scholarly journals Phase I, open-label study of pasireotide in patients with BRAF-wild type and NRAS-wild type, unresectable and/or metastatic melanoma

ESMO Open ◽  
2018 ◽  
Vol 3 (5) ◽  
pp. e000388 ◽  
Author(s):  
Reinhard Dummer ◽  
Olivier Michielin ◽  
Mirjam Chantal Nägeli ◽  
Simone M. Goldinger ◽  
Federico Campigotto ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Antitumour Activity ◽  
Study Drug ◽  
High Dose ◽  
Wild Type ◽  
Open Label ◽  
High Dose Level ◽  
Long Acting

IntroductionSomatostatin analogues exert antitumour activity via direct and indirect mechanisms. The present study was designed to assess the safety and efficacy of pasireotide in patients with BRAF-wild type (WT) and NRAS-WT metastatic melanoma.Patients and methodsPatients with unresectable and/or metastatic melanoma or Merkel cell carcinoma were eligible. Pasireotide was administered at different doses for ≤8 weeks in dose-escalation phase, followed by long-acting pasireotide 80 mg or lower dose in case of toxicity in follow-up phase up to six additional months. Primary endpoint was safety in the first 8 weeks of dose-escalation phase.ResultsThe study was terminated early due to slow recruitment. Of the 10 patients with metastatic melanoma enrolled, only four reached the high dose level: two patients reached 3600 µg in dose-escalation and follow-up phases and two patients reached 3600 µg in dose-escalation and long-acting pasireotide 80 mg in follow-up phases and were stable for >5 months. Most common adverse events (AEs) during dose-escalation phase in ≥2 patients (20%) were: diarrhoea (50%), nausea (50%), fatigue (20%), hyperglycaemia (20%), hypophosphatemia (20%), chills (20%) and tumour pain (20%). Grade 3 or 4 study drug-related AEs were diarrhoea and nausea, reported in one patient. Partial response was documented in one patient and stable disease in another.ConclusionsPasireotide was well tolerated, and safety results were similar to those previously reported in other indications. Further studies are needed to evaluate its antitumour activity alone and in combination with other drugs in melanoma.

Phase I trial of IL-2 plasmid DNA with electroporation in metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8578-8578 ◽  
Author(s):  
J. M. Richards ◽  
R. Gonzalez ◽  
P. Schwarzenberger ◽  
E. Whitman ◽  
K. Stardal ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Dose Escalation ◽  
Plasmid Dna ◽  
San Diego ◽  
Interleukin 2 ◽  
Study Drug ◽  
High Dose ◽  
Grade 3 ◽  
Observation Period

8578 Background: Significant toxicity limits the systemic delivery of high-dose recombinant Interleukin-2 (IL-2). An alternative method for extended dosing of IL-2 that may reduce toxicity is by intratumoral injection of IL-2 plasmid DNA (pDNA) with electroporation (EP). Methods: A phase I dose-escalation trial is ongoing in subjects with metastatic melanoma to evaluate the safety of intratumoral delivery of IL-2 pDNA (VCL-IM01, Vical Inc., San Diego, CA) followed by EP (MedPulser DNA EPT System, Inovio, San Diego, CA). Eligible subjects have recurrent metastatic melanoma; an injectable lesion = 1 cm2 and < 25 cm2; ECOG 0 or 1; LDH = 1.5 × ULN, and no brain or liver metastases. In the dose-escalation stage of the trial, 3 subjects in each dose cohort received up to 2 cycles of treatment, each consisting of 4 weekly injections followed by a 4-week observation period. Dose levels included 0.5, 1.5, 5.0 mg/tumor, and 15.0 mg (5 mg in each of 3 tumors). A safety assessment was conducted for each cohort prior to enrollment of the next cohort. In the 2nd trial stage, 17 subjects are to be enrolled at the maximum tolerated dose (MTD). The observation period is shortened to 2 weeks between cycles. For all subjects, safety is assessed at every visit. Results: 12 subjects (7 male, 5 female) were enrolled in the dose escalation stage, 3 subjects at each dose. Ages range from 38 to 86 years. No Grade 3 or 4 adverse events (AEs) were reported related to study drug or procedures. All related AEs (12 reported) were Grade 1: 5 related to study drug, 4 to the EP procedure, and 3 to both. Injection site pain was the most common AE. No dose-limiting toxicities occurred; thus the MTD was defined as the 15 mg dose (5 mg/tumor in 3 tumors). To date, 6/17 subjects in Stage 2 of the trial (5 mg/tumor, up to 3 tumors injected) have been enrolled with no Grade 3 or 4 AEs related to study drug or injection/EP procedures. Physicians have observed responses in treated and untreated lesions. Overall response data will be presented. Conclusions: Intratumoral administration of IL-2 pDNA with EP appears safe and well tolerated in 18 patients with metastatic melanoma when given up to a 15 mg dose (5 mg/tumor). Preliminary indications of decreased tumor size suggest local and systemic activity of IL-2 pDNA with EP. No significant financial relationships to disclose.

scholarly journals Phase 1, Open-Label, Dose Escalation Study of I-131-CLR1404 in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4485-4485
Author(s):  
Sikander Ailawadhi ◽  
Patrick J. Stiff ◽  
Michele Maharaj ◽  
Katherine Oliver ◽  
Natalie Scott Callander
Keyword(s):  
Radiation Therapy ◽  
Adverse Events ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase 1 ◽  
Study Drug ◽  
External Beam Radiation ◽  
Open Label ◽  
Label Dose

Abstract Background: I-131-CLR1404 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the exquisite radiosensitivity of MM, I-131-CLR1404 is being examined in RRMM in an open-label, dose escalation Phase 1 trial (NCT02278315) evaluating up to 5 cohorts and a maximum of 37.5 mCi/m2. Methods: The primary objective is to determine safety and tolerability of I-131-CLR1404 with and without dexamethasone (dex) in RRMM. Secondary objectives are to determine the recommended Phase 2 dose (RP2D) and therapeutic activity in RRMM. Eligibility criteria include progressive, relapsed/refractory MM, and at least one previous exposure to proteasome inhibitor (PI) and immunomodulatory (IMiD) drugs. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (≤ 20% of total marrow irradiated). There is no limit to the number of prior therapies. I-131-CLR1404 is administered intravenously as a single 30 minute infusion on day 1 with 40 mg dex orally weekly for 12 weeks. Dose-escalation uses a minimally modified, standard 3+3 schema with dose-limiting toxicities (DLTs) assessed through day 85 post-infusion. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the International Myeloma Working Group Uniform Response Criteria. Results: Ten patients have been enrolled in the study with data presented as of 30 Jun 2016 for 8 patients. Accrual is ongoing in the additional cohorts. Five patients were enrolled to cohort 1 (12.5 mCi/m2 + dex); 4 were evaluable and 1 patient was taken off study for rapid disease progression. Five patients have been enrolled to cohort 2 (18.75 mCi/m2 + dex), with data presented on 3 enrolled prior to data cutoff. The median age was 68.5 (range 55-85) and included 5 males and 3 females. All patients were standard risk (karyotyping) and median bone marrow plasma cell involvement was 25% (range 4-50%). Median number of prior therapies was 4 (range 2-12) (Table 1). Four of 8 patients previously underwent ASCT and 25% were previously treated with radiation therapy. Hematologic AEs (grade 3+) and non-hematologic AEs (grade 2+) potentially related to study drug are shown in Table 1. No difference in the toxicity profile was noted for patients with previous radiation therapy. Two serious adverse events (SAEs) have been reported, both in patients treated with 18.75 mCi/m2 I-131-CLR1404. One patient was hospitalized for a seizure (Day 62), assessed as unrelated to study drug and another patient was hospitalized for a grade 1 upper GI bleed in the setting of grade 4 thrombocytopenia (Day 23). This is believed to be the result of rapidly progressive disease, however relationship to I-131-CLR1404 could not be ruled out. Stable disease was achieved in 100% of evaluable patients (n=7). One subject in cohort 1 demonstrated a > 30% reduction in serum m-protein. Figure 1 provides a summary of percent change in serum free light chain assay (FLC) from baseline. Three patients had a reduction in FLC > 50%, 2 in cohort 1 and 1, to date, in cohort 2. Three patients had a stable FLC response through at least 22 days following treatment and 1 subject was unresponsive with regard to FLC. Median follow-up is 6.8 months (range 1.2-14.2). Patients did not receive subsequent systemic therapy for a median of 3.5 months (range 0.6-4.7). Furthermore, 1 subject in cohort 2 maintains stable disease and has not initiated subsequent treatment. Median progression free survival (PFS) is 3 months and included 4 patients with stable disease at the end of the 85 day study follow-up. In patients with progression after I-131-CLR1404, treatment included daratumumab (n=4), ASCT (n=1), and bortezomib, lenalidomide, and dex (VRD) (n=1). Conclusions: I-131-CLR1404 represents a unique, first in class targeted radiotherapeutic for MM. Preliminary data from this trial show an acceptable and expected safety profile with an efficacy signal in the initial 2 of a potential 5 cohorts. All evaluable patients, despite extensive previous therapy and refractoriness to new therapies, achieved disease stabilization. The study is ongoing to determine the RP2D and long term efficacy. Disclosures Ailawadhi: Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Oliver:Cellectar Biosciences: Employment.

Phase II Study of Temozolomide Plus Thalidomide for the Treatment of Metastatic Melanoma

2003 ◽  
Vol 21 (17) ◽  
pp. 3351-3356 ◽  
Author(s):  
Wen-Jen Hwu ◽  
Susan E. Krown ◽  
Jennifer H. Menell ◽  
Katherine S. Panageas ◽  
Janene Merrell ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase Ii Study ◽  
Stage Iv ◽  
Complete Response ◽  
Open Label ◽  
Open Label Phase ◽  
Metastatic Sites

Purpose: To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases. Patients and Methods: Patients with histologically confirmed advanced-stage metastatic melanoma were enrolled in an open-label, phase II study. The primary end point was response rate. Patients received temozolomide (75 mg/m2/d × 6 weeks with a 2-week rest between cycles) plus concomitant thalidomide (200 mg/d with dose escalation to 400 mg/d for patients < 70 years old, or 100 mg/d with dose escalation to 250 mg/d for patients ≥ 70 years old). Treatment was continued until unacceptable toxicity or disease progression occurred. Results: Thirty-eight patients (median age, 62 years) with stage IV (three patients with M1a, eight with M1b, and 26 with M1c) or stage IIIc (one patient) melanoma and a median of four metastatic sites were enrolled, and received a median of two cycles of therapy. Twelve patients (32%) had an objective tumor response, including one with an ongoing complete response of 25+ months’ duration and 11 with partial responses. Five patients achieving partial response with a more than 90% reduction of disease were converted to a complete response with surgery. Treatment was generally well tolerated. Median survival was 9.5 months (95% confidence interval, 6.05 to 19.38 months), with a median follow-up among survivors of 24.3 months. Conclusion: The combination of temozolomide plus thalidomide seems to be a promising and well-tolerated oral regimen for metastatic melanoma that merits further study.

scholarly journals Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study

The Lancet ◽  
2014 ◽  
Vol 384 (9942) ◽  
pp. 504-513 ◽  
Author(s):  
Vincenzo Libri ◽  
Cihangir Yandim ◽  
Stavros Athanasopoulos ◽  
Naomi Loyse ◽  
Theona Natisvili ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
High Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Neurological Effects

scholarly journals Impact of paliperidone palmitate one-month formulation on relapse prevention in patients with schizophrenia: A post-hoc analysis of a one-year, open-label study stratified by medication adherence

2018 ◽  
Vol 32 (6) ◽  
pp. 691-701 ◽  
Author(s):  
Tianmei Si ◽  
Nan Li ◽  
Huafei Lu ◽  
Shangli Cai ◽  
Jianmin Zhuo ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Hazard Ratio ◽  
Paliperidone Palmitate ◽  
Open Label ◽  
First Relapse ◽  
Continued Use ◽  
One Year ◽  
Long Acting ◽  
Post Hoc

Background: Limited data are available to help identify patients with schizophrenia who are most likely to benefit from long-acting injectable antipsychotics. Aim: To investigate the efficacy of long-acting injectable antipsychotic paliperidone palmitate one-month formulation for preventing relapses, factors influencing time to first relapse, and the effect of different antipsychotic adherence levels on time to first relapse in Chinese patients with schizophrenia. Methods: This was a post-hoc analysis from an open-label, single-arm study of stable patients (Positive and Negative Syndrome Scale total score <70; n=367) receiving paliperidone palmitate one-month formulation at the end of an acute 13-week treatment phase, who entered a naturalistic one-year follow-up period, either continuing with flexibly dosed paliperidone palmitate one-month formulation (75–150 mg eq.) or switching to another antipsychotic(s). Results: There were 362/367 patients (age=31.4±10.75 years) included in the analysis of time to first relapse (primary outcome) and 327/362 patients (39/327, poor antipsychotic adherence (<80%)) willing to receive antipsychotics were included in the exposure/adherence analysis. Overall, 84.6% (95% confidence interval=79.2–88.7) patients remained relapse-free. Poor adherence during follow-up (hazard ratio=2.97, 95% confidence interval=1.48–5.98, p=0.002) and frequent hospitalizations in the previous year (hazard ratio=1.29, 95% confidence interval=1.02–1.62, p=0.03) were associated with a significant risk of shorter time to first relapse in the univariate analysis. In patients with poor adherence, ‘no use’ (hazard ratio=13.13, 95% confidence interval=1.33–129.96, p=0.03) and ‘interrupted use’ (hazard ratio=11.04, 95% confidence interval=1.03–118.60, p=0.047) of paliperidone palmitate one-month formulation (vs continued use) showed a significantly higher risk of relapse; this was not observed in patients with good (≥80%) antipsychotic adherence. No new safety concerns were identified. Conclusion: Continued use of paliperidone palmitate one-month formulation/long-acting injectable antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence.

Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4112-4112
Author(s):  
Jonathan R. Strosberg ◽  
Martyn E Caplin ◽  
Pamela L. Kunz ◽  
Philippe B Ruszniewski ◽  
Lisa Bodei ◽  
...  
Keyword(s):  
Overall Survival ◽  
Neuroendocrine Tumors ◽  
High Dose ◽  
Radioligand Therapy ◽  
Phase 3 ◽  
Long Term Follow Up ◽  
Long Acting ◽  
Safety Signals

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

scholarly journals DOP60 Vedolizumab treatment persistence and safety in an extended access program (XAP)

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S099-S100
Author(s):  
S Danese ◽  
K Subramanian ◽  
J Van Zyl ◽  
S Adsul ◽  
D Lindner ◽  
...  
Keyword(s):  
Data Analysis ◽  
Adverse Events ◽  
Dose Escalation ◽  
Open Label ◽  
Dose Escalation Study ◽  
Extended Access ◽  
Dosing Frequency ◽  
Access Program

Abstract Background Vedolizumab, a gut-selective, α 4β 7 integrin antagonist, has been established as an effective and safe treatment for patients with UC or CD in the GEMINI phase 3 program and long-term safety (LTS) study. An extended access program (XAP) was initiated to provide continued access to patients who were benefiting from vedolizumab in GEMINI LTS and to monitor safety. We now report persistence and safety results from a 2-year data analysis. Methods Vedolizumab XAP (NCT02743806) is a phase 3b/4 prospective, open-label, multinational interventional study. A rollover from GEMINI LTS (NCT00790933) to the XAP, patients reduced dosing frequency from vedolizumab 300 mg IV every 4 weeks (Q4W) to every 8 weeks (Q8W) or remained on vedolizumab 300 mg IV Q4W if medically indicated. This 2-year data analysis assessed persistence on Q8W dosing after dosing frequency reduction, need for escalation to Q4W dosing, incidence of relapse (defined as dose escalation, study withdrawal due to adverse event, loss of adequate benefit from vedolizumab, or increased corticosteroid [CS] or immunomodulator dose), and safety 2 years after rollover from GEMINI LTS. Results A total of 311 patients (142 UC, 169 CD) from GEMINI LTS enrolled in the XAP. Median (range) duration of exposure to vedolizumab prior to the XAP was 8.0 years (5.2–10.0) for patients with UC and 7.5 years (5.4–9.9) for patients with CD. Of patients with UC and CD, 93.0% and 84.6%, respectively, reduced dosing frequency to Q8W at XAP start, and 87.3% and 77.5%, respectively, remained on Q8W after 2 years. At baseline, 93.0% of all patients with UC and 88.2% of all patients with CD were in CS-free remission; patients who maintained Q4W dosing at baseline had lower CS-free remission rates (62.5% in UC and 69.2% in CD). Of patients who initiated Q8W dosing at enrolment in the XAP, 95% had no relapse for ≥6 months (97.0% UC, 93.7% CD; Table 1). Only 7.3% of patients required dose escalation to Q4W, and 11.6% experienced relapse during the 2-year follow-up. Times to dose escalation and relapse were similar in patients with UC and CD (Figures 1 and 2). At 2 years, 4 of 8 patients with UC and 4 of 12 patients with CD who required dose escalation to Q4W discontinued vedolizumab early due to loss of benefit or adverse events. Adverse events related to vedolizumab were infrequent; no new or serious events attributed to vedolizumab were reported. Conclusion High patient persistence on Q8W vedolizumab was observed in the first 2 years after reduction of dosing frequency in the XAP. Overall, there were low rates of Q4W dose escalation and CD or UC disease relapse. The safety profile was consistent with previous reports with no new signals observed.

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