• 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial

      Earl, H; Hiller, L; Vallier, A; Loi, S; McAdam, K; Hughes-Davies, L; Harnett, A; Ah-See, M; Simcock, R; Rea, D; et al. (2019)
      BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5á4 years (IQR 3á6-6á7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89á4% (95% CI 87á9-90á7) in the 6-month group and 89á8% (88á3-91á1) in the 12-month group (hazard ratio 1á07 [90% CI 0á93-1á24], non-inferiority p=0á011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0á0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0á0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.
    • Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial.

      Cameron, D; Morden, J; Canney, P; Velikova, G; Coleman, R; Bartlett, J; Agrawal, R; Banerji, J; Bertelli, G; Bloomfield, D; et al. (2017-07)
      Adjuvant chemotherapy for early breast cancer has improved outcomes but causes toxicity. The UK TACT2 trial used a 2×2 factorial design to test two hypotheses: whether use of accelerated epirubicin would improve time to tumour recurrence (TTR); and whether use of oral capecitabine instead of cyclophosphamide would be non-inferior in terms of patients' outcomes and would improve toxicity, quality of life, or both.
    • Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial.

      Earl, H; Hiller, L; Howard, H; Dunn, J; Young, J; Bowden, S; McDermaid, M; Waterhouse, A; Wilson, Gregory; Agrawal, R; et al. (2017-06)
      The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel.
    • Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.

      Hiller, L; Dunn, J; Loi, S; Vallier, A; Howe, D; Cameron, D; Miles, D; Wardley, Andrew M; Earl, H; Warwick Clinical Trials Unit, University of Warwick, Coventry (2018-04-05)
      Twelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost.
    • PARTNER: randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

      Abraham, J; Vallier, AL; Qian, W; Machin, A; Grybowicz, L; Thomas, S; Weiss, M; Harvey, C; McAdam, K; Hughes-Davies, L; et al. (2019)
      Background: No specific targeted therapies are available for triple negative breast cancer (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for basal TNBC and/or gBRCA BC is safe and improves efficacy (pathological complete response (pCR)). Methods: Trial design: 3-Stage open label randomised Phase II/III trial of neoadjuvant CP: Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 +/- olaparib 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and / or gBRCAm patients are eligible for inclusion. Tumour infiltrating lymphocytes and basal profile are assessed at baseline. Stage 1 and 2: Patients are randomised (1:1:1) to CP: CP + olaparib from day (D) –2: or CP + olaparib from D 3. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. Primary end-points: Stage 1 – Safety; Stage 2 - Schedule selection criteria by pCR rate and completion rate of olaparib protocol treatment. 53 patients in each research arm will be evaluated within a “pick the winner” design. Null hypothesis of pCR ?35% versus alternative hypothesis of pCR ?55% will be tested with 90% power and 5% one sided significance level in each of the research arms. Stage 3 - Efficacy: anticipated pCR ~45-55% for all trial patients and ~50-60% for gBRCA patients. The trial is powered to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to chemotherapy (enriched design). Enrichment design is applied with overall significance level 0.05(?) = 0.025(?all) + 0.025(?gBRCA) and 80% power. Current enrolment: 133 of planned 527 patients. Stage 1 accrual is complete. Stage 2 began in August 2017. 19 sites open and 12 more in active set-up. Clinical trial information: NCT03150576.
    • Patient reported experiences (PREs) from the PERSEPHONE early breast cancer (EBC) trial

      Dunn, J; Wilcox, M; Balmer, C; Gasson, S; Hiller, L; Vallier, L; Hulme, C; Raynes, K; Howe, D; Higgins, H; et al. (2018)
    • PERSEPHONE: a randomised phase 3 non-inferiority trial of 6 versus 12 months (m) of adjuvant trastuzumab in patients with HER2 positive (+) early breast cancer (EBC)

      Earl, H; Hiller, L; Vallier, L; Loi, S; Howe, D; Higgins, H; McAdam, K; Hughes-Davies, L; Harnett, A; Ah-See, L; et al. (2018)
    • Quality of life with weekly, dose-dense versus standard chemotherapy for ovarian cancer in the Icon8 study.

      Blagden, S; Cook, A; Poole, C; Howells, L; McNeish, I; Dean, A; Galardo, D; Kim, J; O'Donnell, D; Hook, J; et al. (2017)
    • A randomised placebo-controlled trial of weekly paclitaxel and saracatinib (AZD0530) in platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

      McNeish, I; Ledermann, J; Webber, L; James, L; Kaye, S; Hall, M; Hall, G; Clamp, Andrew R; Earl, H; Banerjee, S; et al. (2014-07-28)
      We investigated whether the Src inhibitor saracatinib (AZD0530) improved efficacy of weekly paclitaxel in platinum-resistant ovarian cancer.
    • A randomized controlled trial to evaluate the role of interferon as initial and maintenance therapy in patients with follicular lymphoma.

      Rohatiner, Ama; Radford, John A; Deakin, David P; Earl, H; Love, S B; Price, O; Wilson, A; Lister, T Andrew; ICRF Medical Oncology Unit, St. Bartholomew's Hospital, London, West Smithfield, EC1A 7BE. (2001-07-06)
      The purpose of this study was to evaluate the role of interferon as initial and maintenance therapy in patients with newly diagnosed follicular lymphoma. Between 1984 and 1994, 204 patients with newly diagnosed Stage III or Stage IV follicular lymphoma were randomized to receive either, Chlorambucil (CB): 10 mg daily for 6 weeks, followed by a 2-week interval, with 3 subsequent 2-week treatment periods at the same dose, separated by 2-week intervals, or, CB given concurrently with interferon (IFN). IFN was given at a dose of 3 x 10(6)units thrice weekly, subcutaneously, throughout the 18-week treatment period. Responding patients were subsequently randomized to receive maintenance IFN at the dose and schedule described above, or to expectant management. The overall response rate was 161/204 (78%), complete remission being achieved in 24% of patients. Neither the addition of IFN to the initial treatment, nor the use of maintenance IFN influenced response rate, remission duration or survival. This study was undertaken to determine whether IFN, given in combination with, and then subsequent to, CB would alter the clinical course of patients with follicular lymphoma. Disappointingly, this objective was not achieved, no advantage having been demonstrated for the addition of IFN.
    • A randomized phase-II study of BB-10010 (macrophage inflammatory protein- 1alpha) in patients with advanced breast cancer receiving 5-fluorouracil, adriamycin, and cyclophosphamide chemotherapy.

      Clemons, Mark; Marshall, E; Dürig, J; Watanabe, K; Howell, Anthony; Miles, D; Earl, H; Kiernan, Julie; Griffiths, Audrey; Towlson, K; et al. (1998-09-01)
      BB-10010 is a variant of the human form of macrophage inflammatory protein-1alpha (MIP-1alpha), which has been shown in mice to block the entry of hematopoietic stem cells into S-phase and to increase their self-renewal capacity during recovery from cytotoxic damage. Its use may constitute a novel approach for protecting the quality of the stem cell population and its capacity to regenerate after periods of cytotoxic treatment. Thirty patients with locally advanced or metastatic breast cancer were entered into the first randomized, parallel group controlled phase II study. This was designed to evaluate the potential myeloprotective effects of a 7-day regimen of BB-10010 administered to patients receiving six cycles of 5-fluorouracil (5-FU), adriamycin, and cyclophosphamide (FAC) chemotherapy. Patients were randomized, 10 receiving 100 microgram/kg BB-10010, 11 receiving 30 microgram/kg BB-10010, and nine control patients receiving no BB-10010. BB-10010 was well-tolerated in all patients with no severe adverse events related to the drug. Episodes of febrile neutropenia complicated only 4% of the treatment cycles and there was no difference in incidence between the treated and nontreated groups. Studies to assess the generation of progenitor cells in long-term bone marrow cultures were performed immediately preceding chemotherapy and at the end of six dosing cycles in 18 patients. Circulating neutrophils, platelets, CD 34(+) cells, and granulocyte/macrophage colony-forming cell (GM-CFC) levels were determined at serial time points in cycles 1, 3, and 6. The results showed similar hemoglobin and platelet kinetics in all three groups. On completion of the six treatment cycles, the average pretreatment neutrophil levels were reduced from 5.3 to 1.7 x 10(9)/L in the control patients and from 4.3 to 1.9 and 4.5 to 2.5 x 10(9)/L in the 30/100 microgram/kg BB-10010 groups, respectively. Relative to their pretreatment values, 50% of the patients receiving BB-10010 completed the treatment with neutrophil values significantly higher than any of the controls (P = .02). Mobilization of GM-CFC was enhanced by BB-10010 with an additional fivefold increase over that generated by chemotherapy alone, giving a maximal 25-fold increase over pretreatment values. Bone marrow progenitor assays before and after this standard regimen of chemotherapy indicated little long-term cumulative impairment to recovery from chemotherapy. Despite the limited cumulative damage to the bone marrow, which may have minimized the protective value of BB-10010 during this regimen of chemotherapy, better recovery of neutrophils in the later treatment cycles with BB-10010 was indicated in a number of patients.
    • Statistical considerations in a non-inferiority trial: results from the PERSEPHONE early breast cancer herceptin duration trial

      Dunn, JA; Hiller, L; Howe, D; Vallier, AL; Raynes, K; Higgins, H; Cameron, DA; Miles, D; Wardley, Andrew M; Earl, H; et al. (2019)
    • Trastuzumab-associated cardiac events in the Persephone trial.

      Earl, H; Vallier, A; Dunn, J; Loi, S; Ogburn, E; McAdam, K; Hughes-Davies, L; Harnett, A; Abraham, J; Wardley, Andrew M; et al. (2016-12-06)
      We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer.