A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3592-3592 ◽  
Author(s):  
M. G. Fakih ◽  
L. Pendyala ◽  
K. Toth ◽  
P. Creaven ◽  
N. Soehnlein ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Stable Disease ◽  
Phase I Study ◽  
Fixed Dose ◽  
Combination Methods ◽  
Disease Stabilization ◽  
Thymidilate Synthase ◽  
Tumor Biopsies ◽  
Dose Levels

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.

A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4088-4088 ◽  
Author(s):  
M. G. Fakih ◽  
L. Pendyala ◽  
P. Smith ◽  
P. Creaven ◽  
K. Toth ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Standard Dose ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Recommended Dose ◽  
Down Regulation ◽  
Combination Methods ◽  
Thymidilate Synthase ◽  
Tumor Biopsies

4088 Background: At 5μM, vorinostat decreases thymidilate synthase (TS) expression by ∼ 40 fold, which translates into synergistic antitumor activity when added to 5-FU. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design with a planned expansion of the maximum tolerated dose (MTD) cohort to 10 patients (pts). Vorinostat (100mg, 200mg, 300mg, 400 mg dose levels) was given twice daily for 1 week followed by 1 week break. FOLFOX was administered at a fixed standard dose every 2 weeks on the 4th day of vorinostat. Tumor biopsies were obtained from liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 19 pts were treated on study (M/F: 12/7; median age: 58; ECOG 0/1: 6/13). All pts had failed prior FOLFOX therapy. Dose-limiting toxicities (DLT) were noted in 3 pts: 2/4 pts at dose level (DL)4 (vorinostat 400mg BID) consisting of grade (G) 3 fatigue, & diarrhea in 1 pt and G3 fatigue in the other; 1/8 pts at DL3 (MTD, vorinostat 300mg BID) consisting of G3 fatigue, anorexia, nausea, and dehydration. 8 pts have been treated at the MTD for a total of 38 cycles. “All Cycles” G3–4 toxicities at the MTD consisted of 2 pts with G3 neutropenia and 2 pts with G3 thrombocytopenia along with the above described DLT. Responses were evaluable in 17 pts: 0 Objective Response, 8 Stable Disease (4 confirmed). TS expression by IHC and by RT-PCR showed modest decreases in 2/6 patients after vorinostat treatment. Cmax of SAHA was < 2μM at all investigated DL, which could explain the lack of adequate TS down-regulation. Conclusions: vorinostat 300mg PO BID × 1 week every 2 weeks in combination with FOLFOX is the established recommended dose. The lack of significant TS down-regulation may be due to the suboptimal serum vorinostat concentrations. Alternate shorter vorinostat schedules may allow for further daily dose escalations and hence for better likelihood of TS down-regulation. This study was partly supported by CTEP, NCI. No significant financial relationships to disclose.

A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9523-9523 ◽  
Author(s):  
D. R. D’Adamo ◽  
K. Scheu ◽  
S. Singer ◽  
G. K. Schwartz ◽  
R. G. Maki
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase I ◽  
Stable Disease ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Xenograft Model ◽  
Fixed Dose ◽  
Preclinical Model ◽  
Combination Methods

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.

A phase I study of the safety and pharmacokinetics (PK) of XMT-1001 given as an intravenous (IV) infusion once every three weeks to patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2574-2574
Author(s):  
E. Sausville ◽  
L. Garbo ◽  
G. J. Weiss ◽  
S. Anthony ◽  
D. Shkolny ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Stable Disease ◽  
Phase I Study ◽  
Study Drug ◽  
Water Soluble ◽  
Therapeutic Window ◽  
Infusion Reactions ◽  
Dose Levels

2574 Background: XMT-1001 is a water soluble macromolecular conjugate of camptothecin (CPT). In this novel CPT pro- drug, CPT is conjugated with a 70 kDa biodegradable hydrophilic polyacetal, poly (1-hydroxymethylethylene hydroxymethylformal). XMT-1001 demonstrated an improved therapeutic window as compared with CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for its clinical development. Methods: This is an open label, dose escalation study of XMT- 1001 administered as an IV infusion once every 3 weeks. The objectives of this phase I study are to determine the maximum tolerated dose and to assess safety and PK of XMT-1001. Initially 3 patients (pts) are entered at each dose level. The cohort is expanded to 6 pts if a patient experiences a dose limiting toxicity. Analyses of plasma and urine were performed for XMT-1001 (conjugated CPT), 2 major drug release products, and for unconjugated (free) CPT. Results: Thirty two pts with refractory solid tumors have received 82 cycles of XMT-1001 at 8 dose levels ranging from 1.0 to 20.5 mg CPT equivalents/m2. Two pts had Gr 3 infusion reactions consistent with hypersensitivity to study drug. Symptoms reversed upon discontinuation of study drug. After the introduction of new clinical trial material with an improved formulation, to date, no infusion reactions suggestive of hypersensitivity have occurred (11 patients, 22 cycles). No hemorrhagic cystitis or ≥ Gr 3 diarrhea was noted. Myelosuppression was observed in 3 pts treated at 15.4 mg CPT equiv/m2 dose level. Stable disease was observed in 7 pts with the following tumor types and dose levels expressed in mg CPT equivalents/m2: NSCLC (1.0 mg/m2, 6 wks), ovarian (4.9 mg/m2, 12 wks), pancreas (4.9 mg/m2, 36 wks), appendiceal (7.3 mg/m2, 12 wks), bile duct (9.1 mg/m2, 18 wks), basal cell (11.6 mg/m2, 6 wks), and colon (15.4 mg/m2, 6 wks). PK demonstrates dose proportional increases in plasma levels of XMT-1001 (conjugated CPT) and confirms the formation of its expected release products. To date, levels of free CPT in urine are low. Conclusions: 1. XMT-1001 can be given safely to patients; 2. XMT-1001 has a favorable PK profile; 3. Prolonged stable disease was observed in patients with refractory tumors. [Table: see text]

A phase I study of bortezomib in combination with 5FU/LV plus oxaliplatin in patients (pts) with advanced colorectal cancer (CRC): EORTC 16029

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4090-4090 ◽  
Author(s):  
D. A. Lacombe ◽  
F. Caponigro ◽  
A. Anthoney ◽  
J. Bauer ◽  
A. Govaerts ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Phase I Study ◽  
Sensory Neuropathy ◽  
Reversible Inhibitor ◽  
Disease Rate ◽  
Clinical Activity ◽  
Starting Dose ◽  
Proteasome Pathway ◽  
Dose Levels

4090 Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2. No significant financial relationships to disclose.

A phase I study of investigational agent SGI-110 combined with irinotecan in previously treated metastatic colorectal cancer patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS797-TPS797 ◽  
Author(s):  
Judy Sing-Zan Wang ◽  
Elske C. Gootjes ◽  
Jennifer N. Uram ◽  
Marianna Zahurak ◽  
Anthony B. El-Khoueiry ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Response To Therapy ◽  
Metastatic Colon Cancer ◽  
Combination Methods ◽  
Previously Treated ◽  
Level 1 ◽  
Tumor Biopsies

TPS797 Background: Studies have suggested that epigenetic modifications may play a role in oncogenesis and acquired chemoresistance in certain cancers including colorectal cancer (CRC). Our preclinical data has shown that DNA hypermethylation may confer acquired chemoresistance, and that combining a hypomethylating agent can re-induce tumor sensitivity to irinotecan in CRC cell lines. We propose a phase I study to assess the safety and tolerability of SGI-110 with irinotecan therapy in metastatic colon cancer previously treated with irinotecan. This will be followed by a randomized phase II study to evaluate efficacy of the combination. Methods: We will enroll 12-22 patients at two institutions with metastatic colon adenocarcinoma previously treated with irinotecan to our phase I study. Dose escalation will be performed in a traditional 3+3 design, where patients receive SGI-110 30-45mg/m2 SQ days 1-5 in combination with irinotecan 125mg/m2 days 1, 8, and 15 (depending on the dose level) every 28 days, with or without G-CSF. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and periodic CT scans to assess response to therapy. In addition, pharmacokinetic studies on peripheral blood and paired tumor biopsies will be obtained to assess for global demethylation and evaluation of biomarkers. Major eligibility criteria include measureable disease with accessibility for paired tumor biopsies, and prior treatment with irinotecan without limit on number of total therapies. Current Enrollment: Dose level 1 enrolled 6 patients and encountered 1 DLT following expansion for safety assessment. Dose level -1 enrolled 3 patients and encountered 2 DLTs, which has since prompted amendments for additional dose levels with modifications to scheduled growth factor support. Dose level -1G enrollment began in September 2014. Clinical trial information: NCT01896856.

Phase I study of gemcitabine, docetaxel, and imatinib in refractory and relapsed solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13538-e13538
Author(s):  
B. Saraiya ◽  
V. Karantza-Wadsworth ◽  
M. N. Stein ◽  
R. Chugh ◽  
J. Mehnert ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Stable Disease ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Fixed Dose ◽  
Tumor Control ◽  
Best Response ◽  
Ecog Ps

e13538 Background: The combination of the tyrosine kinase inhibitor imatinib with cytotoxic chemotherapy targets multiple pathways of tumor progression. In a previous phase I study, the combination of gemcitabine and imatinib was tolerable and had broad activity. The maximally tolerated dose (MTD) was gemcitabine 1500 mg/m2/150 minute and imatinib 400 mg days 1–5, 8–12, and 15–19. Given the activity seen when combining gemcitabine and docetaxel in some solid tumors, this phase I trial studied the addition of docetaxel to gemcitabine/imatinib. Methods: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study at the Cancer Institute of New Jersey and University of Michigan. The mean age was 64, mean ECOG PS 1. Five patients had lung cancer; 5, sarcoma; 3 ampullary-biliary tumors; 2 mesothelioma and bladder, 3, other. Imatinib was administered at 400 mg daily on days 1–5, 8–12 and 15–19. Gemcitabine was started at 600 mg/m2 at the fixed dose infusion of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m2 on day 10. Results: Because of unexpectedly severe hematological toxicities seen with escalating either gemcitabine or docetaxel, the protocol was amended to eliminate days 15–19 of imatinib. The MTD is gemcitabine 600 mg/m2, on days 3 and 10, docetaxel 30 mg/m2 on day 10, and imatinib 400 mg PO given on days 1–5 and 8–12. The dose limiting toxicities were neutropenic fever, pleural and pericardial effusion after cycle 1 of chemotherapy. The best response achieved was stable disease at 6 cycles in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two other patients with NSCLC had stable disease at 4 cycles. Discussion: An unexpectedly low MTD for this triplet was identified, an outcome different from prior experience with the doublets gemcitabine/imatinib or gemcitabine/docetaxel where much higher dosages are tolerated. Our results suggest possible drug-drug interactions that amplify toxicities with little initial evidence of improved tumor control. Given the unexpectedly high toxicity of the combination of gemcitabine, docetaxel and imatinib at low dosages, further development of this regimen is not indicated. [Table: see text]

A phase I study of combination of panitumumab and bevacizumab in KRAS wild-type colorectal cancer patients who were previously treated with fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 759-759
Author(s):  
Naoki Takahashi ◽  
Satoru Iwasa ◽  
Masanori Tachikawa ◽  
Masaru Fukahori ◽  
Kazuki Sudo ◽  
...  
Keyword(s):  
Partial Response ◽  
Adverse Events ◽  
Phase I ◽  
Phase I Study ◽  
Performance Status ◽  
Recommended Dose ◽  
Fixed Dose ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

759 Background: Clinical benefit of combination of panitumumab and bevacizumab (PB) based on the BBP strategy in third-line chemotherapy is unclear. There was no prospective data about the pharmacokinetic interaction between bevacizumab and panitumumab. Methods: This study composed two parts; 1) PB part: phase I study of PB to estimate its recommended dose, 2) CPB part: feasibility study to investigate the safety in combination of bevacizumab and panitumumab at the recommended dose in the phase I part with irinotecan (CPT-11) at the dose used in the prior chemotherapy. Inclusion criteria was as follows; 1) Age: ≥ 20 and < 76 years old, 2) performance status ≤ 1, 3) histologically colorectal adenocarcinoma with KRASwild-type, 4) patients who previously received fluoropyrimidine, oxaliplatin, CPT-11 and bevacizumab for unresectable metastatic disease. Three dose levels of panitumumab (Level 1: 6mg/kg, Level 0: 5mg/kg, Level -1: 4mg/kg) was set in PB part and starting dose level was Level 0. Bevacizumab was administered at fixed-dose of 5mg/kg regardless of dose levels of panitumumab. All drugs were administered on day1 and repeated every 2 weeks. Definition of dose limiting toxicity (DLT) was grade 4 hematological adverse events or ≥ grade3 non-hematological adverse events despite the supportive care observed in 28 days from day1 of cycle 1. Results: There were no cases showing DLT at level 0 (n = 3) and level 1 (n = 3) in the PB part and recommend dose was determined as panitumumab 6mg/kg and bevacizumab 5mg/kg. In the whole treatment course at level 1, grade 3 rash acneiform was observed in 2 patients and 2 patients achieved partial response. In six patients (CPT-11 150mg/m2, biweekly n = 3, 120mg/m2n = 3) enrolled in the CBP part, grade 3 toxicities were leukopenia/neutropenia (n = 1), mucositis (n = 1), diarrhea (n = 1), rash acneiform (n = 1), thromboembolic event (n = 1). Two out of 6 patients achieved partial response in CPB regimen. Conclusions: The recommended dose of PB regimen were panitumumab 6mg/kg and bevacizumab 5mg/kg. Combination of panitumumab and bevacizumab showed manageable toxicity. Clinical trial information: UMIN000009362.

Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion.

1994 ◽  
Vol 12 (8) ◽  
pp. 1621-1629 ◽  
Author(s):  
W H Wilson ◽  
S L Berg ◽  
G Bryant ◽  
R E Wittes ◽  
S Bates ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Liver Metastases ◽  
Phase Ii ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Minor Response ◽  
Tumor Biopsies ◽  
Mdr 1

PURPOSE A phase I study of paclitaxel infused over 96-hours was performed to determine toxicity, maximum-tolerated dose (MTD), and pharmacokinetics in patients with incurable lymphomas and solid tumors. A phase II study was performed at the MTD of paclitaxel in patients with doxorubicin/mitoxantrone-refractory metastatic breast cancer. PATIENTS AND METHODS In the phase I study, paclitaxel dose levels ranged from 120 to 160 mg/m2, administered on a 21-day cycle. Patients with metastatic breast cancer who had either no response or a partial response (PR) to doxorubicin or mitoxantrone and had measurable disease were eligible for the phase I and II studies. Expression of the multidrug resistance (mdr-1) gene was determined in tumor biopsies by mRNA quantitative polymerase chain reaction. RESULTS Twelve patients received a total of 73 cycles of paclitaxel on the phase I study. Dose-limiting mucositis and/or grade IV granulocytopenia was reached at 160 mg/m2, and 140 mg/m2 was selected as the phase II dose. Thirty-six consecutive patients with metastatic breast cancer were treated, of whom three were not assessable. The median age was 49 years, with disease in the liver and/or lung in 76%. Patients received a median of two prior regimens for metastatic disease, and 73% had no response to prior doxorubicin or mitoxantrone. Of 33 patients treated with paclitaxel, 16 patients (48%) achieved a PR and five (15%) achieved a minor response (MR). With a median potential follow-up duration of 60 weeks, the median progression-free and overall survival durations were 27 and 43 weeks, respectively. No correlation was found between extent of prior treatment or prior response to doxorubicin/mitoxantrone, and response to paclitaxel. Paclitaxel pharmacokinetics showed a correlation between both granulocyte and mucosal toxicity, and serum steady-state concentrations (Css) more than 0.07 mumol/L. Patients with liver metastases had significantly decreased paclitaxel clearance and higher paclitaxel Css. Levels of mdr-1 were uniformly low in all tumor biopsies studied. CONCLUSION The recommended phase II dose of paclitaxel is 140 mg/m2 in patients without liver metastases and 105 mg/m2 in patients with liver metastases. Ninety-six-hour infusions of paclitaxel were effective and well tolerated in patients with doxorubicin/mitoxantrone-refractory breast cancer. Prolonged infusion schedules may be more effective than shorter schedules and deserve further study.

Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2616-2616
Author(s):  
John F. Deeken ◽  
Hongkun Wang ◽  
John Marshall ◽  
Deepa Suresh Subramaniam ◽  
Jimmy J. Hwang ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Benefit ◽  
Germ Line ◽  
Acquired Resistance ◽  
Clinical Activity ◽  
Clinical Benefit Rate ◽  
Combination Methods ◽  
Grade 3 ◽  
Tumor Biopsies ◽  
Dose Levels

2616 Background: Acquired resistance to anti-EGFR MoAb therapy may be via EGFR-ErbB2 heterodimerization and pathway reactivation. Dual anti-EGFR treatment was recently found to be active in colon cancer. We performed a phase I trial of CET and LAP to determine the DLTs, MTD, and clinical activity of the combination. Methods: Pts received CET at 400mg/m2 then 250 mg/m2 weekly, combined with daily LAP in a 3+3 dose escalation trial. LAP dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg. Cycles lasted 3 weeks, toxicity was assessed through C2, and pts were restaged every 2 cycles. Baseline and post-C1 tumor biopsies were analyzed for phosphoprotein activation in 36 EGFR/ErbB2 pathway proteins. Germ-line pharmacogenetic (PGx) variations were correlated with efficacy and toxicity. Results: Between 10/2010 and 10/2012, 22 pts were enrolled - colon (8), lung (8), head and neck (4), and anal cancers (2) - and 59% had prior anti-EGFR therapy. 18 pts were evaluable for toxicity, and 18 for response. Mean treatment was 3.8 cycles (range 1 - 12); 3 patients are still on trial. One DLT occurred at DL1 (gr 3 rash) and DL2 (gr 3 diarrhea). No pt on DL3 experienced a DLT. No pt experienced a gr 4 toxicity; gr 3 toxicities anytime on therapy included rash (17%), diarrhea (6%), fatigue (6%), lymphopenia (6%), and hypomagnesemia (6%). Rash was experienced by 94% of pts (gr 1=50%, gr 2=28%, and gr 3=17%). Partial responses (PR) occurred in 4 pts (22%), stable disease (SD) in 8 (44%), and disease progression in 6 (33%), for a clinical benefit rate of 67%. Seven of 13 (54%) pts on prior EGFR therapy had SD or PR. Down-regulation of phosphorylated EGFR/ErbB2 pathway components correlated with response; distinct pathway components were up-regulated in non-responders, including PI3K, Jak/Stat, MAPK, and IGF. PGx variants in FcRII correlated with response (p=0.045); no variants correlated with toxicity. Conclusions: The RP2D is CET 250 mg/m2 weekly and LAP 1250mg daily. Treatment was well tolerated with few grade 3 toxicities and a significant 67% clinical benefit rate. Non-responders showed up-regulation of EGFR pathway components – components which are druggable, warranting further study. A trial in colorectal cancer is ongoing. Clinical trial information: NCT01184482.

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

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