Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4015-4015 ◽  
Author(s):  
Maeve Aine Lowery ◽  
Ghassan K. Abou-Alfa ◽  
Howard A. Burris ◽  
Filip Janku ◽  
Rachna T. Shroff ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Enzyme Inhibitor ◽  
Phase Iii ◽  
Controlled Study ◽  
Metabolic Enzyme ◽  
Expansion Cohort

4015 Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC. Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses. Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year. Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy). Clinical trial information: NCT02073994.

A phase I study of HM781-36B, a novel pan-HER inhibitor, in patients (pts) with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3076-3076 ◽  
Author(s):  
Tae Min Kim ◽  
Keun-Wook Lee ◽  
Do-Youn Oh ◽  
Jong-Seok Lee ◽  
Seock-Ah Im ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Advanced Solid Tumors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Expansion Cohort ◽  
Positive Breast Cancer

3076 Background: HM781-36B is a pan-HER tyrosine kinase inhibitor, which showed a potent activity against the gefitinib- or erlotinib-resistant, EGFR L858R/T790M double mutant cells. A phase I study was conducted to determine the MTD, pharmacokinetics, and antitumor activity. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3+3 scheme was used in the dose escalation part, and additional 12 pts were enrolled in the expansion cohort of molecular enrichment. Results: In dose-escalation part, 43 pts (median age: 55 yrs (range 25-82), M:F=25:18, ECOG PS 0/1/2/3: 23/17/2/1, median prior chemotherapy: 4) were treated. DLTs were G3 diarrheas in 5 pts, one at 12 mg, 16 mg, 24 mg, and two at 32 mg. The MTD was determined as 24mg. The most common drug-related adverse events were diarrhea, stomatitis, rash, pruritus, and anorexia. Among 41 evaluable pts, 4 pts achieved PR (1 unconfirmed, duration of response: 11.9 mo, 7.07 mo+, 4.5 mo+), and 19 pts had SD. Two of 4 PR pts were Her2-positive breast cancer pts. The median duration of treatment in pts with PR or SD was 3.87 (2.47- 15.17) months. In the dose range of 0.5 to 24 mg, it showed linear pharmacokinetics proportional to dose-escalation, relatively short half-life, and little accumulation. Additional 12 pts in the expansion cohort are under treatment at 24 mg (6 pts: EGFR-mutant NSCLC, 3 pts: Her2-positive gastric cancer, 2 pts: Her2-positive breast cancer, 1 pt: rectal cancer). Conclusions: HM781-36B was safe and well tolerable in advanced solid tumors. Preliminary evidence of anticancer activity has been observed. Updated data will be presented at the meeting.

Phase I study of the combination of alisertib (MLN8237) and gemcitabine in advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3589-3589
Author(s):  
Jasmine Huynh ◽  
Justin Chen ◽  
Edward Jae-Hoon Kim ◽  
David R. Gandara ◽  
Thomas John Semrad ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pancreatic Adenocarcinoma ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Open Label ◽  
Expansion Phase ◽  
Grade 3 ◽  
Advanced Pancreatic Adenocarcinoma

3589 Background: Aurora Kinase A (AKA) is a key mitotic regulator overexpressed in multiple solid tumors. This open-label dose escalation and expansion phase I study evaluated the safety and tolerability of alisertib (MLN8237), an oral AKA inhibitor, in combination with gemcitabine. Methods: In dose escalation, patients (pts) > 18y with refractory solid tumors received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at 1000mg/m2. Four dose levels (DL) of alisertib (20-50mg) were given per 3+3 design to investigate dose limiting toxicities (DLT) in cycle 1, to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D). In dose expansion, advanced pancreatic adenocarcinoma pts received the MTD dose twice daily on a modified dosing schedule to allow for pharmacokinetic (PK) evaluation. Anti-tumor activity was assessed by response rate (RECIST 1.1) and progression-free survival (PFS). PK evaluation of plasma gemcitabine and alisertib was performed on all pts enrolled in the dose expansion. PK sampling was performed before treatment, immediately after gemcitabine infusion, and at other pre-specified post-infusion timepoints. Results: Twenty-six pts were treated in total: 21 pts in dose escalation and 5 pts in dose expansion. Overall, median age was 57y [42-82]; 50% male; 62% PS 1 (16 pts); 2 [0-7] median prior therapies. In the dose escalation phase, 9 tumor types were included and NSCLC was most common (7 pts). Maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). The dose expansion phase enrolled 5 pts with advanced pancreatic adenocarcinoma; median age 63y [48-82]; 60% male; 60% PS 1 (3 pts); 2 [1-2] median prior therapies. Grade ≥3 TRAEs were observed in 73% of all pts and were predominantly hematologic, including neutropenia (54%), leukopenia (50%), and lymphopenia (31%). Similar TRAEs were seen at DL4; all 14 pts experienced neutropenia with 64% experiencing grade ≥3 neutropenia. Fourteen of 23 evaluable pts (61%) had stable disease and 2 pts (9%) had partial response (PR) as best overall response. Median PFS was 2.9 months (95% CI 2.0-4.2). Analysis of PK data is ongoing and will be reported. Conclusions: Alisertib can be safely administered with gemcitabine. RP2D for alisertib is 50 mg PO BID in combination with full dose gemcitabine. Best response was at least stable disease in a majority of pts with PR observed in 9% of this heavily pretreated group of patients. Most grade ≥3 TRAEs were hematologic. Results of PK studies will also be reported. Clinical trial information: NCT01924260 .

A phase I study of selumetinib (AZD6244/ARRY-142866) in combination with cetuximab (cet) in refractory solid tumors and KRAS mutant colorectal cancer (CRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3103-3103 ◽  
Author(s):  
Dustin A. Deming ◽  
William R. Schelman ◽  
Sam Joseph Lubner ◽  
Daniel Mulkerin ◽  
Noelle K. LoConte ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Growth Factor Receptor ◽  
Fixed Dose ◽  
Kras Mutations ◽  
Best Response ◽  
Expansion Cohort ◽  
Anti Tumor Activity

3103 Background: KRAS mutations have been recognized as clinically important predictors of resistance to EGFR-directed therapies in CRC. Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor receptor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cet in KRAS mutant CRC. A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cet, with an expanded cohort in KRAS mutant CRC at the MTD dose to evaluate preliminary anti-tumor activity. Methods: In the dose escalation portion, patients (pts) with advanced solid tumors received fixed dose cet with escalating doses of selumetinib in cohorts of 3-6 pts. In the expansion cohort, 14 pts with KRAS mutant CRC were enrolled at the MTD level. Results: 15 pts (9 M, 6 F), average age of 60 (41-73) years were treated at 3 dose levels in the dose escalation cohort and 14 pts were treated in the expansion cohort. Pts had the following tumor types: CRC 73%, NSCLC 13%, and H&N 13%, and had received a median of 4 (1-8) prior lines of therapy. 33% (only CRC) had prior EGFR-directed therapies. ECOG PS 0 (40%), 1 (53%), 2 (7%). 13 of 15 pts were evaluable for tolerability and response. One DLT for grade 4 hypomagnesemia occurred, and no other grade 4 toxicities were seen. Grade 3 (20%) toxicities included; rash, hyponatremia, and headache. The most common cycle 1 grade 1 and 2 adverse events included acneiform rash (100%), fatigue (54%), nausea/vomiting, (54%), diarrhea (54%), dry skin (46%), fever (23%), and hypomagnesemia (15%). Most pts (60%) required no dose modifications. The MTD was established at selumetinib 75 mg PO BID and cet 250 mg/m2 weekly following a 400 mg/m2load. Best response included 2 PR in pts with CRC and SD in 4 pts (1 SCC of the tonsil, 1 NSCLC, and 2 CRC). Conclusions: The combination of selumetinib and cet is well tolerated, and preliminary anti-tumor activity was observed in multiple pts. Results of the KRAS mutant CRC expansion cohort will be presented.

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3022-3022
Author(s):  
Nagla Fawzy Abdel Karim ◽  
Mahran Shoukier ◽  
Ihab Eldessouki ◽  
Ahmed Khaled ◽  
John Morris
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Weekly Schedule ◽  
Dose Escalation Study ◽  
Grade 3

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
Arif Manji ◽  
Daniel A. Morgenstern ◽  
Yvan Samson ◽  
Rebecca Deyell ◽  
Donna Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Low Dose ◽  
Pediatric Patients ◽  
Novel Approach ◽  
Best Response ◽  
Grade 3 ◽  
Relapsed Disease

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.

scholarly journals Dose escalation of intravenous irinotecan using oral cefpodoxime: A phase I study in pediatric patients with refractory solid tumors

2011 ◽  
Vol 58 (3) ◽  
pp. 372-379 ◽  
Author(s):  
Lisa M. McGregor ◽  
Clinton F. Stewart ◽  
Kristine R. Crews ◽  
Michael Tagen ◽  
Amy Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Pediatric Patients

scholarly journals Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors

2020 ◽  
Vol 38 (6) ◽  
pp. 1763-1773
Author(s):  
Jaffer A. Ajani ◽  
Milind Javle ◽  
Cathy Eng ◽  
David Fogelman ◽  
Jackie Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Stable Disease ◽  
Phase I Study ◽  
Potent Inhibitor ◽  
Pharmacokinetic Analysis ◽  
Gastrointestinal Cancers ◽  
Chemotherapy Treatment ◽  
Favorable Safety ◽  
Combination Regimens

Summary 5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

scholarly journals Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors

2018 ◽  
Vol 36 (16) ◽  
pp. 1594-1602 ◽  
Author(s):  
Anish Thomas ◽  
Christophe E. Redon ◽  
Linda Sciuto ◽  
Emerson Padiernos ◽  
Jiuping Ji ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platinum Refractory

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

Phase I study of bortezomib and oxaliplatin (BOX) in solid tumors: Improved neurotoxicity (NT) profile with lower bortezomib (B) dose

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12007-12007
Author(s):  
R. A. Kosloff ◽  
J. Wright ◽  
P. Ivy ◽  
J. Escalon ◽  
B. Norwood ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Major Contributor ◽  
Organ Function ◽  
Dose Escalation Study ◽  
Adequate Organ Function ◽  
Dose Levels ◽  
Platinum Agents

12007 Background: B inhibits proteasome function and may be synergistic in causing apoptotic death with platinum agents. We were interested in combining B with OX but concerned with dose limiting (DL) NT based on our prior B phase I study [Hamilton et al., JCO 2005]: therefore this Phase I dose-escalation study (alternating increases of B and OX) focusing on NT was planned. Methods: Patients (pts) with metastatic solid tumors, PS 0–2, platinum or taxane naive, no peripheral neuropathy and adequate organ function, received B (D1, 4, 15, 18) and OX (D1, 15) every 28 days in a dose escalation design (see table ). Baseline and monthly assessments were performed by an independent neurologist. Results: 27 (18 gastrointestinal, 3 melanoma, 3 ovarian, 3 others) were accrued; pt characteristics: 14 male/13 female; median age 55 years (range 35–75); 2 median cycles (range 1–10). NT was not DL because it did not occur within the first cycle. Late and limiting NT was observed in levels 2–5 after 2–9 cycles, but serial neurologic evaluations showed reversible NT. With an amended new dose level to lower B to 1.0 mg/m2 (level 6) to avoid late NT, NT was not observed. Of 22 evaluable pts, there were 3 partial responses (ampullary, GE junction, biliary), 6 stable disease, and 13 disease progression by RECIST criteria. Conclusions: biweekly BOX is tolerable at B 1.0 mg/m2 and OX 85 mg/m2 with no DL NT. Additional observations on late NT are ongoing. This suggests B is a major contributor to NT observed in dose levels 2–5 and may potentiate the effects of OX. [Table: see text] [Table: see text]

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