Months In Arm Research Articles

A randomised, multicentre open-label phase II study to evaluate the efficacy, tolerability and pharmacokinetics of oral vinorelbine plus cisplatin versus intravenous vinorelbine plus cisplatin in Chinese patients with chemotherapy-naive unresectable or metastatic non-small cell lung cancer.

A phase II study to evaluate the efficacy, tolerability and pharmacokinetics of oral or intravenous vinorelbine (VRL) plus cisplatin (CDDP) in Chinese patients with non-small cell lung cancer (NSCLC). One hundred and thirty-one patients were randomised to oral VRL 60 mg/m2 (arm A) or intravenous VRL 25 mg/m2 (arm B) on days 1 and 8, plus CDDP 80 mg/m2 on day 1 (both arms). VRL was increased to 80 mg/m2 (arm A) or 30 mg/m2 (arm B) in cycles 2-4 in the absence of toxicity. Primary efficacy endpoint was objective response rate (ORR). VRL pharmacokinetics was evaluated for possible drug-drug interactions with CDDP. ORR was 25.8% in arm A and 23.1% in arm B. Disease control rate was 72.7% in arm A, 72.3% in arm B. Median overall survival was 16.1 months in arm A and 19.0 months in arm B. Median progression-free survival was 4.6 months in arm A and 4.9 months in arm B. Forty-three point nine percent and 86.2% of patients had grade 3/4 neutropenia in arms A and B, respectively; incidence of febrile neutropenia was low (6.1% and 9.2%, respectively). Frequency of grade 3/4 non-haematological adverse events was also low. VRL pharmacokinetics was not affected by co-administration of CDDP. Oral and intravenous VRL in combination with CDDP is effective and well-tolerated in Chinese patients with advanced NSCLC. VRL pharmacokinetics is unaffected by CDDP co-administration. Oral VRL could be an effective alternative to intravenous VRL as a first-line treatment for NSCLC, as it optimises treatment convenience while maintaining high efficacy.

Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.

Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m2 twice daily administered as 7 days on and 7 days off, intravenous (IV) bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily. The primary end point was progression free survival (PFS) and secondary endpoints included objective response rate (ORR) and tolerability. An exploratory endpoint included correlation of PFS with cytokine levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To examine cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy and to Arm B where levocetirizine was started 7 days prior to chemotherapy. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Forty-seven patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 23 patients and Arm B enrolled 24 patients. Fifty percent of patients had progressive disease and 62% of patients had stable disease in each arm as best response. There was no demonstrable difference in PFS between the two arms (log-rank test P=0.83). Median time to progression was 3.4 months in Arm A and 3.5 months in Arm B. Median PFS in the trial was comparable to and appeared to be better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine measurement with IL-8 levels did not show any correlation with progression free survival but patients with stable disease showed overall lower levels of IL-8 as compared to patients with progressive disease in the cytokine analysis.

Paclitaxel/carboplatin with or without cetuximab for treatment of carcinoma with unknown primary (PACET-CUP): Results of a multi-center randomized phase II AIO trial.

4120 Background: Paclitaxel/carboplatin is one of the standard regimens for empiric treatment of patients (pts) with carcinoma with unknown primary (CUP) when a specific therapy is not available. The EGFR antibody cetuximab demonstrated efficacy in several cancer types. Methods: Pts with newly diagnosed non-resectable, undifferentiated or adeno-CUP were randomized to 6 cycles paclitaxel 175 mg/m² and carboplatin AUC 5 every three weeks (arm A) or the same chemotherapy plus cetuximab (400 mg/m², then 250 mg/m² weekly; arm B) at 13 German centres. CUP pts belonging to favorable prognosis groups [i.e. women with isolated peritoneal carcinomatosis or axillary lymph node metastases, men with retroperitoneal lymph nodes, pts with specific tumor entities according to histology / immunohistochemistry] were excluded from the trial. The primary endpoint was progression-free survival (PFS), secondary endpoints were response rate (RR) and overall survival (OS). Results: Between 03/2010 and 03/2017, 72 pts were randomized to arm A and 78 pts to arm B. The median age was 61 years, 84 pts were male (40 and 44 pts in arm A and B). 58 pts had a performance status (PS) of 0 (24 and 34 pts), 89 pts a PS of 1 (47 and 42 pts in arm A and B), and one patient in arm A had a PS of 2. PFS and OS did not differ between arms. The median PFS was 3.7 [95%CI: 3.0 - 4.4] and 4.6 [95%CI: 2.9 - 6.2] months in arms A and B (HR 0.98 [95%CI: 0.70-1.37]), the median OS 8.1 [95%CI: 6.5 - 9.8] and 7.4 [95%CI: 5.1 - 9.6] months in arms A and B, respectively (HR 1.10 [95%CI: 0.77 - 1.56]). There was a statistically non-significant trend towards a higher RR with cetuximab: 11 pts had a partial response in arm A (15% [95%CI: 7.9 - 26%]), and 17 pts in arm B (22% [95%CI: 13%-33%], p = 0.30). Twenty-five pts in each arm had stable disease, and 36 pts in each arm had progressive disease or were not evaluable for response. Conclusions: This study represents one of the largest trials in pts with CUP and demonstrates that randomized trials are feasible in this disorder with high medical need. The outcome of CUP pts in the unfavorable prognosis group was not improved by adding cetuximab to empiric therapy paclitaxel/carboplatin. Clinical trial information: NCT00894569.

Abstract PD1-11: nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer

Abstract Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is <1.2. Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-11.

Randomized Phase 2 Study of Trebananib (AMG 386) with or without Continued Anti-Vascular Endothelial Growth Factor Therapy in Patients with Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib – Results of NCI/CTEP Protocol 9048

Background:In renal cell carcinoma (RCC), angiopoietin (Ang) 2 is elevated at the time of progression on anti-vascular endothelial growth factor (VEGF) therapy and may contribute to resistance.Objective:We tested trebananib, an Ang 1 and 2 neutralizing peptibody in patients with RCC progressing on anti-VEGF treatment.Methods:Patients with measurable RCC progressing despite an anti-VEGF agent within 12 weeks, any number of prior treatments, and good PS were randomized to trebananib 15 mg/kg IV weekly without (Arm A) or with (Arm B) continuation of the prior anti-VEGF agent. The primary endpoint for each arm was tumor response (RECIST 1.1). Secondary endpoints included progression free survival and adverse events.Results:Of 41 enrolled patients, 35 were eligible and started treatment (17 Arm A, 18 Arm B) with median age 60 (46–76) and 3 prior treatments (1–8). Four died prior to documented progression and 27 progressed as their first event. Both arms were stopped after interim analysis, 2 responses (11%; 95% C.I. 1–35%) were observed in Arm B. Median PFS of 2.7 (95% C.I. 2.3–4.7) months in Arm A and 5.2 (95% C.I. 2.7–10.8) months in Arm B did not support continued study. Common adverse events including fatigue, nausea, and increased creatinine were generally grade 1–2 and numerically higher in Arm B. The most common grade 3 or higher adverse events were hypertension and dyspnea.Conclusions:While tolerable, trebananib either without or with continued anti-VEGF therapy did not show promising activity in RCC patients who recently progressed on anti-VEGF therapy alone.

Phase II randomised study of maintenance treatment with bevacizumab or bevacizumab plus metronomic chemotherapy after first-line induction with FOLFOXIRI plus Bevacizumab for metastatic colorectal cancer patients: the MOMA trial

BackgroundAlternating induction and maintenance phases is a common strategy in metastatic colorectal cancer (mCRC). Metronomic chemotherapy (metroCT) may represent a well-tolerated chemotherapy backbone for maximising bevacizumab effect during maintenance. The MOMA trial was designed to compare metroCT plus bevacizumab versus bevacizumab alone as maintenance following 4 months of induction with FOLFOXIRI plus bevacizumab. Patients and methodsIn this phase II study, patients with unresectable mCRC were randomised to receive up to 8 cycles of FOLFOXIRI plus bevacizumab, followed by bevacizumab (arm A) or the same regimen followed by bevacizumab plus metroCT (capecitabine 500 mg/three times per day and cyclophosphamide 50 mg/die, arm B) until disease progression. The primary end-point was progression-free survival (PFS). According to the Rubinstein and Korn's design, to detect a hazard ratio[HR] of 0.75 favouring arm B, with 1 sided-alpha and beta errors of 15% and 80%, 173 events and 222 patients were required. ResultsBetween May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomised in 16 Italian centres.At a median follow-up of 47.8 months, 210 and 164 progression and death events were registered. The primary end-point was not met. Median PFS was 10.3 and 9.4 months in arm B and A, respectively (HR: 0.94 [70% confidence interval {CI}: 0.82–1.09], p = 0.680). No significant differences were reported in terms of overall survival (OS) (median OS arm B/A: 22.5/28 months; HR: 1.16 [95%CI: 0.99–1.37], p = 0.336).Response rate with FOLFOXIRI plus bevacizumab was 63% (arm B/A: 58%/68%). In the liver-limited subgroup, the secondary resection rate was 49% (arm B/A: 45%/55%). ConclusionsThe addition of metroCT to maintenance with bevacizumab does not significantly improve PFS of mCRC patients. The activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS/BRAF mutations treated with a 4-months induction. Trial registrationwww.clinicaltrials.gov NCT02271464.

Updated Results from the Phase 2 Centaurus Study of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM)

Updated Results from the Phase 2 Centaurus Study of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM)

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Sorafenib plus tegafur-uracil (UFT) versus sorafenib as first line systemic treatment for patients with advanced stage HCC: a Phase II trial (ESLC01 study).

BackgroundPhase II trials found that tegafur–uracil (UFT) is an effective drug in hepatocellular carcinoma (HCC), while preclinical data suggested that its combination with sorafenib may have a promising activity. Our Phase II randomized trial aimed to evaluate efficacy and tolerability of sorafenib plus UFT vs sorafenib in advanced HCC.MethodsPatients with advanced HCC, with no prior systemic therapy, were randomized to receive either UFT at 125 mg/m2 twice daily for 4 out of 5 weeks plus sorafenib at 400 mg twice daily (arm 1) or single agent sorafenib at 400 mg twice daily (arm 2). Primary end point was time to progression (TTP).ResultsBetween March 2012 and March 2014, 76 eligible patients – out of 143 preplanned – were randomized. The study was terminated early because of futility. This is the final analysis of the study, after a median follow-up of 10.2 months and death of 86% of randomized patients (n=64). Median TTP was 7.5 months and 8.2 months in arms 1 and 2 respectively (HR: 1.07; 95% CI, 0.52–2.22; P=0.855), while the median overall survival was 8.2 months and 10.5 months respectively (HR: 1.58; 95% CI: 0.90–2.76, P=0.112). Nine patients (25%) in the combination arm discontinued treatment because of toxicity vs eight patients (21.1%) in the sorafenib monotherapy arm (P=0.899).ConclusionIn patients with advanced HCC, adding UFT to sorafenib is feasible, but it did not improve efficacy outcome over sorafenib monotherapy.

Phase 2 Randomized Study of Radiation Therapy and 3-Year Androgen Deprivation With or Without Concurrent Weekly Docetaxel in High-Risk Localized Prostate Cancer Patients

Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3years of luteinizing hormone-releasing hormone analogues. A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score ≥8 (77.3%), prostate-specific antigen level >20ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT+9 weekly cycles of docetaxel+3years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. No difference between the arms of the study was found in biochemical recurrence (93.4% at 60months for arm A vs 85.3% for arm B; P=.3297). PFS at 60months was 93.4% and 83.7% in arms A and B, respectively (P=.2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level ≤0.2ng/mL at 3months after the end of treatment was seen in 81.25% of patients in arm A compared with 90.48% of patients in arm B (P=.2028). BRFS was not significantly different between treatment arms. Diarrhea was the main nonhematologic toxicity. Long-term follow-up has not yet been enough to meet median PFS and OS. Concurrent weekly docetaxel can be administered safely with standard doses of RT without a significant increase in the toxicity profile. No statistically significant differences for 5-year BRFS, PFS, and OS have been observed when docetaxel was added to conventional treatment.

Treat to target (drug-free) inactive disease in DMARD-naive juvenile idiopathic arthritis: 24-month clinical outcomes of a three-armed randomised trial

QuestionWhich is the best strategy to achieve (drug-free) inactive disease in juvenile idiopathic arthritis (JIA)?MethodsIn a randomised, single-blinded, study in disease-modifying anti-rheumatic drug (DMARD)-naive patients with JIA, three treatment-strategies were...

Retrospective Study of The Corticosteroids Administration in Glioblastoma Patients as A Prognostic Factor in The Disease

Background: Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors. Optimum management consists of maximal safe surgical resection, followed by concurrent chemo-radiotherapy treatment then adjuvant chemotherapy with temozolomide. A considerable part from the care of patients with GBM involves general medical management, containing corticosteroids. Despite steroids common use, there is experimental and clinical evidence that corticosteroids have direct effects on tumor cell proliferation and apoptosis. Aim of the Work: was to discuss the clinical relation between corticosteroids usage in Glioblastoma Multiforme (GBM) patients and quality of life as well as the disease progression free survival according to the recorded data from the joined hospitals. Patients and Methods: Retrospective analysis of 66 adult patients diagnosed with GBM by surgery or imaging criteria. In order to assess the relation between corticosteroid dependence and the survival, patients were recruited into two groups (arms) according to dependency. Arm (A) was steroid dependent (34 patients) and arm (B) was steroid non-dependent (32 patients). Results: Corticosteroids dependency was statistically significant correlated to both Overall Survival (OS)(median 2.5 in arm (A) vs. 13.1 months in the arm (B), p < 0.001), and Progression-free survival ratio (PFS)(median 2.3 in arm (A) vs. 9.4 months in arm (B), p = 0.035). Also, steroid dependency was independent prognostic factor by doing the COX regression analysis. Conclusion: Dependence on corticosteroids during course of treatment is identified as a poor prognostic factor.

Retrospective Study of The Corticosteroids Administration in Glioblastoma Patients as A Prognostic Factor in The Disease

Background: Glioblastoma multiforme (GBM) is the most common and most malignant of the glial tumors. Optimum management consists of maximal safe surgical resection, followed by concurrent chemo-radiotherapy treatment then adjuvant chemotherapy with temozolomide. A considerable part from the care of patients with GBM involves general medical management, containing corticosteroids. Despite steroids common use, there is experimental and clinical evidence that corticosteroids have direct effects on tumor cell proliferation and apoptosis. Aim of the Work: was to discuss the clinical relation between corticosteroids usage in Glioblastoma Multiforme (GBM) patients and quality of life as well as the disease progression free survival according to the recorded data from the joined hospitals. Patients and Methods: Retrospective analysis of 66 adult patients diagnosed with GBM by surgery or imaging criteria. In order to assess the relation between corticosteroid dependence and the survival, patients were recruited into two groups (arms) according to dependency. Arm (A) was steroid dependent (34 patients) and arm (B) was steroid non-dependent (32 patients). Results: Corticosteroids dependency was statistically significant correlated to both Overall Survival (OS)(median 2.5 in arm (A) vs. 13.1 months in the arm (B), p < 0.001), and Progression-free survival ratio (PFS)(median 2.3 in arm (A) vs. 9.4 months in arm (B), p = 0.035). Also, steroid dependency was independent prognostic factor by doing the COX regression analysis. Conclusion: Dependence on corticosteroids during course of treatment is identified as a poor prognostic factor.

Dose escalation to 84 Gy with concurrent chemotherapy in stage III NSCLC appears excessively toxic: Results from a prematurely terminated randomized phase II trial

ObjectivesConcurrent chemoradiotherapy is the mainstay treatment for NSCLC stage III disease. To investigate whether radiation dose escalation based on individual normal tissue constraints can improve outcome, the Swedish lung cancer study group launched this randomized phase II trial. Materials and MethodsNSCLC patients with stage III disease, good performance status (0–1) and adequate lung function (FEV1 > 1.0 L and CO diffusion capacity > 40%) received three cycles of cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 day 1 and 8) every third week. Radiotherapy started concurrently with the second cycle, with either 2 Gy daily, 5 days a week, to 68 Gy (A) or escalated therapy (B) based on constraints to the spinal cord, esophagus and lungs up to 84 Gy by adding an extra fraction of 2 Gy per week. ResultsA pre-planned safety analysis revealed excessive toxicity and decreased survival in the escalated arm, and the study was stopped. Thirty-six patients were included during 2011–2013 (56% male, 78% with adenocarcinoma, 64% with PS 0 and 53% with stage IIIB). The median progression-free survival (PFS) and overall survival (OS) were 11 and 17 months in arm B compared to the encouraging results of 28 and 45 months in the standard arm. The 1- and 3-year survival rates were 56% and 33% (B) and 72% and 56% (A), respectively. There were seven toxicity-related deaths due to esophageal perforations and pneumonitis: five in the escalated group and two with standard treatment. ConclusionDose-escalated concurrent chemoradiotherapy to 84 Gy to primary tumor and nodal disease is hazardous, with a high risk of excessive toxicity, whereas modern standard dose chemoradiotherapy with proper staging given in the control arm shows a promising outcome with a median survival of 45 months and a 3-year survival of 56% (NCT01664663).

Abstract PD5-07: A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226

Abstract Background: Anastrozole depletes estrogen via aromatase inhibition and fulvestrant binds and degrades estrogen receptor. In a Phase III trial we compared the concurrent use of these agents to anastrozole alone or sequential anastrozole and fulvestrant in first-line therapy of hormone receptor-positive metastatic breast cancer in postmenopausal women, and demonstrated improved progression-free (PFS) and overall survival (OS)-NEJM 2012. Now we report PFS and OS five years after the initial positive findings. Methods: A total of 707 patients were randomized to either 1 mg anastrozole P.O. daily (Arm 1) or to the combination of anastrozole and fulvestrant (Arm 2). Fulvestrant was administered as a loading dose of 500 mg on day 1, 250 mg on days 14, 28 and monthly thereafter. Randomization was stratified by adjuvant tamoxifen use. The primary endpoint was PFS with OS a secondary outcome. 40% patients not in visceral crisis crossed over to fulvestrant after progression on arm 1. Analysis of survival was by 2-sided stratified log-rank tests and Cox regression using intent-to-treat. Subset analyses include treatment effect by adjuvant tamoxifen exposure, initial sites of metastases and time from diagnosis. Results: There were 646 PFS events (328 and 318 for arms 1 and 2, respectively) among 694 eligible patients (345 and 349, respectively). Overall, median PFS was 13.5 months for arm 1 and 15.0 months for the arm 2 (log-rank p=0.007; HR=0.81 (95% CI 0.69-0.94)). This benefit extended similarly in visceral and non-visceral subgroups. In subset analysis for Arms 1 and 2, respectively, in tamoxifen-naive women (60%, n=414), median PFS was 12.7 vs. 16.7 months (log-rank p=0.002; HR=0.73 (95% CI 0.60-0.89) while in women exposed to tamoxifen, median PFS was 13.9 vs. 13.6 months (log-rank p=0.57; HR=0.93 (95% CI 0.73-1.19)). An improved OS in the combination arm was seen, median OS 42 and 50 months in arms 1 and 2, based on 261 and 247 deaths, respectively (log-rank p=0.028; HR=0.82 (95% CI 0.69-0.98)). In subset analysis in tamoxifen-naive women, median OS was 40.3 vs. 52.2 months for Arms 1 and 2, respectively (log-rank p=0.007; HR=0.73 (95% CI 0.58-0.92)) while in women exposed to tamoxifen, median OS was 43.5 vs. 48.2 months (log-rank p=0.85; HR=0.97 (95% CI 0.74-1.27). Patients with initial diagnosis &amp;gt;10 years benefitted most from the combination (HR=0.66 (95% CI 0.49-0.89)) regardless of tamoxifen exposure. Patients in Arm 1 who crossed over had post-progression survival similar to post-progression survival of Arm 2 patients. Conclusion: The addition of fulvestrant to anastrozole was associated with improved long-term PFS and OS compared to anastrozole alone, despite the use of fulvestrant at a dose lower than the approved, and despite the substantial cross over to fulvestrant after progression on anastrozole alone. The benefit was especially notable in those without recent exposure to adjuvant endocrine therapy. Ongoing translational medicine studies will further refine the need for up front fulvestrant. ClinicalTrials.gov:NCT00075764. Funding: NIH/NCI U10CA180888, U10CA180819 and AstraZeneca. Citation Format: Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NL, Lew DL, Hayes DF, Gralow JR, Linden HM, Livingston RB, Hortobagyi GN. A phase III randomized trial of anastrozole and fulvestrant versus anastrozole or sequential anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: Final survival outcomes of SWOG S0226 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-07.

Intraperitoneal immunotherapy with the bispecific anti-EpCAM x anti-CD3 directed antibody catumaxomab for patients with peritoneal carcinomatosis from gastric cancer: Final results of a randomized phase II AIO trial.

4 Background: The peritoneal surface is a common location for metastases in gastric cancer (GC). Intraperitoneal (i.p.) application of the bispecific (anti-EpCAM/CD3) monoclonal antibody catumaxomab (CATU) in addition to i.v. chemotherapy may improve elimination of peritoneal carcinomatosis (PC). Methods: This randomized open-label phase II study aimed to investigate the efficacy of i.p. CATU following i.v. chemotherapy in patients (pts) with GC and PC (Gilly stages P1-4). Pts were randomly allocated to receive four cycles of FLOT (5FU, LV, Oxaliplatin, Docetaxel) followed by i.p. CATU at escalating doses (10, 20, 50, 150µg) on days 0, 3, 7, 10 or FLOT alone. Secondary gastrectomy and peritonectomy were allowed to achieve complete resection of all malignant lesions. The primary endpoint was to show an increased rate of macroscopic complete remission of PC at second-look surgery. Secondary endpoints included toxicity, progression-free and overall survival (PFS/OS). Results: Of 35 pts screened, 31 were enrolled. Median follow-up time is 52 months. 15 pts were allocated to FLOT-CATU (arm A) and 16 to FLOT alone (arm B). Complete remission rate of PC was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects with i.p. CATU were nausea (15%), fever (23%), abdominal pain (31%), and elevated liver enzymes (gGT 31%, bilirubin 23%). Adverse events tended to be more common during FLOT-CATU compared to FLOT alone. Median PFS was not significantly different in both arms with 6.7 months in arm A compared to 5.4 months in arm B (p = 0.71). Median OS was 13.2 and 13.0 months. Conclusions: Addition of i.p. CATU as part of a multimodal treatment approach revealed feasible and tolerable in pts with GC and PC. Although the primary endpoint was not met, the results are promising for future trials investigating i.p. immunotherapy in this patient population. Clinical trial information: NCT01504256.

Activity and safety of Nab-FOLFIRI and Nab-FOLFOX as first-line treatment for metastatic pancreatic cancer (phase II NabucCO study).

351 Background: FOLFIRINOX is an approved regimen for metastatic pancreatic cancer (mPC). We performed a modification in FOLFIRINOX schedule, using nab-paclitaxel (nab-p) to obtain two regimens that could be as effective and less toxic than the original triplet. NabucCO study was a randomized phase II trial to assess activity and toxicity of nab-p instead of either oxaliplatin (Nab-FOLFIRI) or irinotecan (Nab-FOLFOX) in first line setting. Previous dose–finding NabucCO study defined that maximum tolerated dose of nab-p with FOLFIRI is 120 mg/m2, and with FOLFOX is 160 mg/m2. Methods: The study was a 1:1 parallel arm, open label, not comparative one to assess overall response rate (ORR) of Nab-FOLFIRI and Nab-FOLFOX as primary end-point. Patients (pts) with PS 0-1, untreated for mPC were randomized to receive leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2, irinotecan 180 mg/m2 plus nab-p 120 mg/m2 (arm A) or leucovorin 400 mg/m2, 5FU bolus 400 mg/m2, 5FU 48h ci 2400 mg/m2 and oxaliplatin 85 mg/m2 iv plus nab-p 160 mg/m2 (arm B) every 2 weeks for up to 12 cycles. Secondary end points were clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS), and safety. Results: From November 2015 to January 2017, 84 pts were treated (42 for each arm). Median age was 60 years (29-65) in arm A and 64 years (47-64) in arm B. The ORR was 31 % for both schedules, with a CBR of 69% and 71%, respectively. At a median follow-up of 11.4 months for arm A and 14.5 months for arm B (censored on august, 31th 2017), 1-year survival is 41% and 50%, respectively. For Nab-FOLFIRI PFS and mOS were 6 months (90% CI: 4.9-8.0) and 13.2 months (90% CI: 8.3-14.8), while in Nab-FOLFOX were 5.6 months (90% CI:4.9-7.2) and 10.8 months (90% CI: 8.4-12.8). Grade ≥3 toxicities in arm A were neutropenia (19%) and febrile neutropenia (12%). In arm B, main grade ≥3 toxicities were neutropenia (29%), fatigue (14%), peripheral neuropathy (7%). No toxic death were registered. Conclusions: Nab-FOLFIRI and Nab–FOLFOX demonstrated a similar activity to FOLFIRINOX, with better safety profile in terms of neutropenia, fatigue and neuropathy. These results could justify a future phase III evaluation. Clinical trial information: NCT02109341.

Capecitabine and Oxaliplatin versus 5-Fluorouracil in the Neoadjuvant Chemoradiation for Patients with Locally Advanced Rectal Carcinoma: A Comparative Study

Aim of work: This study aimed to evaluate the resectability rate, rate of conservative surgery, toxicity, local control, and disease free survival for oxaliplatin and capecitabine based chemoradiation compared to standard 5-FU based chemoradiation in locally advanced cancer rectum. Patients and methods: 65 patients were eligible; 33 patients received oxaliplatin and capecitabine based chemoradiation (arm I) and 32 patients received 5-FU based chemoradiation (arm II). Results: The overall response rate in arms I and II were 78.7% and 87.5% respectively. Conservative surgery was done in 81.81% and 53.13% of patients with arms I and II, pathologic complete response (pCR) rate was significantly better in arm I than arm II (30.3% vs. 21.9%, P ; the median disease free survival (DFS) were 30 months and 15 months in arms I and II respectively. Grade III anemia, grade IV diarrhea and severe proctitis were developed in a significantly large number of patients with arm I; in addition deep venous thrombosis (DVT) was developed in 15.15% of patients with arm I but none in arm II. Conclusion: The addition of oxaliplatin to the preoperative chemo radiation increased the response rate mainly pCR rate which was considered a target goal in the neoadjuvant treatment, but it was not recommended because of higher toxicity and no significant effect on DFS in different response groups of arm I when compared to arm II, but longer follow up may be needed to evaluate the overall survival.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508)

BackgroundCixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. MethodsBevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). ResultsOf 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4–7.1) in arm A versus 7 months (95% CI 5.7–7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65–1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. ConclusionsThe addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. ClinicalTrials.gov IdentifierNCT00955305

Parallel (Randomized) Phase II Evaluation of Tivantinib (ARQ197) and Tivantinib in Combination with Erlotinib in Papillary Renal Cell Carcinoma: SWOG S1107.

Background:Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC.Methods:Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2). Target max accrual was 70 patients (35 per arm) with interim analysis planned after enrollment of 20 patients per arm.Results:Six % of patients had type 1 pRCC, 42% had type 2, and 52% had no subtype assigned. The study was closed after the first stage when both arms yielded RR of 0%. Median progression free survival (PFS) was 2.0 and 3.9 months, and OS was 10.3 and 11.3 months in Arms 1 and 2 respectively. Treatment was well tolerated. Exome of tumor tissue from 16 patients were successfully sequenced using Agilent SureSelect probes. Only 1 of 16 samples harbored MET mutation. Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1 and NF2.Conclusions:Tivantinib - either alone or in combination with erlotinib has no clinical activity in patients with advanced pRCC. The S1107 cohort had a low proportion of patients with MET alterations. MET remains a reasonable therapeutic target in pRCC, but selection of patient subsets exhibiting MET activation may be required to better benefit from therapy with MET inhibitors.