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Abstract P1-13-05: GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses
Abstract
Background: GAIN-2 compares the effectiveness and safety of a predefined intense dose-dense regimen (EnPC) vs. a dose-dense regimen with modification of single doses depending on individual hematological and non-hematological toxicities (dtEC-dtD) (NCT01690702). Moreover, the Trastuzumab substudy compares the subcutaneous administration of the drug to the abdominal wall vs. thigh.
Methods: The primary objective of the GAIN-2 trial is to compare the invasive disease-free survival (iDFS) in patients with high-risk primary breast cancer (luminal A ≥4 N+; luminal B N+; HER2+ and TNBC N0/N+). Patients are randomized between EnPC (epirubicin 150 mg/m2 q2w x 3, nab-Paclitaxel 330 mg/m2 q2w x 3, cyclophosphamide 2000 mg/m2 q2w x 3) or dtEC-dtD (dd/tailored epirubicin/cyclophosphamide q2w x 4 followed by dd/tailored docetaxel q2w x 4) Two safety interim analyses after 200 (Noeding et al. Ann Oncol 2014) and 900 patients who have completed chemotherapy were planned. We present the results of the second safety analysis. In addition to the standard analyses for hematological and non-hematological toxicities, any affections of the cranial nerves as well as the rate of macula degenerations and anaphylactic reactions are of special interest.
Results: Between 09/2012 and 05/2015 a total of 1473 patients have been randomized (EnPC n=734; dtEC-dtD n=739). Among those, 84 patients have been included in the trastuzumab substudy. No safety data are currently available for the substudy. Median age was 52 years and median body-mass-index 26. In terms of hematological adverse events, the rate of febrile neutropenia grade 3-4 (12% vs. 8%) and thrombopenia grade 3-4 (12% vs. 5%) was significantly increased in the EnPC arm. As for non-hematological side effects, there were significantly more patients developing an increase in alkaline phosphatase (59% vs. 40%), ALAT (69% vs. 59%), peripheral sensory neuropathy (83% vs. 68%), arthralgia (63% vs. 49%), myalgia (48% vs. 41%) and bone pain (25% vs. 17%) in the EnPC arm, whereas nosebleed (10% vs. 25%), edema (13% vs. 26%) and hand-foot syndrome (12% vs. 28%) were more common in the dtEC-dtD arm. We observed two treatment related deaths, both in the dtEC-dtD arm (cause of death: acute respiratory distress syndrome and pneumonia). There were no differences between the treatment arms for the toxicities of special interest. In the EnPC arm, overall 30% of the patients required dose-reductions due to hematological toxicities compared with only 10% in the dtEC-dtD arm (p<0.001). The dose could be escalated to the maximum (epirubicin/cyclophosphamide 120/1200 mg/m2 followed by docetaxel 100 mg/m2) in more than one third of the patients receiving dtEC-dtD. In 9% of women a reduction was required in the 4th cycle of docetaxel.
Conclusion: This interim safety analysis from a prospectively randomized trial investigating iddEnPC with predefined doses and a toxicity adapted idd/tailored strategy (dtEC-dtD) showed no additional or unexpected safety signals in the iddEnPC or dtEC-dtD arm. Therefore, no modifications in the conduction of the study are necessary and the study continues as expected.
Citation Format: Möbus V, Lück H-J, Forstbauer H, Wachsmann G, Ober A, Schneeweiss A, Christensen B, von Abel E, Grischke E-M, Höffkes H-G, Klare P, Yon-Dschun K, Schmatloch S, Furlanetto J, Burchardi N, von Minckwitz G, Loibl S. GAIN-2: Adjuvant phase III trial to compare intense dose-dense (idd) treatment with EnPC to tailored dose-dense (dt) therapy with dtEC-dtD for patients with high-risk early breast cancer: Results of the second safety interim analyses. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-05.
... Therefore, a total of 32 phase II and III interventional randomized BC studies were initially considered. The present analysis included a total of 17 trials in which fatal events [5] GeparQuattro [6] GeparQuinto [7] GeparSixto [8] GeparSepto [9] GeparOcto [10] Genevieve [11] ICE [12] NNBC-3 [13] GAIN [14] GAIN-2 [15] Penelope [16] ICE2 [17] Tabea [18] Monica [19] E-Vita [20] occurred ( Fig. 1). Inclusion and exclusion criteria and all trial designs were previously published [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. ...
... The present analysis included a total of 17 trials in which fatal events [5] GeparQuattro [6] GeparQuinto [7] GeparSixto [8] GeparSepto [9] GeparOcto [10] Genevieve [11] ICE [12] NNBC-3 [13] GAIN [14] GAIN-2 [15] Penelope [16] ICE2 [17] Tabea [18] Monica [19] E-Vita [20] occurred ( Fig. 1). Inclusion and exclusion criteria and all trial designs were previously published [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. All patients starting on study medication were included in the analysis. ...
Background
Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials.
Methods
Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies.
Results
From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35–84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m²; 65.9% 1–3 and 22.7% ≥ 4 comorbidities; 61.4% 1–2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline–taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients.
Conclusions
Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.
... The ongoing phase III GAIN-2 study (NCT01690702; planned N = 2886) compares nab-paclitaxel on a less common dose-dense schedule (330 mg/m 2 q2w) plus EC vs EC followed by docetaxel using invasive disease-free survival as the primary endpoint (https://clinicaltrials. gov/ct2/show/NCT01690702, [28]). Among the 1473 patients who have been randomized, those in the nabpaclitaxel arm demonstrated higher rates of grade ≥3 febrile neutropenia (12 vs 8%) and peripheral sensory neuropathy (83 vs 68%) and required more dose reductions due to hematologic toxicities (30 vs 10%; P < 0.001). ...
PurposeThe purpose of this systematic review is to discuss recent studies and ongoing trials of nab-paclitaxel in breast cancer and to examine the potential role of nab-paclitaxel as a backbone for immuno-oncology therapies. Methods
PubMed and selected congress proceedings were searched for studies of nab-paclitaxel in breast cancer published between 2013 and 2015. All phase II and III clinical trials, retrospective analyses, and institutional studies were included. Active, ongoing, phase II or III trials on nab-paclitaxel that were listed on ClinicalTrials.gov were also included. ResultsSixty-three studies, including 23 in early-stage and 30 in metastatic breast cancer (some studies not classifiable by setting), were included in this analysis. Trials of neoadjuvant nab-paclitaxel–containing regimens have reported pathological complete response rates ranging from 5.7 to 53%. Median overall survival in metastatic breast cancer studies ranged from 10.8 to 23.5 months, depending on dose and regimen. Adverse event profiles of nab-paclitaxel were generally similar to those reported from previous studies. Several ongoing trials are evaluating nab-paclitaxel in the early-stage and metastatic settings, including in combination with immuno-oncology agents. Conclusionsnab-Paclitaxel continues to demonstrate promising efficacy in breast cancer. Recent studies demonstrate high pathological complete response rates in early-stage breast cancer, particularly in triple-negative breast cancer, an area of high unmet need, and encouraging overall survival in metastatic breast cancer across doses and schedules. Ongoing trials will provide further insights into the role of nab-paclitaxel in breast cancer including use as a potential backbone chemotherapy agent for immuno-oncology therapies such as checkpoint inhibitors.
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