A first-in-human phase I study to evaluate the fully human monoclonal antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
Anthony W. Tolcher ◽  
Rashmi Chugh ◽  
Glenda Chambers ◽  
Villette Thorpe ◽  
Jakob Dupont ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Phase I ◽  
Dose Escalation ◽  
Human Monoclonal Antibody ◽  
Notch Pathway ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Stem And Progenitor Cells ◽  
Grade 3 ◽  
Cancer Agent

3025 Background: The Notch pathway plays a central role in embryonic development, the regulation of stem and progenitor cells, and is implicated centrally in many human cancers. OMP-59R5 is a fully human IgG2 originally identified by binding to Notch2. It inhibits the signaling of both Notch2 and Notch3 receptors. Mouse xenograft studies using minimally-passaged, patient-derived xenografts show that OMP-59R5 impedes tumor growth and eliminates cancer stem cells (CSCs) in many tumor types. OMP-59R5 modulates the expression of stromal genes and genes associated with the function of tumor vascular pericytes. As such, OMP-59R5 is a novel anti-cancer agent that inhibits tumor growth through direct actions on tumor cells, including CSCs, and effects the stroma and vasculature. Methods: A phase I dose escalation study (3+3 design) was initiated in solid tumor patients. OMP-59R5 was administered to study safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and to determine the maximum tolerated dose (MTD). Results: Twenty-four patients have been enrolled in 5 dose-escalation cohorts at doses of 0.5, 1, 2.5, and 5mg/kg administered weekly (QW) and 5mg/kg administered every other week (QOW). The most frequently reported drug-related adverse events were: mild to moderate diarrhea, fatigue, nausea, vomiting, decreased appetite, and constipation. Diarrhea was dose related and occurred at doses ≥2.5mg/kg weekly and appears less pronounced with every other week dosing. Two dose-limiting toxicities (grade 3 diarrhea and grade 3 hypokalemia) occurred at 5mg/kg QW and 2.5mg/kg was established as an MTD for QW dosing. A QOW dosing schedule is currently under investigation. The PK of OMP-59R5 was characterized by fast and dose-dependent clearance. Two patients (Kaposi’s sarcoma at 5mg/kg and adenoid cystic carcinoma at 2.5mg/kg) had prolonged stable disease for ≥110 days. PD analyses for Notch pathway modulation are ongoing. Conclusions: OMP-59R5 is generally well tolerated. An MTD of 2.5mg/kg QW has been established and a QOW schedule is currently under study. Updated results will be presented.

A phase I dose escalation study of pemetrexed in patients with advanced head and neck squamous cell cancer (HNSCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6055-6055 ◽  
Author(s):  
P. H. Morrow ◽  
B. S. Glisson ◽  
L. E. Ginsberg ◽  
S. M. Lippman ◽  
M. S. Kies ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Cell Cancer ◽  
Maximum Tolerated Dose ◽  
Vitamin Supplementation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels ◽  
Neck Squamous Cell Cancer

6055 Background: Despite recent advances in therapy, patients (pts) with recurrent or metastatic HNSCC continue to demonstrate a poor median survival. In these pts, early trials with pemetrexed, a novel antimetabolite that acts upon several enzymes involved in pyrimidine and purine synthesis, have demonstrated promising efficacy and tolerability. Prior studies found that the administration of oral dexamethasone with pemetrexed reduced the incidence of skin rash. Later, vitamin supplementation (B12 and folic acid), given in addition to the dexamethasone, further diminished side effects. However, no trial has yet evaluated the appropriate steroid dose and its relation to the dosing of pemetrexed, in the setting of vitamin supplementation. We conducted a phase I trial to determine the maximum tolerated dose, toxicity, and preliminary efficacy of pemetrexed when given with different schedules of, or in the absence of, dexamethasone in pts with advanced HNSCC who had been treated with at least one or more chemotherapy regimens. Methods: Eligible pts had metastatic or recurrent HNSCC, prior treatment with one or more chemotherapy regimens, ECOG PS =2, and life expectancy >3 months. A conventional algorithm-based dose escalation design was applied, with three predefined dose levels (DL) of pemetrexed (500 mg/m2, 600 mg/m2, and 700 mg/m2) within each schedule of dexamethasone (none, 20 mg IV on day 1, and 4 mg orally bid for 3 days). Results: A total of 23 pts have been enrolled; 18 pts were evaluable. Median age was 57 years (range 47–82). Median ECOG PS was 1 (range 0–2), and 75% of pts were male. Number of prior chemotherapy regimens were as follows: 1 (40%), 2 (35%), 3 (15%), and 4 (10%). Preliminary data demonstrated only 2 treatment-related adverse events that were grade 3 or greater: anemia (DL1) and pneumonia (DL 1). In all, 13 pts have received pemetrexed with less than standard recommended dexamethasone dosing (none or IV), including 7 pts who received no dexamethasone. Of the 18 evaluable pts, 1 pt had a partial response and 2 pts had stable disease. Conclusions: This represents the first study that demonstrates that steroids may not be required as premedication with pemetrexed. Due to the limited toxicity observed, trial enrollment continues with dose escalation. [Table: see text]

Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5182-5182 ◽  
Author(s):  
Ajai Chari ◽  
Lawrence Kaplan ◽  
Charles Linker ◽  
Lloyd E. Damon ◽  
Willis H. Navarro ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Progressive Disease ◽  
Liposomal Doxorubicin ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Level 1 ◽  
Grade 3

Abstract Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma. Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated. Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study. Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation. The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable. Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate. Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

scholarly journals Multicenter, Phase I, Dose-Escalation Trial of Lenalidomide Plus Bortezomib for Relapsed and Relapsed/Refractory Multiple Myeloma

2009 ◽  
Vol 27 (34) ◽  
pp. 5713-5719 ◽  
Author(s):  
Paul G. Richardson ◽  
Edie Weller ◽  
Sundar Jagannath ◽  
David E. Avigan ◽  
Melissa Alsina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Median Overall Survival ◽  
Progressive Disease ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Previously Treated ◽  
Grade 3

PurposeLenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose-escalation study (ie, NCT00153933) evaluated safety and determined the maximum-tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM.Patients and MethodsPatients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m2on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination.ResultsThirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months.ConclusionLenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM.

2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

1993 ◽  
Vol 11 (4) ◽  
pp. 671-678 ◽  
Author(s):  
A Saven ◽  
H Kawasaki ◽  
C J Carrera ◽  
T Waltz ◽  
B Copeland ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Intravenous Infusion ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Malignant Astrocytoma ◽  
Dose Escalation Study ◽  
Tissue Samples ◽  
Grade 3 ◽  
Higher Doses ◽  
Experienced Grade

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

scholarly journals Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas

ESMO Open ◽  
2018 ◽  
Vol 3 (2) ◽  
pp. e000303 ◽  
Author(s):  
Walter Fiedler ◽  
Sara Cresta ◽  
Henning Schulze-Bergkamen ◽  
Sara De Dosso ◽  
Jens Weidmann ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Phase I ◽  
Dose Escalation ◽  
Antitumour Activity ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Epidermal Growth

BackgroundChanges in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).Patients and methodsForty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.ResultsA maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.ConclusionTomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

Phase I, Dose-Escalation Study of 2 Dosing Regimens of AS703569, An Inhibitor of Aurora and Other Kinases, Administered Orally in Patients with Advanced Hematological Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2963-2963 ◽  
Author(s):  
Anne Sonet ◽  
Carlos Graux ◽  
Johan Maertens ◽  
Christine-Maria Hartog ◽  
Justus Duyster ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Hematological Malignancies ◽  
Single Agent ◽  
Gi Bleeding ◽  
Dose Escalation Study ◽  
Inhibition Of Proliferation ◽  
Dosing Regimens ◽  
Grade 3

Abstract Background: AS703569 is a novel, orally bioavailable, potent ATP-competitive, small molecule that inhibits all three aurora kinase isoforms (A, B, and C), and shows inhibitory activity across other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. AS703569 has been tested as a single agent and in combination with standard-of-care anticancer agents in leukemia cell lines, freshly isolated leukemic cells, and tumor xenograft models. The strong inhibition of proliferation and the triggering of apoptosis induced by AS703569 lead to significant anti tumor activity resulting in tumor regression or growth delay, and prolongation of animal survival. AS703569 is currently being tested in phase I studies as a single agent and in combination; the main objectives are to establish the MTD (based on dose-limiting toxicities [DLTs]) and evaluate the safety and PK/PD effects of different regimens. Study design: This is an open-label, phase I, two-arm, dose-escalation study in patients (pts) with AML, CML, MDS, and MPD. Patients were sequentially assigned to one of two AS703569 dosing regimens: Regimen 1: once daily (QD), days 1–3 and 8–10 of a 21-day cycle; Regimen 2: QD, days 1–6 of a 21-day cycle. In both treatment arms, AS703569 was administered at escalating dose levels (DL; 3, 6, 10, 15, 21, 28, and 47 mg/m2/day) using a 3+3 cohort design. Repeated cycles were permitted until disease progression or unacceptable toxicity. Patient characteristics: Pt characteristics are summarized in the Table. Pts had primary AML (n=20), secondary AML (n=13), CML (n=6), MDS (n=5), and MPD (n=1). Pts were heavily pretreated and had failed previous chemotherapy. Safety: The median number of AS703569 cycles received per pt was 2 for Regimen 1 (range 1–7) and 1 for Regimen 2 (range 1–6). In Regimen 1, at DL 7 (47 mg/m2/day, n=3), 2 subjects reported DLTs: 1 case of grade 3 diarrhea with hyponatremia and sepsis with a fatal outcome, and 1 case of grade 3 diarrhea with GI bleeding. In Regimen 2, at DL 7 (n=5), 3 subjects reported DLTs: 2 cases of grade 4 mucositis and 1 case of neutropenic infection. Consequently, the dose was de-escalated to 37 mg/m2/day for both regimens and enrollment is ongoing at this DL to confirm the MTD. Grade ≥3 toxicities reported throughout the study mainly included infections (18 pts), neutropenia and febrile neutropenia (17 pts), thrombocytopenia (15 pts), anemia (11 pts), and GI disorders including mucositis, diarrhea and GI bleeding (8 pts). Alopecia was reported in some pts. PK: Preliminary data for 37 pts (DL 1–6) show an increased exposure with dose, a Tmax of 2–4 h (range 0.5–8 h), and an effective half-life of ~10–20 h. Activity (preliminary data): In Regimen 1, 1 pt with refractory CML (mut. T315I) has received 7 treatment cycles and shown a hematological and cytogenetic response; 5 pts with AML received 5–7 cycles, 3 achieved reduction in BM and/or peripheral blasts. In Regimen 2, 1 pt with MDS received 6 cycles and achieved a PR; 2 pts with AML received 3 cycles and did not progress. Conclusions: These data indicate that AS703569, QD, days 1–3 and 8–10 every 21 days or on days 1–6 every 21 days is generally well tolerated in pts with advanced hematological malignancies. Most grade 3/4 toxicities are commonly seen in pts with advanced hematological malignancies and are in part linked to the underlying disease. A DL with an unacceptable frequency of DLTs was reached and enrollment continues at a lower DL to confirm the MTD. Early evidence of activity was observed in pts with CML, AML, and MDS. Regimen 1 Regimen 2 N 24 21 Median (range) age, years 69.5 (48–83) 71 (49–82) Sex, M/F 15/9 12/9 ECOG PS, 0-1-2 5-12-7 3-12-6 Median (range) previous lines of therapy 3 (1–6) 2 (1–6)

A Q7D phase I study of TPI 287, a novel taxane, in advanced malignancies: Imaging studies, pharmacokinetics (PK) and circulating tumor cell (CTC) quantitation

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12008-12008 ◽  
Author(s):  
J. J. Hwang ◽  
J. L. Marshall ◽  
S. Malik ◽  
H. Chun ◽  
T. Ahmed ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Study ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Tumor Measurements ◽  
Grade 3

12008 Background: Taxanes have demonstrated activity across a broad range of cancers, but resistance remains an issue. TPI 287 is a third generation taxane designed to overcome issues of resistance secondary to mdr and mutant tubulin. The purpose of this Phase I study was to determine the maximum tolerated dose and pharmacokinetics of IV TPI 287. Methods: Phase I study: TPI 287 is administered IV on days 1, 8, 15 of a 28 day cycle (Q7D) with at least 3 patients treated per dose escalation, in a typical phase I design. Dosing began at 7 mg/m2 and has advanced to the fifth cohort of patients, who are being treated at a dose of 85 mg/m2. Tumor response is assessed after every second cycle via imaging and tumor measurements. Samples are collected for PK analysis and circulating tumor cell (CTC) quantitation. Results: Sixteen pts have been enrolled (9 males, median years = 60.11; 7 females, median years = 50.71: median number of previous chemotherapies = 4). Diagnoses included colorectal (4), prostate (3), breast, kidney, cervical, brain, lung, osteosarcoma, basal cell, endometrial, ovarian cancers. Of 16 pts, 8 and 5 have completed 1, 2 cycles, respectively. Only one drug related grade 3 adverse event (hypersensitivity reaction) occurred, at 14 mg/m2. No other reported toxicities are related to TPI 287. PK and CTC studies are ongoing. Conclusions: These initial results show that TPI 287 is well tolerated at a dose up to 56 mg/m2 administered Q7D, and dose escalation continues. [Table: see text]

Phase I study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13553-13553
Author(s):  
W. A. Messersmith ◽  
M. A. Rudek ◽  
D. Laheru ◽  
M. Zhao ◽  
P. He ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Advanced Colorectal Cancer ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Total Daily Dose ◽  
Dose Escalation Study

13553 Background: ABT-751 (A) is an orally (PO) bioavailable sulfonamide with antimitotic properties. We are performing a non-randomized phase I/II dose-escalation study of A in combination with capecitabine (C), irinotecan (I) and bevacizumab (B) to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) in patients with advanced colorectal cancer (1st or 2nd line). Methods: Patients are treated with A QD for 7d (lead-in) and then begin 21-d cycles of treatment with A (QD) and C (BID) d1–14 PO, I d1 IV, and B d1 IV. Dose escalation started at dose level (DL) 1 at A 150 mg, I 200 mg/m2, and C 1600 mg/m2 (total daily dose) and escalated to full dose CAPIRI (I 250 mg/m2, and C 2000 mg/m2) for DL2. B was then added as standard of care at 7.5 mg/kg for DL2b (and later, DL1b). Blood samples were collected for pharmacogenomics (PG), pharmacodynamics (PD), steady-state PK of A and A metabolites when administered alone or in combination with C, I, and B, and PK of I and I metabolites. Serial dynamic contrast MRI’s, before and after the ABT-751 monotherapy lead-in period, are being performed in a subset of subjects. Results: Eight patients have been treated at dose levels 1 (3), 2 (2), and 2b (3). One patient on DL2 experienced g3 transaminitis and another on DL2b had F&N which were dose-limiting. Dose level 1 is being expanded to 6 patients, now with B (DL1b). Other g3/4 toxicities have included g4 neutropenia (1 subject DL2, 1 DL2b). The formation of A glucuronide appears decreased during combination therapy (see table). I PK, PD, and PG samples were collected and analysis is pending. Of 8 subjects, there have been 4 PD and 4 SD after 2 cycles. Conclusions: The combination therapy of A 150 mg and 20% dose-reduced CAPIRI appears well-tolerated. Patient accrual continues at DL1b. [Table: see text] No significant financial relationships to disclose.

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