4592 Background: MLN2704 is an immunoconjugate designed to deliver the maytansinoid anti-microtubule agent DM1 directly to prostate cancer cells through the prostate-specific membrane antigen (PSMA) targeted monoclonal antibody MLN591. Preclinical models have indicated significant activity in human prostate cancer xenografts. We report the results of the first phase I trial of MLN2704 in patients with CMPC. METHODS The study was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and immunogenicity of a single ascending dose of MLN2704 administered intravenously over 2.5 hours. Based on emerging safety and PK data, repeat dosing at 4-week intervals was subsequently permitted. Patients with progressive CMPC and adequate organ function were eligible for enrollment. RESULTS 23 patients have received MLN2704 at doses ranging from 18 to 343 mg/m2 in this ongoing trial. 17 patients have received ≥ 3 doses. PK of antibody related analytes (J591-DM1, Total J591 and free J591) has been typical of monoclonal antibodies. Plasma levels of free DM1 have been detectable. No autoantibodies against MLN2704, MLN591 or DM1 have been detected. MLN2704 has been well-tolerated in the majority of patients. Transient elevations in hepatic transaminases, infusion-related fever/chills, nausea, and fatigue have been observed. Only one DLT, an uncomplicated febrile neutropenia, has been reported at the highest dose level (343 mg/m2). This patient also demonstrated a sustained > 50% PSA decline and remains on study at a reduced dose. One patient treated at the 264 mg/m2 dose level has experienced a PR by RECIST, improvement in intradermal metastatic lesions, and a durable 70% decline in PSA. This patient has received 7 doses and remains on study at 24 weeks. CONCLUSIONS Anti-tumor activity has been observed at well tolerated doses of MLN2704. MTD is 343 mg/m2 or higher. Support: T32 CA-09207 [Table: see text].

Nursing Management of Patients With Castration-Resistant Prostate Cancer Undergoing Radium-223 Dichloride Treatment

BACKGROUND Radium-223 dichloride, or radium-223, is a first-in-class alpha emitter that selectively targets bone metastases with high-energy, short-range alpha particles and is approved for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Nurses are essential in educating patients about radium-223. OBJECTIVES This article provides oncology nurses with information from the randomized phase III Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, as well as important handling, administration, and safety details unique to radium-223. METHODS Data from the ALSYMPCA trial and related published information on radium-223 were reviewed. FINDINGS Radium-223 is the only alpha-emitting radiopharmaceutical that has been shown to improve overall survival in patients with CRPC, as demonstrated in the ALSYMPCA trial. In addition, radium-223 delays time to first symptomatic skeletal event, and it is well tolerated with a low incidence of myelosuppression and gastrointestinal adverse events. Delivered on an outpatient basis, radium-223 requires universal precautions for handling and administration. Because of the potential for additive myelosuppression, the concomitant use of radium-223 with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy is not recommended.

Hormonal induction followed by rapid hormonal cycling for prostate cancer (PC): the MEN's Cycle

4609 Background: Continuous androgen deprivation (AD) is a standard therapy for systemic PC. Rapid cyclic AD and androgen repletion (AR) after a 1 month induction with castration was shown to be feasible. This trial explores a longer induction period followed by rapid cyclic AD and AR in patients (pts) with limited prior hormone exposure. METHODS Eligible pts had a rising PSA after surgery or radiation, or radiographic metastases, and ≤ 6 months of prior hormone exposure. Treatment consisted of a 3 month induction (GnRH analog monthly & bicalutamide x 1 month) followed by monthly cycles of AR (topical testosterone (T) daily x 7 days) and AD (GnRH analog monthly). A PSA of ≤1ng/ml after induction was required to proceed with cycling. PSA and T levels were monitored post ablation (troughs) and post repletion (peaks). The primary endpoint was the proportion of pts with serially declining PSA troughs after 6 cycles. Treatment failures were defined as 3 sequential increases in PSA troughs prior to 6 cycles. RESULTS 23 pts were enrolled (5 pts: rising PSA only; 18 pts: metastatic disease). The median baseline PSA was 63ng/ml (2.6-546). The median baseline T level was 383ng/dl (181-654). All cycling pts achieved T levels within the normal reference range during AR and castrate troughs during AD. 5 pts (22%) did not achieve a PSA of ≤1ng/ml after induction and did not cycle. 3 pts were inevaluable. Of the 15 evaluable pts who cycled, 6 pts met the primary endpoint and 3 pts are still being evaluated at < 6 cycles. 6 pts were treatment failures (all continued standard AD off study, of whom 5 pts had further PSA declines). No pt progressed radiographically. Common toxicities included grade 1 fatigue and hot flashes. CONCLUSION Rapid hormonal cycling using a 3 month induction is feasible, well-tolerated, and successive declines in the PSA troughs can be achieved. Some pts did show evidence of AD resistance within 3 months by not achieving a PSA of ≤1ng/ml after induction. Based on these results, we have designed a phase II clinical trial using rapid hormonal cycling with no induction in combination with docetaxel in pts with limited prior hormone exposure. Support: CCPP, CA05826, Prostate Cancer Foundation No significant financial relationships to disclose.

Recognizing Symptom Burden in Advanced Prostate Cancer: A Global Patient and Caregiver Survey

Background Bone metastases in men with prostate cancer are often initially asymptomatic, resulting in delayed identification, diagnosis, and appropriate treatment. To assess how patients with advanced prostate cancer (aPC) communicate symptoms to health care providers, an international patient survey was conducted. Methods An online and phone survey was conducted by Harris Poll in 11 countries (Brazil, France, Germany, Japan, Italy, Netherlands, Singapore, Spain, Taiwan, United Kingdom, United States) from February 12 to October 27, 2015, in men with aPC (ie, those who reported as having PC beyond the prostate [metastatic]) and their caregivers. Cell weighting was used to ensure equal weight of data across countries. Percentages are based on weighted n values. Results A total of 927 men with aPC (weighted n = 664) and 400 caregivers completed the survey. Most commonly reported symptoms were fatigue (73%), urinary symptoms (63%), sexual function symptoms (62%), and bone pain (52%). Of 568 patients with bone metastases (weighted n = 421), most (73%) noticed pain before receiving a diagnosis of metastatic PC. Most patients with aPC (56%) were uncertain if their pain was cancer related, 55% felt they had to live with daily pain, 45% sometimes ignored pain, and 39% had difficulty talking about pain. Patients who had a caregiver were more likely than those without to discuss pain at every visit (45% vs. 32%, P < .05). Conclusions Disease symptoms in aPC are often underrecognized. Tools encouraging effective communication among patients, caregivers, and health care providers on early symptom reporting may lead to enhanced symptom and disease management. Micro‐Abstract An international survey was conducted in 927 men with advanced prostate cancer (aPC) and 400 caregivers to assess symptom communication. Patients with aPC often ignore pain and pain‐related symptoms, do not discuss pain with their physician, and have difficulty discussing symptoms. Effective communication among patients, caregivers, and health care providers may improve symptom and disease management and patient quality of life.