Dose Level 1 Research Articles

Phase I feasibility study of carboplatin plus capecitabine followed by maintenance capecitabine in patients (pts) with recurrent platinum-sensitive epithelial ovarian cancer (EOC)

5564 Background: In a previous study, we noted a response rate (RR) of 61% for the 3 drug combination of carboplatin, epirubicin and capecitabine in platinum-sensitive recurrent EOC. This combination however resulted in excessive grade (G) 3–4 haematological toxicity (55%) (BJC 2006; 94:74). The current trial therefore assessed the feasibility and efficacy of the 2 drugs, carboplatin and capecitabine as second- or third-line treatment. Methods: Pts were administered carboplatin (AUC5) day 1 and capecitabine at a starting dose of 750 mg/m2 bd, days 1–21, q21 (dose level 1). The capecitabine dose was deescalated to 625 mg/m2 (dose level -1) and 500 mg/m2 (dose level -2) according to toxicity. Pts with an objective response or stable disease received maintenance capecitabine (at the same dose level) for up to 12 months or until progression. Responses were assessed with RECIST criteria and CA-125. Results: 19 of the 20 pts enrolled were evaluable for toxicity and response. Dose-limiting toxicity was observed at dose level 1 (G3 fatigue, G3 diarrhoea, G3 neutropenia of > 14 days; n = 3/5), dose level -1 (G3 angina (n = 2), G3 vomiting, G3 palmar plantar erythema; n = 4/7) and dose level-2 (diarrhoea / fatigue; n = 1/7). One patient had a G3 carboplatin hypersensivity reaction. 8 pts received maintenance capecitabine which was well tolerated. The overall RR was 53% with 10 partial responses and 5 stable diseases. The median progression free survival (PFS) was 6.5 months (m) and the 6mPFS was 63% with 2 pts currently ongoing treatment. The median PFS on maintenance was 3.2 m. Conclusions: The combination was well tolerated at the recommended phase II dose of carboplatin (AUC 5) and capecitabine (500 mg/m2 bd) with partial responses in over half of the cases. [Table: see text]

Phase I study of satraplatin and docetaxel in solid malignancies

2570 Background: Satraplatin (S) is a novel, orally administered platinum compound with broad antitumor activity. Preclincal studies have shown synergy with docetaxel (TAX). Here we report the results of a phase I study of S with TAX with and without G-CSF support in patients with advanced solid tumors. Methods: Patients with metastatic solid malignancies were enrolled. All pts had an ECOG performance status of < 2, adequate hematologic, renal and liver function. Prior chemotherapy/XRT had to have been completed 4 weeks prior to enrollment. Other exclusion criteria included prior XRT to > 30% of the marrow, neuropathy grade > 1, and previous platinum or TAX chemotherapy within 3 months of enrollment. TAX was given as a 1-hour infusion on day 1 (starting dose 60 mg/m2) in combination with S (starting dose 50 mg/m2/day, rounded to nearest 10 mg) administered orally in the fasted state, days 1–5 of a 21-day cycle. Results: 23 patients with a median of 3 prior cytotoxic chemotherapy regimens were enrolled. At dose level 1, 2/7 patients developed grade 3/4 neutropenia lasting > 5 days, exceeding the MTD. At dose level-1 (TAX 60 mg/m2, S 40 mg/m2/d), 1/6 patients developed grade 3/4 ANC. The protocol was subsequently amended to re-escalate with G-CSF (300 mcg SQ days 6–15) support. With G-CSF support, no DLT was observed and further dose escalation to level 2 (TAX 70 mg/m2, S 50 mg/m2/d) resulted in only 1/6 patients developing significant neutropenia. The most commonly reported adverse event was neutropenia (22%), followed by anemia, diarrhea and fatigue. Conclusions: The S and TAX combination is feasible with neutropenia as the main toxicity. Of note, this was a heavily pretreated cancer population. The recommended phase II dose is TAX 60 mg/m2 IV day 1 with SA 40 mg/m2 PO days 1–5, without G-CSF, and TAX 70 mg/m2 IV day 1 with SA 50 mg/m2 PO days 1–5, with G-CSF support, repeated in 3-week cycles. Preliminary data shows encouraging activity in men with high-grade castrate-refractory prostate cancer. As a result, this combination is currently being explored in an expanded cohort assessing the safety/tolerability/efficacy in men with chemo-naive, castrate-refractory prostate cancer. No significant financial relationships to disclose.

Phase I Study of Clofarabine with Standard-Dose Infusional Cytarabine (Ara-C) as Intensive Induction Therapy for Newly-Diagnosed De Novo Acute Myeloid Leukemia in Older Adults Age ≥60 Years.

Background The median age of AML is approximately 70 years, and the survival of older adults age ≥60 years remains poor with standard therapy. Clofarabine (CLO) has significant single agent activity in AML, and in vitro studies demonstrate synergy with Ara-C. We therefore performed a phase I study to determine the maximum tolerated dose (MTD) of CLO with standard dose Ara-C (100mg/m2/day D1-7 by 24hr continuous infusion) as AML induction therapy. CLO was administered daily × 5 days beginning D2 to allow for pharmacokinetic (PK) & pharmacodynamic (PD) studies.Methods Enrollment was restricted to newly-diagnosed de novo AML patients age ≥60 years considered candidates for intensive therapy; those with prior MDS or hypoplastic AML (<20% bone marrow cellularity) were excluded. Pts were treated in cohorts of 3–6 to determine MTD of CLO with standard dose infusional Ara-C (100mg/m2 × 7). DLT was defined as grade III/IV non-hematologic toxicity occurring in >1 pt per cohort. The CLO starting dose was 30mg/m2/day ×5 (dose level 1), with the intention to increase to CLO 40mg/m2 if tolerated. However, CLO dose reductions of 25% (CLO 22.5 mg/m2/day × 5, dose level -1) & 50% (CLO 15mg/m2/day ×5, dose level -2) were allowed in the event of dose-limiting toxicity (DLT). Pts achieving complete remission (CR) received 2 cycles consolidation with CLO ×5 & Ara-C 100mg/m2 × 5.Results A total of 13 pts (median age 69 yrs, range 61–77; 10 male) have been treated. DLT was observed at dose level 1 (Table 1), and the protocol was amended to mandate additional hydration with CLO, and antibiotic/antifungal prophylaxis. At dose level -1, 1 pt died from PE on D27 after hematologic recovery, considered treatment-related per protocol, mandating dose de-escalation to dose level -2. Pt 13 is in active induction therapy, and not yet evaluable for response, although DLT has not been encountered. Febrile neutropenia occurred in 11/13 pts. The MTD in this study is CLO 15mg/m2/day × 5 with standard infusional Ara-C (dose level -2). Significant clinical activity was observed, particularly at higher CLO doses, including CR in 2 pts with complex karyotype. In contrast, only 1/5 evaluable pts at dose level-2 achieved CR. PK & PD studies are in progress.Conclusions In contrast to prior reports using intermediate dose bolus Ara-C (1g/m2), the MTD of CLO combined with standard dose infusional Ara-C in older adults with AML is lower, and the toxicity profile appears different. Significant clinical activity was noted at higher CLO dose levels & with complex karyotype. Based on this observation an escalation to CLO 20mg/m2 is now planned.CLO & Standard Dose Infusional Ara-C: Toxicity & EfficacyPatientCLO Dose LevelAgeCytogeneticsResponse (CR Duration)DLT11 (30mg)66−7DeathInfection/Renal2161−7, complexCR (15 mths)none3169intermediateCR (2 mths)none41775q-, complexDeathInfection/Renal/Vasc Leak5−1 (22.5mg)75+8DeathPneumonia6−167diploidCR (5 mths)none7−1719q-DeathPulm Embolism Day 278−2 (15mg)745q-, complexFailnone9−264diploidFailnone10−263diploidFailnone11−273complexCR (5 mths)none12−272diploidFailnone13−263diploid--Fail - failure to achieve CR

The Anti-CD19 Bispecific T-Cell Engager (BiTE) MT103 (MEDI-538), Induces Dose-Dependent Complete and Partial Responses in Relapsed Non-Hodgkin Lymphoma (NHL): Phase I Study MT103-104.

MT103 (MEDI-538), a bispecific, single chain construct specific for CD19 and CD3, is a member of a novel class of highly active antibody derivatives that direct T-cells to target cells. The primary objective of this study is to evaluate the safety and tolerability of a 4- to 8-week continuous intravenous infusion at increasing dose levels in patients with relapsed NHL, starting at dose level 1 (DL1) of 0.5μg/m2/24h. Dose-limiting toxicities (DLTs) were assessed during the first 2 weeks of infusion. To date, 31 patients have been included up to a dose level of 30μg/m2/24h. No DLTs were observed from DL1 to DL3 (5μg/m2/24h. At DL4 (5μg/m2/24h on day 1, followed by 15 μg/m2/24h maintenance dose), 7 patients (pts) were treated. One of the 7 pts had elevated liver enzymes up to CTC grade 3 after 2 weeks, and another patient showed reversible confusion, assessed as a DLT on the 2nd treatment day. For further optimization of safety and convenience of the initiation phase, the stepwise increase was modified to a constant infusion rate. This regimen was well tolerated and showed a favorable safety profile. Due to these modifications a total of 13 pts were treated at 15μg/m2/24h. At 30μg/m2/24h, 6 pts were treated; one DLT (metabolic acidosis, grade 4) was recorded. Confounding factors for this event were pre-existing renal insufficiency, fever and increasing anemia. The adverse events (AEs) were transient and the most common ones observed so far in all cohorts, regardless of causality, were (overall/grade 3 or 4) leucopenia (63%/37%), lymphopenia (59%/59%), pyrexia (55%/7%) elevated liver enzymes (44%/4%). At the dose level of 15μg/ m2/24h, MT103 induced 1 complete (CR) and 2 partial responses (PRs) in indolent lymphoma, which had not been observed at the previous dose levels. A total of 5 pts including the responders at this dose level had bone marrow involvement by indolent lymphoma. MT103 induced complete disappearance of lymphoma cells from the bone marrow in 3 and partial reduction in 2 of the 5 cases. One of these 5 patients had lymphoplasmocytoid lymphoma pre-treated with fludarabine. MT103 induced a 60% reduction of paraprotein. At the dose level of 30μg/m2/24h, clinical benefit was observed in mantle cell lymphoma (MCL), which had not been noted at the previous dose levels. One out of 3 evaluable pts with MCL enrolled at this dose level experienced a CR and one showed complete disappearance of lymphoma cells from the bone marrow. Best responses in the 26 evaluable pts overall were 2 CRs, 2 PRs, 2 minimal responses (MRs) and 13 SDs. Best responses in 14 evaluable patients starting at the dose level of 15μg/m2/24h were 2 CRs, 2 PRs, 2 MRs and 5 SDs.Conclusions: The current data suggest a favorable safety profile of MT103 administered as continuous 4 to 8 week infusion. MT103 induces CRs and PRs in relapsed indolent lymphoma and MCL in an apparently dose dependent fashion. Pronounced effects on lymphoma bone marrow infiltration have further demonstrated the clinical activity of MT103. Determination of the optimal biological dose is ongoing.

A phase I clinical trial of low-dose interferon-α-2A, thalidomide plus gemcitabine and capecitabine for patients with progressive metastatic renal cell carcinoma

We have conducted a phase I trial to determine the maximum tolerated dose of gemcitabine in combination with interferon, thalidomide and capecitabine. Patients received oral capecitabine 1,000 mg/m(2 )per day, divided in 2 daily doses, 2 weeks on, 1 week off; subcutaneous interferon-alpha 1 mIU twice a day without an interruption; daily oral thalidomide 200 mg/day for the first 7 days, then escalated to 400 mg/day without an interruption. Gemcitabine was given by intravenous administration over 30 min on day 1, week 1 and day 8, week 2. Initial dose level of gemcitabine was 400 mg/m(2). The dose of gemcitabine was the phase I variable. One cycle was 3 weeks. We treated 12 patients, 6 patients were entered at a dose level of 0 (gemcitabine 400 mg/m(2)) and 6 patients entered at a dose level-1 (gemcitabine 200 mg/m(2)). Eight of 12 patients completed at least 12 weeks of therapy. Three partial responses and two stable disease were observed. The remaining patients had progressive disease. Non-hematologic toxicity was either grade 1 or 2. Hematologic toxicity at dose level 0 consisted of 3 patients with grade 3/4 neutropenia, and 1 patient with grade 3 thrombocytopenia. At dose level-1 grade 1/2 neutropenia was observed. The completion of our phase I experience determined our maximum tolerated dose to be dose level-1. The phase II trial is currently being proposed for patients with rapidly growing clear cell, other histologies that may contain sarcomatoid elements or collecting duct tumor.

Phase I study of bi-weekly pemetrexed (P) plus cisplatin (C) in patients with advanced cancer

2580 Background: Cisplatin and pemetrexed have demonstrated clinical activity in several malignant tumors including mesothelioma and non small cell lung cancer. There is preclinical evidence of synergism between both agents as well as clinical non-overlapping toxicities, thus providing the rationale for their evaluation in combination. Our aim was to develop a well-tolerated combination of bi-weekly CP able to deliver higher dose intensity than the every 3-week standard. Methods: Escalating doses of P from a starting dose level of 300 mg/m2, with a fixed-dose of C 50 mg/m2, both biweekly on 28-day cycles, were administered to patients with refractory advanced solid malignancies and calculated creatinine clearance = 45 mL/min. Results: Twenty one patients (5 female/16 male); median age 61 (39–76); ECOG 0 (16), 1 (5); lung cancer (9); soft-tissue sarcoma (3); unknown primary, bladder, breast, rectum, esophagus, melanoma, mesothelioma, prostate, and tonsil (1, each) have received a total of 48 courses (median 2, range 0–5), at P dose levels of 300 mg/m2 [8 pts, Dose level 1 (DL1)], 400 mg/m2 (7 pts, DL2), and 500 mg/m2 (6 pts, DL3), with full doses of C. Four patients were non-evaluable (2 at DL1, 1 at DL2 and 1 at DL3) because of early PD (2) and non-drug related serious adverse event (2 pt). Dose Limiting Toxicities (DLT) were G4 neutropenia (1 pt) at 300 mg/m2; and prolonged G 1/2 thrombocytopenia (1 pt) at 500 mg/m2. There were also 2 pts with non-DLT G4 neutropenia at DL3. The rest of toxicities were mild to moderate being the most frequent asthenia, nausea, anorexia, stomatatis, and sensory neuropathy. DL3 was considered the Maximum Tolerated Dose (MTD) and the previous level with P at 400 mg/m2 was declared the recommended phase II dose. Three additional patients were treated at DL2 for dose confirmation. A PR has been observed in 2 pts with NSCLC, 1 pt with breast, and 1 with esophagus cancer. Conclusions: Biweekly administration of pemetrexed (400 mg/m2) plus cisplatin (50 mg/m2) is clinically well tolerated and can be used safely. The regimen delivers higher dose intensity of P and equal of C as the standard. This regimen is currently being studied in a phase 2 trial in patients with locally advanced, non resectable or metastatic urothelial cancer. No significant financial relationships to disclose.

Phase 1b study defining the optimal dosing combinations of the mTOR inhibitor AP23573 and Paclitaxel (PTX)

3509 Background: AP23573 is a novel mTOR inhibitor with demonstrated anti-tumor activity in clinical trials. In vitro, AP23573 exhibits at least additive anti-proliferative activity in combination with a variety of agents including taxanes. This trial studied the combination of AP23573 and paclitaxel (PTX) in patients with advanced solid tumors. Methods: This was a modified, sequential (3+3) dose finding study with starting doses of 25 mg AP23573 i.v. and 80 mg/m2 PTX i.v. as Dose Level 1 (DL1) on days 1, 8 and 15 of a 28 day cycle. Doses of either drug were adjusted in successive cohorts. Blood samples and skin biopsies were collected for pharmacokinetic (PK) and pharmacodynamic (PD) studies. Dose limiting toxicity definitions included neutrophils &lt;500/μL; thrombocytopenia = Grade 3 (CTC), any non- hematologic toxicities = Grade 2; missing 2 consecutive doses due to any toxicity. For PK and PD analysis, AP23573 and PTX were administered one day apart at the start of Cycle 1, reversing the sequence at Day 8. Results: Enrollment is complete and 29 patients with a variety of tumors (sarcoma, pancreatic, H&amp;N, melanoma, thymoma) have been treated. Grade 3 thrombocytopenia and Grade 2 mouth sores were seen at DL1 as well as missed doses due to moderate (Grade 2) neutropenia. Adverse events include mouth sores and fatigue which were mild and reversible. Available PK data for AP23573 and PTX suggest no interaction. PD analysis in peripheral blood mononuclear cells demonstrates no interference by PTX on mTOR inhibition by AP23573. PD data in skin biopsies are forthcoming. Both 12.5 mg AP23573/80mg/m2 PTX and 37.5mg AP23573/60mg/m2 PTX are maximal dose combinations that appear to be well tolerated. Activity has been observed at multiple AP23573 mg/PTX mg/m2 dose levels (25/60, 12.5/80, 25/80). Five patients have been on study for &gt;4 cycles, including 2 patients with partial responses (H&amp;N and pancreatic). Conclusions: Combined therapy with AP23573 and PTX is safe. It is notable that evidence of anti-tumor activity was observed at modest doses of each drug when in combination. Combinations of these agents at both doses cited would be recommended for evaluation in trials examining efficacy in specific tumors. No significant financial relationships to disclose.

Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors

7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine-threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan. Patients with incurable solid malignancies received UCN-01 intravenously (IV) as a 3-h infusion on day 1 and irinotecan IV over 90 min on days 1 and 8 of a 21-day cycle. Doses of UCN-01 for subsequent cycles were half the starting dose. Dose level 1 (DL1) consisted of UCN-01 and irinotecan doses of 50 and 60 mg/m(2), respectively. Blood samples were collected in cycle 1 for UCN-01, irinotecan, and irinotecan metabolites. A total of 16 patients were enrolled on the trial at UCN-01/Irinotecan doses of 50/60 mg/m(2) (DL1; n = 1), 70/60 mg/m(2) (DL2; n = 6), 90/60 mg/m(2) (DL3; n = 4), and 70/90 mg/m(2) (DL4; n = 5). Two dose-limiting toxicities were observed each in DL3 and DL4 (2 grade 3 hypophosphatemia, 1 grade 4 hyperglycemia and grade 3 hypophosphatemia, 1 grade 4 febrile neutropenia). Fatigue, diarrhea, nausea, and anorexia were the most prevalent toxicities. No objective responses were documented, and four patients had stable disease for at least ten cycles. The long half-life (292.0 +/- 135.7 h), low clearance (0.045 +/- 0.038 l/h), and volume of distribution (14.3 +/- 5.9 l) observed for UCN-01 are consistent with prior UCN-01 data. There was a significant decrease in C(max) of APC, AUC of APC and SN-38, and AUC ratio of SN-38:irinotecan when comparing days 1 and 8 PK. APC and SN-38 exposure decreased when administered in combination with UCN-01. The MTD of the combination based on protocol criteria was defined as 70 mg/m(2) of UCN-01 on day 1 and 60 mg/m(2) of irinotecan on days 1 and 8 in a 21-day cycle.

Dose-escalated CHOP plus etoposide (MegaCHOEP) followed by repeated stem cell transplantation for primary treatment of aggressive high-risk non-Hodgkin lymphoma

AbstractFeasibility, safety, and efficacy of a 4-course high-dose chemotherapy (HDT) protocol including autologous stem cell transplantation (SCT) after courses 2, 3, and 4 was investigated in 110 patients, aged 18 to 60 years, with primary diagnosis of aggressive NHL (aNHL), and lactic dehydrogenase (LDH) levels above normal. At dose level 1 (DL1), course 1 consisted of cyclophosphamide 1500 mg/m2, doxorubicin (Adriamycin) 70 mg/m2, vincristine 2 mg, etoposide 450 mg/m2, and prednisone 500 mg. With courses 2 and 3 cyclophosphamide and etoposide were escalated to 4500 mg/m2 and 600 mg/m2, respectively. With course 4 cyclophosphamide and etoposide were given at 6000 mg/m2 and 1000 mg/m2, respectively. At DL2 etoposide was further increased to 600, 960, 960, and 1480 mg/m2 with courses 1 to 4, respectively. Therapy as per protocol was completed by 81.8% of patients. Overall survival at 5 years was 67.2%, freedom from treatment failure (FFTF) was 62.1%, and treatment-related mortality was 4.5%. There was a trend to better FFTF at DL2 compared to DL1 (66.9% versus 54.2%). Repetitive HDT with escalated CHOP plus etoposide is feasible and effective treatment of patients with aNHL. DL2 of this therapy is being used in an ongoing phase 3 study.

Dose Escalated CHOP + Etoposide Followed by Repetitive Autologous Stem Cell Transplantation (MegaCHOEP) with or without Rituximab for Primary Treatment of Aggressive NHL.

Whilst safety and efficacy of adding rituximab to standard therapy has been reported, less information is available on the combination of rituximab (R) with HDT and autologous SCT. The German Study Group for High-Grade NHL (DSHNHL) developed a repetitive HDT program consisting of 4 courses dose escalated CHOP + Etoposide +/− R. Patients aged 18 to 60 years and elevated LDH at diagnosis were included. Mega-CHOEP consisted of four cycles of chemotherapy. Cycles 2 to 4 were followed by autologous SCT. At dose level 3 (DL3) cumulative doses of drugs were as follows: C 19.5 g/m2, H 280 mg/m2, O 8 mg, E 5.04 g/m2, P 2000 mg. When feasibility and safety of MegaCHOEP at DL3 had been demonstrated, rituximab was added (DL3R). Six cycles of rituximab (375 mg/m2) were given: one dose of rituximab prior to each cycle of chemotherapy and two additional doses 3 and 6 weeks after the last cycle of chemotherapy, respectively. From September 1999 to may 2001 35 pts with validated diagnosis of aggressive B-NHL received MegaCHOEP DL3, from June 2001 to February 2003, 72 pts received DL3R. There was a higher percentage of B-cell NHL patients with ECOG performance status > 1 at DL3 (42.9 %) than at DL3R (19.7 %, p = 0.012) and as consequence more patients with age-adjusted IPI high risk at DL3 (34.3 %) than at DL3R (12.7 %, p = 0.029). We observed significant differences in the incidence of WHO grade III/IV infections (DL3 9 of 123 cycles (7.3%), DL3R 48 of 236 cycles (20.3%); p=0.001) and in the percentage of patients receiving the complete program of chemotherapy (DL3:91 %, DL3R 71%; p=0.017). There were no relevant differences in other types of non-hematologic toxicity or hematopoietic recovery between treatment groups. Median observation times of patients at DL3 and DL3R were 2.6 years and 4.5 years, respectively. In univariate analysis, there was a trend to better overall survival with rituximab (75%) than without rituximab (57%) at three years (p=0.168) and a significantly better freedom from treatment failure in patients receiving DL3R as compared to DL3 with 70 % vs 50 % at 3 years (p = 0.040). In a Cox regression model adjusted for IPI, there was a trend to a higher relative risk of treatment failure of MegaCHOEP without rituximab (RR 1.8); this, however, was not statistically significant (p = 0.087). Rituximab may have beneficial influence on lymphoma control in this setting; its use, however, is accompanied by higher incidence of serious infections which subsequently compromise the dose intensity of this aggressive treatment program. The DSHNHL is currently performing a randomized study comparing MegaCHOEP+R with CHOEP−14+R.

Dose escalated CHOP + etoposide and repetitive autologous stem cell transplantation (MegaCHOEP) with and without rituximab for primary treatment of aggressive NHL

6654 Background: The role of high dose chemotherapy (HDT) +/- Rituximab (R) in primary treatment of aggressive NHL is still controversial. Methods: Patients at an age of 18 to 60 years and elevated LDH at diagnosis received 4 courses of dose escalated CHOP + Etoposide +/- R(MegaCHOEP) in a dose escalation trial (primary endpoint: time to treatment failure). Cycles 2 to 4 were followed by autologous SCT. At dose level 3 (DL3) cumulative doses of drugs were as follows: C 19.5 g/m2, H 280 mg/m2, O 8 mg, E 5.04 g/m2 P 2000 mg. In a further step, six cycles of rituximab (375 mg/m2) were added: one dose of R prior to each cycle of chemotherapy and two additional doses 3 and 6 weeks after the last cycle of chemotherapy, respectively. Results: From July 1999 to February 2003, 51 pts were enrolled at DL3, and 89 pts were enrolled at DL3R. There was a higher percentage of pts with ECOG performance status > 1 at DL3 (42.9%) than at DL3R (19.7%, p = 0.012) and with IPI high risk at DL3 (34.3%) than at DL3R (12.7%, p ...

A phase I/II study of cetuximab in combination with 5-fluorouracil (5-FU)/folinic acid (FA) plus weekly oxaliplatin (L-OHP) (FUFOX) in the first-line treatment of patients with metastatic colorectal cancer (mCRC) expressing epidermal growth factor receptor (EGFR). Preliminary results

3644 Background: Cetuximab (Erbitux) is an EGFR-targeting IgG1 monoclonal antibody that showed in combination with 5-FU/FA/L-OHP (FOLFOX4) one of the highest response rates ever reported in 1st-line treatment of mCRC. Methods: This phase I/II trial of standard dose cetuximab in combination with L-OHP and infusional 5-FU/FA in a weekly schedule (AIO FUFOX protocol) was conducted in order to investigate the recommended dose and the efficacy of this combination at the respective dose level. In the phase I part cetuximab and L-OHP/FA were given at their fixed doses while two dose levels of 5-FU were investigated (cetuximab 400 mg/m2 i.v. in week 1 followed by 250 mg/m2 i.v. weekly; L-OHP 50 mg/m2; FA 500 mg/m2, 5-FU 1,500 mg/m2 [dose level 1] or 2,000 mg/m2 [dose level 2] i.v. over 24h weekly for 4 weeks followed by 1 week rest). Results: 49 pts have been enrolled, M/F 31/18, median age 62 years (39 - 78), median ECOG performance status 0 (0 - 2). 48 pts are assessable for safety and efficacy. In the phase I part dose limiting toxicities consisting of diarrhea gr 3 occurred in 1 (14%) out of 7 pts and in 3 (20%) out of 15 pts treated at dose level 1 (DL1) and 2 respectively. Consequently, DL2 using cetuximab together with L-OHP/5-FU/FA at their standard doses was considered as recommended dose (RD) for phase II and was expanded to 41 pts. Common gr 3/4 toxicities (pts ≥ 5%, multiple cycles at the RD): neutropenia 10%, mucositis 7%, gr 3 toxicity: diarrhea 24%, neurological 10%, skin 17%. Efficacy: 54% (95% CI 38 - 69%) confirmed remission including one CR was achieved in 41 pts at the RD and 5 (71%, 95% CI 29 - 96%) out of 7 pts at DL1 showed a PR. 3 PR pts at the RD underwent surgery for metastases. Median progression free survival time will be presented. Conclusion: The combination of cetuximab and FUFOX showed at the RD an acceptable safety profile and promising efficacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck KGaA Merck KgaA, sanofi-aventis Merck KgaA, sanofi-aventis Merck KgaA, sanofi-aventis

Phase I/II study of a docetaxel (DOC) and gemcitabine (GEM) combination for early recurrent (≤12 months)(ER) or refractory (R) epithelial ovarian cancer (EOC): Kansai Clinical Oncology Group, Japan

5046 Background:There is no standard chemotherapy regimen for EOC that does not respond to platinum-based chemotherapy (R-EOC), or responds but progresses within 12 months after completing chemotherapy (ER-EOC). Purpose: To determine the efficacy of a DOC and GEM combination for R-EOC or ER-EOC, we conducted phase 1/2 study. Methods:Between October 2000 and November 2003, R-EOC or ER-EOC patients (pts) entered this multi-institutional study. Eligible criteria: histologically verified EOC, age 16 -75 years, ECOG-PS ≤2, adequate bone marrow, hepatic, and renal function, and written informed consent. GEM was administered on days 1 and 8, and DOC on day 8. This treatment was repeated every 3 weeks. The doses were escalated as follows: dose level 1 (DL1); DOC 70 mg/m2, GEM 800 mg/m2, DL2: DOC 70 mg/m2, GEM 1000 mg/m2. Toxicities were assessed according to NCI-CTC ver2.0J and responses were assessed according to both RECIST for measurable disease and Rustin's criteria for CA125. Results:Thirty-four pts were enrolled and administered 95 cycles. The median cycle was 3 (1–7 cycles), median age was 56 years (21 to 74 years), and median interval from prior chemotherapy was 2 months (1 to 12 months). Seventeen pts received more than 3 chemotherapy regimens before the enrollment. Three pts experienced no dose-limiting toxicities (DLTs) in DL1. Two of the three pts in DL2 were experienced DLTs: febrile neutropenia grade 3 (1), and thrombocytopenia grade 4 (1). Then, 28 patients were subjected to the phase 2 study with DL1 as a recommended dose. Thirty-two patients were assessable for response. Response rate was 19.1% (6/32) with 1CR (3.1%), 5PR (16%), and 9SD(28%). One-year and 2-year survival were 51.2% and 23.4%, respectively. The median survival time was 13 months. Toxicities were mainly hematological (G3/G4): neutropenia (16%/50%), thrombocytopenia (19%/0%), anemia (13%/0%), and febrile neutropenia (3%/0%). There were no grade 3 or 4 non-hematological toxicities. Conclusions:A DOC and GEM combination for R-EOC and ER-EOC with DL1 is active and well tolerable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Japan K.K.

Phase I/II study of a docetaxel (DOC) and gemcitabine (GEM) combination for early recurrent (≤12 months)(ER) or refractory (R) epithelial ovarian cancer (EOC): Kansai Clinical Oncology Group, Japan

5046 Background:There is no standard chemotherapy regimen for EOC that does not respond to platinum-based chemotherapy (R-EOC), or responds but progresses within 12 months after completing chemotherapy (ER-EOC). Purpose: To determine the efficacy of a DOC and GEM combination for R-EOC or ER-EOC, we conducted phase 1/2 study. Methods:Between October 2000 and November 2003, R-EOC or ER-EOC patients (pts) entered this multi-institutional study. Eligible criteria: histologically verified EOC, age 16 -75 years, ECOG-PS ≤2, adequate bone marrow, hepatic, and renal function, and written informed consent. GEM was administered on days 1 and 8, and DOC on day 8. This treatment was repeated every 3 weeks. The doses were escalated as follows: dose level 1 (DL1); DOC 70 mg/m2, GEM 800 mg/m2, DL2: DOC 70 mg/m2, GEM 1000 mg/m2. Toxicities were assessed according to NCI-CTC ver2.0J and responses were assessed according to both RECIST for measurable disease and Rustin's criteria for CA125. Results:Thirty-four pts were enrolled and administered 95 cycles. The median cycle was 3 (1–7 cycles), median age was 56 years (21 to 74 years), and median interval from prior chemotherapy was 2 months (1 to 12 months). Seventeen pts received more than 3 chemotherapy regimens before the enrollment. Three pts experienced no dose-limiting toxicities (DLTs) in DL1. Two of the three pts in DL2 were experienced DLTs: febrile neutropenia grade 3 (1), and thrombocytopenia grade 4 (1). Then, 28 patients were subjected to the phase 2 study with DL1 as a recommended dose. Thirty-two patients were assessable for response. Response rate was 19.1% (6/32) with 1CR (3.1%), 5PR (16%), and 9SD(28%). One-year and 2-year survival were 51.2% and 23.4%, respectively. The median survival time was 13 months. Toxicities were mainly hematological (G3/G4): neutropenia (16%/50%), thrombocytopenia (19%/0%), anemia (13%/0%), and febrile neutropenia (3%/0%). There were no grade 3 or 4 non-hematological toxicities. Conclusions:A DOC and GEM combination for R-EOC and ER-EOC with DL1 is active and well tolerable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Japan K.K.

Phase I trial of bortezomib (PS-341) in combination with docetaxel in patients with advanced solid tumors

3052 Background: Bortezomib (PS-341), a first-in-class dipeptidyl boronic acid, is an inhibitor of the 26S proteasome, an ATP-dependent multicatalytic protease central to the ubiquitin-proteasome degradation pathway. The principal mode of bortezomib detoxification is via deboronization involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. A phase I study combining bortezomib and docetaxel is being performed to determine the MTD/toxicities and pharmacokinetics (PK) of this combination in refractory solid tumor pts. Methods: Pts received escalating doses of weekly docetaxel (d1 and d8) and twice-weekly bortezomib (d2, d5, d9, and d12) in 3-wk cycles. Two pts were enrolled at each dose level, with cohort expansion to 6pts for DLT (occurring in cycles 1 or 2). Dose level 1 (DL1), 2 (DL2), and 3 (DL3) consisted of docetaxel/bortezomib 25/0.8 mg/m2, 25/1.0 mg/m2, and 30/1.0 mg/m2, respectively. CYP3A activity, determined using the erythromycin breath test (ERMBT), and docetaxel PK were evaluated during weeks 1 (docetaxel alone) and 5 (docetaxel + bortezomib). Results: Thirteen pts (10 M/3 F; mean (range) age, 62 (40–76) years; ECOG PS, 0–1) received a total of 31 cycles. DL2 was expanded for DLT which occurred in 2 of 6 pts (febrile neutropenia [1 pt] and thrombocytopenia [1pt]), thus exceeding the MTD. DL1 was then expanded to 6 pts where no DLTs occurred; one additional patient will be enrolled to replace a pt not evaluable for toxicity to define the MTD at DL1. One pt received 2 cycles at DL3 with dose-reduction to DL2; gr 3 thrombocytopenia occurred at cycle 3. Both episodes of gr3 thrombocytopenia were transient (<7d) without clinical sequelae. The ERMBT parameter, 14C-exhaled/h (%), and docetaxel clearance did not change between weeks 1 and 5; mean (SD) values were 1.99 (0.84)% vs 2.31 (0.81)% (P=.44) and 29.2 (13.5) L/h vs 27.0 (14.6) (P = .49), respectively. Conclusions: The MTD of docetaxel given weekly for 2 of 3 weeks with bortezomib twice-weekly (4 doses) has been defined. Bortezomib treatment did not alter CYP3A activity and docetaxel CL demonstrating lack of a drug interaction with this drug combination. Supported by U01 CA70095 and Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis (Speaker's Bureau) Aventis