Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer.

BACKGROUND: Women with hormone-responsive metastatic breast cancer (MBC) may respond to or have stable disease with a number of hormone therapies. We explored the efficacy and safety of the steroidal aromatase inactivator exemestane as first-line hormonal therapy in MBC in postmenopausal women. PATIENTS AND METHODS: Patients with measurable disease were eligible if they had received no prior hormone therapy for metastatic disease and had hormone receptor positive disease or hormone receptor unknown disease with a long disease-free interval from adjuvant therapy. They were randomized to tamoxifen 20 mg/day or exemestane 25 mg/day in this open-label study. RESULTS: Blinded independently reviewed response rates for exemestane and tamoxifen were 41% and 17%, respectively. Fifty-seven per cent of exemestane- and 42% of tamoxifen-treated patients experienced clinical benefit, defined as complete or partial response, or disease stabilization lasting at least 6 months. There was a low incidence of severe flushing, sweating, nausea and edema in women who received exemestane. One exemestane-treated patient had a pulmonary embolism with grade 4 dyspnea. CONCLUSIONS: Exemestane is well tolerated and active in the first-line treatment of hormone-responsive MBC. An ongoing EORTC phase III trial is comparing the efficacy, measuring time-to-disease progression, of exemestane and tamoxifen.

Promising results with exemestane in the first-line treatment of metastatic breast cancer: a randomized phase II EORTC trial with a tamoxifen control.

Because tamoxifen (TAM), a nonsteroidal antiestrogen, is routinely used in the adjuvant setting, other hormone therapies are needed as alternatives for first-line treatment of metastatic breast cancer (MBC). Currently, exemestane (EXE) and other antiaromatase agents are indicated for use in patients who experience failure of TAM. In this multicenter, randomized, open-label, TAM-controlled (20 mg/day), phase II trial, we examined the activity and tolerability of EXE 25 mg/day for the first-line treatment of MBC in postmenopausal women. Exemestane was well tolerated and demonstrated substantial first-line antitumor activity based on intent-to-treat analysis of peer-reviewed responses. In the EXE arm, values for complete, partial, and objective response, clinical benefit, and time to tumor progression (TTP) exceeded those reported for TAM although no statistical comparison was made. Based on these encouraging results, a phase III trial will compare EXE and TAM.

The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, 'Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients'.

BACKGROUND: The impact of aromatase inhibitors (AIs) on non-cancer-related outcomes, which are known to be affected by oestrogens, has become increasingly important in postmenopausal women with hormone-dependent breast cancer. So far, data related to the effect of AIs on lipid profile in postmenopausal women is scarce. This study, as a companion substudy of an EORTC phase II trial (10951), evaluated the impact of exemestane, a steroidal aromatase inactivator, on the lipid profile of postmenopausal metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: The EORTC trial 10951 randomised 122 postmenopausal breast cancer patients to exemestane (E) 25 mg (n = 62) or tamoxifen (T) 20 mg (n = 60) once daily as a first-line treatment in the metastatic setting. Exemestane showed promising results in all the primary efficacy end points of the trial (response rate, clinical benefit rate and response duration), and it was well tolerated with low incidence of serious toxicity. As a secondary end point of this phase II trial, serum triglycerides (TRG), high-density lipoprotein cholesterol (HDL), total cholesterol (TC), lipoprotein a (Lip a), and apolipoproteins (Apo) B and A1 were measured at baseline and while on therapy (at 8, 24 and 48 weeks) to assess the impact of exemestane and tamoxifen on serum lipid profiles. Of the 122 randomised patients, those who had baseline and at least one other lipid assessment are included in the present analysis. The patients who received concomitant drugs that could affect lipid profile are included only if these drugs were administered throughout the study treatment. Increase or decrease in lipid parameters within 20% of baseline were considered as non-significant and thus unchanged. RESULTS: Seventy-two patients (36 in both arms) were included in the statistical analysis. The majority of patients had abnormal TC and normal TRG, HDL, Apo A1, Apo B and Lip a levels at baseline. Neither exemestane nor tamoxifen had adverse effects on TC, HDL, Apo A1, Apo B or Lip a levels at 8, 24 and 48 weeks of treatment. Exemestane and tamoxifen had opposite effects on TRG levels: exemestane lowered while tamoxifen increased TRG levels over time. There were too few patients with normal baseline TC and abnormal TRG, HDL, Apo A1, Apo B and Lip a levels to allow for assessment of E's impact on these subsets. The atherogenic risk determined by Apo A1:Apo B and TC:HDL ratios remained unchanged throughout the treatment period in both the E and T arms. CONCLUSIONS: Overall, exemestane has no detrimental effect on cholesterol levels and the atherogenic indices, which are well-known risk factors for coronary artery disease. In addition, it has a beneficial effect on TRG levels. These data, coupled with E's excellent efficacy and tolerability, support further exploration of its potential in the metastatic, adjuvant and chemopreventive setting.

Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer

AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients.

PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks.

RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy.

CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naïve patients with chronic hepatitis C: a randomized phase II study.

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. CONCLUSION: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

Docetaxel, cisplatin, and fluorouracil; docetaxel and cisplatin; and epirubicin, cisplatin, and fluorouracil as systemic treatment for advanced gastric carcinoma: a randomized phase II trial of the Swiss Group for Clinical Cancer Research

This randomized phase II trial evaluated two docetaxel-based regimens to see which would be most promising according to overall response rate (ORR) for comparison in a phase III trial with epirubicin-cisplatin-fluorouracil (ECF) as first-line advanced gastric cancer therapy.

Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK

BACKGROUND: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. RESULTS: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. CONCLUSION: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.

A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

PURPOSE: Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. EXPERIMENTAL DESIGN: We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. RESULTS: SCR was observed in 9 of 35 [26%; 95% confidence interval (CI); 13%-43%] participants randomized to imatinib and 10 of 37 (27%; 95% CI, 14%-44%) randomized to rituximab. Six (17%; 95% CI, 7%-34%) patients in the imatinib arm and 5 (14%; 95% CI, 5%-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27(+)) were seen at enrollment in rituximab-treated patients who had treatment success (P = 0.01), but not in imatinib-treated patients. CONCLUSIONS: These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.