scholarly journals Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study

2020 ◽  
Author(s):  
Toshihiro Kudo ◽  
Yoshiyuki Murai ◽  
Yoshitsugu Kojima ◽  
Kenji Uehara ◽  
Taroh Satoh
Keyword(s):  
Body Weight ◽  
Ascitic Fluid ◽  
Dose Escalation ◽  
Urine Volume ◽  
Fluid Volume ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Dose Escalation Study ◽  
The Mean

Abstract Objective This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. Methods In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5–7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. Results The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: −2304.3 ml, minimum: −27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). Conclusions Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75–30 mg/day.

scholarly journals Open-Label, Dose Escalation Study of the Safety and Pharmacokinetic Profile of Tefibazumab in Healthy Volunteers

2005 ◽  
Vol 49 (3) ◽  
pp. 959-962 ◽  
Author(s):  
Sandra Reilley ◽  
Eric Wenzel ◽  
Laurie Reynolds ◽  
Beth Bennett ◽  
Joseph M. Patti ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Dose Escalation ◽  
Maximum Concentration ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Open Label ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Label Dose ◽  
The Mean

ABSTRACT Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (C max) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (T max) was 1.0 h for each dose. The mean elimination half-life (t 1/2) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.

A phase Ib/II, open-label, dose escalation study to evaluate the safety, pharmacokinetics, and efficacy of SM88 in patients with prostate cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2615-TPS2615 ◽  
Author(s):  
Giuseppe Del Priore ◽  
Steve Hoffman ◽  
Daniel W. Nixon
Keyword(s):  
Prostate Cancer ◽  
Dose Escalation ◽  
Androgen Deprivation ◽  
Phase 2 ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Patient Reported

TPS2615 Background: Non-hormonal treatments for biochemically recurrent non-metastatic prostate cancer (nmPC) are limited. SM88 is a novel combination of proprietary tyrosine isomer (TI) and other repurposed agents (CYP3a4 inducer, mTOR inhibitor and catalyst) designed to selectively increase metabolic oxidative stress in cancer cells. Early data reported SM88 activity in solid tumors without significant toxicity (Hoffman et al J Clin Oncol 2013; e22095, Hoffman et al Ann Onc 2016: vi551). Methods: This is an open-label multi-center, dose escalating, dose expansion study in nmPC who have failed or refused androgen deprivation. The study includes a dose escalation phase Ib and dose expansion phase 2. The primary objectives are to determine the effect of SM88 on circulating tumor cells (CTC), and progression-free survival. Secondary objectives are: LDH, bone-specific alkaline phosphatase, urinary N-telopeptide, neutrophyll/llymphocyte ratio, cutaneous hyper-pigmentation correlation, PSA doubling times, safety, and patient reported outcomes. As of Jan ‘17, Phase 1b cohorts 1 and 2, with TI and component PK evaluations, have completed enrollment with adequate numbers to establish the Phase 2 dose without DLT. Phase 2 has begun, with 33 patients planned for at least 6 cycles (@28d) to reach the desired power. This would be followed by a pivotal Phase 3 study in the same group of patients. We propose to conduct a pivotal randomized phase 3 of SM88 in rising PSA, nmPC versus patient’s and clinician’s choice, limited to 2 options i.e. observation or ADT therapy. Inclusion would include doubling time < 9 months, elevated CTCs and recurrent disease after localized curative intent therapy (the same population as our completed Phase I and ongoing phase II). Outcomes will include delay of radiographic PFS, and delay of time to subsequent toxic therapy i.e. cytotoxic systemic chemo and/or radiation therapy. We proposed this pivotal trial will lead to a successful NDA for an indication in this population of patients. Rapid accrual is expected at several institutions because of the urgent need for less toxic alternatives to androgen deprivation therapy.

scholarly journals 502 Recommended phase 2 dose, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the IL-15 superagonist SO-C101 as monotherapy in patients with advanced/metastatic solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A534-A534
Author(s):  
Aurelien Marabelle ◽  
Stéphane Champiat ◽  
Vladimir Galvao ◽  
Aung Naing ◽  
Filip Janku ◽  
...  
Keyword(s):  
Partial Response ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Stable Disease ◽  
Cell Activation ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study

BackgroundSO-C101 is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 was investigated in a multicenter, open-label, dose escalation study as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic tumors (NCT04234113).MethodsThe SO-C101 monotherapy part of the study followed a classical 3+3 dose escalation design. Study objectives were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D).The evaluation period for dose-limiting toxicities in each dose step was 21 days. The RP2D was defined as MTD or below, also considering pharmacokinetic and pharmacodynamic parameters.The study is ongoing (data cut-off 21 June 2021).ResultsThirty patients with a median of 3 (range 1–9) lines of previous systemic therapies were treated at doses 0.25, 0.75, 1.5, 3.0, 6.0., 9.0, 12.0, and 15 µg/kg. At 15 µg/kg, 2 of 3 patients had a dose-limiting toxicity (hyperbilirubinaemia grade [G] 4 and transaminase increase G3). The MTD was reached at 12 µg/kg. This dose was determined as the RP2D, supported by a dose-dependent increase in NK- and CD8+ T cell activation, the latter reaching a plateau at 12 µg/kg. SO-C101 plasma concentration increased dose-proportionally (Tmax was 5.5 hours and T1/2 was 4 hours).The most common adverse events (AEs) were G1 or G2 lymphopenia, local injection site reactions, transaminase increase, flu-like syndrome, and CRS-related symptoms such as fever and chills. Study drug-related AEs >G2 that occurred more than once were lymphopenia and transaminase increase. No treatment-related death was reported.One patient with cutaneous squamous cell carcinoma, who had previously progressed on cemiplimab, showed a partial response at 6.0 µg/kg (duration >4 months, target lesion decrease of 58%). After progression, the patient was put on combination treatment (SO-C101 and pembrolizumab) and again achieved a significant partial response. Two other patients treated with doses below the RP2D had confirmed stable disease for 6 and 15 weeks.At the RP2D, one patient out of 6 discontinued due to progression, while 5 are stable and receiving treatment (range 4–11 weeks).ConclusionsThe RP2D was defined at 12 µg/kg. SO-C101 administration induced a strong activation of peripheral NK and CD8+ T cells reproducible after each dosing. Related AEs were manageable and resolved quickly. Preliminary clinical efficacy signals including stable disease and partial response were observed in this heavily pretreated patient population. SO-C101 monotherapy has the potential to provide additional clinical benefit to patients with solid tumors.Trial RegistrationNCT04234113Ethics ApprovalThis study was approved by the FDA (IND 140011) and by the Ethics Boards of participating institutions.

scholarly journals Efficacy and safety of oral tolvaptan in patients undergoing hemodialysis: a Phase 2, double-blind, randomized, placebo-controlled trial

2020 ◽  
Author(s):  
Hiroaki Ogata ◽  
Naoko Shimofurutani ◽  
Tadashi Okada ◽  
Hisashi Nagamoto ◽  
Tadao Akizawa
Keyword(s):  
Placebo Group ◽  
Confidence Interval ◽  
Urine Volume ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Fluid Removal ◽  
Interdialytic Weight Gain ◽  
The Mean ◽  
Total Fluid

Abstract Background Loop diuretics are used to manage fluid retention in patients with end-stage kidney disease undergoing hemodialysis (HD). This randomized, double-blind, placebo-controlled, Phase 2 trial evaluated the efficacy and safety of tolvaptan, a vasopressin V2 receptor antagonist, in Japanese HD patients. Methods A total of 124 patients (24-h urine volume ≥500 mL) on thrice-weekly HD were randomized to receive oral tolvaptan 15 mg/day (n = 40), tolvaptan 30 mg/day (n = 40) or placebo (n = 44) for 24 weeks. Efficacy endpoints were change from baseline in 24-h urine volume, total fluid removal by HD per week and interdialytic weight gain (IDWG). Safety was assessed via the incidence of treatment-emergent adverse events (TEAEs). Results At treatment end, the difference (95% confidence interval) from the placebo group in the mean change from baseline in 24-h urine volume was significant in the tolvaptan 15 mg {429.1 mL [95% confidence interval (CI) 231.0, 627.2]; P &lt; 0.0001} and 30 mg [371.6 mL (95% CI 144.1, 599.2); P = 0.0017] groups. The mean changes from baseline in total fluid removal by HD and IDWG were not significantly different in the tolvaptan groups versus the placebo group. Although the proportion of patients with TEAEs was lower in the placebo group (77.3%) than in the tolvaptan groups (92.3%), tolvaptan was safe and well-tolerated during the study period. Conclusions Tolvaptan significantly sustained diuretic action for 24 weeks in HD patients but did not reduce total fluid removal by HD per week and IDWG to the same extent.

MDV3100-08: A phase I open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS668-TPS668
Author(s):  
Anthony D. Elias ◽  
Jennifer K. Richer ◽  
Patricia LoRusso ◽  
Amy C. Peterson ◽  
Joyce Leta Steinberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dose Escalation ◽  
Nuclear Translocation ◽  
Phase 1 ◽  
Vital Signs ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Er Positive ◽  
Overall Survival Benefit

TPS668 Background: MDV3100 is a novel, orally administered small molecule that directly binds the androgen receptor (AR) to potently inhibit AR-mediated signaling via three mechanisms: inhibition of androgen binding to AR; inhibition of AR nuclear translocation; and inhibition of nuclear AR association with DNA. MDV3100 is not known to agonize AR signaling, can be taken without prednisone, and demonstrated an overall survival benefit in post-docetaxel prostate cancer at 160 mg/day. AR expression is observed in ~70% of all breast cancer (BCa) regardless of histologic subtypes (estrogen receptor [ER] positive, HER2+, and triple negative [TN] disease). MDV3100 has demonstrated preclinical activity in AR+/TN and AR+/ ER+ BCa and could be a potential therapeutic strategy in patients with AR+ BCa. Methods: This Phase 1 study has 2 stages: a standard 3+3 dose-escalation stage (S1), evaluating safety, tolerability, and pharmacokinetics (PK) of MDV3100, starting at 80 mg MDV3100; and a dose-expansion stage (S2), evaluating the recommended Phase 2 dose in ~15 women with AR+ BCa. All patients must have received ≥2 chemotherapy-containing regimens for their incurable BCa, or ≥3 anti-HER2 containing regimens for their incurable HER2+ BCa to be eligible; ER+ patients must be post-menopausal. In S1, patients will receive their assigned dose of MDV3100 on Day 1, and PK samples will be collected through Day 8. Daily dosing will begin on Day 8 and will continue until predefined discontinuation criterion is met. Dose-limiting toxicities will be recorded through Day 35 and used to determine the Phase 2 dose. Extensive PK sampling is performed on Days 1 and 50 with predose PK samples collected throughout. In S2, patients with AR+ BCa (defined as 10% or more tumor cells with nuclear AR expression) will take daily MDV3100 at the recommended Phase 2 dose; there is no single dose PK period. Tumor tissue submission is mandatory in S2. Safety and tolerability will be documented by frequent assessments of adverse events, vital signs, and laboratory assessments. Tumor assessments occur at 2 months then approximately every 3 months thereafter. Enrollment of 27 subjects is anticipated.

Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study

The Lancet ◽  
2016 ◽  
Vol 388 (10063) ◽  
pp. 3017-3026 ◽  
Author(s):  
Richard S Finkel ◽  
Claudia A Chiriboga ◽  
Jiri Vajsar ◽  
John W Day ◽  
Jacqueline Montes ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Dose Escalation ◽  
Muscular Atrophy ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose
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