Tasisulam-sodium in combination with liposomal doxorubicin in patients with ovarian cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5551-5551
Author(s):  
D. Scott McMeekin ◽  
Lee S. Rosen ◽  
Alberto Bessudo ◽  
Datchen Fritz Tai ◽  
Robert L. Ilaria ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Therapeutic Range ◽  
Dose Escalation ◽  
Liposomal Doxorubicin ◽  
Complete Response ◽  
Dose Finding ◽  
Finding Study ◽  
Early Closure ◽  
Grade 3

5551 Background: Tasisulam-sodium (TASI) is a novel, highly albumin-bound small molecule that induces tumor cell apoptosis and has antiangiogenic activity. This phase 1b study was designed as a dose-finding study for TASI in combination with liposomal doxorubicin (DX) in patients (pts) with advanced solid tumors, followed by a dose-confirmation phase in platinum-resistant DX-naïve ovarian cancer (OvCa) pts. However, the study was stopped early for business reasons. Nonetheless, the dataset allowed partial characterization of the safety and antitumor activity of TASI + DX among OvCa pts who achieved an albumin-corrected exposure (AUCalb) within a hypothesized therapeutic range identified in phase II monotherapy trials. Methods: In the dose-escalation phase (3+3 schema), pts received TASI (escalating Cmax targets of 300-380 μg/mL, 2-h IV) plus DX (40 mg/m2, 1-h IV) every 28 days. Pharmacokinetic and safety analyses identified an AUCalb target of 3500 h*μg/mL for the dose-confirmation phase. We analyzed data for OvCa pts from both phases who achieved TASI AUCalbof 1200-6400 h*μg/mL in cycle 1. Results: Of the 13 OvCa pts who completed the dose-escalation phase and 6 OvCa pts who completed the dose-confirmation phase, 10 had AUCalbof 1200-6400 h*μg/mL in cycle 1. For these pts, the most common possibly drug-related Grade 3-4 adverse event was neutropenia (see table). Although no pt achieved complete response, 2 pts achieved partial response. Data from the other OvCa pts will also be presented. Conclusions: The early closure of the study did not allow complete assessment of TASI in combination with DX; however, acceptable tolerability and some antitumor activity were observed for OvCa pts with TASI AUCalbwithin the hypothesized therapeutic range. Clinical trial information: NCT01214668. [Table: see text]

Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation.

1997 ◽  
Vol 15 (3) ◽  
pp. 987-993 ◽  
Author(s):  
F M Muggia ◽  
J D Hainsworth ◽  
S Jeffers ◽  
P Miller ◽  
S Groshen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase Ii ◽  
Liposomal Doxorubicin ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Complete Response ◽  
Computed Tomographic ◽  
Free Doxorubicin ◽  
Grade 3 ◽  
Dose Modifications

PURPOSE A phase II study of liposomal doxorubicin was conducted in patients with ovarian cancer who failed to respond to platinum- and paclitaxel-based regimens. Liposomal doxorubicin was selected as a result of its superior activity against ovarian cancer xenografts relative to free doxorubicin and activity in refractory ovarian cancer patients that was noted during the phase I study. PATIENTS AND METHODS Thirty-five consecutive patients were accrued in two institutions (22 in one and 13 in the other). All had progressive disease after either cisplatin or carboplatin and paclitaxel, or at least one platinum-based and one paclitaxel-based regimen. Patients received intravenous (I.V.) liposomal doxorubicin 50 mg/m2 every 3 weeks with a dose reduction to 40 mg/m2 in the event of grade 3 or 4 toxicities, or a lengthening of the interval to 4 weeks (and occasionally to 5 weeks) with persistence of grade 1 or 2 toxicities beyond 3 weeks. RESULTS Nine clinical responses (one complete response [CR], eight partial responses [PRs]) were observed in 35 patients (25.7%), with seven of these having been confirmed by two consecutive computed tomographic (CT) measurements. The median progression-free survival was 5.7 months with an overall survival of 1.5 to 24+ months (median, 11 months). Although 13 patients experienced grade 3 or 4 nonhematologic skin and mucosal toxicities (either hand-foot syndrome or stomatitis), with dose modifications, the treatment was very well tolerated. Nausea that was clearly attributable to the drug, hair loss, extravasation necrosis, or decreases in ejection fraction did not occur. CONCLUSION Liposomal doxorubicin has substantial activity against ovarian cancer refractory to platinum and paclitaxel. The responses achieved with liposomal doxorubicin were durable and maintained with minimal toxicity. This liposomal formulation should be evaluated further in combination with other drugs in less refractory patients.

Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer

2020 ◽  
Vol 16 (1) ◽  
pp. 4289-4301 ◽  
Author(s):  
Jeffrey W Clark ◽  
D Ross Camidge ◽  
Eunice L Kwak ◽  
Robert G Maki ◽  
Geoffrey I Shapiro ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Daily Maximum ◽  
Human Dose ◽  
Solid Malignancies ◽  
Finding Study ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Favorable Safety

Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily–300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195

Safety and Antitumor Activity of Anti–PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer

2015 ◽  
Vol 33 (34) ◽  
pp. 4015-4022 ◽  
Author(s):  
Junzo Hamanishi ◽  
Masaki Mandai ◽  
Takafumi Ikeda ◽  
Manabu Minami ◽  
Atsushi Kawaguchi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Adverse Events ◽  
Survival Time ◽  
Large Scale ◽  
Progression Free Survival ◽  
Complete Response ◽  
Overall Response ◽  
Platinum Resistant ◽  
Grade 3

Purpose Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti–PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. Patients and Methods Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. Results Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. Conclusion This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).

scholarly journals A phase I study of combined trabectedin and pegylated liposomal doxorubicin therapy for advanced relapsed ovarian cancer

2021 ◽  
Author(s):  
Shunji Takahashi ◽  
Munetaka Takekuma ◽  
Kenji Tamura ◽  
Kazuhiro Takehara ◽  
Hiroyuki Nomura ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Liposomal Doxorubicin ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Japanese Patients ◽  
Pharmacokinetic Analysis ◽  
Dependent Manner ◽  
Drug Concentrations ◽  
Grade 3

Abstract Background Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited. Methods This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m2 immediately after PLD 30 mg/m2; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1. Results Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m2. Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%. Conclusions Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m2 once every 21 days. Clinical trial registration number: JapicCTI-163164

Pegylated liposomal doxorubicin re-challenge in patients with ovarian cancer relapse: a multicenter retrospective study

2019 ◽  
Vol 29 (1) ◽  
pp. 153-157 ◽  
Author(s):  
Elisa Tripodi ◽  
Gennaro Cormio ◽  
Ugo De Giorgi ◽  
Giorgio Valabrega ◽  
Daniela Rubino ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Liposomal Doxorubicin ◽  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Complete Response ◽  
Recurrent Ovarian Cancer ◽  
Hematological Toxicity ◽  
Cancer Relapse ◽  
Platinum Agent

BackgroundPegylated liposomal doxorubicin (PLD) is an active and well-tolerable treatment in ovarian cancer relapse, either alone or in combination with other drugs. No data are available on the possibility to rechallenge PLD treatment in long survivor patients with recurrent ovarian cancer, as evaluated for platinum agent, paclitaxel and gemcitabine. The aim of the present study was to evaluate the anti-tumor activity and the toxicity profile of re-challenge of PLD in recurrent ovarian cancer patients.MethodsData on 27 patients with epithelial ovarian cancer treated in the last ten years (2007-2017) with palliative PLD rechallenge were included in this multicenter retrospective Italian study.ResultsThe objective response rate to PLD re-treatment were complete response in 19%, partial response in 30% and stable disease in 37%. Only 1 case of G4 hematological toxicity was reported. No patient experienced severe cardiac impairment (G2-4).ConclusionPLD rechallenge represents an active and safe possibility of treatment for long survivor ovarian cancer patients.

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

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