A phase I trial combining carboplatin/doxorubicin with tocilizumab,an anti-IL-6R monoclonal antibody,and interferon-α2b in patients with recurrent epithelial ovarian cancer

BackgroundThe immune system is important in epithelial ovarian cancer (EOC). Interleukin-6 is associated with chemoresistance and an immune-suppressive tumor microenvironment. We investigated whether a combination of chemotherapeutics, blockade of interleukin 6 (IL-6) receptor (IL-6R; tocilizumab), and immune enhancer interferon-&agr; (Peg-Intron) is feasible, safe, and able to enhance immunity in patients with recurrent EOC.Patients and methodsIn this dose-escalation study, patients received tocilizumab 1, 2, 4, or 8 mg/kg i.v., q4 weeks during the first three cycles of carboplatin (AUC5) plus doxorubicin [pegylated liposomal doxorubicin (PLD) 30 mg/m² or doxorubicin 50 mg/m² i.v., day 1, q4 weeks, for six cycles]. At the highest tocilizumab dose (8 mg/kg), Peg-Intron (1 µg/kg s.c.) was added. Peripheral blood mononuclear cells were collected for immunomonitoring at baseline, after three and six cycles. Dose-limiting toxicity (DLT), CA-125, and radiologic response were evaluated.ResultsIn the 23 patients enrolled, no DLT was established. The most frequent grade 3/4 adverse events (CTCAE v4.03) were neutropenia (23%), febrile neutropenia (19%), and ileus (19%). No treatment-related deaths occurred. Using CT evaluation, 11 of 21 assessable patients responded, 6 had stable disease and 3 progressive disease. Patients receiving highest dose tocilizumab showed a functional blockade of IL-6R with increased levels of serum IL-6 (P = 0.02) and soluble IL-6R (P = 0.008). Consequently, immune cells displayed decreased levels of pSTAT3, myeloid cells produced more IL-12 and IL-1&bgr; while T cells were more activated and secreted higher amounts of effector cytokines interferon-γ and tumor necrosis factor-&agr;. An increase in sIL-6R was potentially associated with a survival benefit (P = 0.03).ConclusionsFunctional IL-6R blocking is feasible and safe in EOC patients treated with carboplatin/(pegylated liposomal)doxorubicin, using 8 mg/kg tocilizumab. This combination is recommended for phase II evaluation based on immune parameters.Clinical trial registerNCT01637532.     

Phase I study of inhaled Doxorubicin for patients with metastatic tumors to the lungs.

PURPOSE: To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung. EXPERIMENTAL DESIGN: The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 mum and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO(2) >90%). RESULTS: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m(2). The most common histologic diagnoses were sarcoma (n = 19) and non-small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m(2) dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m(2) dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. CONCLUSIONS: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m(2) every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.     

A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer

Purpose  This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. Patients and methods  Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m² of bortezomib with 15 mg/m² of doxorubicin to 1.5 mg/m² of bortezomib with 20 mg/m² of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. Results  The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m² bortezomib, 20 mg/m² doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m² bortezomib, 15 mg/m² doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. Conclusions  Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m² intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m² intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease. Supported by grant: U01 CA062491 “Early Clinical Trials of Anti-Cancer Agents With Phase I Emphasis, NCI” and M01 RR03186 “General Clinical Research Center Program of The National Center for Research Resources, NIH”.     

Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma

BackgroundPatients with severe depletion of skeletal muscle (sarcopenia) are prone to dose-limiting toxicity (DLT) during fluoropyrimidine therapy. We hypothesized that sarcopenia may also predict toxicity of targeted therapy drugs.Materials and methodsMetastatic renal cell cancer (RCC) patients (n = 55) received sorafenib 400 mg b.i.d. Weight, height and skeletal muscle cross-sectional area at the third lumbar vertebra were measured by computed tomography (CT). Toxicity was assessed.ResultsDLT occurred in 22% of patients overall, of which three-quarters were dose reductions to 400 mg and the remainder entailed termination of treatment. DLT was most common (41%) in sarcopenic patients whose body mass index (BMI) was <25 kg/m² and least common (13%) in patients who were not sarcopenic and/or overweight or obese (P = 0.03). Toxicity was especially prevalent in sarcopenic male patients with BMI < 25, with 71% of men with these characteristics being unable to continue treatment at 800 mg/day. By contrast, only 5% of male patients whose muscle index was above the cut-off for sarcopenia and only 11% of male patients whose BMI was >25 experienced a DLT.ConclusionBMI < 25 kg/m² with diminished muscle mass is a significant predictor of toxicity in metastatic RCC patients treated with sorafenib.     

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     

A dose finding,safety and pharmacokinetic study of AVE1642, an anti-insulin-like growth factor-1 receptor (IGF-1R/CD221) monoclonal antibody,administered as a single agent and in combination with docetaxel in patients with advanced solid tumours

PurposeAVE1642, a humanised mAb, binds the human IGF-1R specifically and with high affinity. This study aimed to select the dose of AVE1642 alone and then combined with docetaxel 75 mg/m² (D).Material and methodsAVE1642 was administered alone at cycle (cy) 1 and then combined with D from cy2, q3w.ResultsA total of 27 patients received a median number of 5 cy (range, 1–10). The most common tumour types were sarcoma (18.5%), osseous tumours (11.1%) and colon cancer (11.1%). Two DLTs were reported in cy1 at dose level (DL) 18 mg/kg and dose escalation was stopped. No major safety issue was observed. No anti-drug antibodies were detected. The Maximal Tolerated Dose of AVE1642 was 12 mg/kg. The dose selected for further combinations is 6 mg/kg, based on PK/PD data. Three objective responses, (two in sarcoma and one breast cancer) were observed but only one was confirmed. Eleven patients appeared to benefit from treatment with prolonged disease stabilisation ?4 months.ConclusionAVE1642 is well tolerated as a single agent and combined with D. The selected dose of AVE1642 combined with D is 6 mg/kg. Promising activity was seen in sarcoma and breast cancer patients.     

A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors

Purpose

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine^® administered in combination with doxorubicin.

Study design

Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine^® IV on days 1–4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m² and Triapine^® 25 mg/m². PK analysis was performed at various time-points before and after treatment.

Results

Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m², Triapine^® 45 mg/m²), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m²) with Triapine^® 45 mg/m². The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine^® were reduced to 45 and 25 mg/m², respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.

Conclusions

Pretreated patients with advanced malignancies can tolerate the combination of Triapine^® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m² on day 1 and Triapine^® 25 mg/m² on days 1–4 of a 21-day cycle.     

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer

Background:Gemcitabine is active in patients with otherwiseresistant or refractory ovarian cancer. As the drug is well tolerated, studiesusing gemcitabine combined with other antineoplastic agents are needed. Theaim of the study was to determine the maximum tolerated dose (MTD) ofepirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methods:Patients with platinum-resistant orrefractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800mg/m² day 1 and 8; 200 mg/m² escalation per level) andepirubicin (E) (starting dose 60 mg/m² day 1; 15 mg/m²escalation per level) were given every 21 days for four to six cycles. G-CSF(filgrastim 5 µg/kg/die) was given in case of grade 4 neutropenia(levels without support) or from day 9 up to leukocyte count>10,000/mm³ after nadir (levels with support). Cohorts of threepatients were enrolled at each level, and another three patients were planned,if one dose-limiting toxicity (DLT) was registered. MTD was determined firstwithout and then with G-CSF. Results:Four levels were studied (G 800 + E 60; G 1000 + E 60;G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and threepatients enrolled, respectively. DLT (grade 4 febrile neutropenia) wasobserved in two patients at level 3. Thus, G1000 + E 60 mg/m² wasthe MTD without G-CSF. The addition of prophylactic G-CSF did not allow afurther increase of the dose and grade 4 thrombocytopenia was the DLT at level4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in fourpatients. Among the 13 patients with measurable or evaluable disease, 3partial responses were observed for an overall response rate of 23.1%. Conclusions:The combination of gemcitabine 1000 mg/m²(day 1, 8) and epirubicin at 60 mg/m² (day 1) is a feasibletherapy. Grade 4 neutropenia is frequent and G-CSF support is often required.With prophylactic support of G-CSF, the DLT is thrombocytopenia.     

High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label,randomized controlled trial

BackgroundMetastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients.Patients and methodsAdvanced STS patients aged 18–65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m², day 1–5), ifosfamide (2.5 g/m², day 1–4), carboplatin [area under the curve (AUC) 5/day 2–4] and etoposide (300 mg/m², day 1–4) with PBSC reinjection at day 7.ResultsFrom 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70–2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3–4 toxicity.ConclusionThis study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.     

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 IB study of the combination of docetaxel,gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen

BackgroundTo assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated.Patients and methodsThirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m² was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m², bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m², every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry.ResultsThe median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome.ConclusionsThe combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.     

Doxorubicin,Paclitaxel and Gemcitabine: a Phase I Study of a New Sequential Treatment in Stage III B - IV Breast Cancer

Abstract

Based on the synergistic interactions of the sequence doxorubicin-paclitaxelgemcitabine obtained in our preclinical study, a Phase I trial was conducted to evaluate the feasibility of this new sequence in breast cancer. Patients with stage IIIBIV breast cancer received doxorubicin on day 1, paclitaxel on day 2 and gemcitabine on day 6 and 13 (steps IIa, III and V) in cohorts of 3 patients. From March 1999 to December 2000, 9 patients were treated. The most important toxicity was hematological. The maximum tolerated dose was reached at the second level because dose-limiting toxicity occurred in 3 patients. Non hematological toxicities were alopecia, diarrhea, asthenia, nausea, mucositis, paresthesia and myalgia. A Phase II trial is ongoing to further investigate the activity of this new sequential treatment with doxorubicin (50 mg/m² day 1), paclitaxel (160 mg/m² day 2) and gemcitabine (800 mg/m² day 6) in advanced breast cancer.     

Erlotinib and chemoradiation in patients with surgically resected locally advanced squamous cell carcinoma of the head and neck: a GICOR phase I trial

BackgroundStandard treatment of advanced squamous cell carcinoma of the head and neck (SCCHN) is concurrent chemoradiation. Erlotinib is an oral tyrosine kinase inhibitor of epidermal growth factor receptor, which has shown activity in SCCHN. Phase I study aims to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of adding erlotinib to chemoradiation therapy in patients with surgically resected locally advanced SCCHN.Patients and methodsInclusion criteria—SCCHN patients with T3 or T4 primary lesion (except T3N0 with negative resection margins); pathologic N2–N3 disease; poor prognostic findings; age 18–70 years; Eastern Cooperative Oncology Group performance status of zero to one; no evidence of metastasis; adequate organic function and written informed consent. Study design—dose-escalating phase I study with three cohorts of three to six patients each that received increasing doses of erlotinib (100–150 mg/day p.o.) and cisplatin (30–40 mg/m² i.v., day 1) for 7 weeks. Radiotherapy—standard regimen of 1.8 Gy daily (5 fractions/week) to a maximum total dose of 63 Gy in 7 weeks.ResultsThirteen male (median age: 57 years) were enrolled. Overall, the regimen was well tolerated. Two of three patients treated at dose level III (erlotinib: 150 mg/day; cisplatin: 40 mg/m²) developed DLT consisting of grade 3 infection and grade 3 mucositis. Other toxic effects included diarrhea, asthenia, and rash. Recommended dose for additional studies: erlotinib 150 mg/day p.o.; cisplatin 30 mg/m²/week i.v.ConclusionErlotinib can be safely combined with chemoradiation without requiring dose reduction of chemo- or radiotherapy in this postsurgical population.     

High dose ifosfamide, doxorubicin, dacarbazine and G-CSF for patients with metastatic or locally advanced soft tissue sarcoma

SOFTTISSUESARCOMAS(STS)accountforapproximatelyl%ofadultmalignanciesandl5%ofpediatricmalignancies.Theuseofradicalsurgeryisthem0steffectivemethodfortreatmentofearystageSTS.Unfortunately,manypatientsarediagnosedlate0rreceiveinadequateprimarysurgerysothatmetastasesultimatelyoccULAlthoughsalvagetreatthentbyexcisionofthemetastasesissuccessfulforsomepatients,themajoritywilldiefromprogressivedisease.Doxorubicin(Adriamycin,ADR)isthemostactivesingleagentinsofttissuesarcomas,witharesponserate…     

Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies

BackgroundSF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies.Patients and methodsSF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained.ResultsForty four patients were treated at 9 dose levels (90–1110 mg/m²/day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m² (diarrhoea). Exposure measured by peak concentration (C_max) and area under the time-concentration curve (AUC_0-t) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m². The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m². A CLL patient who progressed on rituximab [R] achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling.ConclusionSF1126 is well tolerated with SD as the best response in patients with advanced malignancies.     

Ifosfamide,vincristine, doxorubicin and dacarbazine in adult patients with advanced soft-tissue sarcoma

Summary A total of 37 adult patients with locally advanced or metastatic soft-tissue sarcoma (STS) entered a pilot study of combination chemotherapy based on the CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine) regimen, in which cyclophosphamide was replaced by ifosfamide and mesna (1 g/m² ifosfamide given daily on days 1–5 as 2-h infusions, 1.5 mg/m² vincristine given on day 1 as a bolus injection, 50 mg/m² doxorubicin given on day 1 as a 5-min infusion, and 250 mg/m² dacarbazine given daily on days 1–5 as 30-min infusions). The overall response rate in 24 patients who were evaluable for response was 46% [95% confidence interval (CI), 25%–67%] and that in subjects who had not undergone prior chemotherapy was 50% (CI, 27%–73%). In all, 4 patients achieved a complete response (17%; CI, 5%–37%) and 2 remain in remission; 3 additional subjects were surgically rendered disease-free after they had shown a partial response. Overall, 31 patients were evaluable for toxicity. Toxicity was mainly hematological; in 3 patients the nadir WBC was <0.5×10⁹/l, and in 2 cases the nadir platelet count was <50×10⁹/l. During neutropenia, infections requiring intravenous antibiotics occurred in 8 patients (26%) and in 14 of 190 cycles (7.5%); 1 of these was fatal. We conclude that this new regimen offers promise for the treatment of advanced STS, producing acceptable toxicity.This study was supported in part by grants from Finska Läkaresällskapet (Finnish Medical Society)     

An Open-Label,Multicenter, Randomized,Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non–Small Cell Lung Cancer

IntroductionType 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting.MethodsIn this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m² pemetrexed, and 75 mg/m² cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed.ResultsThe mean age of the intent-to-treat population (n = 172) was 59 years (range 32–83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81–1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64–1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred.ConclusionsEfficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported.     

Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer

BackgroundThis was an open-label, nonrandomized, multicenter, 2-stage phase I trial of safety and preliminary efficacy of nonpegylated liposomal doxorubicin (NLD) in combination with trastuzumab in advanced breast cancer, with emphasis on cardiac toxicity.Patients and MethodsForty patients (median age, 48 years; range, 30–74 years) with HER2/neu 2+ or 3+ tumors (by immunohistochemistry) were recruited December 1999 to November 2002. Patients were eligible if they received ≤ 1 previous trastuzumab regimen, ≤ 2 cytotoxic regimens for advanced breast cancer, and lifetime cumulative anthracycline doses ≤ 240 mg/m². The study regimen comprised NLD 60 mg/m² every 3 weeks and trastuzumab loading dose 4 mg/kg followed by 2 mg/kg weekly. Treatment cycles lasted 21 days. Clinical cardiac assessments were performed with multigated acquisition scans every 2 cycles. Patients were evaluated for cardiac toxicity after receiving ≥ 1 cycle. Cardiac safety was assessed after completing ≥ 4 full treatment cycles.ResultsThirty out of 40 patients (75%) received ≥ 4 treatment cycles and were evaluable for cardiac safety. Five patients (13%), 4 who were doxorubicin pretreated, developed left ventricular ejection fraction reductions to < 50%, and 2 (5%) of these patients experienced clinical cardiac toxicity. Fifty percent of the patients had objective tumor responses; median progression-free survival was approximately 21 weeks. Twenty-six patients (65%) had grade 3/4 neutropenia; 2 patients experienced febrile neutropenia.ConclusionNonpegylated liposomal doxorubicin plus trastuzumab is active in HER2-positive patients with advanced breast cancer and is associated with a lower risk of cardiac toxicity than conventional doxorubicin plus trastuzumab.     

Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors

BackgroundType 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments.PatientsPatients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m² (B) docetaxel, 1250 mg/m² gemcitabine/100 mg erlotinib (C1), or 60 mg/m² doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3.ResultsFifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m² gemcitabine/75 mg erlotinib) and D2 (50 mg/m² doxorubicin). Grade 3–4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ≥12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ± 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 ± 21 ng/ml with disease control (P < 0.001).ConclusionAVE1642 was tolerable with 75–100 mg/m² docetaxel and 1000 mg/m² gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response.     

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