Phase II trial of iboctadekin (rhIL-18) on a daily X 5 schedule in metastatic melanoma (MM)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10043-10043 ◽  
Author(s):  
J. M. Kirkwood ◽  
R. Kefford ◽  
T. Logan ◽  
P. N. Mainwaring ◽  
M. Millward ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
Tolerability Profile ◽  
Open Label ◽  
Two Phase ◽  
Stage 1 ◽  
Dose Levels

10043 Background: Interleukin-18 (IL-18) is an immunostimulatory cytokine with potent antitumor activity in preclinical models. Two phase I studies of recombinant human (rh) IL-18 explored a wide dose range (0.03–1.0 mg/kg) without reaching a maximum tolerated dose (MTD) on the daily × 5 schedule. Pharmacodynamic data including inflammatory cytokine production and activation of lymphocyte subsets revealed optimal biologic activity at the lower end of the dose range (0.01–0.2 mg/kg) as did 2 unconfirmed partial responses (PRs) in a MM and a renal cancer patient (pt) at 0.1 mg/kg. Methods: An open-label, randomized, phase II trial in 60 adult pts with previously untreated MM was conducted to evaluate the efficacy and safety of rhIL-18 administered as a 2-hour IV infusion daily × 5 every 28 days for 6 cycles. Pts with PS ≤ 1, without known CNS involvement, and with adequate end organ function were randomized in stage 1 to 3 dose levels of IL-18 stratified according to AJCC M stage 1a/b vs. 1c. Two confirmed responses for a given dose level in Stage 1 were required to enroll 20 additional pts/level in Stage 2. The 1° objective was determination of overall response rate (ORR) for each dose level. Progression-free survival (PFS), tolerability, and immunogenicity were 2° endpoints. Results: 64 pts were treated at 3 dose levels. Nine pts remain on study. One pt experienced a confirmed PR. Based on preliminary data, the difference in PFS 6 months (mos) was significant (p=0.03) for 0.01 vs 0.1 mg/kg. Most common toxicities were mild to moderate fever, rigors, chills, n/v, and headache. Anti-IL18 antibody (Ab) development correlated with dose level. No clinically significant adverse events were associated with Ab development. Conclusion: Iboctadekin has an acceptable tolerability profile and has activity in MM but insufficient confirmed responses have been observed at this time to initiate Stage 2. Preliminary PFS 6 months indicates an advantage for pts treated at the lowest dose. [Table: see text] [Table: see text]

Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3055-3055
Author(s):  
I. D. Davis ◽  
B. Brady ◽  
M. Millward ◽  
B. K. Skrumsager ◽  
U. Mouritzen ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Stage Iv ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Two Stage ◽  
Two Phase ◽  
Study Results

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]

Phase II trial of sorafenib combined with dacarbazine in metastatic melanoma patients

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8012-8012 ◽  
Author(s):  
P. Lorigan ◽  
P. Corrie ◽  
D. Chao ◽  
P. Nathan ◽  
T. Ahmad ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Study Drug ◽  
Progression Free Survival ◽  
Open Label ◽  
Eligibility Criteria ◽  
Stage 1

8012 Background: Sorafenib inhibits tumor cell proliferation and angiogenesis through blockade of multiple kinases including Raf, VEGFR-2/-3, and PDGFR-β. In Phase I/II trials, sorafenib was generally well tolerated as a monotherapy or in combination with other agents. A Phase I study in combination with dacarbazine (DTIC) showed encouraging activity, which warranted this Phase II study. Methods: This multi-center, open-label, two-stage (30 patients in Stage 1; 52 in Stage 2), uncontrolled Phase II trial was performed to evaluate the primary endpoints of efficacy (according to RECIST) and tolerability of sorafenib in combination with DTIC in patients with advanced metastatic melanoma. Eligibility criteria included ECOG 0 or 1, life expectancy ≥12 weeks, adequate bone marrow, liver, and renal function. Oral sorafenib 400 mg twice daily (bid) was administered with repeated 3-week cycles of DTIC 1000 mg/m2. Results: At this interim end of Stage 1 analysis, 30 patients with metastatic melanoma had been treated (median age 61 years [range 30–78]; 73.3% male; 96.7% white). Five (16.7%) patients had PR as best response (two confirmed, three currently unconfirmed), 13 (43.3%) had SD, 10 (33.3%) had PD, and two (6.7%) were unevaluable for tumor response. The patients with confirmed PR continue on study drug at 6.4 months. Median progression-free survival for all patients was 3.6 months (range 0.9–6.1 months). The most frequently reported drug-related adverse events (AEs) were dermatologic (rash/desquamation [43%], hand-foot skin reaction [HFS, 33%]); gastrointestinal (constipation [47%], nausea [37%], diarrhea [27%]); constitutional (fatigue [43%]); and blood/bone marrow (neutrophils [40%], platelets [30%]). The most common grade 3/4 drug-related AEs were blood/bone marrow (neutrophils [23%], platelets [17%]), and fatigue (7%), while HFS and hypertension were observed in <5%. Conclusions: Continuous sorafenib 400 mg bid is generally well tolerated and shows promising preliminary anti-tumor activity in combination with DTIC. No toxicities were observed above those expected from either agent alone. Updated results will be presented, including the decision whether to proceed to Stage 2 of the study. [Table: see text]

A phase I/II trial of weekly docetaxel and cisplatin for locoregionally recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15523-15523
Author(s):  
S. Chia ◽  
J. J. Laskin ◽  
S. D’Aloisio ◽  
B. Vinduska ◽  
M. Webster ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Recommended Dose ◽  
Weekly Dose ◽  
Weekly Schedule ◽  
Phase Ii Trials ◽  
Weekly Docetaxel ◽  
Duration Of Response ◽  
Dose Levels

15523 Background: Docetaxel and cisplatin are both active agents in the treatment of advanced SCCHN. In phase II trials the combination of docetaxel and cisplatin delivered on a 3 weekly schedule in recurrent/metastatic SCCHN demonstrated response rates (RR) of 33–46%, however it is associated with significant morbidities and treatment related mortalities. In a phase IB trial design we sought to determine the maximal tolerated dose (MTD) and the recommended dose for weekly docetaxel and cisplatin to further study in a phase II trial. Methods: Patients with measurable locoregionally recurrent and/or metastatic SCCHN with no prior chemotherapy for advanced disease were eligible. Four dose levels were planned, starting with docetaxel 25 mg/m2 and cisplatin 20 mg/m2 weekly (dose level 1) to docetaxel 35 mg/m2 and cisplatin 25 mg/m2 (dose level 4) for three consecutive weeks followed by a one week break (=1 cycle). Pharmacokinetics (PK) were performed during cycle 1 and 2. Response was assessed following every 2nd cycle. Patients were followed for safety, tolerability, duration of response and survival. Results: 16 patients were enrolled from Aug 2003-Oct 2005. 80% were male, median age 61 years (36–72), median PS 1 (0–2), 30% had prior platinum exposure as a radio-sensitizer, and two-thirds had metastatic SCCHN. MTD was not achieved with dose level 4. Median number of cycles delivered was 3 (1–6) with no significant dose reductions or delays. No G3/4 hematological toxicities or febrile neutropenia was seen across all the dose levels. One G3 dysphagia, one G3 emesis and three G3 metabolic toxicities were seen. There was no treatment related deaths. 1 CR, 2 PR and 7 stable diseases were seen with a median duration of response/stable disease of 3 months (2–19). Conclusions: Combination weekly docetaxel and cisplatin is a well tolerated and active regimen in recurrent/metastatic SCCHN. The recommended dose is docetaxel 35 mg/m2 and cisplatin 25 mg/m2 (3 consecutive weeks out of 4) in the planned phase II trial. [Table: see text]

scholarly journals Safety and efficacy of N-acetylcysteine in hospitalized patients with HIV-associated tuberculosis: An open-label, randomized, phase II trial (RIPENACTB Study)

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0235381 ◽  
Author(s):  
Izabella Picinin Safe ◽  
Marcus Vinícius Guimarães Lacerda ◽  
Vitoria Silva Printes ◽  
Adriana Ferreira Praia Marins ◽  
Amanda Lia Rebelo Rabelo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Hospitalized Patients ◽  
Open Label ◽  
Safety And Efficacy ◽  
Randomized Phase Ii

scholarly journals An open-label, single-arm, phase II trial of buparlisib in patients with melanoma brain metastases not eligible for surgery or radiosurgery—the BUMPER study

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Teresa Amaral ◽  
Heike Niessner ◽  
Tobias Sinnberg ◽  
Ioannis Thomas ◽  
Andreas Meiwes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Pi3k Inhibitor ◽  
Open Label ◽  
Preclinical Data ◽  
Overall Response ◽  
Intracranial Disease ◽  
Dismal Prognosis

Abstract Background Patients with melanoma brain metastasis (MBM) still carry a dismal prognosis. Preclinical data originated in xenograft models showed that buparlisib therapy was highly effective in therapy-naïve MBM. Patients and Methods In this open-label, phase II trial, we investigate the safety and efficacy of monotherapy with buparlisib, a PI3K inhibitor, in patients with asymptomatic MBM who were not candidates for local therapy. These patients had also progressed under immunotherapy if BRAF wild-type or under targeted therapy with BRAF/MEK inhibitors if carrying a BRAFV600E/K mutation. The primary endpoint was the intracranial disease control rate assessed by the investigators. The secondary endpoints were overall response rate, duration of response (DOR) of intracranial disease, overall response, progression-free survival (PFS), overall survival (OS), safety, and tolerability of buparlisib. Results A total of 20 patients were screened and 17 patients were treated with buparlisib. Twelve patients had progressed under more than 2 systemic therapy lines and 17 had received at least 1 previous local therapy. There were no intracranial responses. Three patients achieved intracranial stable disease; the median DOR was 117 days. The median PFS was 42 days (95% confidence interval [CI]: 23–61 days) and the median OS was 5.0 months (95% CI: 2.24–7.76 months). No new safety signs were observed. Conclusions Buparlisib was well tolerated but no intracranial responses were observed. These results might be explained in part by the inclusion of only heavily pretreated patients. However, preclinical data strongly support the rationale to explore PI3K inhibitor-based combinations in patients with MBM displaying hyperactivation of the PI3K–AKT pathway.

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