- Anti-cancer drug development in academia and biotechnology in USA and in Europe.Therapeutic areas include: translati... moreAnti-cancer drug development in academia and biotechnology in USA and in Europe.Therapeutic areas include: translational oncology and neurology, biomarkers, clinical pharmacology, new chemotherapy and targeted agents, monoclonal antibodies, cancer immunotherapy and vaccines, gene therapy.edit
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4006 BACKGROUND: DX is a novel hexacyclic, water-soluble, topoisomerase-1 inhibitor. DX has single-agent and combination activity with GEM in APC (D'Adamo, et al. ASCO, 2001; O'Reilly, et al. ASCO, 2002). A multicenter, randomized... more
4006 BACKGROUND: DX is a novel hexacyclic, water-soluble, topoisomerase-1 inhibitor. DX has single-agent and combination activity with GEM in APC (D'Adamo, et al. ASCO, 2001; O'Reilly, et al. ASCO, 2002). A multicenter, randomized phase III trial comparing DX + GEM to GEM alone in APC was conducted. METHODS Eligibility included KPS ≥ 60%; locally advanced or metastatic pancreatic adenocarcinoma; no prior chemotherapy. Radiation (RT) alone for locally advanced disease was permitted. Patients (pts) were randomized on a 1: 1 basis to DX + GEM or GEM alone. Pts were stratified by KPS, 60%, 70-80%, ≥ 90%, locally advanced vs metastatic disease, prior RT vs. no RT. For the DX + GEM arm, DX was dosed at 2.0mg/m2; GEM at 1,000mg/m2 on a days 1 and 8, q 3 weeks. GEM alone was dosed at 1,000mg/m2 up to 7 weeks in the 1st cycle, then weekly x 3, q 4 weeks. Tumor assessment was performed every 6 weeks. The primary endpoint was overall survival. An intent-to-treat analysis was used. An independent data safety monitoring board monitored the trial. RESULTS From 8/01 to 1/03, 349 patients were randomized, 175 to DX + GEM, and 174 to GEM alone. Twenty-four pts (6.9%) were not treated. The treatment arms were well-balanced for extent of disease, KPS, and prior RT. The median survival time was 6.7 months for DX + GEM and 6.2 months for GEM alone (p=0.52). The median TTP for DX + GEM was 3.7 months and 3.8 months for GEM alone (p=0.22). There was an improvement in time-to-worsening of pain and analgesic consumption for DX + GEM compared to GEM alone. However, time-to-worsening of KPS and weight were similar for both treatment arms. Tumor response rates were 8.2% for DX + GEM and 6.3% for GEM alone. Grade 3-4 toxicity was higher for the DX + GEM arm for neutropenia (30% vs 15%, p=0.001), thrombocytopenia (17% vs 4%, p=0.0004) and vomiting (11% vs 5%, p=0.04). The rates of febrile neutropenia were 4% for DX + GEM and 2% for GEM alone, p=0.24. The relative dose-intensities were similar for both arms: 83% and 81% of projected doses for the DX and GEM arm compared to 92% for GEM alone. CONCLUSIONS DX + GEM was not superior to GEM alone with respect to overall survival in the front-line treatment of APC. There was a trend in favor of clinical benefit for the combination arm. The results do not alter the standard of care for treatment of APC. [Table: see text].
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5140 Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. Previously, a PSA response rate of 25% was observed when Pico monotherapy was... more
5140 Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. Previously, a PSA response rate of 25% was observed when Pico monotherapy was infused at 120 mg/m2 Q3W (N = 20). Recently, a 34-patient Phase I study was performed to investigate the safety and efficacy of Pico in combination with docetaxel (D) + prednisone (pred) as first-line therapy for metastatic CRPC. Picoplatin therapy was well-tolerated at a dose of 120 mg/m2 and 19 of 32 evaluable pts (59%) achieved a confirmed PSA response. Methods: 32 patients with chemotherapy-naïve CRPC and disease progression received Pico (120 mg/m2) and D (75 mg/m2) Q3W with pred 5 mg po bid for up to 10 cycles. PSA responses were defined as a reduction from baseline of at least 50% maintained for at least 4 weeks. CT and bone scans were also evaluated. Tumor response was measured using RECIST. Results: Patients received a median of 10 cycles (range = 1–10). Median baseline PSA was 340.8 ng/mL (range 5.6–3019). One pt had no baseline PSA data. Of the 24 patients with evaluable post-treatment PSA, 83% (95% CI 64–93%) had PSA decreases <50% of baseline, and in 8 of these (33% of the evaluable population), PSA reached normal levels (< 4 ng/mL). In the intent-to-treat population, the PSA response rate was 63% (95% CI 45–77%). 13 patients evaluated by CT scan had measurable disease; 6 pts had SD by RECIST, 4 had PD, and 3 were not evaluable. The most common adverse events were alopecia (36%), asthenia (32%), neutropenia (29%), increased creatinine (23%), and thrombocytopenia (19%). No neurotoxicity ≥ grade 2 was observed. Conclusions: Picoplatin was safely administered to patients with CRPC as 1st-line therapy at 120 mg/m2 Q3W with full doses of docetaxel and prednisone, resulting in a PSA response rate of 83% of evaluable patients. These results support further development of picoplatin as a novel combination with docetaxel for the treatment of CRPC. [Table: see text]
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7002^ Background: Picoplatin is a new platinum compound designed to overcome platinum resistance and has demonstrated less neurotoxicity and nephrotoxicity than other platinum agents. The SPEAR study was designed to assess the efficacy... more
7002^ Background: Picoplatin is a new platinum compound designed to overcome platinum resistance and has demonstrated less neurotoxicity and nephrotoxicity than other platinum agents. The SPEAR study was designed to assess the efficacy and safety of picoplatin + BSC (pico) vs. BSC for the treatment of SCLC, nonresponsive or progressive within 6 months of platinum-based therapy. Methods: 401 pts were randomly assigned 2:1 to pico IV 150 mg/m2 q3w, n = 268 or BSC, n = 133. Overall survival (primary endpoint), progression-free survival (PFS), response rate, and time-to-progression (TTP) were assessed. Adverse events (AEs) were assessed with NCI-CTCAE v3. Results: Pt demographics were balanced with a median age of 58 yrs, 84% male, 88% Caucasian, 85% PS 0-1, 15% PS 2. Median pico cycles = 3 (1-15). With a hazard ratio (HR) of 0.8, median survival time (MST) for pico vs BSC was 21 wks (CI 19-25) vs 20 wks (CI 16-24) (p = 0.09). However, refractory pts (pts who never responded or pts who relapsed within 45 days...
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10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We... more
10062 Background: 17-AAG is a benzoquinone ansamycin that binds to and inhibits the HSP90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0–2, and adequate hematologic, hepatic, renal and cardiac functions received CNF1010 by 1 h intravenous infusion, twice-a-week, three weeks out of four, starting at 6 mg/m2 per dose. Doses were escalated sequentially in single pts (6 and 12 mg/m2) and 3–6 pts (≥ 25 mg/m2) cohorts according to a modified Fibonacci’s schema. Plasma pharmacokinetic (PK) profiles were obtained on days 1 and 18. Biomarkers were measured in PBMC’s (HSP70) and plasma (HER-2 ectodomain (HER-2 ECD)). Results: 30 pts (M/F: 14/16; median age 63, range 48–78) with colorectal cancer (11), pancreatic cancer (5), melanoma (5), ovarian (2), ...
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2017 Background: DX-8951f (exatecan mesylate) is a novel camptothecin analog active in GI tumors such as pancreatic cancer. Its dose limiting toxicities (DLT) include neutropenia and thrombocytopenia. Because of its hepatic metabolism, a... more
2017 Background: DX-8951f (exatecan mesylate) is a novel camptothecin analog active in GI tumors such as pancreatic cancer. Its dose limiting toxicities (DLT) include neutropenia and thrombocytopenia. Because of its hepatic metabolism, a dose escalation study was performed in liver dysfunction patients (pts). Methods: Pts were classified in hepatic dysfunction cohorts defined by a modified NCI Organ Dysfunction Working Group (NCI) schema. Once a DLT was observed, pts were divided into minimally pretreated (MP) and heavily pretreated (HP) groups. Both the NCI and the FDA-recommended Child-Pugh classifications were used for data analysis. Results: Overall, 42 pts received 0.1–0.5 mg/m2/d DX x 5 q3 wks and 33 pts had PK data available. Dose escalation reached 0.5, 0.5, 0.4, and 0.2 mg/m2 for MP pts and 0.4, 0.4, 0.2, 0.1 mg/m2 for HP pts in Groups A, B, C and D, respectively. DLT's were neutropenia and low platelets, observed at 0.4 and 0.2 mg/m2 for MP and HP in group C, respectively. The MTD and drug clear...
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2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more... more
2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more potent than both paclitaxel and docetaxel. METHODS This first-in-human study assessed the maximum tolerated dose [MTD], dose limiting toxicities [DLT] and PK of DJ-927 administered as a single oral 3-weekly dose. Pts were stratified based on prior therapy into minimally (MP) and heavily (HP) pretreated cohorts. The starting dose of DJ-927, 1.5 mg/m2, was increased in 100% increments until grade 2 toxicities occurred during course 1 and by 50% thereafter, until consistent DLT were observed. RESULTS To date, 40 pts have received 109 courses [median-2; range 1-8] at the following doses: 1.5 mg/m2 [3], 3 mg/m2 [3], 6 mg/m2 [3], 12 mg/m2 [3], 18 mg/m2 [4], 27 mg/m2 [8], 35 mg/m2 [8] and 40 mg/m2 [8]. Demographics: 23 male / 17 female; median [range] age- 57 [31-81]; PS 0 [7], PS 1 [31], and PS 2 [2]. Primary tumors are colorectal [15], breast [4], pancreas [5], renal cell [3], soft tissue sarcoma [3] and others [10]. Minimal drug-related toxicities were observed at doses 5 days duration [7] and grade 3 thrombocytopenia [4] were the predominant hematological toxicities observed at 40 and 35 mg/m2 doses. Non-hematological toxicities included: transient grade 3 peripheral sensory neuropathy after 3 cycles [1] at 27 mg/m2, grade 3 diarrhea and grade 3 mucositis [1] at 40mg/m2. Minor responses were seen in taxane-refractory breast carcinoma [1] and transitional cell carcinoma of the bladder [1]. Disease stabilization for >3 months was noted in 8 pts. Plasma PK of DJ- 927 were dose proportional over the dose range explored. The Cmax, mean (CV%) 58.83 (70.2) μg/L, AUC (inf) 1792.7 (36.4) h*μg/L), clearance/F 45.93 (48.6) L/h, and terminal half-life 175.5 (38.2) h were seen at 40 mg/m2 dose (8). CONCLUSIONS DJ-927 generates predictable systemic drug exposures and has been well tolerated when orally administered. Dose escalation ceased due to DLT in 2/3 MP + 2/5 HP at 40 mg/m2 and 2/6 MP + 2/2 HP at 35 mg/m2. MTD has been defined as 27 mg/m2 for MP and HP patients. [Table: see text].
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: Exatecan mesylate (DX‐8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT‐11, including watersolubility, greater potency against topoisomerase I, lack of esterase‐dependent... more
: Exatecan mesylate (DX‐8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT‐11, including watersolubility, greater potency against topoisomerase I, lack of esterase‐dependent activation, broad antitumor activity, and low cross‐resistance against MDR‐1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose‐limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX‐8951 and lactone DX‐8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose‐dependent and reversible. Neutropenia was dose‐limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose‐limiting in heavily pretreated patients. Non‐hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting>diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non‐small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT‐11 and topotecan‐resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX‐8951f‐induced neutropenia in individual patients was developed. The daily ×5, every 3‐week schedule with the drug administered as a 30‐minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
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It has been hypothesized that multiple sclerosis (MS) has hormonal influences, and testosterone may have anti-inflammatory functions in this context. Given prior reports of lower testosterone levels in men with MS in archival serum... more
It has been hypothesized that multiple sclerosis (MS) has hormonal influences, and testosterone may have anti-inflammatory functions in this context. Given prior reports of lower testosterone levels in men with MS in archival serum samples, we evaluated the prevalence of hypogonadism in the clinical setting and its association with disability in men with MS. Subjects were screened for symptoms of hypogonadism using a clinical instrument, and those with positive screens had total and free morning testosterone levels checked. Of the 64 subjects who were screened, 50 (78%) had positive results, and 46 (92%) had morning testosterone levels checked. Among the latter, 5 were found to have testosterone levels below lower limit of normal. Other than the expected inverse relation with BMI, testosterone did not correlate with demographic or disease related factors. Baseline testosterone did not predict risk of EDSS or T25-FW progression or future MRI activity.
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Carcinoma in situ is a form of superficial transitional cell carcinoma, which is characterized by a lateral spread along the bladder epithelium, with high-grade malignancy and poor prognosis. Early radical cystectomy is considered the... more
Carcinoma in situ is a form of superficial transitional cell carcinoma, which is characterized by a lateral spread along the bladder epithelium, with high-grade malignancy and poor prognosis. Early radical cystectomy is considered the definitive treatment even in the absence of associated invasive cancer. In six prospective phase II studies, 123 carcinoma in situ patients were administered intravesical TICE bacillus Calmette-Guerin (BCG). Treatment consisted of at least six weekly instillations (induction) followed by twelve monthly instillations (maintenance) of BCG (50 mg: 1 to 8 x 10(8) colony-forming units). Of 119 evaluable patients, 90 (76%) achieved complete remission including 45 of 63 (71%) patients who received prior intravesical chemotherapy. Forty-five responders (50%) remain in complete remission with negative urine cytology with a median duration of response projected to be greater than or equal to forty-eight months. There is no difference in survival between BCG responders and nonresponders, but there is a significant difference in cystectomy rates: 10 of 90 (11%) responders vs. 16 of 29 (55%) nonresponders (P less than 0.0001, Fisher's exact test) and time to cystectomy (31 vs. 74 mos.) (P less than 0.001, log-rank test). Delaying cystectomy does not seem to affect survival and improves quality of life. Treatment was well tolerated with some major adverse effects. Intravesical TICE BCG is an effective treatment for bladder carcinoma in situ patients with or without prior chemotherapy.
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Background Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival. Methods Analyses evaluate... more
Background Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival. Methods Analyses evaluate predictive blood tests to identify patients who often survive 1 and 2 years. A four-test model includes: albumin, absolute neutrophil count, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio. Individual tests include: alkaline phosphatase, lymphocytes, white blood count, platelet count, and hemoglobin. Eligible patients have advanced: resistant 3rd line colorectal, and both resistant and new pancreatic and intrahepatic bile duct cancers. Eligibility characteristics include: biopsy-proven, measurable metastatic disease, NCI grade 0–2 blood tests, Karnofsky Score 100–50, and any adult age. Drugs are given at 1/4–1/3 of their standard dosages biweekly: gemcitabine, irinotecan, fluorouracil, leucovorin, and day 2 oxaliplatin every 2 weeks. In ...
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A new HPLC method for the determination of Cefoperazone in serum is described.
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A phase II clinical trial of high-dose cisplatin (120 mg/m2 iv every 3 weeks), with fluid and mannitol-induced diuresis, was conducted in 81 patients with advanced lung cancer. Partial remissions were documented in 26% of 75 evaluable... more
A phase II clinical trial of high-dose cisplatin (120 mg/m2 iv every 3 weeks), with fluid and mannitol-induced diuresis, was conducted in 81 patients with advanced lung cancer. Partial remissions were documented in 26% of 75 evaluable cases for a median duration of 3.5 months. Adenocarcinoma and small cell anaplastic carcinoma were more responsive than epidermoid carcinoma, with partial response rates of 35%, 30%, and 18%, respectively. The median survival of responders (8.5 months) was significantly longer than the survival of nonresponders (4 months) (P less than 0.02). Myelosuppression was mild. Renal toxicity with peak serum creatinine greater than 2.5 mg/100 ml occurred in eight patients, with one death occurring due to toxicity. Cisplatin is an active drug in advanced lung cancer.
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e16158 Background: A sequence of drug combinations produces > 1 median (M) -strong 2-year (yr) survival (S) (Bruckner et al AACR 14 Antica Res (ACR) 16, 18 SIGO 19). Trials included high-risk patients (pts). Each initial series has... more
e16158 Background: A sequence of drug combinations produces > 1 median (M) -strong 2-year (yr) survival (S) (Bruckner et al AACR 14 Antica Res (ACR) 16, 18 SIGO 19). Trials included high-risk patients (pts). Each initial series has 5-yr Ss, after pts were referred for hospice care. Prognostic ALAN blood tests (Ts) have been validated for stage IV (Adv) Cholangiocarcinoma (CCA) (Salati et al EuJCa18). Other Ts predict unexpected favorable (F) S of pts with gastric ca, PS 2-3. Bruckner et al JAMA, 82); but, there is little known about Ts for resistant (R) Ca. Methods: Planned Kaplan-Meier intent to treat analysis to find Ts that: expand eligibility (El) for therapy; identify biomarkers that predict therapy can prolong S and identify new hypotheses for therapy. El pts have:R to test drugs, Pancreatic (PC), Intrahepatic bile duct, CCA, Colon, CRC and new (N) APC. All series: -/+ high risk, -/+ aged, PS 0-2. El: Helsinki criteria- consent, recovered from severe (gr3) toxicity; able to...
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e16160 Background: Advanced (Adv) intrahepatic IH Cholangiocarcinoma BD trials found multi-drug, sequences (GFLIO) safely expand eligibility (El) for patients (pts) of all ages -/+ resistant Ca (R). Two series had response/survival (S) of... more
e16160 Background: Advanced (Adv) intrahepatic IH Cholangiocarcinoma BD trials found multi-drug, sequences (GFLIO) safely expand eligibility (El) for patients (pts) of all ages -/+ resistant Ca (R). Two series had response/survival (S) of 80% / > 2 years (yr) (Bruckner et al Anti Ca Res 16). Therapy reverses R to key drugs, improves the pts' many immune functions and exposure to neoantigens, (Caraglia RT et al Front Oncol 19.) A.L.A.N.(AS) blood tests (Ts) predict chances of S (Salati et al EuJCa 18). Methods: Kaplan-Meier analyses examine prognostic Ts as El criteria for real-world pts. El included poor risk pts: any adult age, +/- R (-/+ prior test drugs). El: Intent to treat; consent; adv measurable IHBD; active progression (pg); Performance 0-2 and expected 6 wks S. The inE have 2ary CNS, require IVs; are unable to reach office, or have gr3-4 toxicity. GFLIO every 2 wks in mg/M2: Gemcitabine 500; 5-Fluorouracil 1200 over 24 hrs; Leucovovorin 180 Irinotecan 80 and day (D)2...
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SCOPUS: ar.jinfo:eu-repo/semantics/publishe
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219 cases of small cell carcinoma of the lung are reviewed. The 5-year survival rate is less than 5%. Four patients survived more than 5 years, out of 9, whose tumors were resected with curative intention. Palliative resections do not... more
219 cases of small cell carcinoma of the lung are reviewed. The 5-year survival rate is less than 5%. Four patients survived more than 5 years, out of 9, whose tumors were resected with curative intention. Palliative resections do not enhance the survival rate. Combined radiotherapy and polychemotherapy have a high response rate and tend to extend the median survival rate Thus, small cell carcinoma requires an accurate pathological diagnosis and extensive staging. Only small, localized peripheral tumors (T1N0M0, T2N0M0) should be resected.
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PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce... more
PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu–overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu–overexpressing and low HER-2/neu–expressing breast and ovarian cancers in a phase I clinical trial.PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12).RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase–polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downreg...
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PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3... more
PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors. PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status ≤ 2, were entered. The starting dose of DX-8951f was 0.15 mg/m2; the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred. RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m2 and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m2, grade 2 hematologic toxicity was observed. Of the six...
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Research Interests: Kidney diseases, Humans, Female, Male, Sarcoma, and 9 moreCisplatin, European, Aged, Middle Aged, Adult, Drug evaluation, Elsevier, Creatinine, and Soft Tissue Neoplasms
Introduction: Clinical studies have demonstrated that picoplatin (Pico), a new‐generation platinum analogue designed to overcome platinum resistance, has activity when administered IV in solid tumors patients (pts); over 1,100 pts have... more
Introduction: Clinical studies have demonstrated that picoplatin (Pico), a new‐generation platinum analogue designed to overcome platinum resistance, has activity when administered IV in solid tumors patients (pts); over 1,100 pts have received pico. The primary toxicity is hematological. Clinically significant nephro‐, oto‐, or neurotoxicity has rarely been observed ( Methods: The effect of pico on the QT/QTc interval as measured by the ECG was evaluated. The correlation between the QTcF interval and platinum concentration in plasma and plasma ultrafiltrate (PUF) was evaluated. ECG was recorded continuously with a Holter monitor. Triplicate 20 second ECG readings were extracted at 3 times before (baseline reference) and at 8 times in the 24 hrs after pico administration in Cycle 1. Triplicate 12‐lead ECGs were obtained at the end of the pico infusion in subsequent cycles. Blood samples were collected before study drug administration and immediately after each ECG timepoint in Cycle 1 for pharmacokinetic analysis. The primary endpoint was the Fredericia corrected QT (QTcF). Time‐averaged and time point analyses for QTcF were performed. Heart rate, PR, QRS, QT, QTcB (Bazett9s) and morphological changes were also evaluated. Results: 45 pts (28 women and 17 men), age 44–79 years (median = 60) received 150 mg/m2 pico as a 1‐hr IV infusion. The time‐averaged mean change from baseline of QTcF duration during Cycle 1 was +2.2 ms, which is considered a nonsignificant increase. At each time point in Cycle 1 and in subsequent cycles, there were only minimal changes from baseline in QTcF duration. Other ECG changes from baseline were unremarkable: ST depression was noted in 9% of pts at baseline and new T‐wave changes in 7% of pts in Cycle 1. Mean ± SD Cmax in plasma and PUF were 5566 ± 1079 ng/mL and 4034 ± 674 ng/mL, respectively. The change in QTcF vs. platinum concentration in plasma or PUF showed a Cmax effect of 5–6 ms with an upper confidence interval of 8–9 ms, suggesting no clear effect of picoplatin on QTcF. Conclusions: Pico had no effect on the QTcF interval or any other ECG parameter, supporting the clinical data showing that Pico does not increase the risk of serious ventricular arrhythmias. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B212.
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A rapid, easy and reproducible method of determination of a new antineoplastic compound, 2-Formylpyrimidine thiosemi-carbasone, is described. Separation of free from protein-bound drug is achieved with a disposable cartridge SEPPAK filled... more
A rapid, easy and reproducible method of determination of a new antineoplastic compound, 2-Formylpyrimidine thiosemi-carbasone, is described. Separation of free from protein-bound drug is achieved with a disposable cartridge SEPPAK filled with a reverse phase of octadécylsilane (BONDAPAK Cl8/Porasil B) permeable to proteins. After elution of the adsorbed free 2-Formylpyridine thiosemicarbazone (2-FPTS) with DMSO, a spectrophotometry dosage at 330nm is performed. The sensitivity of the method makes it useful for clinical use.
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DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute... more
DX-8951f is a novel hexacyclic camptothecin-analogue topoisomerase I inhibitor with both in vitro antileukemic activity and myelosuppression as a dose-limiting toxicity in solid tumor Phase I studies. DX-8951f is active in a human acute myeloid leukemia (AML) severe combined immunodeficient mouse model. In a leukemia Phase I study, we investigated the toxicity profile and pharmacokinetics of DX-8951f in patients with primary refractory or relapsed AML or acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myelogenous leukemia in blastic phase (CML-BP). DX-8951f was given as an i.v. infusion over 30 min daily for 5 or 7 days. The starting dose was 0.6 mg/m(2)/day for 5 days (3.0 mg/m(2)/course). Courses were given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty-five patients (AML, 21 patients; myelodysplastic syndrome, 1 patient; acute lymphocytic leukemia, 2 patients; CML-BP, 1 patient) were treated. Stomatitis was the dose-limiting toxicity, oc...
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Introduction: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5‐FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose‐limiting... more
Introduction: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5‐FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose‐limiting oxali‐related neurotoxicity. The incidence of grade (G) 3–4 neurotoxicity with single‐agent Pico across studies was Methods: Each pt with no prior chemotherapy for advanced CRC received LV and infusional FU per FOLFOX Q2W. Pts received Pico Q4W (150 mg/m 2 ) or oxali Q2W (85 mg/m 2 ). Tumor response was assessed by RECIST using CT scans. Adverse events (AEs) were assessed with CTCAE and neuropathy was evaluated using the FACT‐Neurotoxicity questionnaire and by a neurologist blinded to treatment. Results: 51 pts received FOLPI and 50 received FOLFOX. Platinum exposure was similar between treatment arms. With FOLFOX, the most frequent G 3/4 AEs were neutropenia (22%), neuropathy (16%) and thrombocytopenia (12%). With FOLPI, the most frequent G 3/4 AEs were neutropenia (57%), thrombocytopenia (43%) and anemia (22%). There was no G3/4 neuropathy on the FOLPI arm. FOLPI had significantly less neurotoxicity (G 2–4) than FOLFOX (p Conclusions: Neurotoxicity with FOLPI was less frequent and less severe compared to FOLFOX. Hematologic toxicity with FOLPI was manageable. FOLPI treatment of 1st line CRC had similar disease control and survival rates to FOLFOX supporting picoplatin as a potential neuropathy‐sparing alternative to the use of oxaliplatin. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B49.
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e16763 Background: Gemcitabine (G), 5-fluorouracil (F), leucovorin (L), irinotecan (I), and oxaliplatin (O), (GFLIO) is safe, employs moderate 1/2-1/3 dosages, offers expanded eligibility (0-2 ECOG PS; no age limit)). Each step reverse... more
e16763 Background: Gemcitabine (G), 5-fluorouracil (F), leucovorin (L), irinotecan (I), and oxaliplatin (O), (GFLIO) is safe, employs moderate 1/2-1/3 dosages, offers expanded eligibility (0-2 ECOG PS; no age limit)). Each step reverse resistance (RR) to CT; drug synergism 4-6 simultaneous pairs) improve responses (Rs) and survival (S) (Bruckner ASCO 05, 08, 11, AntiCancer Res 2016; 36 (1), 2018; 38 (1) (ACR), and the immune system (Correale P: J. Immunother 2014; 37). M Caraglia: Front Oncol. 2019). Methods: Eligibility: intent to treat active metastatic PANC, no prior CT: any age: PS 0-2 and expected > 6 weeks S. IRB required safety < 1/10 severe events. ALGO in mg/m2: G 500, F 12-1500 over 24 hrs, L 180, I 80, day2 O (GFLIO) q2 wks, and on progression added in sequence, day 2, docetaxel 20-25 and good counts only mitomycin C 3-6 then bevacizumab 10mg/kg with prior monitoring and modifications (ACR). Median 12, 18, 24 mos Overall Survival (OS), Kaplan Meier estimates with 95...
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RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. To evaluate the safety,... more
RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject w...
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Research Interests: Enzyme Inhibitors, Humans, Female, Male, Thrombocytopenia, and 6 moreAged, Middle Aged, Neoplasms, Camptothecin, neutropenia, and leukopenia
Background/Aim To evaluate DX-8951f by population pharmacokinetics (PPK).Methods: Plasma and urine data were simultaneously modeled using PPK analyses (IT2S® and NONMEM®).Design: Six non-comparative dose-escalation studies were... more
Background/Aim To evaluate DX-8951f by population pharmacokinetics (PPK).Methods: Plasma and urine data were simultaneously modeled using PPK analyses (IT2S® and NONMEM®).Design: Six non-comparative dose-escalation studies were included.Setting: Patients were treated at hospitals.Participants: 153Intervention: Dosing regimens varied from 30-minute infusions to 21-day continuous infusions at varying frequencies. Initial doses ranged from 0.05 to 4mg/m2.Results: A linear 2-compartment PK model best described