Leonard M. Reyno

Suramin Therapy for Patients With Symptomatic Hormone-Refractory Prostate Cancer: Results of a Randomized Phase III Trial Comparing Suramin Plus Hydrocortisone to Placebo Plus Hydrocortisone

PURPOSE Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic-dependent pain. PATIENTS AND METHODS A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared. RESULTS Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for suramin responders (median, 240 v 69 days; P =.0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P =.01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically. CONCLUSION Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

Suramin, an Active Drug for Prostate Cancer: Interim Observations in a Phase I Trial

BACKGROUND Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotoxicity of this agent is closely related to sustained plasma drug concentrations of 350 micrograms/mL or more. PURPOSE This phase I clinical trial in patients with solid tumors was designed to determine whether plasma concentrations resulting in both antitumor activity and manageable toxicity could be achieved with short, intermittent infusions of suramin. METHODS Thirty-seven patients, including 33 with metastatic, hormone-refractory prostate cancer, collectively received 43 courses of suramin designed to maintain a plasma concentration range of 200-300, 175-275, or 150-250 micrograms/mL. Patients received a test dose of 200 mg and an initial loading dose of 1000 mg/m2 on day 1 of therapy. Subsequent suramin doses and schedules were individually determined using a strategy of adaptive control with feedback, which used a maximum a posteriori Bayesian algorithm to estimate individual pharmacokinetic parameters. Patients were treated until dose-limiting toxicity or progressive disease developed. RESULTS Thirty-five of the 37 study patients and 31 of the 33 with prostate cancer were assessable for toxicity and response. Treatment was discontinued in 28 patients because of dose-limiting toxicity consisting of a syndrome of malaise, fatigue, and lethargy; recurrent reduction in creatinine clearance of 50% or more; or axonal neuropathy. Evidence of major antitumor activity was observed in patients with prostate cancer treated at all three plasma drug concentrations. Measurable responses (one complete response and five partial responses) were noted in six of 12 patients with measurable disease. Twenty-four (77%) of 31 patients had a reduction in prostate-specific antigen of 50% or more, and 17 (55%) of 31 had a reduction of 75% or more. Twenty (83%) of 24 patients reported reduction in pain. CONCLUSIONS Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible. Suramin is active against hormone-refractory prostate cancer. IMPLICATIONS Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types.

Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer.

PURPOSE This phase I study was designed with the following objectives: (1) to describe the overall and dose-limiting toxicity (DLT) of suramin administered by intermittent short intravenous infusions until DLT or disease progression; (2) to determine the ability of an adaptive control with feedback (ACF) dosing strategy to maintain suramin plasma concentrations within a preselected range; (3) to develop a population model of suramin pharmacokinetics; and (4) to identify preliminary evidence of antitumor activity. PATIENTS AND METHODS Seventy-three patients with advanced, incurable, solid tumors (including 69 with hormone-refractory prostate cancer) received an initial 5- to 7-day daily loading treatment followed by intermittent infusions individually determined by ACF using a Bayesian algorithm and relying on population models of suramin pharmacokinetics. Treatment was given to three cohorts of patients based on target plasma suramin concentration ranges (peak, 30 minutes postsuramin, and trough on morning of the treatment day), as follows: cohort 1, 175 to 300 micrograms/mL (27 patients); cohort 2, 150 to 250 micrograms/mL (23 patients); and cohort 3, 100 to 200 micrograms/mL (23 patients). All patients were to receive suramin until DLT or disease progression. RESULTS The DLT was most commonly seen in cohort 1 and included a syndrome of malaise and fatigue, associated with weight loss, anorexia, and changes in taste. Other reversible toxicities were neurologic, renal, cutaneous, edema, lymphopenia and anemia, ophthalmologic, and alopecia. Forty of 67 assessable patients (60%) had a 50% reduction and 25 of 67 (37%) a 75% reduction in prostate-specific antigen (PSA) levels that lasted more than 4 weeks, seven of 18 (40%) had measurable responses, and 18 of 37 (49%) demonstrated major pain improvement. The overall times to disease progression and survival were 170 and 492 days, respectively. CONCLUSION We have characterized all toxicities with suramin in a pharmacologically guided phase I study designed to maintain plasma suramin concentrations of 100 to 300 micrograms/mL (cohorts 1 to 3). The incidence of grade 3 to 4 neurologic abnormalities was relatively low, particularly in cohorts 2 and 3 (100 to 250 micrograms/mL). Evidence of significant and durable antitumor activity was seen in all three cohorts.

Phase III Study of N,N-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19

PURPOSE N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer. PATIENTS AND METHODS Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m(2) intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m(2). Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS). RESULTS A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P =.021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected. CONCLUSION This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.

Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer.

PURPOSE To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes. METHODS Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes. RESULTS The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single-agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival. CONCLUSION Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.

Effects of storage on the binding of carboplatin to plasma proteins.

Plasma ultrafiltrates are routinely used in pharmacokinetic studies of carboplatin. Experiments were performed to detect and quantitate artifactual decreases in the platinum concentration of ultrafiltrates prepared from plasma samples stored at −20°C and −70°C. Carboplatin was added to anticoagulated, whole human blood to produce a 20 μg/ml concentration. Plasma produced from the blood was stored frozen at either −20°C or −70°C. Aliquots from each storage condition were thawed and ultrafiltered once a week for up to 100 days. Platinum concentrations in ultrafiltrates and plasma were determined by flameless atomic absorption spectrometry. There was no loss of ultrafilterable platinum in plasma samples stored at −70°C, whereas there was a steady decrease in free platinum concentration in ultrafiltrates prepared from plasma samples stored at −20°C. These results imply that pharmacokinetic studies of carboplatin should use ultrafiltrates prepared immediately or that plasma for such studies should be stored at −70°C. Storage of carboplatincontaining plasma at −20°C and subsequent ultrafiltration is not acceptable, because measurement of platinum in such ultrafiltrates will be artifactually low.

Phase 1 Trials of anti-ENPP3 antibody drug conjugates in advanced refractory renal cell carcinomas.

Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5–141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399–406. ©2018 AACR.

Comparison of Iterative-Two Stage and Bootstrap Sampling Approaches in the Development of a Population Pharmacokinetic Model

Abstract The kinetics of an antineoplastic drug, suramin, described by a three-compartment, open, linear model is studied in this report. A population pharmacokinetic model, describing the pharmacokinetics of suramin, was developed using the iterative-two stage approach, with maximum a posteriori-Bayesian priors. It was further validated using data from a subsequent study (validation data set). The population pharmacokinetic parameters were also estimated by generating bootstrap samples from the validation data set. When the prior distribution was close to the population distribution, there was no significant difference between the estimates obtained using the iterative-two stage approach and the bootstrap approach. However, when estimating population pharmacokinetic parameters, the iterative-two stage approach was less sensitive to prior distribution specification