Tumor-Selective Response to Antibody-Mediated Targeting of αvβ3 Integrin in Ovarian Cancer

The α_vβ₃ integrin is expressed on proliferating endothelial cells and some cancer cells, but its expression on ovarian cancer cells and its potential as a therapeutic target are unknown. In this study, expression of the α_vβ₃ integrin on ovarian cancer cell lines and murine endothelial cells was tested, and the effect of a fully humanized monoclonal antibody against α_vβ₃, Abegrin (etaracizumab), on cell invasion, viability, tumor growth, and the Akt pathway were examined in vitro and in vivo. We found that etaracizumab recognizes α_vβ₃ on the ovarian cancer cell lines SKOV3ip1, HeyA8, and A2780ip2 (at low levels) but not on murine endothelial cells. Etaracizumab treatment decreased ovarian cancer proliferation and invasion. In vivo, tumor-bearing mice treated with etaracizumab alone gave variable results. There was no effect on A2780ip2 growth, but a 36% to 49% tumor weight reduction in the SKOV3ip1 and HeyA8 models was found (P < .05). However, combined etaracizumab and paclitaxel was superior to paclitaxel in the SKOV3ip1 and A2780ip2 models (by 51–73%, P < .001) but not in the HeyA8 model. Treatment with etaracizumab was then noted to decrease p-Akt and p-mTOR in SKOV3ip1, but not in HeyA8, which is Akt-independent. Tumors resected after therapy showed that etaracizumab treatment reduced the proliferating cell nuclear antigen index but not microvessel density. This study identifies tumor cell α_vβ₃ integrin as an attractive target and defines the Akt pathway as a predictor of response to function-blocking antibody.     

Randomized phase 2/3 trial of CpG oligodeoxynucleotide PF‐3512676 alone or with dacarbazine for patients with unresectable stage III and IV melanoma

BACKGROUND:

The primary objective of this phase 2 study was to assess the objective response rate (complete response [CR] + partial responses [PR]), by Response Evaluation Criteria in Solid Tumors, of PF‐3512676, a CpG oligodeoxynucleotide, alone in 2 doses or in combination with dacarbazine (DTIC) in patients with unresectable stage IIIB/C or stage IV malignant melanoma, with the aim of selecting an arm to take forward to a phase 3 portion of the study.

METHODS:

A total of 184 patients were randomized to 1 of 4 treatments: PF‐3512676 10 mg (low dose), at 40 mg (high dose), 40 mg plus DTIC (850 mg/m²), or DTIC (850 mg/m²) alone. Patients received PF‐3512676 subcutaneously weekly in a 3‐week cycle and received DTIC intravenously on the first week of the cycle.

RESULTS:

The objective response rate (PR or CR, confirmed or unconfirmed) in the 40 mg + DTIC arm was 16% (7 patients) compared with 8% (3 patients) with DTIC alone. One (2%) patient in the 10‐mg and 0 patients in the 40‐mg arms achieved an objective response. Best response of CR or PR or stable disease (SD), with no minimum duration defined for SD, was achieved by 15 (33%) patients in the 40 mg + DTIC arm, 15 (38%) patients in the DTIC‐only arm, 8 (17%) patients in the 10‐mg arm, and 9 (20%) patients in the 40‐mg arm. The most frequently reported adverse events were classified as local injection site reactions or systemic flu‐like symptoms, specifically fatigue, rigors, and pyrexia.

CONCLUSIONS:

PF‐3512676 at the doses used was generally well tolerated. The modest objective response rates observed in all arms did not warrant continuation to the phase 3 portion of the study. Cancer 2009. © 2009 American Cancer Society.     

The treatment of multiple myeloma using vincristine,carmustine, melphalan,cyclophosphamide, and prednisone (VBMCP) alternating with high‐dose cyclophosphamide and α2β interferon versus VBMCP

BACKGROUND:

A randomized controlled trial tested the hypothesis that aggressive initial therapy using high‐dose cyclophosphamide (HiCy) and α₂β interferon (IFN) may be superior to standard combination alkylating agent regimens in the treatment of newly diagnosed myeloma.

METHODS:

This Eastern Cooperative Oncology Group trial evaluated 268 previously untreated patients with active multiple myeloma randomized to vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) or VBMCP plus HiCy and recombinant IFN.

RESULTS:

The overall objective response was 62% in the VBMCP regimen and 68% in the VBMCP + HiCy + IFN group. The near complete response and complete response rates were 8.1% and 8.9%, respectively. Progression‐free survival was 22.1 and 25.3 months, respectively. The median overall survival was 37.1 months for patients treated with VBMCP and 41.3 months for those treated with VBMCP + HiCy + IFN (P = .38). The 5‐year overall survival rates were not significantly different between the 2 arms: 26.4% and 33%, respectively. Lethal toxicities occurred in 15 patients, including 10 from infection, but there was no significant difference in lethal toxicities between the 2 regimens.

CONCLUSIONS:

The study showed no significant benefit with the addition of HiCy and IFN to VBMCP. Cancer 2009. © 2009 American Cancer Society.     

AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney

BACKGROUND:

This study evaluated the tolerability and antitumor activity of AMG 386, a peptibody (a peptide Fc fusion) that neutralizes the interaction of angiopoietin‐1 and angiopoietin‐2 with Tie2 (tyrosine kinase with immunoglobulin‐like and EGF‐like domains 2), plus sorafenib in patients with clear cell metastatic renal cell carcinoma (mRCC) in a randomized controlled study.

METHODS:

Previously untreated patients with mRCC were randomized 1:1:1 to receive sorafenib 400 mg orally twice daily plus intravenous AMG 386 at 10 mg/kg (arm A) or 3 mg/kg (arm B) or placebo (arm C) once weekly (qw). Patients in arm C could receive open‐label AMG 386 at 10 mg/kg qw plus sorafenib following disease progression. The primary endpoint was progression‐free survival (PFS).

RESULTS:

A total of 152 patients were randomized. Median PFS was 9.0, 8.5, and 9.0 months in arms A, B, and C, respectively (hazard ratio for arms A and B vs arm C, 0.88; 95% confidence interval [CI], 0.60‐1.30; P = .523). The objective response rate (95% CI) for arms A, B, and C, respectively, was 38% (25%‐53%), 37% (24%‐52%), and 25% (14%‐40%). Among 30 patients in arm C who had disease progression and subsequently received open‐label AMG 386 at 10 mg/kg qw, the objective response rate was 3% (95% CI, 0%‐17%). Frequently occurring adverse events (AEs) included diarrhea (arms A/B/C, 70%/67%/56%), palmar‐plantar erythrodysesthesia syndrome (52%/47%/54%), alopecia (50%/45%/50%), and hypertension (42%/49%/46%). Fifteen patients had grade 4 AEs (arms A/B/C, n = 3/7/5); 4 had fatal AEs (n = 2/1/1), with 1 (abdominal pain, arm B) considered possibly related to AMG 386.

CONCLUSIONS:

In patients with mRCC, AMG 386 plus sorafenib was tolerable but did not significantly improve PFS compared with placebo plus sorafenib. Cancer 2012. © 2012 American Cancer Society.     

A phase 1‐2 study of imexon plus dacarbazine in patients with unresectable metastatic melanoma

BACKGROUND:

Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy.

METHODS:

Sixty‐eight chemotherapy‐naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m²) and imexon (570‐1300 mg/m²), both daily for 5 days every 3 weeks.

RESULTS:

There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m². Dose‐limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment‐related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression‐free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports.

CONCLUSIONS:

Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study. Cancer 2010. © 2010 American Cancer Society.     

Upfront,randomized, phase 2 trial of sorafenib versus sorafenib and low‐dose interferon alfa in patients with advanced renal cell carcinoma

BACKGROUND:

The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low‐dose interferon‐alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC).

METHODS:

Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression‐free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers.

RESULTS:

Eighty patients were enrolled. The median follow‐up was 19.7 months (range, 0‐34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%‐46.5%) in the sorafenib arm and 25% (95% CI, 12.7%‐41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib‐alone arm (95% CI, 5.52‐9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19‐11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00‐1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02‐1.29; P = .0173).

CONCLUSIONS:

The addition of low‐dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required. Cancer 2010. © 2010 American Cancer Society.     

A Randomized Study of Interferon α‐2b Versus No Treatment as Consolidation After High Dose Therapy and Autologous Stem Cell Transplantation for Patients With Relapsed Lymphoma

Background.

Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) α-2b was given in a prospective randomized international trial.

Methods.

In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (arm A: 117 patients) or IFNα-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients).

Results.

In arm B, 21 patients (20%) did not receive IFNα-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were alive and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes.

Conclusion.

In this trial, post-autograft IFNα-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.     

A phase II,multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer

BackgroundThis phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel–carboplatin (CP) plus motesanib or bevacizumab.Patients and methodsChemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs).ResultsORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C_max and C_min values were consistent with its pharmacokinetic properties observed in previous studies.ConclusionsThe efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.     

Chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha2b and interleukin-2 versus two cycles of dacarbazine followed by chemoimmunotherapy in patients with metastatic melanoma: a randomised phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group

BackgroundChemoimmunotherapy for patients with metastatic melanoma is associated with high toxicity, and only a subset of patients will benefit. This randomised phase II study was performed with the primary objective of exploring whether two cycles of dacarbazine monotherapy could select the subset of patients that would benefit most from more intensive chemoimmunotherapy.Patients and methodsPatients with metastatic melanoma were randomised to either receive chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha and interleukin-2 (arm A) or initial treatment with two cycles of dacarbazine monotherapy followed irrespective of response by the same 4-drug regimen of chemoimmunotherapy (arm B). Chemoimmunotherapy was continued in the absence of disease progression for a maximum of four cycles. Primary end-point was the disease stabilisation rate.ResultsA total of 93 patients were randomised, and 89 patients were eligible. Disease stabilisation (complete/partial response or stable disease) was achieved in 19 patients (42.2%) in arm A and 9 patients (20.5%) in arm B. In arm B 32 of the 44 patients continued chemoimmunotherapy after two cycles of dacarbazine. Of 20 patients with progressive disease (PD) after two cycles of dacarbazine in arm B, only 2 patients achieved an objective response. Median overall survival (OS) in arms A and B was 10.5 months and 9.5 months, respectively.ConclusionsDespite a lower initial stabilisation rate, the strategy of starting with 2 courses of DTIC prior to a 4-drug regimen led to comparable median overall survival. Only few transient responses were achieved with the 4-drug regimen in patients with disease progression on DTIC, suggesting frequent cross resistance. Two cycles of dacarbazine monotherapy cannot be recommended to select patients for more intensive chemoimmunotherapy.     

Immune modulation of minimal residual disease in early chronic phase chronic myelogenous leukemia: a randomized trial of frontline high-dose imatinib mesylate with or without pegylated interferon alpha-2b and granulocyte-macrophage colony-stimulating factor

BACKGROUND:

Most patients with chronic myelogenous leukemia (CML) harbor residual disease, as evidenced by molecular techniques even after treatment with high‐dose imatinib (ie, 800 mg/d). Interferon alpha (IFN α) is efficacious in CML likely due to its immunomodulatory properties, and is synergistic in vitro with imatinib and granulocyte macrophage‐colony stimulating factor (GM‐CSF).

METHODS:

A study was undertaken to determine whether adding pegylated (PEG) IFN α‐2b and GM‐CSF to high‐dose imatinib may improve the complete molecular response rate in patients with CML in chronic phase. Ninety‐four patients were treated with imatinib 800 mg/d for the first 6 months, then randomly assigned to continue high‐dose imatinib alone (n = 49) or in combination with PEG IFN α‐2b 0.5 μg/kg/wk and GM‐CSF 125 mg/m² 3× weekly (n = 45).

RESULTS:

The median follow‐up for all patients was 54 months (range, 7‐70 months). There were no differences in the rates of complete cytogenetic response (87% vs 90%; P = 1.0), or of major (77% vs 77%; P = 1.0) or complete (11% vs 13%; P = 1.0) molecular response (on the international scale) at 12 months between the 2 arms, or at any time during the study. Adverse events led to PEG IFN α‐2b discontinuation in all patients.

CONCLUSIONS:

The addition of PEG IFN α‐2b and GM‐CSF to high‐dose imatinib therapy does not improve significantly the cytogenetic or molecular response rates compared with high‐dose imatinib alone. The high dropout rate in the PEG IFN α‐2b arm may have compromised its potential immunomodulatory benefit. Cancer 2011. © 2010 American Cancer Society.     

Multicenter phase III randomized trial of polychemotherapy (CVD regimen) versus the same chemotherapy (CT) plus subcutaneous interleukin-2 and interferon-alpha2b in metastatic melanoma.

BACKGROUND: The addition of cytokines to chemotherapy (CT) has obtained encouraging but contradictory results in metastatic melanoma. In this phase III trial, we compared the effects of CT [cisplatin, vindesine and dacarbazine (CVD)] with those of concurrent biochemotherapy (bioCT) consisting of CVD plus interleukin-2 and interferon-alpha2b. PATIENTS AND METHODS: A total of 151 untreated metastatic melanoma patients were randomized, 75 on arm A (cisplatin 30 mg/m2 on days 1-3, vindesine 2.5 mg/m2 on day 1 and dacarbazine 250 mg/m2 on days 1-3), and 76 on arm B (same CVD scheme plus interferon-alpha2b on days 1-5 and interleukin-2 on days 1-5 and 8-15, both administered subcutaneously), either recycled every 3 weeks. Response was assessed every two cycles. RESULTS: Ten percent of the patients were alive at a median of 52 months from start of therapy. We observed a response rate (RR) of 21% on arm A versus 33% on arm B; three patients (4%) given bioCT had complete responses (CRs). Median time to progression (TTP) was identical; median overall survival (OS) time was 12 months on arm A and 11 months on arm B. CONCLUSIONS: BioCT is not better than CT alone; the trend in favor of the bioCT in terms of RR did not translate into better TTP or OS. Therefore, bioCT cannot be recommended as standard first-line therapy for metastatic melanoma.     

A phase 1 study of weekly dosing of trastuzumab emtansine (T‐DM1) in patients with advanced human epidermal growth factor 2–positive breast cancer

BACKGROUND:

We conducted a phase 1, multicenter, open‐label, dose‐escalation study (TDM3569g) to assess the safety, tolerability, and pharmacokinetics of single‐agent trastuzumab emtansine (T‐DM1) administered weekly and once every 3 weeks in patients with HER2‐positive metastatic breast cancer previously treated with trastuzumab. The weekly dose results are described here.

METHODS:

Patients were administered escalating doses of T‐DM1 weekly, starting at 1.2 mg/kg. Additional patients were enrolled at the maximum tolerated dose (MTD) to better characterize tolerability and pharmacokinetics.

RESULTS:

Twenty‐eight patients received weekly T‐DM1, and the MTD was determined to be 2.4 mg/kg. In general, T‐DM1 was well tolerated, requiring few dose modifications or discontinuations because of adverse events (AEs). Grade ≥3 AEs were reported in 19 patients (67.9%); treatment‐related AEs occurred in 25 (89.3%) patients. Exposure to weekly T‐DM1 was dose‐proportional at ≥1.2 mg/kg, and accumulation of T‐DM1 and total trastuzumab was observed. Objective partial tumor responses were reported in 13 (46.4%) patients; the median duration of response was 18.6 months, and the 6‐month clinical benefit rate was 57.1%.

CONCLUSION:

The results suggest that a weekly dose of T‐DM1 2.4 mg/kg has antitumor activity and is well tolerated in patients with HER2‐positive metastatic breast cancer. Cancer 2012. © 2012 American Cancer Society.     

A randomized phase 2 trial comparing 3‐hour versus 96‐hour infusion schedules of paclitaxel for the treatment of metastatic breast cancer

BACKGROUND:

This study was performed to compare efficacy and toxicity profiles of paclitaxel using 3‐hour versus 96‐hour infusion schedules.

METHODS:

Patients with metastatic breast cancer (MBC) were randomly assigned to receive paclitaxel starting at a dose of 250 mg/m² intravenously (iv) over 3 hours every 21 days or paclitaxel starting at a dose of 140 mg/m² iv over 96 hours every 21 days. Stratification variables included number of prior chemotherapy regimens and previous response to anthracyclines. Response was assessed every 2 cycles using bidimensional measurements. Patients were allowed to cross over at disease progression or therapy intolerance.

RESULTS:

A total of 214 patients received therapy (107 patients per arm). Response rates were similar: 23.4% in the 3‐hour arm and 29.9% in the 96‐hour arm (P = .28). The median duration of response (8.9 months vs 5.7 months; P = .75) and progression‐free survival (5.0 months vs 3.8 months; P = .17) slightly favored the 96‐hour arm. Overall survival was slightly longer in the 3‐hour arm (14.2 months vs 12.7 months; P = .57). One patient who crossed over to the 96‐hour arm (N = 18) developed a partial response; no response was noted with crossover to the 3‐hour arm (N = 10). Myalgia/arthralgia and neuropathy were more frequent in the 3‐hour arm, whereas mucositis, neutropenic fever/infection, and diarrhea were more common in the 96‐hour arm.

CONCLUSIONS:

Paclitaxel given by 3‐hour or 96‐hour infusion was active in MBC. The 96‐hour paclitaxel regimen did not significantly improve response or time to disease progression, was more cumbersome to administer, and was associated with greater myelosuppression (but less neuropathy and myalgia) compared with the 3‐hour schedule. Cancer 2010. © 2010 American Cancer Society.     

Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study

The aim of this randomized four-arm phase III study was to evaluate whether there is a difference in activity between regimens containing dacarbazine and regimens without dacarbazine in metastatic melanoma, whether there is a dose-effect relationship for dacarbazine, and whether non-dacarbazine-containing aggressive regimens are in any way superior to non-aggressive ones. A total of 219 patients with metastatic cutaneous melanoma were included in this study; 196 of them were evaluable for activity. The patients were randomized into four treatment arms: arm A (standard dose dacarbazine arm), vincristine 1.4 mg/m2 on day 1, carmustine (BCNU) 60 mg/m2 on day 1, and dacarbazine 300 mg/m2 per 24 h on days 2-5; arm B (high-dose dacarbazine arm), vincristine and BCNU as in arm A and dacarbazine 600 mg/m2 per 24 h on days 2-5; arm C ('aggressive' regimen without dacarbazine), vindesine 3 mg/m2 on day 1, bleomycin 7 mg/m2 per 24 h on days 1-4, and cisplatin 30 mg/m2 per 24 h on days 5-8; arm D ('non-aggressive' regimen without dacarbazine), BCNU 100 mg/m2 on day 1 and procarbazine 90 mg/m2 per 24 h on days 1-10. The four arms were well balanced with regard to patient- and disease-related characteristics. On an intend-to-treat basis, the response rate was 11 out of 49 (22%) in arm A, nine out of 47 (19%) in arm B, 16 out of 63 (25%) in arm C and nine out of 60 (15%) in arm D. There was a large overlap between the 95% confidence intervals and no significant differences in the response rates between the four arms. Median survival in the four treatment arms was 4, 5, 6 and 4 months, respectively, again with no significant differences. Median survival for responders (8, 11, 10 and 13 months, respectively) in all four arms was significantly longer than in non-responders (4, 3, 5 and 4 months, respectively). Arms A, B and C were significantly more toxic compared with arm D, which was for all practical purposes devoid of toxicities. The efficacy of all four regimens thus appeared comparable both in terms of response rate and survival. Responders in all four arms achieved a survival benefit. There does not seem to be a dose-effect relationship for dacarbazine in metastatic melanoma. Chemotherapy from arm D, might be well suited for 'fragile' or elderly patients due to the lack of toxicity.     

Results of a multicenter,randomized, double‐blind,dose‐evaluating phase 2/3 study of lenalidomide in the treatment of metastatic malignant melanoma

BACKGROUND:

There are currently no systemic treatments for stage IV melanoma, which have been proven in randomized trials to benefit overall survival (OS). Lenalidomide has efficacy against melanoma in animal models and safety in phase 1 trials. The authors reported the results of a phase 2/3 study comparing the safety and efficacy of 2 doses of lenalidomide in patients with relapsed metastatic melanoma disease refractory to previous treatment with dacarbazine, temozolomide, interleukin‐2, or interferon‐α.

METHODS:

A total of 294 patients were randomized to oral lenalidomide at 5 mg or 25 mg dose. Tumor response, time to progression, and OS were evaluated. Treatment continued until disease progression or unacceptable adverse events.

RESULTS:

No significant differences in response rate, OS, or time to progression were observed between lenalidomide 25 mg versus 5 mg (overall response rate: 5.5% vs 3.4%, P = .38; median OS: 6.8 months vs 7.2 months, P = .71; and median time to progression: 2.2 months vs 1.9 months, P = .24). Myelosuppression was observed in 37.0% of patients in the 25 mg group and 13.7% of patients in the 5 mg group. Treatment‐related serious adverse events were seen in 39.0% of patients at the 25 mg dose and 35.4% of patients at the 5 mg dose.

CONCLUSIONS:

Despite the occurrence of treatment‐related serious adverse events, ～80% of patients continued treatment. The higher dose of lenalidomide did not improve response rate, time to progression, or OS of patients with relapsed/refractory stage IV melanoma. A parallel placebo‐controlled study has been conducted to further assess the efficacy of lenalidomide in stage IV melanoma patients. Cancer 2009. © 2009 American Cancer Society.     

An open-label, phase 2 trial of RPI.4610 (Angiozyme) in the treatment of metastatic breast cancer

BACKGROUND:

Serum and plasma levels of vascular endothelial growth factor (VEGF) correlate with prognosis in patients with metastatic breast cancer (MBC). VEGF binds to 2 receptors on endothelial cells, VEGFR‐1 and VEGFR‐2. RPI.4610 (Angiozyme0) is an antiangiogenic ribozyme targeting the VEGFR‐1 mRNA. Preclinical and phase 1 studies suggested that RPI.4610 is a well‐tolerated agent with clinical activity in solid tumors. The authors' trial evaluated the efficacy of RPI.4610 in the treatment of patients with progressive MBC.

METHODS:

This phase 2, multicenter, single‐arm study was designed to assess the objective response rate of RPI.4610 in patients with MBC who had experienced disease progression with at least 1 course of chemotherapy for MBC. Patients received daily subcutaneous injections of RPI.4610 100 mg/m² for 12 weeks.

RESULTS:

Most patients (93%) had received at least 2 lines of chemotherapy previously; 69% of patients had received at least 3 lines of chemotherapy. Median follow‐up was 2.76 months (range, 0.89‐36.6 months). No partial responses nor complete responses were found. Median progression‐free survival was 1.41 months (95% confidence interval [CI], 1.35‐1.45). The median overall survival from start of treatment was 11.89 months (95% CI, 4.11‐23.66). Treatment‐related adverse events (AEs) were primarily grade 1 to 2 in intensity. Most common AEs were: injection site reactions, abdominal pain, anorexia, chromaturia, constipation, dyspnea, fatigue, headache, pain at the injection site, nausea, vomiting, and fever.

CONCLUSIONS:

Although RPI.4610 demonstrated a well‐tolerated safety profile, its lack of clinical efficacy precludes this drug from further development. Cancer 2012.© 2012 American Cancer Society.     

Nab-paclitaxel(abraxane)-based chemotherapy to treat elderly patients with advanced non-small-cell lung cancer:a single center,randomized and open-label clinical trial

Background:The purpose of this study is to evaluate the clinical efficacy and safety of abraxane-based chemotherapy with/without nedaplatin in elderly patients with non-small-cell lung cancer(NSCLC).Materials and methods:From October 2009 to January 2013,48 elderly patients(>65 years) with NSCLC were investigated in this clinical trial.The patients were randomized and equally allocated into arms A and AP:(A) abraxane(130 mg/m~2,days 1,8);(B) abraxane + nedaplatin(20 mg/m~2 days 1-3,q3w).The parameters of objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS) and side effects were evaluated between two arms.Results:Over 80%of the patients completed four cycles of chemotherapy.The total ORR was 21.3%,DCR was 55.3%,PFS 4.5 months and OS 12.6 months.No significant difference was found between arms A and AP in terms of ORR(16.7%vs.26.1%,P=0.665) or DCR(55.3%vs.56.5%,P=0.871).The median PFS in arm A was 3.3 months[25-75%confidence interval(CI):3.1-7.2]and 5.5 months(25-75%CI:3.2-7.0) in arm AP with no statistical significance(P=0.640).The median OS in arm A was 12.6 months(25-75%CI:5.7-26.2) and 15.1 months(25-75%CI:6.4-35.3) in arm AP with no statistical significance(P=0.770).The side effects were mainly grade 1-2.The incidence of grade 3-4 toxicities was 29.1%in arm A and 62.5%in arm AP with a statistical significance(P=0.020).Conclusions:Compared with combined therapy,abraxane alone chemotherapy was beneficial for elderly NSCLC patients with better tolerability and less adverse events,whereas did not significantly differ in terms of ORR,DCR,PFS or OS.     

Health‐related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized,controlled, BOLERO‐2 trial

BACKGROUND:

The randomized, controlled BOLERO‐2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression‐free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health‐related quality of life (HRQOL).

METHODS:

Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ‐C30 include global health status wherein higher scores (range, 0‐100) indicate better HRQOL. This analysis included a protocol‐specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10‐point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log‐rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history.

RESULTS:

Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10‐point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017).

CONCLUSIONS:

In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE. Cancer 2013. © 2013 American Cancer Society.     

Quantitative HER2 protein levels predict outcome in fluorescence in situ hybridization‐positive patients with metastatic breast cancer treated with trastuzumab

BACKGROUND:

Only a portion of breast cancer patients currently selected for trastuzumab therapy respond.

METHODS:

Using a novel assay (HERmark) to quantify total human epidermal growth factor receptor 2 (HER2) expression, the authors examined outcomes in 102 trastuzumab‐treated metastatic breast cancer patients previously assessed as immunohistochemistry (IHC) 3+ by local but not central IHC, or fluorescence in situ hybridization (FISH) positive, and then retested by central FISH.

RESULTS:

Of 102 MBC patients previously scored as IHC 3+ or 2+/FISH‐positive and treated with trastuzumab‐containing regimens, 98 had both central FISH and HER2 total expression values. Sixty‐six of 76 central FISH‐positive patients (87%) had high HER2 total expression levels (concordant positive), and 19 of 22 central FISH‐negative patients (86%) were HER2 total expression low (concordant negative). Fourteen percent (3 of 22) of central FISH‐negative patients were HER2 total expression high (discordant HER2 total expression high), and 13% (10 of 76) of central FISH‐positive patients were HER2 total expression low (discordant HER2 total expression low). The concordant positive group had a significantly longer time to progression (TTP, median = 11.3 months) compared with the concordant negative group (median TTP, 4.5 months; hazard ratio [HR] = 0.42, P < .001), and also compared with the discordant HER2 total expression low group (median TTP, 3.7 months; HR = 0.43, P = .01). The discordant HER2 total expression low group behaved similarly compared with concordant negatives (HR = 1, P = .99). In analyses restricted to central FISH‐positive patients only (n = 77), Cox proportional hazards multivariate regression identified HER2 total expression as an independent predictor of TTP (HR = 0.29, P = .0015) and overall survival (HR = 0.19, P < .001).

CONCLUSIONS:

A subset of patients with HER2 gene amplification by FISH express low levels of HER2 protein and have reduced response to trastuzumab‐containing therapy, similar to FISH‐negative patients. This cohort represents a training dataset, and the observed relationships and derived cutoffs require validation in an independent cohort of trastuzumab‐treated metastatic breast cancer patients. Cancer 2010. © 2010 American Cancer Society.     

Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer

BACKGROUND:

Although many trials have shown the efficacy of preoperative chemoradiotherapy (CRT) or postoperative CRT compared with surgery alone, the optimal sequence of radiotherapy and surgery is unclear. The authors reported the final results of this single institution prospective randomized phase 3 trial comparing preoperative CRT with postoperative CRT using capecitabine in survival, local control, sphincter preservation, and toxicity for the treatment of locally advanced rectal cancer.

METHODS:

Patients with locally advanced rectal cancer (cT3, potentially resectable cT4 or N+) were randomly assigned to receive preoperative or postoperative CRT. CRT consisted of 50 Gy/25 fractions and concurrent capecitabine (1,650 mg/m²/day). Total mesorectal excision was performed.

RESULTS:

From March 2004 to April 2006, 240 patients were enrolled. Clinical characteristics were well balanced between both arms, except for more low‐lying (<5 cm from anal verge) tumors in the preoperative CRT arm (60% vs 46%, P = .041). After a median follow‐up time of 52 months, the 3‐ and 5‐year disease‐free survival, overall survival, and cumulative incidence of local recurrence were similar between both arms. However, for the patients with low‐lying tumors, the preoperative CRT arm had a higher rate of sphincter preservation (68% vs 42%, P = .008). Acute and late complication rates were similar between both arms.

CONCLUSIONS:

Although significant benefit of preoperative CRT in local control and survival was not demonstrated, the data showed that increased rate of sphincter preservation was possible in low‐lying tumors without jeopardizing local control and surgical complication by preoperative CRT. Cancer 2011;. © 2011 American Cancer Society.