Phase Ib study of drozitumab combined with cetuximab (CET) plus irinotecan (IRI) or with FOLFIRI with or without bevacizumab (BV) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 532-532 ◽  
Author(s):  
A. D. Baron ◽  
C. L. O'Bryant ◽  
Y. Choi ◽  
S. Royer-Joo ◽  
C. C. Portera
Keyword(s):  
Dose Escalation ◽  
Death Receptor ◽  
Agonistic Interaction ◽  
Death Receptor 5 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

532 Background: Drozitumab is a monoclonal antibody that triggers tumor cell apoptosis by selective agonistic interaction with the Apo2 ligand/TNF-related apoptosis-inducing ligand death receptor 5. This study assessed the safety of drozitumab combined with two standard IRI- containing regimens in previously treated mCRC pts. Methods: Multicenter, open-label, dose-escalation study with treatment until disease progression or treatment intolerance. For CET+IRI regimen (Cohorts 1-4), a 21-day cycle (cy) = drozitumab on Day 1 at escalating doses of 1, 4, 10, or 15mg/kg, IRI on Day 1, and CET on Days 1, 8, and 15. For FOLFIRI (Cohort 5), a 14-day cy = drozitumab on Day 1 given as a 10 mg/kg loading dose followed by 7 mg/kg in continuing cys, with FOLFIRI (plus BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 doses of drozitumab (29 days for CET+IRI; 28 days for FOLFIRI). Adverse events (AE) were recorded through all cys. Response was assessed by RECIST. Results: 14 pts received a median of 6.5 cys (range 2-21) of drozitumab with CET+IRI and 6 pts received a median of 12 cys (range 3-21) of drozitumab with FOLFIRI. No DLTs occurred at the time of dose escalation. The most frequent AEs were diarrhea (85%), fatigue (80%), nausea (80%), alopecia (70%), neutropenia (70%), and decreased appetite (50%). Most of the toxicities were grades 1-2. The most frequent grade ≥3 AEs were neutropenia (60%), diarrhea (15%), hypokalemia (15%), and leukopenia (15%). Two pts discontinued due to AEs: 1 grade 2 fatigue, 1 grade 3 pyrexia. Among the 20 total pts, best responses included 3 partial responses (2 confirmed, 1 unconfirmed), 12 stable disease and 5 progressive disease. The study enrollment was stopped early by the sponsor for reasons unrelated to safety or efficacy. Conclusions: The addition of drozitumab to two standard second-line IRI-containing regimens (CET+IRI or FOLFIRI ± BV) was well tolerated in mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses suggest no adverse interactions between drozitumab and the chemotherapy evaluated in this study. [Table: see text]

An Open Label, Dose Escalation Study of AVE9633 Administered as a Single Agent by Intravenous (IV) Infusion Weekly for 2 Weeks in 4-Week Cycle to Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1850-1850 ◽  
Author(s):  
Ollivier Legrand ◽  
Maria B. Vidriales ◽  
Xavier Thomas ◽  
Charles Dumontet ◽  
Anne Vekhoff ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Single Agent ◽  
Additional Patient ◽  
Open Label ◽  
Dose Escalation Study ◽  
Tubulin Inhibitor ◽  
Preliminary Results ◽  
Label Dose ◽  
Grade 3 ◽  
Refractory Aml

Abstract AVE9633/huMy9-6-DM4 is an immunoconjugate composed of a humanized monoclonal IgG1 antibody, huMy9-6, which specifically targets the CD33 antigen, conjugated through a disulfide link to the maytansine derivative DM4, a potent tubulin inhibitor. The CD33 antigen is expressed on the surface of myeloid cells. After the conjugate is bound to the CD33 antigen it is internalized and the cytotoxic is released within the target cell. We report preliminary results of the ongoing phase I dose escalation study of AVE9633 in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 and Day 8 of a 28-day cycle. To date, dose levels of 30 (n=1), 50 (n=3), 75 (n=3), 105 (n=3) and 130 (n=3) mg/m2 on Day 1 and Day 8 have been investigated. Patients received 1 (n=2), 2 (n=5), 3 (n=2) and 4 (n=4) cycles of AVE9633. No dose-limiting toxicity was noted so far. Nine patients experienced mild to moderate infusion reactions, mostly on Day1 of Cycle1. One patient at 130 mg/m2 presented grade 3 ALT elevation of 3 days duration. Free DM4, measured by LC/MS/MS was detectable at 105 and 130 mg/m2 in the range of 5 to 10 ng/mL. AVE9633/huMy9-6-DM4 exposure (measuring, by ELISA method, all antibodies containing at least one molecule of DM4) increased proportionally with the administered dose. Using Flow Cytometry Assay, saturation and down regulation of CD33 on peripheral and marrow blasts were observed from the dose of 50 mg/m2. There was one CRp in a 68-year old woman with refractory AML, achieved after 4 cycles of AVE9633 given at 105 mg/m2 × 2, with a 4-month continuing CRp as of 7/07 (she is receiving AVE9633 105 mg/m2 once monthly). One PR occurred in a 81-year old woman with refractory AML after one cycle at 130 mg/m2 × 2, persistent after the second cycle (third cycle is ongoing). Two patients had >50% decrease in bone marrow blasts, at 105 mg/m2 × 2 (from 25% to 8% after two cycles) and at 130 mg/m2 × 2 (from 35% to 9% after one cycle). One additional patient at 75 mg/m2 × 2 presented clearance of peripheral blasts by Day 10 of Cycle1. Mean DM4/IgG on the surface of peripheral blasts (available for one patient at 130 mg/m2) progressively decreased after the infusion, from 3.09 on day 1 to 0.28 on Day 8, and then increased to 2.64 after the second infusion of AVE9633 on Day 8. These preliminary results show that AVE9633 is well tolerated, with manageable safety profile, allowing outpatient treatment. Evidence of anti-leukemia activity was observed in 5 patients. The study is continuing with the evaluation of 150 mg/m2 × 2. Evaluation of closer drug administrations which might enhance efficacy appears warranted.

Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14525-e14525 ◽  
Author(s):  
C. K. Kollmannsberger ◽  
H. Hurwitz ◽  
G. Vlahovic ◽  
C. Maroun ◽  
J. Dumouchel ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Development ◽  
Daily Administration ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Grade 3

e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]

Phase Ib study of dulanermin combined with FOLFIRI (with or without bevacizumab [BV]) in previously treated patients (Pts) with metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3543-3543 ◽  
Author(s):  
Saifuddin M. Kasubhai ◽  
Johanna C. Bendell ◽  
Mark Kozloff ◽  
Amy V. Kapp ◽  
Avi Ashkenazi ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Disease Progression ◽  
Open Label ◽  
Label Dose ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Apoptotic Pathways ◽  
Best Responses ◽  
Dose Limiting Toxicity

3543 Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic pathways by binding to the pro-apoptotic death receptors DR4 and 5. This is the final update of the study assessing the safety of dulanermin combined with FOLFIRI (± BV) in previously treated mCRC pts. Methods: This was a multicenter, open-label, dose-escalation and cohort expansion study. Dulanermin was administered intravenously in 14-day cycles on Days 1, 2 and 3 at 9 mg/kg or 18 mg/kg, with FOLFIRI (+ BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 cycles (28 days). Adverse events (AE) were recorded through all cycles. Response was assessed with RECIST (v1.0). Results: A total of 27 pts received 1-48 cycles (median 10) of dulanermin with FOLFIRI (1 pt received BV). No DLTs were reported and no relationship between dulanermin dose level and AE incidence or severity was detected. The most frequent AEs reported as dulanermin-related were fatigue (37%), anemia (19%), diarrhea, nausea, stomatitis, and weight decreased (15% each). The most frequent Grade ≥3 AEs reported as dulanermin-related were fatigue (15%), anemia, febrile neutropenia and vomiting (7% each). Serious AEs reported as dulanermin-related included: vomiting, dehydration, and febrile neutropenia (1 pt each). Some of these events were reported as related to dulanermin and other study drugs. One pt died on study due to disease progression. Other reasons for discontinuation of study treatment included disease progression (21 pts, 78%), and physician’s decision and pt’s decision (2 pts each, 7%). One pt is still receiving treatment. Among the 27 pts, best responses included 6 (22%) partial responses (5 confirmed, 1 unconfirmed), 17 (63%) stable disease, 3 (11%) progressive disease and 1 (4%) pt with no on-study tumor assessment. Conclusions: The addition of dulanermin to FOLFIRI (± BV) was well tolerated in previously treated mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses were consistent with treatment response to FOLFIRI in this patient population.

scholarly journals A phase 1/2, open‐label, dose‐escalation study of midostaurin in children with relapsed or refractory acute leukaemia

2018 ◽  
Vol 185 (3) ◽  
pp. 623-627 ◽  
Author(s):  
C. Michel Zwaan ◽  
Stefan Söderhäll ◽  
Benoit Brethon ◽  
Matteo Luciani ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Acute Leukaemia ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

scholarly journals MON-282 Treatment of Hyperprolactinemia with Ropinirole: An Open-Label Dose Escalation Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Amanda Tsang ◽  
Cara Dimino ◽  
Alexander G Khandji ◽  
Sunil Kumar Panigrahi ◽  
Gabrielle Page-Wilson
Keyword(s):  
Dose Escalation ◽  
Tumor Size ◽  
Low Cost ◽  
Total Daily Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Biochemical Status ◽  
Label Dose ◽  
Study Completion ◽  
Cardiac Valve Disease

Abstract Purpose Treatment of hyperprolactinemia and prolactinomas with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. Ropinirole (ROP) is a low cost selective D2/D3 receptor non-ergot DA, approved for treatment of Parkinson’s disease and Restless Leg Syndrome, that has been shown to acutely lower prolactin levels (PRL). This study investigated the efficacy and tolerability of long-term ROP therapy in patients with hyperprolactinemia. Methods & Results Ten healthy women (21-45 yrs) with hyperprolactinemia were treated with ROP (0.25-6.0mg/d) for 6 months in an open-label dose escalation study. Clinical and biochemical status was assessed monthly and ROP doses were up-titrated to achieve normal PRL levels, restore menses, and eliminate galactorrhea. Two subjects had macroprolactinomas, 7 had microprolactinomas, and 1 had idiopathic hyperprolactinemia. 8/10 had previously been treated with cabergoline and/or bromocriptine. 5/10 were intolerant and 1/10 was resistant to ergot DAs. Pituitary MRIs were performed at baseline and 6 months.ROP was initiated at 0.25mg QHS in 9/10 subjects. One subject with severe DA intolerance was initiated on 0.125mg QHS. Subjects reaching a total daily dose (TDD) > 2.0mg/d were transitioned to ROP extended release. At study completion, TDDs ranged from 1-6mg/d, with a median TDD of 2mg/d. Baseline PRL levels were 136 ± 49ng/ml (1.9-25ng/ml). Stable PRL normalization was achieved in 50% of subjects. Of the subjects achieving normal PRL, 4 had microadenomas and 1 had idiopathic hyperprolactinemia, and the median effective TDD was 1mg/d (1-4mg/d, range). Among those not achieving PRL normalization, PRL decreased 46 ± 5.4% (Mean ± SEM) from baseline, at a median TDD of 4.0mg/d (2-6mg/d, range). In the subject with documented resistance to ergot DAs, PRL decreased from 529 to 320ng/ml, after 3 months of ROP on the maximum dose studied (6mg/d), but rose to 690ng/ml at 6 months. During ROP treatment, menses normalized in 57%, and galactorrhea resolved in 67% of affected subjects. At study completion, tumor size was unchanged in 7/8 prolactinomas. A 20% decrease in tumor size was observed in one macroadenoma, accompanied by a 30% reduction in PRL levels. There were no changes in BP, HR, weight, renal or kidney function. Mild adverse effects (AEs) were recorded in 80% of subjects. Fatigue (60%), nausea (40%), and headache (20%) were most common. Reported AEs declined after month 1 and ROP was not discontinued due to intolerance. Conclusion These data provide support for the efficacy of ROP in the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia. While further study is needed, ROP treatment for hyperprolactinemia could be considered in patients with ergot DA intolerance or significant cardiac valve disease.

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