Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE)

Background Treatment for ovarian cancer includes platinum-based chemotherapy, but many women become resistant to chemotherapy, becoming platinum-resistant. Standard of care for these women is weekly paclitaxel chemotherapy, but cancers can often become paclitaxel resistant. TAK228, an investigational dual TORC1/2 inhibitor, is an oral therapy that can be added to standard treatment. The DICE trial is a phase II international multicentre, parallel-group, superiority clinical trial with 1:1, open label randomisation which has the aim of investigating the effectiveness of TAK228 plus weekly paclitaxel. The planned sample size is 124 women (62 per treatment arm) with platinum-resistant ovarian cancer. Objective To outline the planned analyses for DICE in a statistical analysis plan (SAP) before database hard lock and the start of analysis. This ensures that bias is minimised during the analysis phase. Results This SAP provides detailed descriptions of the analysis principles and statistical procedures for analysing primary and secondary outcomes of the trial. The primary outcome is overall progression-free survival (PFS). Secondary outcomes include progression-free survival (PFS) at 24 weeks, overall response rate (ORR), duration of response (DoR), time to progression (TTP), clinical benefit rate (CBR) at 4 months, Cancer Antigen 125 (CA125) response according to Gynaecological Cancer Intergroup (GCIG) criteria, overall survival (OS), safety and tolerability as assessed by adverse events and the quality-of-life questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28). This detailed description includes significance levels, sensitivity analyses and compliance analysis. Discussion The DICE trial will determine whether the addition of TAK228 to weekly paclitaxel chemotherapy shows a statistically significant improvement to participant’s progression free and overall survival and that the adverse events (AEs) and quality of life (QoL) are not significantly worse than the standard treatment. The study commenced recruitment in September 2018. An interim analysis was performed in early 2021, the results of which advised continuation of the trial. The study recruitment is ongoing and is due to complete by the end of 2021. Trial registration ClinicalTrials.govNCT03648489. Registered on 27 August 2018

Neoadjuvant Therapy with Doxorubicin-Cyclophosphamide Followed by Weekly Paclitaxel in Early Breast Cancer: A Retrospective Analysis of 200 Consecutive Patients Treated in A Single Center with A Median Follow-Up of 9.5 Years.

Purpose We analyzed outcomes of doxorubicin-cyclophosphamide(AC) followed by weekly paclitaxel as neoadjuvant chemotherapy(NAC) for breast cancer(BC), in an everyday practice with long-term follow-up of patients. Methods All patients (n=200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007(n=99); and subsequently every 2 weeks (dose dense)(dd)(n=101). Clinical pathologic features, treatment course and outcome information were recorded. Complete pathologic response(pCR) was analyzed according to BC subtype, dose regimen and stage. Results Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human-epidermal-growth-factor receptor(HER 2)-positive 32.5% (of whom 82% received trastuzumab), hormone-receptor positive/HER2 negative 53%, triple negative 14.5%. Breast conserving surgery(BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival(EFS), and overall survival(OS) is 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. Conclusions- NAC for BC with AC-paclitaxel can be safely administered in the “real-world’ setting with high efficacy. Current efforts are aimed at Increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

948 Final results from AIPAC: A phase IIb comparing eftilagimod alpha (a soluble LAG-3 protein) vs. placebo in combination with weekly paclitaxel in HR+ HER2- MBC

BackgroundEftilagimod alpha (efti; IMP321) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by CD8 T-cells. Weekly paclitaxel is a standard of care chemo-regimen after failure of endocrine-based therapy for metastatic breast carcinoma (MBC). AIPAC (Active Immunotherapy PAClitaxel) investigated the addition of efti to weekly paclitaxel in these patients (pts).MethodsThis placebo-controlled, double-blinded, 1:1 randomized phase IIb trial enrolled pts with measurable disease, HR+ HER2- MBC after endocrine-based therapy. Pts received paclitaxel (80 mg/m² IV on D1, D8, D15) + efti (30 mg) or placebo on D2, D16 (every 2 weeks) for up to 24 weeks following efti/placebo for up to 52 weeks. The primary endpoint (EP) was progression-free survival (RECIST1.1) by BICR. Secondary EPs included overall survival (OS), PFS (local read), overall response rate (ORR), biomarker, quality of life. Exploratory EPs included univariate/multivariate analyses.Results227 pts were randomized (Jan2017-Jul2019). All except 1 received ≥1 treatment and were included in the full analysis set [efti (n=114); placebo (n=112)]. Data cut-off was 14May2021 (min. follow-up= 22 months). Median age was 60 yrs with ECOG 0 in 61.5%. 91.6% had visceral disease. Pts were mostly endocrine resistant (84%) and partially pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Median OS was 20.4 (95% CI: 14.3-25.1) months in the efti group vs. 17.5 (95% CI: 12.9-21.9) in the placebo group. HR was 0.88 (95%CI: 0.64-1.19; p=0.197). In predefined univariate analyses, younger pts, low baseline monocytes and luminal B showed significant/clinically meaningful improvement in OS (table 1).Efti increased PBMC/T cell (CD4/CD8) count vs. placebo, correlating with improved OS (Spearman Rho=0.6, p=0.02 for CD8 T cells). In a whole population multivariate cox regression model, increasing BMI and prior treatment with CDK4/6 were independent significant poor prognostic markers for PFS and OS.TEAEs leading to discontinuation were similar at 5.3%(efti) & 6.3%(placebo). PFS (Primary EP) and safety were reported at SABCS 2020 (Abstract#132).Abstract 948 Table 1Overall survival by subgroups at final analysisConclusionsEfti added to paclitaxel led to a non-significant 2.9 months median OS increase in HR+ HER2- MBC pts after endocrine-based therapy. Effects were significant in pts <65yrs, with low monocytes and more aggressive disease (luminal B). Efti increased circulating CD4/CD8 T cells, which significantly correlated to improved OS. Weekly paclitaxel + efti should be further investigated in MBC.Trial RegistrationThe trial identifiers are IMP321-P011 (code for sponsor), 2015-002541-63 (EudraCT) and NCT02614833 (ClinicalTrials.gov).Ethics ApprovalThe study was approved by relevant ethic committees and institutional review boards.

Pathological Response Rate of Paclitaxel Based Dose Dense and Conventional Neoadjuvant Chemotherapy in Locally Advanced Female Breast Cancer Patients

BACKGROUND Locally advanced female breast cancer patients have the highest risk of recurrence and distant metastasis. Taxane-based neoadjuvant chemotherapy gives a more pathological response. The purpose of this study was to assess the pathological response rate of paclitaxel-based dose-dense and conventional neoadjuvant chemotherapy in locally advanced female breast cancer patients. METHODS In this observational study, a total of hundred locally advanced female breast cancer patients were randomly selected for neoadjuvant chemotherapy. Fifty patients received three weekly paclitaxel 200 mg/m2 (4 courses) and other fifty patients received weekly paclitaxel 80 mg/m2 (10 courses) along with three weekly doxorubicin 50 mg/m2(4 courses in both arms). Chemotherapy-induced clinical response in both arms was weekly assessed by tumour and lymph node size measurements, change in consistency and fixity. Pathological response of chemotherapy in each arm was assessed by taking the difference of mean tumour volumes and presence of chemotherapy-induced fibrosis and collections of histiocytes in lymph nodes. RESULTS There was statistically significant pathological reduction after neoadjuvant chemotherapy was seen in three weekly arms (68.18 cm3 to 37.22 cm3 P-value 0.000), in the weekly arm (68.42 cm3 to 18.04 cm3 P-value 0.000) and difference in reduction of tumour volume (more in weekly arm -50.38 cm3 versus 30.86 cm3, Pvalue 0.000). CONCLUSIONS Locally advanced female breast cancer patients receiving neoadjuvant chemotherapy with paclitaxel showed a better pathological response rate. It was more in the weekly paclitaxel arm. KEY WORDS Pathological Response Rate, Neoadjuvant Chemotherapy, Locally Advanced.