An investigator-initiated monocentric phase I dose escalation trial of temsirolimus and irinotecan (TEMIR) in patients with relapsing glioblastoma multiforme (reGBM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2086-2086
Author(s):  
Max E. Scheulen ◽  
Heike Richly ◽  
Halime Kalkavan ◽  
Andreas-Claudius Hoffmann ◽  
Isabel Virchow ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Standard Dose ◽  
Mammalian Target Of Rapamycin ◽  
Rp Hplc ◽  
Cyp3a4 Enzyme ◽  
Mild Toxicity ◽  
Downstream Mediator

2086 Background: Deregulation of the PI3K/AKT pathway has been preclinically involved in the pathophysiology of GBM. The mammalian target of rapamycin (mTOR) is an important downstream mediator of PI3K/AKT signalling. The mTOR-inhibitor temsirolimus (Tem) achieves significant drug levels in brain. Thus, Tem may be effectively combined with irinotecan (Iri) which has shown promising results in combination with bevacizumab in patients (pts) with reGBM refractory to temozolomide (Tmz) in phase II. Exposure to Tem as well as Iri is substantially reduced in pts receiving CYP3A4 enzyme-inducing anticonvulsants (CYP3A4-Ind). Methods: TEMIR is a phase I trial of escalating doses of Tem in combination with Iri in pts with reGBM refractory to Tmz depending on the cotreatment with CYP3A4-Ind. In pts without CYP3A4-Ind dose escalation of Tem was performed according to the “3+3 protocol” from 15 via 20 to 25 mg iv wkly together with 85 mg/m2 Iri iv wkly. In pts with CYP3A4-Ind the doses of Tem were 30, 40 and 50 mg iv wkly together with 170 mg/m2 Iri iv wkly, respectively. The determination of the pharmacokinetics (PK) of Tem and its influence on the PK of Iri and its active metabolite SN38 was performed by validated RP-HPLC methods with fluorescence detection. Results: Up to now, 14 pts [4 female and 10 male, median age 47 yrs (range 41-65 yrs), 9 without and 5 with CYP3A4-Ind] have been treated. All 9 pts without CYP3A4-Ind (3 pts on 15, 20 and 25 mg Tem each) are evaluable for safety with only mild toxicity [highest CTC-grade ≥2 (gr) per pt]: diarrhea 4 (gr2) and 1 (gr3), neutropenia 1 (gr3), thrombopenia 1 (gr2), anemia 1 (gr2), pneumonia 2 (gr2), rash 1 (gr2). PK parameters of Iri and SN38 were in agreement with previously published studies and there was no significant effect of 15 to 25 mg Tem combined with 85 mg/m2 Iri on the PK of Iri and SN38. In 7 pts evaluable for efficacy there was no remission (RECIST) and median time to symptomatic and/or MRT progression was 10 wks (7, 9+, 10, 10+, 11, 15, 20 wks). Conclusions: The combination of Tem in standard dose of 25 mg iv wkly with 85 mg/m2 Iri wkly is safe in pts with reGBM without CYP3A4-Ind. Tem has no significant effect on the PK of Iri and SN38.

Determination of chemically reduced pyrrolobenzodiazepine SJG-136 in human plasma by HPLC-MS/MS: application to an anticancer phase I dose escalation study

2007 ◽  
Vol 43 (1) ◽  
pp. 42-52 ◽  
Author(s):  
M. Wade Calcutt ◽  
Wooin Lee ◽  
Igor Puzanov ◽  
Mace L. Rothenberg ◽  
David L. Hachey
Keyword(s):  
Phase I ◽  
Human Plasma ◽  
Dose Escalation ◽  
Dose Escalation Study

A Multicenter Phase I/II Dose Escalation Study of Lenalidomide in Combination with Melphalan and Dexamethasone in Subjects with Newly-Diagnosed Light-Chain (AL)-Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1732-1732
Author(s):  
Philippe Moreau ◽  
Arnaud Jaccard ◽  
Lotfi Benboubker ◽  
Bruno Royer ◽  
Valerie Coiteux ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Response Rate ◽  
Standard Dose ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Open Label ◽  
Dose Escalation Study

Abstract A recent prospective randomized trial comparing standard-dose to high-dose melphalan in patients presenting with newly diagnosed AL-amyloidosis showed that oral melphalan-dexamethasone (M-dex) given monthly could be considered the current standard of care, with a median survival of 56 months (Jaccard, N Engl J Med 2007). The use of a combination of lenalidomide and dexamethasone has also been tested in patients with symptomatic AL-amyloidosis. The initial dose of lenalidomide at 25 mg/day was poorly tolerated. However, a 15 mg/day dose regimen was well tolerated and effective, with both hematologic and organ responses (Dispenzieri, Blood 2007 & Sanchorawala, Blood 2007). Combining M-dex with lenalidomide (M-dex-rev) could increase the response rate but the toxicity of this regimen is still unknown. Thus we have initiated a multicenter single-arm open-label phase I/II dose escalation study of lenalidomide administered in combination with M-dex. The primary endpoint was the incidence of dose limiting toxicities (DLT) during the first cycle of lenalidomide at a given dose level in order to determine the maximum tolerated dose (MTD). In addition to melphalan 0.18mg/kg/day from day 1–4 of each 28 day cycle and dexamethasone 40mg/day from day 1– 4 of each 28 day cycle, 3 cohorts of 3 subjects were successively exposed to escalating doses of lenalidomide (5, 10 and 15mg once daily on days 1–21 of a 28 day cycle). DLT was defined using National Cancer Institute (NCI) common toxicity criteria during the first 4 weeks of treatment (one cycle) as the following: at least grade 2 cardiac arrhythmia, at least grade 3 non hematologic toxicity, grade 4 neutropenia lasting >7 days or any other Grade 4 hematologic toxicity, or treatment delay due to toxicity that occurred during the first cycle. No DLT was observed among the first 3 patients treated at 5, 10 and 15 mg lenalidomide/day. 9 additional subjects will be enrolled at 15 mg/day to better define the safety profile and estimate the hematologic and organ response rate. Final results regarding both toxicity and efficacy will be presented during the meeting.

A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS663-TPS663 ◽  
Author(s):  
Pamela N. Munster ◽  
Kathy Miller ◽  
Ian E. Krop ◽  
Navreet Dhindsa ◽  
Joe Reynolds ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Standard Therapy ◽  
Phase I Study ◽  
Liposomal Doxorubicin ◽  
Her2 Positive ◽  
Her 2

TPS663 Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and led to the exploration of anthracycline-free regimens, particularly with HER2-positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2-overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This first-in-human phase I study evaluates the safety of MM-302 in patients and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients aged > 18 years with histologically confirmed HER-2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists who have adequate performance status, bone marrow reserve, and organ function, are eligible for the study. Following a standard 3 + 3 dose escalation design, the maximum tolerated dose (MTD) or maximum feasible dose (MFD) is determined and up to 25 additional patients with HER-2+ ABC will be enrolled for a planned total of 40-49 patients. The primary endpoint is determination of the MTD/MFD. Secondary endpoints include determination of dose-limiting toxicity, adverse event(s), and pharmacokinetic and immunogenicity profiles of MM-302, as well as overall response and clinical benefit rates of MM-302. MM-302 is administered intravenously weekly in 4-week cycles. At the time of this submission, 8 patients have been enrolled in the dose escalation portion.

scholarly journals Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma

2015 ◽  
Vol 17 (9) ◽  
pp. 1275-1283 ◽  
Author(s):  
Patrick Y. Wen ◽  
Antonio Omuro ◽  
Manmeet S. Ahluwalia ◽  
Hassan M. Fathallah-Shaykh ◽  
Nimish Mohile ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
High Grade Glioma ◽  
High Grade ◽  
Dose Escalation Study

Phase I clinical trial of the intraperitoneal (IP) administration of a novel nanoparticle formulation of paclitaxel (NTX).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2558-2558
Author(s):  
Stephen K. Williamson ◽  
Jo Wick ◽  
Julia A. Chapman ◽  
Gary Johnson ◽  
Greg Reed ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Stable Disease ◽  
Standard Dose ◽  
Systemic Exposure ◽  
Ascites Fluid ◽  
Pharmacokinetic Data ◽  
Primary Malignancy ◽  
Dose Levels

2558 Background: IP therapy is an attractive option for patients with IP carcinomatosis as many of these malignancies remain confined IP. Agents whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Pre-clinical studies of a novel formulation of nanoparticulate paclitaxel in animal tumor models demonstrated superior activity and substantially reduced systemic toxicity. This allowed for significant IP doses and concentrations, yet yielded very low systemic concentrations of paclitaxel. We report here the results of a Phase I trial of IP administered NTX. Methods: Patients (ECOG≤2) had relapsed, treatment refractory solid IP tumors and adequate organ function. NTX was administered IP as a bolus injection after 500 ml saline followed by IP administration of up to 2 L of saline. We utilized an accelerated dose escalation scheme until one DLT occurred during cycle 1, followed by a standard dose escalation (3+3 design) based on CTCAE V3 toxicities. The pharmacokinetics of IP administered NTX were characterized in plasma and ascites fluid. Secondary objectives were to define the recommended phase 2 dose of NTX, and characterize preliminary activity and toxicity. Results: 20 patients were treated at dose levels from 50 – 275 mg/M2 q 28 days. Primary malignancy was ovarian cancer (74%). Treatment was well tolerated at all dose levels. Common toxicities potentially related to NTX were: gastrointestinal (68%), constitutional (42%), and pain (42%). Average number of cycles received was 2 (range 1 to 6). Best response was stable disease (4 patients, 21%). Median length of disease stability was 99 days (range 85 to 151 days); median time on study patients with stable disease was 313 days (range 142 to 740 days). All Cmax in plasma were less than 35 ng/mL, with ascites fluid Cmax generally greater than 1000 ng/mL. Conclusions: IP NTX is well tolerated. MTD has not yet been reached. Pharmacokinetic data demonstrate significant, persistent IP exposure to paclitaxel with minimal systemic exposure. Accrual at the 275 mg/M2 dose level continues; updated results will be presented. Further clinical development of NTX is indicated. Clinical trial information: NCT00666991.

Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5021-5021 ◽  
Author(s):  
Michael J. Morris ◽  
Hans J. Hammers ◽  
Christopher Sweeney ◽  
Emmanuel S. Antonarakis ◽  
Steve Y. Cho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
Bone Metastases ◽  
Dose Escalation ◽  
Standard Dose ◽  
Safety Data ◽  
High Energy ◽  
Combination Methods ◽  
Radium 223

5021 Background: Ra-223, a first-in-class α-emitting pharmaceutical, targets bone metastases (mets) with high-energy α-particles of very short range (< 100 µm). D is an approved chemotherapy with demonstrated survival benefit for patients progressing after castrating hormone therapy. We are exploring the hypothesis that simultaneously targeting the tumor and the bone is clinically superior to targeting either alone. We therefore conducted a phase I study of Ra-223 + D in patients with CRPC and bone mets to establish the safety of the combination. Methods: Eligible patients had confirmed symptomatic CRPC with ≥ 2 bone mets and were candidates for treatment with D. Dose escalation followed a 3 + 3 design, with no intrapatient dose escalation or overlapping of cohorts. Patients were to receive 2 combined doses of Ra-223 q6wk + D q3wk (cohort 1: Ra-223/D = 25 kBq/kg /75 mg/m2; cohort 2: Ra-223/D = 25 kBq/kg /60 mg/m2; and cohort 3: Ra-223/D = 50 kBq/kg /60 mg/m2). Dose-limiting toxicity was assessed 6 weeks after first Ra-223 + D injection. Long-term safety data were collected every 3 months after end of study treatment for up to 1 year after start of study treatment. Results: 17 patients were treated, 7 each in cohorts 1 and 3 (1 patient in each cohort discontinued early and was replaced), and 3 in cohort 2. There was no discontinuation or delay of Ra-223 due to adverse events, and so far no reports of long-term toxicity during follow-up. 4 cases of febrile neutropenia occurred during study treatment (12 wk): 3 occurred in cohort 1 (1 was 7 days after first Ra-223 + D, and 2 were in the same subject, both occurring 1 wk after first and second doses of D alone [wk 4 and 10]); 1 occurred in cohort 3, 1 week after second Ra-223 + D (wk 7). Other safety data were as expected based on Ra-223 and D monotherapy data. Conclusions: The phase IIa regimen of Ra-223 + D utilizes a regimen of D 60 mg/m2 q3wk × 10 + Ra-223 50 kBq/kg q6wk × 5. The regimen is currently being explored in a randomized 2:1 open-label expanded safety cohort comparing Ra-223 + D versus D 75 mg/ m2 alone (standard dose). Clinical trial information: NCT01106352.

scholarly journals Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy

Oncotarget ◽  
2016 ◽  
Vol 7 (41) ◽  
pp. 67521-67531 ◽  
Author(s):  
Haeseong Park ◽  
Ignacio Garrido-Laguna ◽  
Aung Naing ◽  
Siqing Fu ◽  
Gerald S. Falchook ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Hdac Inhibitor ◽  
Mtor Inhibitor ◽  
Dose Escalation Study ◽  
Advanced Malignancy
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