scholarly journals Safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study

2020 ◽  
Author(s):  
Nadine Ezard ◽  
Brendan Clifford ◽  
Adrian Dunlop ◽  
Raimondo Bruno ◽  
Andrew Carr ◽  
...  
Keyword(s):  
Risk Behaviour ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Duration Of Action ◽  
Treatment Services ◽  
Drug Tolerability ◽  
Methamphetamine Dependence ◽  
Global Health Issue ◽  
Clinical Trials Registry

Abstract Background: Methamphetamine (MA) dependence is a growing global health issue with no effective pharmacotherapy. Lisdexamfetamine (LDX) is approved for use in the treatment of attention-deficit/hyperactivity disorder (ADHD) and binge eating disorder (BED) in doses ranging from 30 to 70mg/day. LDX has a longer duration of action and lower abuse potential than other amphetamines, and presents a promising candidate for agonist-type treatment of MA dependence. People seeking treatment for MA dependence may require doses of LDX higher than used in ADHD and BED. We examined the safety of LDX at 250mg/day among adults with MA dependence, approximately equivalent to previously trialled doses of dexamphetamine. Methods: We conducted a dose-escalating, phase-2, open label, single-group study of oral LDX at two Australian drug treatment services. Eligible participants were MA dependent adults who reported use of MA on at least 14 of the preceding 28 days. Once daily, supervised LDX doses of 100 to 250mg/day were provided as a single-blinded, ascending-descending dose regimen over 8 weeks. The primary outcomes were safety, drug tolerability, and regimen completion at the end of Week 4 (maximum dose). Participants were followed through to Week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence; and neurocognitive functioning. Results: Fourteen of 16 participants (87.5%) successfully completed the four week escalation regimen to 250mg/day. Two participants withdrew from the trial in the first week. No participant was withdrawn due to adverse events. MA use decreased significantly (p=0.013) from a median of 21 days (IQR: 16-23) to 13 days (IQR: 11-17) over the four week escalation period.Conclusions: LDX at a dose of up to 250 mg/day was safe and well tolerated in this population, with high retention. Larger trials of LDX as a pharmacotherapy for MA dependence are warranted. Trial Registration : Australian and New Zealand Clinical Trials Registry ACTRN12615000391572.

scholarly journals Safety and tolerability of oral lisdexamfetamine in adults with methamphetamine dependence: a phase-2 dose-escalation study

BMJ Open ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. e044696
Author(s):  
Nadine Ezard ◽  
Brendan Clifford ◽  
Adrian Dunlop ◽  
Raimondo Bruno ◽  
Andrew Carr ◽  
...  
Keyword(s):  
Adverse Events ◽  
Risk Behaviour ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Stimulant Use ◽  
Treatment Services ◽  
Drug Tolerability ◽  
Methamphetamine Dependence ◽  
Icd 10

ObjectivesTo examine the safety of an agonist-type treatment, lisdexamfetamine (LDX), at 250 mg/day among adults with methamphetamine (MA) dependence.DesignA dose-escalating, phase-2, open-label, single-group study of oral LDX at two Australian drug treatment services.SettingThe study was conducted at two Australian stimulant use disorder treatment clinics.ParticipantsThere were 16 participants: at least 18 years old, MA dependent for at least the preceding 2 years using ICD-10 criteria, reporting use of MA on at least 14 of the preceding 28 days.InterventionsDaily, supervised LDX of 100–250 mg, single-blinded to dose, ascending-descending regimen over 8 weeks (100–250 mg over 4 weeks; followed by 4-week dose reduction regimen, 250–100 mg). Participants were followed through to week 12.OutcomesPrimary outcomes were safety, drug tolerability and regimen completion at the end of week 4. Participants were followed to week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence and neurocognitive functioning.ResultsFourteen of 16 participants (87.5%) completed escalation to 250 mg/day. Two participants withdrew from the trial in the first week: one relocated away from the study site, the other self-withdrew due to a possible, known side effect of LDX (agitation). There was one serious adverse event of suicidal ideation which resolved. All other adverse events were mild or moderate in severity and known side effects of LDX. No participant was withdrawn due to adverse events. MA use decreased from a median of 21 days (IQR: 16–23) to 13 days (IQR: 11–17) over the 4-week escalation period (p=0.013).ConclusionsLDX at a dose of up to 250 mg/day was safe and well tolerated by study participants, warranting larger trials as a pharmacotherapy for MA dependence.Trial registration numberACTRN12615000391572.

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.

Safety, tolerability, and pharmacokinetics (PK) of rilotumumab in Japanese patients (pts) with advanced solid tumors.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 130-130
Author(s):  
Toshihiko Doi ◽  
Rui Tang ◽  
Yilong Zhang ◽  
Elwyn Loh ◽  
Richard Lizambri ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Solid Tumors ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label ◽  
Eligibility Criteria ◽  
Dose Escalation Study

130 Background: Rilotumumab (R) is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor, the only known MET receptor ligand. The MET pathway has been identified as a potentially useful target for therapeutic blockade in oncology. R has been studied in multiple phase 2 trials either as monotherapy or combination therapy, including a phase 2 trial in gastric cancer combining R with epirubicin, cisplatin, and capecitabine. A phase 1 study was done to evaluate the safety, tolerability, and PK of R in Japanese pts. Methods: An open-label, dose-escalation study was performed with R at 10 mg/kg (Cohort 1A), escalating to 20 mg/kg (Cohort 1B) if no dose-limiting toxicities (DLTs) were observed. Key eligibility criteria were Japanese pts with unresectable locally advanced or metastatic carcinoma, age ≥ 20 yr, ECOG ≤ 1, and refractory to standard treatment (tx). Pts received R as an intravenous infusion on days 1 and 15 of each 28-day cycle, except for cycle 1 in which the day 15 dose was skipped to facilitate PK analysis. DLTs were evaluated in cycle 1. Results: A total of 9 pts were enrolled (1A, n = 3; 1B, n = 6). No DLTs were noted. As of 17 April 13, tx-emergent AEs were reported in 89% of pts. Tx-emergent AEs occurring in > 1 pt overall were vomiting (33%), diarrhea (22%), decreased hemoglobin (22%), hypoalbuminemia (22%), and nausea (22%). One grade 3 tx-emergent AE was observed (decreased hemoglobin; 10 mg/kg). Tx-related AEs were reported in 56% of pts. One grade ≥ 2 tx-related AE was observed (hypoalbuminemia; 20 mg/kg). 8 pts discontinued R due to disease progression; 1 pt remained on the investigational product. Mean exposure of R (Cmax and AUC) appeared to be doubled as dose increased from 10 to 20 mg/kg. The estimated mean CL was approximately 0.2 mL/hr/kg in both cohorts, suggesting a linear PK from 10 to 20 mg/kg. The terminal half-life of R was about 15 days. Conclusions: R monotherapy had an acceptable safety profile in Japanese pts with advanced solid tumors. These phase 1 safety and PK data support the further evaluation of R combined with chemotherapy in Japanese pts with MET-positive metastatic gastric cancer. Clinical trial information: NCT01791374.

A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with BRAF V600-mutant solid tumors and melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9518-9518 ◽  
Author(s):  
Paolo Antonio Ascierto ◽  
Oliver Bechter ◽  
Pascal Wolter ◽  
Celeste Lebbe ◽  
Elena Elez ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Triple Combination Therapy ◽  
Phase 1B

9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAFV600) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAFV600advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAFV600melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.

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.

A phase Ib/II open label study of IMU-131 HER2/Neu peptide vaccine plus cisplatin and either 5-fluorouracil or capecitabine chemotherapy in patients with HER2/Neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS176-TPS176 ◽  
Author(s):  
Ursula Wiedermann ◽  
Anthony J Good ◽  
Erika Garner-Spitzer ◽  
Yee Chao ◽  
Iurie Bulat ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
B Cell ◽  
Gastroesophageal Junction ◽  
Peptide Vaccine ◽  
Metastatic Breast ◽  
Phase 2 ◽  
Breast Cancer Patients ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase 1B

TPS176 Background: Gastric cancer is the 5th most frequently diagnosed cancer and the 3rd leading cause of cancer deaths. HER2/neu is overexpressed in 15% to 25% of patients with gastric cancer and associated with a poor prognosis. Monoclonal antibodies against HER2/neu have been shown to be effective but alternative treatments are needed due to cost and global availability issues. IMU-131 is a B-cell peptide vaccine composed of 3 B cell epitopes derived from the extracellular domain of HER2/neu. Polyclonal antibodies against IMU-131 peptides binding 3 separate regions (DIII, IV) of HER2/neu have been shown to elicit antitumor activity in vitro and a phase I study demonstrated safety and immunogenicity in Her-2 +/++ metastatic breast cancer patients. Fusion of the single peptides into a hybrid peptide conjugated to CRM197 in conjunction with the adjuvant Montanide (P467-CRM-Montanide) improved formulation and stability of the vaccine. With the present Phase 1b/2 trial performed in patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma, we hypothesized that administration of IMU-131 in addition to chemotherapy is safe and immunogenic, and will prolong survival and may delay tumor progression and/or reduce tumor burden. Methods: This study is an international open-label multicenter study performed in 16 Asian and Eastern European sites with a maximum of 18 patients enrolled in Phase 1b. This dose escalation study is designed to assess safety, tolerability, immunogenicity and recommended phase 2 dose (RP2D) of IMU-131. Each patient is administered three injections of IMU-131, at a single dose level on Days 0, 14, and 35, accompanied by chemotherapy cycles of cisplatin and 5-fluorouracil or capecitabine every 21 days. The RP2D will be evaluated in the dose expansion Phase 2 study with 68 patients being enrolled. Results: The study is ongoing with the completion of the phase 1b portion in 4Q18. Conclusions: No conclusions can be drawn at this time. Clinical trial information: NCT02795988.

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