A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors

Purpose  Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors. Methods  Patients received bortezomib, 0.9–1.5 mg/m², on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m², on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination. Results  A total of 37 patients with four median prior therapies were treated. Frequent grade 1–2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m², and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m². Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m² levels, bortezomib at 1.3 mg/m² and PLD at 30 mg/m² are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs. Conclusions  A regimen of bortezomib, 1.3 mg/m² on days 1, 4, 8, and 11 with PLD, 30 mg/m², on day 4 of a 21-day cycle, was safe in this study, and merits further investigation. Supported in part by grants from the following: Millennium Pharmaceuticals, Inc., General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health(RR00046), National Cancer Institute SPORE in Breast Cancer (5-P50-CA58223-09A1 H.S. Earp), National Inst. of Health (K23-RR16536 ECD), Leukemia and Lymphoma Society (6096-07 RZO), and National Cancer Institute (RO1 CA102278 RZO).     

Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies

Purpose  To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine. Methods  Eligible adults (advanced solid tumor; performance status ≤2) received capecitabine 500 mg/m² PO BID days 1–14 and FDR gemcitabine (400–1,000 mg/m² escalated by 200 mg/m² increments) at 10 mg/m²/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD. Results  Thirty patients (median age 59 years) were enrolled. The predominant grade ≥3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m² gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia ≥7 days). At dose level 3 (800 mg/m² gemcitabine), one patient had a DLT (grade 3 neutropenia ≥7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m² PO BID days 1–14 with 800 mg/m² FDR gemcitabine days 1 and 8 infused at 10 mg/m² per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas. Conclusions  This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas. The results of this research appeared as abstract ID 13509 at the 2008 American Association of Clinical Oncology meeting in Chicago, IL, USA.     

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer

Background  S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. Methods  Patients with advanced NSCLC received S-1 (80 mg/m²) on days 1–14 and irinotecan (50–80 mg/m²) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. Results  At doses of 50–70 mg/m², no patients experienced any DLT, whereas, at a dose of 80 mg/m², two of four patients experienced DLTs. Two patients experienced grade 3 toxicities — neutropenia and diarrhea. Conclusion  The MTD of weekly irinotecan was 80 mg/m², making its RD for phase II trials 70 mg/m².     

Phase I study of vinorelbine and irinotecan in previously untreated patients with advanced non-small cell lung cancer

Introduction Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Methods Previously untreated patients (≤75 years old) with Stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and irinotecan was given on days 1, 8, and 15 intravenously. To prevent an injection site reaction to vinorelbine, the site was treated with topical clobetasol ointment, and the patients were given intravenous dexamethasone prior to vinorelbine treatment. DLT was defined as grade 4 neutropenia lasting ≥4 days or febrile neutropenia, grade 4 thrombocytopenia, ≥grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. Results A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m² vinorelbine, 50 mg/m² irinotecan), in 2 of 3 at level 4 (25 mg/m², 50 mg/m²), and in 2 of 5 at modified level 4 (20, 60 mg/m²). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. Conclusion Use of 20 mg/m² vinorelbine on days 1 and 8 followed by 50 mg/m² irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II study.     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma

Bortezomib selectively binds and inhibits the 20S proteasome enzyme’s active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/−EIASD). The starting dose in both groups was 0.9 mg/m² intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the −EIASD group was 1.70 mg/m² based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m² without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m² suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m² of bortezomib at 77 ± 12% and in −EIASD patients treated with a dose of 1.7 mg/m² at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas.     

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients

Purpose  This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. Methods  Five dose level combinations with irinotecan (from 180 to 240 mg/m², day 1, q21), capecitabine (1,500–2,000 mg/m² per day, days 2–15, q21) and erlotinib (50–150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results  Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed. Conclusions  The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m² and capecitabine 1,500 mg/m² per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.     

Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced,aggressive T-cell or NK/T-cell lymphoma

The aim of the study was to determine the maximum tolerated dose (MTD) and safety of the combination of bortezomib and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) as first-line therapy in advanced, aggressive T-cell lymphoma. Patients received increasing doses of bortezomib on days 1 and 8 (weekly schedule, 1.0, 1.3, and 1.6 mg/m²/dose) in addition to 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. Thirteen patients, who had stage III/IV chemonaive aggressive T-cell lymphoma, received a total of 55 cycles of treatment. One patient experienced hematologic dose-limiting toxicity (grade 4 neutropenia associated with febrile episode) at the 1.0 mg/m²/dose of bortezomib. There was no dose-limiting non-hematologic toxicity. The MTD was not reached at 1.6 mg/m² dose level of bortezomib. The overall complete remission rate in all patients was 61.5% (95% confidence interval = 31.6–86.1). Bortezomib can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced-stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II studies of bortezomib plus CHOP is 1.6 mg/m²/dose of bortezomib on days 1 and 8 every 3 weeks as first-line treatment.     

Phase I study of docetaxel and topotecan in patients with solid tumors

Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor, have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m² without G-CSF and at 60, 70, and 80 mg/m² with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2, 4, 6, etc.). TOPO 0.75 mg/m² was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.) on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort II with DOC and TOPO doses of 60 and 0.75 mg/m², respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80 and 0.75 mg/m², respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m² and delivered with TOPO 0.75 mg/m² and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of 12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m² given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m² given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC given on day 1 is 70 mg/m² with TOPO 0.75 mg/m² given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on day 4 and TOPO on days 1–4 is not recommended. Received: 18 February 2000 / Accepted: 19 July 2000     

Phase I/II study of bortezomib‐melphalan‐prednisolone for previously untreated Japanese patients with multiple myeloma

This phase I/II study was conducted to evaluate the safety and efficacy of bortezomib‐melphalan‐prednisolone in Japanese patients with previously untreated multiple myeloma who are ineligible for hematopoietic stem cell transplantation. One hundred and one patients were enrolled, and 99 patients received up to nine 6‐week cycles of bortezomib (0.7/1.0/1.3 mg/m²) on days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1–4 and on days 1, 8, 22, and 29 in cycles 5–9, with melphalan (9 mg/m²) and prednisolone (60 mg/m²) on days 1–4 of each cycle. The recommended dose was determined in the phase I portion, and the overall response rate and safety of bortezomib‐melphalan‐prednisolone at the recommended dose were assessed in the phase II portion. The recommended dose of bortezomib was determined to be 1.3 mg/m². Grade 3 or higher non‐hematological adverse events included diarrhea (12%) and peripheral neuropathy (10%); grade 4 hematological adverse events included lymphopenia (41%), neutropenia (30%), and thrombocytopenia (22%). Eleven patients had lung injury associated with bortezomib; two had grade 3 disease, and the other nine had grade 1 or 2 disease. Of the 86 patients treated with 1.3‐mg/m² bortezomib in phases I and II, the median number of treatment cycles was 4.5, and the overall response rate was 70% (95% confidence interval: 59–79%). Bortezomib‐melphalan‐prednisolone with 1.3‐mg/m² bortezomib was considered to be tolerable and effective in Japanese patients with previously untreated multiple myeloma. However, further investigation is needed to refine the administration schedule.     

Phase I study of amrubicin and vinorelbine in non-small cell lung cancer previously treated with platinum-based chemotherapy

Background  Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC. Methods  The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0–1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35–45 mg/m² administered as a 5-min intravenous infusion on days 1–3 and vinorelbine 15–25 mg/m² given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks. Results  All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopenia ≥4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m² and vinorelbine 15 mg/m²) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients. Conclusion  As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m² and 15 mg/m², respectively. Further study should proceed to clarify the efficacy of this regimen.     

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial

This open‐label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30‐minute intravenous infusion on Days 1, 8 and 15 in a 28‐day cycle starting at 20 mg/m² on Day 1/Cycle 1 and 70 mg/m² thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1‐9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4‐8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose‐limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6‐97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m² was well‐tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy‐related events and efficacy.     

Inability to escalate vinorelbine dose intensity using a daily × 3 schedule with and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm², PLT >100 000 m³, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m² per day and dose escalations of 5 mg/m² were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm³ for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm³. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m². Results: At DUMC, DLT was seen at 20 mg/m² in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m² and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m² with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer. Received: 27 October 1997 / Accepted: 16 April 1998     

Phase I and pharmacologic study of irinotecan and amrubicin in advanced non-small cell lung cancer

Purpose We conducted a Phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 as well as the dose-limiting toxicities (DLT) of this combination in patients with advanced non-small cell lung cancer. Patients and methods Eleven patients with stage IIIB or IV disease were treated at 3-week intervals with amrubicin (5-min intravenous injection on days 1–3) plus 60 mg/m² of CPT-11 (90-min intravenous infusion on days 1 and 8). The starting dose of amrubicin was 25 mg/m², and it was escalated in 5 mg/m² increments until the maximum tolerated dose was reached. Results The 30 mg/m² of amrubicin dose was one dose level above the MTD, since three of the five patients experienced DLT during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the DLT, while thrombocytopenia was only a moderate problem. Amrubicin did not affect the pharmacokinetics of CPT-11, SN-38 or SN-38 glucuronide. Except for one patient, the biliary index on day-1 correlated well with the percentage decrease of neutrophils in a sigmoid E _max model. There were five partial responses among 11 patients for an overall response rate of 45%. Conclusion The combination of amrubicin and CPT-11 seems to be active against non-small cell lung cancer with acceptable toxicity. The recommended dose for Phase II studies is 60 mg/m² of CPT-11 (days 1 and 8) and 25 mg/m² of amrubicin (days 1–3) administered every 21 days. This work was presented in part at the 41st Annual Meetings of the American Society of Clinical Oncology, Orlando, FL, USA May 13–17, 2005.     

Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model

BackgroundInsulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination.Patients and methodsEligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m² as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%.ResultsBetween September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1–22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0–6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity.ConclusionThe maximum tolerated dose was doxorubicin 75 mg/m² on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified.Trial registrationClinicalTrials.gov:NCT00789633.     

Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma

BackgroundThe prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient.MethodsA phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3 + 3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (2) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–8; (3) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10; (4) TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years.ResultsNone of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3.ConclusionThe recommended phase II dose in children is TMZ 150 mg/m² on days 1–5 and VP-16 50 mg/m² on days 1–10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.     

A phase I study of doxifluridine combined with weekly paclitaxel for metastatic gastric cancer

Purpose Based on the synergistic effect in preclinical studies, a phase I clinical trial for the combination of paclitaxel and doxifluridine (an intermetabolite of capecitabine) was performed to determine the recommended dose for the treatment of patients with metastatic gastric cancer.Methods The dose of paclitaxel was increased from 60 mg/m² at level 1 to 90 mg/m² at level 5. It was administered as a 1-h infusion on days 1 and 8. The dose of doxifluridine was fixed at 600 mg/m² per day up to level 3, and escalated to 800 mg/m² per day at levels 4 and 5. It was administered orally for 2 weeks. The treatment was repeated every 3 weeks.Results A total of 28 patients were enrolled. No dose-limiting toxicity (DLT) was observed at levels 1 and 2 (paclitaxel 70 mg/m²). A DLT of grade 4 neutropenia lasting for more than 4 days was observed in one patient at level 3 (paclitaxel 80 mg/m²). In addition, the first five of six patients in this group experienced grade 3 neutropenia during the first treatment cycle. A further six patients were added in order to confirm the safety of this dosage level, and no more DLTs except for grade 3 nausea in one patient were observed in the second cohort. No DLT was seen in three patients at level 4 (paclitaxel 80 mg/m²). DLTs (grade 3 neuropathy in one patient and a treatment delay of the second cycle for more than 1 week due to grade 3 neutropenia in another) were observed in two out of six patients at level 5 (paclitaxel 90 mg/m²), and this dose level was determined as the maximum tolerated dose. The tumor response rate was 42% (95% confidence interval 20–67%) in 19 patients with measurable lesions.Conclusions The recommended dose was determined as 80 mg/m² of paclitaxel (days 1 and 8) and 800 mg/m² of doxifluridine (days 1–14) every 3 weeks. The results of this phase I study are encouraging and a phase II trial is thus warranted.     

Carfilzomib,lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m², followed by 27 mg/m². Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.     

Phase I study of weekly cisplatin, vinorelbine, and concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer

Background The combination of chemotherapy and thoracic radiation therapy (TRT) is considered as a standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Although the frequent interaction of anticancer agents and irradiation may produce stronger radio-sensitizing effects, the daily administration of these agents is complicated. We therefore used weekly administration of these agents, and conducted a phase I study of weekly cisplatin, vinorelbine, and concurrent TRT. The purpose of this study was to identify the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the recommended dose of this treatment. Methods Patients with locally advanced NSCLC were enrolled in this study. Both cisplatin and vinorelbine were given intravenously on a weekly schedule for 6 weeks, starting on the first day of TRT, i.e., on days 1, 8, 15, 22, 29, and 36. The total dose of TRT was 60 Gy. The dose of cisplatin was fixed at 20 mg/m² per week. The starting dose of vinorelbine was 15 mg/m² per week (dose level 1). Results Nine patients were enrolled in this study. All three patients at dose level 1 experienced DLTs. We decreased the dose of vinorelbine to 10 mg/m² per week (dose level 0). Two of the six patients at dose level 0 experienced DLTs. Therefore, dose level 1 was considered as the MTD, and dose level 0 as the recommended dose. The DLTs of this treatment were esophagitis, fatigue, infection, and hyponatremia. Conclusion The recommended dose of cisplatin is 20 mg/m² per week and that of vinorelbine is 10 mg/m² per week with standard TRT. A phase II study of this treatment is warranted. The results of this study were presented in part at the 43rd Annual Meeting of the Japan Lung Cancer Society in Fukuoka, Japan, November 21–22, 2002.