Dose Escalation Of Gemcitabine Research Articles

Gemcitabine/Clofarabine/Busulfan: A New Myeloablative Reduced-Toxicity Conditioning Regimen with High Activity for Allogeneic Stem-Cell Transplant (alloSCT) in Aggressive Lymphomas

INTRODUCTION:Stem-cell transplantation (SCT) is standard treatment of relapsed lymphomas. Patients in refractory relapse or relapsed after autoSCT are often considered for an alloSCT, aiming at a graft-vs.-lymphoma (GVL) effect. While reduced intensity conditioning regimens have substantially contributed safety to alloSCT, aggressive lymphomas often progress rapidly afterwards, partly due to tumor cell growth outpacing GVL. Outcomes are particularly poor for patients with active disease at the time of alloSCT. Thus, development of more efficacious conditioning regimens for aggressive lymphomas, avoiding mucotoxic drugs (such as melphalan), is a major need. We previously showed that the combination of 2 nucleoside analogues [gemcitabine (GEM) + clofarabine (CLO)] followed by busulfan (BU) is highly synergistic against B- and T-cell lymphoma cell lines, through inhibition of DNA damage repair. Those observations led us to clinically study a novel high-dose regimen of GEM/CLO/BU with alloSCT for aggressive lymphomas.METHODS:Eligibility included age 12-65; refractory DLBCL, T-cell and Hodgkin lymphomas; acceptable end-organ function, and an 8/8 HLA-matched (A, B, C and DRB1) sibling (MSD) or unrelated donor (MUD). GEM was escalated from dose level 1 to 3; it was given on days -6 (d-6) and d-4 as a loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 40-90 min (total daily dose 475, 675 or 975 mg/m2), to be followed by CLO (40 mg/m2/day x 4, d-6 to d-3) and BU (pharmacokinetically targeted to an average daily AUC of 4,000 μMol•min x 4, d-6 to d-3). AlloSCT was on d0. Patients receiving a MUD transplant received rabbit ATG (0.5, 1.5 and 2 mg/Kg on d-3, d-2, and d-1, respectively). Patients with CD20+ tumors received rituximab (375 mg/m2) on d-14, d-7, d+1 and d+8. The GVHD prophylaxis included tacrolimus (tapered after d+100) and mycophenolate mofetil (from d0 to d+60). Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting >3 days at peak severity. Dose escalation of gemcitabine followed a Bayesian design targeting a maximal DLT probability of 25%. Non-relapse mortality (NRM), relapse incidence, G II-IV or III-IV acute GVHD or chronic GVHD were calculated with the cumulative incidence method with consideration of competing risks.RESULTS:Between 11/12 and 06/17, 48 patients were enrolled: 25 DLBCL (5 double hit), 13 T-NHL and 10 HL (Table); 27 MSD, 20 MUD.All patients received PBPC. The MTD of gemcitabine was level 3. DLT was observed at the following frequencies: level 1: 12.5% (1/8), level 2: 9% (2/9), and level 3: 25% (4/16). Regimen-related toxicities were manageable, including mucositis (47% G2, 42% G3), self-limited transaminitis (21% G2, 49% G3), hyperbilirubinemia (no cases of VOD) (30% G2, 19% G3), and dermatitis (13% G2). There were no cardiac, pulmonary, renal or CNS toxicities. Neutrophils dropped to <0.1 in all patients on median d0 (d-3 to +2), and engrafted on median d+10 (d+9 to +20). Platelets engrafted on median d+12 (d+8 to +38).All patients engrafted; full donor chimerism was established early: a median of 100% (50-100%) on d+28, and 100% (98%-100%) on d+100. The rates of G II-IV and III-IV acute GVHD were 29.8% (35% MSD, 25% MUD) and 10.6% (19% MSD, 0% MUD), respectively. The rates of moderate-severe / severe chronic GVHD were 8.5% / 6.4%. 1/3 HL pts with prior exposure to anti-PD1 developed steroid-responsive hepatic chronic GVHD.The γ-H2AX levels in PBMNC (N=19) increased throughout treatment, to a median of 8.5 fold from baseline (range, 0.4-46.3) (P=0.0001) and PARP-1 decreased to 0.45 fold (0.2-6.3) (P=0.4), indicative of activation of DNA damage response and apoptosis, respectively. The overall response rates on d+30 (in 34 patients with measurable disease) are 77% (DLBCL), 100% (T-NHL), and 75% (HL). Their respective CR rates are 69%, 100% and 75%. The d+100 / 1-year NRM rates were 6.25% / 14.5%. NRM causes were infection (6) and GVHD (1). At median follow-up of 18 months (1-53) the EFS / OS rates of the entire population are 44% / 56%. Outcomes appear especially promising in the DLBCL (EFS / OS, 54% / 54%) and the T-NHL (62% / 69%) subgroups.CONCLUSIONS:GEM/CLO/BU is a new, myeloablative, reduced-toxicity alloSCT regimen with high activity in this population of heavily pretreated and refractory aggressive lymphomas, which warrants further study in disease-specific trials [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Weekly Gemcitabine and Cisplatin in Combination With Radiotherapy in Patients With Locally Advanced Head-and-Neck Cancer: Phase I Study

To define the maximum tolerated dose by describing the dose-limiting toxicity (DLT) of weekly gemcitabine and cisplatin in patients with locally advanced head-and-neck (LAHN) cancer concomitant to irradiation. Patients with LAHN cancer were enrolled in a prospective, dose-escalation Phase I study. Toxicity was graded according to the Common Toxicity Criteria score. Maximum tolerated dose was defined when DLT developed in 2 of 6 patients. The starting dose of cisplatin was 20 mg/m(2) and that of gemcitabine was 10 mg/m(2) in 3 patients, with a subsequent dose escalation of 10 mg/m(2) of cisplatin only for 3 new patients. In the next levels, only a dose escalation of gemcitabine with 10 mg/m(2) for each new cohort was used (Level 1, 10 mg/m(2) of gemcitabine and 20 mg/m(2) of cisplatin; Level 2, 10 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin; and Level 3, 20 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin). Radiation therapy was administered by use of a conformal technique over a period of 6 to 7 weeks in 2.0-Gy daily fractions for 5 consecutive days per week to a total dose of 70 Gy. From 2008 to 2009, 12 patients completing 3 dose levels were included in the study. At Dose Level 3, 1 of 3 patients had DLT with Grade 3 mucositis. Of the next 3 required patients, 2 showed DLT with Grade 3 dermatitis. At a follow-up of 3 months, 10 of 12 evaluable patients (83.3%) obtained a complete response and 1 patient (8.3%) obtained a partial response. Among the complete responders, at a median follow-up of 10 months (range, 6-14 months), 9 patients are alive and disease free. Gemcitabine at low doses combined with cisplatin is a potent radiosensitizer effective in patients with LAHN cancer. The recommended Phase II dose is 10 mg/m(2) of gemcitabine and 30 mg/m(2) of cisplatin with an acceptable tolerability profile.

Phase I Trial of Gemcitabine Dose Escalation with Concurrent Radiotherapy for Patients with Locally Advanced Pancreatic Cancer

Aim: The safety and efficacy, and the dose-limiting toxicity (DLT) of the chemotherapeutic agent gemcitabine administered in conjunction with radiotherapy in patients with locally advanced pancreatic cancer are not yet established. Here, we evaluated the safety and efficacy, DLT, and maximum tolerated dose of gemcitabine with concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Tumor response and time to progression were also assessed. Patients and Methods: Patients with previously untreated pancreatic cancer (n = 12) received gemcitabine intravenously on days 1, 8, and 15. Concurrent radiation therapy was initiated on day 1 (40 Gy in 2 Gy/day × 20 fractions, days 1–5, 8–12, 15–19, 22–26). Patients received limited-field irradiation with three-dimensional radiotherapy. Dose escalation included dose levels 1–3 (gemcitabine 400, 600, and 800 mg/m2). Results: No patient developed DLT in this study. Of the 12 patients, there were 11 sustained responses, 0 partial responses, and 1 progressive disease. Two patients with a sustained response underwent surgery after re-evaluation. The median progression-free survival was 8 months, not including the patients that underwent surgery. Conclusion: Weekly gemcitabine at a dose of 800 mg/m2 with concurrent radiation therapy in patients with locally advanced pancreatic cancer was well tolerated.

Phase I/II Trial of a Novel Gemcitabine and Vinorelbine-Containing Conditioning Regimen in Autologous Hemotopoietic Cell Transplantation for High-Risk Recurrent and Refractory Hodgkin Lymphoma.

Background: High dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) is the most effective treatment for recurrent and refractory Hodgkin lymphoma (HL). Disease recurrence is still a major cause of treatment failure. Augmented BCNU-regimens are reported to have good outcomes but greater pulmonary toxicity. A novel transplant regimen incorporating gemcitabine and vinorelbine, active drugs in HL different from alkylating agents, was tested to establish the maximum tolerated dose (MTD) of gemcitabine and to assess safety and efficacy at the MTD.Methods: In this phase I/II study, dose escalation was performed with gemcitabine in combination with vinorelbine followed by BCNU at reduced dose, etoposide (VP-16), cyclophosphamide (CY) and AHCT. The first 7 patients had dose escalation of gemcitabine before determining the MTD at 1250 mg/m2 on the basis of elevated liver transaminases and a symptom complex of fever, headache, and skin toxicity. For phase II, a total of 92 patients with recurrent or refractory HL have been treated at the MTD to establish safety and efficacy. The regimen consists of gemcitabine 1250 mg/m2 IV at 10 mg/min and vinorelbine 30 mg/m2 on day-13 and day-8, BCNU 10 mg/kg on day-6, VP-16 60 mg/kg on day-4, CY 100 mg/kg on day-2. Regimen-related toxicity, freedom from progression (FFP) and overall survival (OS) were endpoints of the trial.Results: 70 patients were high risk (based on stage IV disease at relapse, failure to achieve minimal disease, or B symptoms at relapse) and 22 patients were low risk (having no risk features). Median age was 33 years. Median follow-up is 2 years (.26–6.8 years). Median time to neutrophil engraftment was 10 days. Regimen-related toxicities of grade 3 skin rash, fever, headache and liver transaminase elevations were transient. Remarkable was the reduction in incidence of systemic steroid-requiring pulmonary toxicity <100 days post-transplant to 15.2% (14 of 92 patients treated at the MTD), as compared to our standard regimen incidence of 35%. Also encouraging is the OS at 2 years for the entire group of 81% (+/−9%) and FFP at 2 years of 71%(+−11%). By risk factors, FFP at 2 years was 95%(+−10%), 75%(+−14%), 64%(+−22%), and 19%(+−31%) for patients with 0, 1, 2, or 3 risk factors. These results compare favorably to the historical FFP of 41% for patients with one or more of these same risk factors (Horning 1997). In the current study, having 1 or 2 risk factors resulted in similar FFP with the new regimen (p=.46) and significantly improved FFP as compared to patients with 3 risk factors (1 vs 3, p<.001; 2 vs 3, p=.004)- see figure.Conclusions: This novel transplant regimen for HL has decreased incidence of pulmonary toxicity compared with augmented BCNU-regimens and is associated with encouraging OS and FFP, even in the high risk groups. [Display omitted]

Selective pulmonary artery perfusion followed by blood flow occlusion: New challenge for the treatment of pulmonary malignancies

Introduction Selective pulmonary artery perfusion (SPAP) is an experimental endovascular technique for the treatment of pulmonary malignancies. This study evaluated blood flow occlusion (BFO) after SPAP and dose-escalation in order to delay washout of gemcitabine from the lung tissue, to augment pulmonary drug exposure and to maintain plasma concentrations equivalent to intravenous administration. Material and methods Six groups of pigs underwent left-sided SPAP using gemcitabine in a clinically applied dose of 1–1.5 g/m 2 after balloon catheterisation. BFO experiment: four groups ( n = 4, each) were treated with SPAP with 1 g/m 2 of gemcitabine during 2 min followed by BFO for 0, 10, 20 and 30 min, respectively. Dose-escalation experiment: two more groups ( n = 3, each) received SPAP with 1.25 and 1.5 g/m 2 of gemcitabine during 2 min followed by 30 min BFO. All pigs underwent left thoracotomy with sampling of lung, liver and blood. The animals were sacrificed after 1 h. The lung and plasma areas under the curve (AUC) were calculated for each group and ANOVA and t-test was used for comparison. Results Thirty minutes BFO resulted in the highest lung AUC compared to 0, 10 and 20 min BFO ( p < 0.001), while no significant differences in plasma AUC and liver levels were observed. Gemcitabine dose-escalation up to 1.25 g/m 2 resulted in significantly higher lung AUC ( p = 0.02) compared to 1 g/m 2, while plasma AUC was equivalent with intravenous treatment. Further dose-escalation to 1.5 g/m 2 did not result in significantly higher lung levels compared to 1.25 g/m 2. Conclusion BFO after SPAP delays the washout of gemcitabine from lung tissue. Dose-escalation resulted in higher lung concentrations, while plasma levels were equivalent with intravenous administration. We advocate 2 min of SPAP with 1.25 g/m 2 of gemcitabine followed by 30 min of BFO to be investigated as a new treatment modality for pulmonary malignancies.

Dose Escalation of Gemcitabine Is Possible With Concurrent Chest Three-Dimensional Rather Than Two-Dimensional Radiotherapy: A Phase I Trial in Patients With Stage III Non–Small-Cell Lung Cancer

To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m(2)/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m(2)/wk and cisplatin 60 mg/m(2). In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m(2)/wk cohort and 2 of 3 patients in the 125-mg/m(2)/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m(2)/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m(2)/wk when using 3D planning. The Phase II dose is 150 mg/m(2)/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.

A phase I study of gemcitabine followed by cisplatin concurrent with whole pelvic radiation therapy in locally advanced cervical cancer: A Gynecologic Oncology Group study

Purpose To determine the maximum tolerated dose (MTD) of gemcitabine followed by cisplatin that can be administered weekly during pelvic radiation therapy in patients with locally advanced cervical cancer. Methods A phase I and feasibility study with dose escalation of gemcitabine in cohorts of three to six patients to determine the MTD (the dose level at which no more than one of six patients experienced a acute dose-limiting toxicity) was conducted. Results Thirteen patients were entered on the phase I trial. Acute dose-limiting toxicity occurred with weekly cisplatin at a dose of 40 mg/m 2 and gemcitabine at a dose of 100 mg/m 2. The study was modified, decreasing the dose of cisplatin to 30 mg/m 2 in an effort to dose escalate gemcitabine. Acute dose-limiting toxicity occurred again with weekly cisplatin at a dose of 30 mg/m 2 and gemcitabine at a dose of 75 mg/m 2 (dose level 3). In addition to acute hematologic and acute and late non-hematologic toxicities, late grade 3 and 4 GI and GU toxicities have occurred in two of six patients at dose level 3. Twelve of thirteen patients remained disease-free following treatment. Conclusion The MTD found in this chemoradiation study was weekly gemcitabine 50 mg/m 2 followed by cisplatin 40 mg/m 2. The alternative drug sequence has been reported by others to allow higher doses of gemcitabine. However, at this dose level chronic toxicity was observed. Further expansion of the feasibility cohort of this study was suspended pending the efficacy and toxicity results of a large trial which has recently been completed.

Biweekly gemcitabine and oxaliplatin (GEMOX) in first-line metastatic or recurrent nasopharyngeal carcinoma (NPC)—An early report

6071 Background: This multicenter phase II study evaluated the activity &amp; safety of oxaliplatin (Ox), a 3rd generation platinum, in combination with gemcitabine (GEM) for the first time in the palliative setting for patients (pts) with undifferentiated/ poorly differentiated NPC. Methods: Pts with untreated metastatic (M1) or locoregionally recurrent (LR) NPC were treated with a biweekly ‘GEMOX’ regimen (D1: GEM, 1,000 mg/m2 at 10 mg/m2/min; D2: Ox, 100 mg/m2 over 2 hrs) for a max. of 12 cycles. Intrapatient dose escalation of GEM to 1,250 mg/m2 was allowed from cycle 2 onwards if no significant toxicity occurred in cycle 1. Response was assessed every 4 cycles (RECIST criteria). Results: 23 pts accrued before 31st July 06 were evaluated for toxicity &amp; response; cut-off date for data analysis was 15th Oct 06. The median age was 53 yrs (range 38–72); 19 were men, all had ECOG status of 0–1. At enrolment, 7 pts (29%) had M1 disease only, 3 (12%) pts had LR only, &amp; the rest both M1 &amp; LR. All 7 pts with only LR received radical radiotherapy (RT) at initial diagnosis. A median of 11 cycles (range 3–13) were administered. Best overall response rate was 52%, with 12 partial responses &amp; 11 stable diseases. The median duration of response was 7 months (range 0.8–15). Grade (gr) 3–4 hematological toxicities (CTCAE ver 3) included neutropenia in 7 pts (30%, only 1 pt had fever), thrombocytopenia in 5 pts (26%, 1 gr 4 case with mild gum bleeding). Gr 3–4 non-hematological toxicities included gr 3 diarrhoea in 2 pts, gr 4 Ox-related hypersensitivity reaction in 1 pt, gr 3 epistaxis in 2 pts. The commonest non-hematological toxicities were gr 1–2 Ox-related sensory neuropathy (22pts). There were no treatment-related deaths &amp; only 1 pt withdrew from study due to drug-related toxicity. Conclusions: GEMOX is a promising regimen among pts with metastatic &amp; recurrent NPC. Accrual is ongoing with a planned total sample of 40 pts. No significant financial relationships to disclose.

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study

We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m(2) and 30 mg/m(2), respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m(2) was conducted and primary objective in the phase II portion was response rate. The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m(2) because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C (max) and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.

Pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) in combination in the salvage treatment of epithelial ovarian cancer (OC)—a Danish Gynaecologic Cancer Group (DGC) study

5094 Background: Ovarian cancer patients (pts) recurring with a short treatment-free interval (TFI) after prior chemotherapy (PCT) have a bad prognosis. DGC has conducted a phase II study of PLD-GEM in combination in OC pts recurring with a TFI of less than 12 months (mo). Methods: All pts must have received at least one platinum-paclitaxel containing regimen; no PCT with GEM or anthracyclines. Regimen: GEM 800mg/m2 day 1+8 and PLD 25mg/m2 day 1, q 21 days. GEM dose escalation to 1g/m2 day 1+8 from 2. cycle in the absence of grade 3–4 toxicity. Primary end point: OS, secondary: PFS, response and toxicity. Pts were grouped according to their response to PCT. Group 1: pts with CR on PCT and TFI 3–12 mo; group 2: pts with CR on PCT and TFI 0–3 mo; group 3: pts with PR/SD on PCT and TFI 0–12 mo. 35 pts with ≥2 prior number of treatments. Results: 82 pts were enrolled (May 2003-Aug 2005); the median age was 59 yrs (range 31 to 77 yrs); 15 pts were entered with rising CA125 only (GCIG criteria). Groups according to their response to PCT: group 1: 44 pts; group 2: 5 pts; group 3: 33 pts. TFI ≤ 6 mo 33 pts, TFI &gt; 6 to ≤ 12 mo 49 pts. To date data on 330 cycles (mean 4.7 cycles) is available; 45 pts are evaluable for PFS and OS; 62 pts are evaluable for response and 71 pts for toxicity. Grade 3–4 toxicity: PPE 6/330 cycles; mucosites 8/330 cycles; febrile neutropenia 4%; treatment delay 9%. No dose reductions performed for PLD. GEM dose escalation to 1000 mg/m2 in 31 pts; dose reduction to 650 mg/m2 at any time in 21 pts; skipped dose day 8 in 44 cycles. Response (RESIST): CR 3 pts; PR 17 pts (CR+PR 32%); SD 39 pts; PD 2 pts. Median PFS 212 days, Median OS 234 days. Conclusions: PLD-GEM in combination in the salvage setting is well tolerated, with acceptable toxicity and clear activity. No significant financial relationships to disclose.

Mistletoe extract/gemcitabine combination treatment: An interim report from the NCCAM/NCI phase I study in patients with advanced solid tumors

3098 Background: European Mistletoe (viscum album L.) extracts (ME) are used in varying doses and schedules as herbal adjunct treatment for solid tumors in Europe. Clinical efficacy remains controversial. Controlled data on safety, toxicity and drug interactions are lacking. Methods: Subjects with stage IV cancer (average age 51 years; breast 5, pancreas 4, colorectal 3, NSCLC 4) enrolled on a 2 stage dose escalation phase I trial of toxicity profile, dose limiting toxicity (DLT), MTD, and gemcitabine (GEM) pharmacokinetics (with and without ME) on s.c.qd ME (HELIXOR A, Helixor GmbH, KG, Rosenfeld, Germany) combined with GEM 750mg/m2i.v. on a weekly x 2 q 21d schedule for 3 cycles. We report on stage I (fixed dose GEM). Starting target ME dose level was 20mg (n=3), with escalations to 50 (n=3), 100 (n=3), 200 (n=5), and 250 mg (n=2). DLT for GEM is neutropenia. GEM and 2’,2’-difluorodeoxyuridine (dFdU) plasma concentrations (Cp) at baseline and week 8 (stable ME dose for 7 days) were determined by HPLC with UV detection o 12 subjects who completed 3 cycles (ME dose 20–200mg). The area under the curve (AUC) was determined using WinNonLin version 4.0. This project was approved by the Navy Clinical Investigation Program Project Number: 02–074 Results: No ME DLT was observed. Ten ME related grade 2 adverse events (AE, injection site reaction 4, flu-like syndrome 4, other local reaction 2), 30 grade 3 GEM-related AE (lymphopenia 12, neutropenia/low WBC 10, thrombocytopenia 2, nausea/vomiting 2, other 4) and 1 GEM related grade 4 lymphopenia were observed. Median baseline and week 8 AUC (664/670 min*nmol/ml, p=0.97) and Cp (47.7/49.7 nmol/ml, p=0.85) of GEM and dFdU (AUC 1038/1099 min*nmol/ml, p= 0.46, Cp 75.7/84 nmol/ml, p=0.67) were equivalent (signed rank test). 1038 of 1059 scheduled ME doses were given (compliance 98.2%). Tow subjects had partial clinical responses (PR) by RECIST (pancreas 1, NSCLC 1) and four subjects had stable disease > 18 wks (pancreas 1, NSCLC 2, rectal 1). Conclusions: The ME/GEM combination has been well tolerated. GEM Cp during infusion was unaffected by ME. Two subjects had a PR. Stage II (GEM dose escalation) will determine if addition of ME alters GEM toxicities and MTD. No significant financial relationships to disclose.

Pilot Study of Fixed-Infusion Rate Gemcitabine with Cisplatinand Dexamethasone in Patients with Relapsed or Refractory Lymphoma

Management of patients with multiple-relapsed lymphoma meets with little success. The optimal use of available drugs in this situation is often unknown. Gemcitabine has documented efficacy in this setting. Pharmacodynamic data suggest that the optimal use may involve a fixed-rate infusion and coadministration with platinum compounds. In this study we explored the use of gemcitabine starting at a dose of 800 mg/m2 administered at a fixed infusion rate of 10 mg/m2 per minute with cisplatin 35 mg/m2 intravenously, both given on day 1, and dexamethasone 20 mg daily for 4 days; the treatment was given every 2 weeks (days 1 and 15 of a 28-day cycle) for the treatment of relapsed Hodgkin's and non-Hodgkin's lymphoma. Dose escalation of gemcitabine was allowed according to phase I criteria. Twentytwo patients with a median of 4 prior treatments were enrolled (Hodgkin's lymphoma, n = 7; B-cell non-Hodgkin's lymphoma, n = 9; T-cell non-Hodgkin's lymphoma, n = 6). Ten patients had relapsed after prior autologous transplantation. Grade 4 thrombocytopenia and neutropenia were the dose-limiting toxicities and occurred in 9 patients (41%) and 4 patients (18%), respectively. Initial dose escalation of gemcitabine was not possible. Responses were observed in 45% of the patients: 2 of 5 with T-cell non-Hodgkin's lymphoma (1 patient withdrew after first treatment and was evaluable only for toxicity), 4 of 7 with Hodgkin's lymphoma, and 4 of 9 with B-cell non-Hodgkin's lymphoma. The coadministration of gemcitabine 800 mg over 80 minutes with low-dose cisplatin and dexamethasone is feasible and sufficiently active in a heavily pretreated patient population with lymphoma.

Radiation therapy with once-weekly gemcitabine in pancreatic cancer: Current status of clinical trials

Clinical trials investigating a variety of gemcitabine-based chemoradiation therapy regimens were initiated several years ago and remain under active investigation for the treatment of patients with pancreatic cancer. These trials are based, in part, on the activity of gemcitabine as a single agent in pancreatic cancer, preclinical studies that demonstrated radiosensitization, and the need for approaches with greater efficacy than that provided by 5-fluorouracil (5-FU)–based chemoradiation therapy. In this review, we describe and compare several Phase I clinical trials investigating dose escalation of once-weekly gemcitabine with concurrent radiation therapy. We also describe a relatively novel approach successfully investigating radiation dose escalation with a standard weekly dose of gemcitabine. Toxicity data from this trial, and the prior trials of gemcitabine dose escalation with more conventional radiation therapy, suggest that the volume of normal tissue radiated in gemcitabine-based chemotherapy regimens may be the most critical consideration for future trial designs. Finally, we highlight the need to fully consider the design of future trials in the context of both local and distant disease control, given the radiosensitizing potential and systemic activity of gemcitabine.