SYNOPSIS PROTOCOL TALBOT

Transcription

1 SYNOPSIS PROTOCOL TALBOT A) CLINICAL TRIAL IDENTIFICATION SPONSOR - PROTOCOL CODE NUMBER : VERSION: SYNOPSIS V4.0-30/06/2015 TRIAL TITLE : Open-label, randomized, multicenter, phase II study, comparing weekly paclitaxel to letrozole + palbociclib combination as initial metastatic treatment among patients with visceral metastases of ER+ Her2- breast cancer ABBREVIATED TITLE : TALBOT PRINCIPAL INVESTIGATOR - UNICANCER Dr Julien GRENIER Institut Sainte Catherine, Avignon Co- PRINCIPAL INVESTIGATOR COORDINATOR- GINECO Pr Thomas BACHELOT Centre Léon Bérard, Lyon number of randomized subjects : 168 Rédaction : S Delaloge, T Bachelot, C Cropet, C Vissac- Sabatier, J Lemonnier, F Bonnetain B) SPONSOR IDENTIFICATION NAME OF THE INSTITUTION : Unicancer R&D 101 rue de Tolbiac Paris Cedex 13 Tél : Fax : CONTACT PERSON : Cécile VISSAC-SABATIER 101 rue de Tolbiac PARIS CEDEX 13 - France Tel. : Fax : c-vissac@unicancer.fr STATISTICIAN : Claire CROPET Direction de la Recherche Clinique et de l Innovation Centre Léon Bérard 28, rue Laënnec LYON Cedex 08 Tel : ; Fax : claire.cropet@lyon.unicancer.fr C) TRIAL GENERAL INFORMATION MEDICAL CONDITION : Patients with untreated metastatic ER+ Her2- breast cancer with visceral involvement 1 / 14

2 METHODOLOGY : Open-label, randomized, multicenter, phase II study, comparing chemotherapy (weekly paclitaxel) to letrozole + palbociclib combination as initial metastatic treatment among patients with measurable metastases of ER+ Her2- breast cancer MAIN OBJECTIVES : The primary objective is to compare the efficacy of letrozole + palbociclib combination vs weekly paclitaxel based on Progression-Free survival, in patients with measurable metastases of ER+ Her2- breast cancer SECONDARY OBJECTIVE(S) To compare between the 2 study arms: 1. Health related quality of life 2. Overall survival 3. Objective response rate (RECIST 1.1) and duration of response 4. Safety according to CTC-AE v PFS in stratified subgroups Exploratory Objective(s) : Translational research To study the predictive and prognostic value of ctdna mutational status on response and progression, respectively 2 / 14

3 INCLUSION CRITERIA : 1) Age > 18 years 2) Performance status, ECOG 0-1 3) Histologically confirmed adenocarcinoma of the breast 4) Metastatic breast cancer, soft tissue or visceral involvement with measurable lesions (RECIST1.1) 5) Patient considered candidate for a first line chemotherapy by their physician 6) ER-positive by IHC (>10%) on primary or metastatic disease 7) HER2-negative by IHC (score 0 or 1+) and/or Fish/Cish negative on primary and metastatic disease 8) No previous Aromatase inhibitor (AI), or relapse > 12 months from end of previous adjuvant AI therapy 9) Pre-menopausal or post-menopausal 10) Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria: o Absolute Neutrophil Count (ANC) 1,500/mm 3 or 1.5 x 10 9 /L o Platelets 100,000/mm 3 or 100 x 10 9 /L o Hemoglobin 9 g/dl o Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) 2.5 x upper limit of normal (ULN) (4x if liver metastasis) o Alkaline phosphatase 2.5 x ULN o Total serum bilirubin 1 x ULN o Serum creatinine 1.5 x ULN or estimated creatinine clearance >60 ml/min as calculated using the method standard for the institution 11) Adequate cardiac functions, including: o 12 Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention o QTc interval 480 msec (mean of replicate values, correction per institutional standard) o No history of Torsades de Pointes or other symptomatic QTc abnormality. 12) Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures 13) Signed informed consent 14) Health insurance coverage 3 / 14

4 EXCLUSION CRITERIA : 1) Bone lesion only or non-measurable lesion (RECIST 1.1) 2) Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them 3) Spinal cord compression and/or symptomatic or progressive brain metastases (Brain metastasis are not acceptable unless asymptomatic or treated and stable off steroids for at least 30 days prior to start of study drug) 4) Patient has received one line of chemotherapy for metastatic disease 5) Patient has received AI for metastatic disease 6) Patient has relapsed while on AI in the adjuvant setting or within one year of ending AI adjuvant therapy 7) Inability to swallow 8) Major problem with intestinal absorption 9) Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix or the breast, and adequately treated basal cell or squamous cell carcinoma of the skin 10) Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV) 11) Active cardiac disease or a history of cardiac dysfunction 12) Any condition which in the Investigator s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol 13) Individuals deprived of liberty or placed under the authority of a tutor 14) Any drug or plant derivative that may interact with palbociclib EVALUATION CRITERIA : PRIMARY EFFICACY ENDPOINT : Progression-free survival in both arms SECONDARY ENDPOINTS : Health related Quality of life in both arms throughout treatments (EORTC QLQ C30 and BR23 module) Clinical/radiological response rates in each treatment arm (RECIST 1.1) Safety (CTC-AE V4.0) PFS in stratified subgroups Overall survival EXPLORATORY ENDPOINTS: Predictive and prognostic value of ctdna mutational status on response and progression, respectively 4 / 14

5 D) DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS INVESTIGATIONAL MEDICINAL PRODUCT : Drug Name (DCI) Commercial Name Pharmaceutical Form Administration Route Posology Palbociblib - Capsules PO 125 mg/day (3weeks/4) Drug Name (DCI) Commercial Name Pharmaceutical Form Administration Route Posology Letrozole Femara Tablets PO 2.5 mg/day NON -INVESTIGATIONAL MEDICINAL PRODUCTS: Drug Name Commercial Pharmaceutical Administration Posology (DCI) Name Form Route Paclitaxel Taxol IV solution IV 90 mg/m2/w 3/4w 5 / 14

6 THERAPEUTIC/STUDY SCHEME Patients are randomly assigned to receive either: - ARM A: Standard Chemotherapy regimen : Paclitaxel administrated at the dose of 90 mg/m 2 IV as a 1-hour infusion, every week, 3 week on/1 week off, (4 weeks cycles) - ARM B: Experimental hormone therapy regimen: letrozole continuous administration of 2.5 mg per day orally (1 tab per day); in combination with oral palbociclib 125 mg q1d 3w/4w (4 weeks cycles). For patients with pre-menopausal status at inclusion, Goserilin, 3,6 mg/4w IM will be added. Duration of one cycle of either treatment : 4 weeks Main study assessments: Before inclusion: medical visit with an oncologist: presentation of the study and informed consent form to be signed by patients giving their agreement for this clinical research Assessment before initial surgery: standard biological tests, blood sampling for soluble biomarkers research and serum sampling for freezing (ct DNA analysis), CT scan, bone scan (petscan can be used instead of bone scan) Tumor evaluation every 2 nd cycle: standard biological tests, serum sampling for freezing (ct DNA analysis), CT scan, bone scan if indicated HRQOL before randomization and every 2 nd cycle until progression After 16 months, tumor evaluation will be done every 3 cycles (12w) At progression: standard biological tests, blood sampling for soluble biomarkers research and serum sampling for freezing (ct DNA analysis), CT scan, bone scan, HRQOL Metastatic ER+ Her2- breast cancer Soft tissue/visceral metastases, Measurable disease First line treatment, AI sensitive R 1:1 letrozole 2,5 mg q1d + palbociclib 125 mg q1d 3w/4 (+ goserilin in premenopausal wn) Paclitaxel 90mg/m² ; 3w/4 Evaluation every 8 weeks PROGRESSION 6 / 14

7 D) DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS ( ) Treatment delay and dose adaptations in case of acute toxicities : Chemotherapy : according to local site procedures letrozole : according to local site procedures palbociclib : to be discussed with Pfizer F) STATISTICS AND SAMPLE SIZE DETERMINATION Stratification according to: - Previous AI / no previous AI - Number of organs involved ( 2 vs > 2) Primary end-point: the primary endpoint of the study is progression-free survival (PFS). The study is designed to detect an improvement in median PFS from 8 months with the control arm (weekly Paclitaxel) (O Shaughnessy et al. SABCS 2009, Abst#207) to 14 months with the experimental arm (HR=0.6). Assuming 24 months of recruitment, 38 months for total follow-up (i.e 14 months for the last included patient), 84 patients per arm are required for a total of 134 events, with a power of 90% and a bilateral alpha risk of 5%. PFS will be measured from the date of randomization until the date of event defined as the first documented progression (RECIST 1.1) or death from any cause. Patients with no event at the time of the analysis will be censored at the date of the last available tumor assessment. PFS will be estimated using the Kaplan-Meier method and will be described in terms of median PFS per arm, and hazard ratio for progression between the 2 arms. Associated 2-sided 95% CIs for the estimates will be provided. PFS distributions will be compared between the 2 study arms using a stratified 2-sided Log-Rank test (significance level of 5%). Health related quality of life 5 targeted dimensions: Global Health, physical and emotional functioning, fatigue and pain of EORTC QLQ C30 Decision rules to conclude for better HRQOL profile in one arm: at least one significant difference for one targeted dimension in favor of one arm without at least one significant difference in favor of the other arm Others dimensions of EORTC QLC30 and BR23 will be regarded as exploratory Method: Bonferroni approach with bilateral alpha type one error of 1% for each targeted dimension. The minimal clinically important difference in score = 5 points. A definitive deterioration of HRQOL score free survival approach will be used as well (Ref Bonnetain f et al EJC 2010, Hamidou Z et al the oncologist 2011, Anota A et al Qual Life Research 2015) using Kaplan Meier estimation and Log-Rank tests. Univariate and multivariate Cox analyses will be performed. 7 / 14

8 F) TRIAL DURATION INCLUSION PERIOD : 24 MONTHS TREATMENT DURATION : UNTIL PROGRESSION FOLLOW-UP DURATION : 38 months OVERALL TRIAL DURATION : 5 YEARS 8 / 14

9 G) RATIONALE - Palbociclib Palbociclib (PD ) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has been under investigation in Phase 1 and 2 clinical trials in multiple indications. PD prevents cell cycle progression from G1 to S phase and has shown antitumor activity in multiple preclinical models, including in estrogen receptor-positive (ER+) luminal breast cancer cell lines. Furthermore, pre-clinical exploration using a breast cancer cell line panel has demonstrated presence of retinoblastoma (Rb) protein and upregulation of cyclin D1 as well as decreased CDKN2A (p16) that were associated with sensitivity to PD as well as with its effects upon cell cycle and growth inhibition. These gene expression findings were also associated with the luminal subtype versus basal-like subtype of BC. These results, together with published data on the interaction of estrogens and CDKs and the important role of cell cycle-related proteins in the genesis and maintenance of breast cancer, led to the initiation of a randomized Phase 2 clinical trial (PALOMA1- A ) investigating the antitumor activity of PD in combination with letrozole and single-agent letrozole in the first-line treatment of ER(+)/HER2(-) ABC patients. The Phase 2 study was divided into 2 parts. In Part 1, patient selection was based only on ER/HER2 status while in Part 2, patients were additionally prospectively selected taking into account tumor CCND1 amplification and/or CDKN2A (p16) loss. After a median follow-up of 16.5 months, preliminary results from Part 1 of this Phase 2 trial suggest that the combination of PD with letrozole is superior to letrozole alone in the selected patient population as demonstrated by prolonged progression-free survival (median 18.2 months vs 5.7 months, respectively), and improved objective response and disease control rates (52% vs 32% and 76% vs 47%, respectively) in patients treated with the combination. The combination therapy was generally well tolerated when compared to letrozole alone with AEs similar to those seen with PD and letrozole when administered alone. Uncomplicated neutropenia, leucopenia, and fatigue were the most frequent adverse events, and the most commonly reported Grade 3 treatment-related adverse events were neutropenia (54%) and leucopenia (21%) in patients treated with the combination therapy. Grade 4 events included neutropenia and fatigue each reported for 6% of patients treated with PD letrozole. No Grade 4 events were reported in the letrozole alone arm. Treatment-related Grade 1/2 AEs reported more frequently in patients in the PD letrozole arm compared with the letrozole alone arm included leukopenia, anemia, fatigue, alopecia, arthralgia, nausea, neutropenia, and thrombocytopenia. Hot flush was the most common Grade 1/2 treatment-related AE reported in patients enrolled in the letrozole alone arm. Overall, 3 (9%) patients in the PD letrozole arm and 1 (3%) patient in the letrozole alone arm discontinued the Phase 2 Part 1 of Study A due to AEs including 1 patient with Grade 4 fatigue (not related to PD ) and 2 patients with Grade 3 neutropenia in the PD letrozole arm and 1 patient with Grade 2 nausea in the letrozole alone arm. The median duration of treatment was 13.7 months in the PD letrozole arm vs 5.4 months in the letrozole alone arm, with PD dosing interruptions and dose reductions due to AEs reported in 61% and 39% of patients enrolled in the PD letrozole arm respectively. The median duration of dosing interruptions was 4.5 days, and the median time to first dosing interruption was 55.5 days. Despite the dosing interruptions and dose reductions, the median dose intensity for PD was 87% across all cycles. 9 / 14

10 Clinical results of randomized trials in ER+ Her2- metastatic breast cancer: The primary results of PALOMA 1 study have been published in early 2015 (Finn et al, Lancet Oncol 2015) and have led to early approval by FDA of the letrozole + palbociclib combination in the first line metastatic setting among ER+ Her2-negative patients with non-ai-resistant disease. In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their estrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomization system, stratified by disease site and diseasefree interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigatorassessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). Findings: Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI ] for the palbociclib plus letrozole group and 27.9 months [ ] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI ) for the letrozole group and 20.2 months ( ) for the palbociclib plus letrozole group (HR 0.488, 95% CI ; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months ( ) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, ; one-sided p<0.0001); in cohort 2 (n=99), median progression-free survival was 11.1 months ( ) for the letrozole group and 18.1 months ( ) for the palbociclib plus letrozole group (HR 0.508, ; one-sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. Interpretation: The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced estrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. These results are expected to be confirmed by PALOMA 2, a randomized phase III study conducted in the same population. 10 / 14

11 The PALOMA 3 study has been presented at the ASCO meeting in June 2015 and concomitantly published in the New Engl J Med (Turner et al 2015). This phase 3 study involved 521 patients with advanced hormone-receptor positive, human epidermal growth factor receptor 2 negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. Palbociclib is currently under evaluation in preoperative and neoadjuvant settings (no data yet available but for safety). - Standard Chemotherapy for MBC: Paclitaxel: Weekly paclitaxel is a widely used standard treatment for first line therapy in HER2 negative MBC. It allows for median TTP of 7 to 8 months. Bevacizumab: Since 2011, the role of bevacizumab in HER2-negative metastatic breast cancer has been examined by various regulatory authorities. The US Food and Drug Administration (FDA) and the European Committee for Medicinal Products for Human Use reviewed the same datasets but drew divergent conclusions. In the USA, the FDA revoked approval of bevacizumab in this setting, whereas the European Commission considered that the benefit/risk balance remains positive for bevacizumab in combination with paclitaxel. Nevertheless, no study to date have shown survival benefice from using bevacizumab, not even a trend in this direction. As a consequence, many authors do not consider this treatment as having a relevant risk/benefit ratio for MBC patients. French ANSM advised to reserve it for aggressive, triple negative metastatic breast cancer patients. For these reasons, this treatment was not considered for the present study. - Differential activity of hormone therapy and chemotherapy as first line treatment of ER+/HER2-ve MBC Few studies have made direct comparison between hormone therapy and chemotherapy as first line treatment in this setting. Most of them are small and all are old (20 years+), using 11 / 14

12 chemotherapy regimen (alkalating agent) and hormone therapy (tamoxifen) that are seldom used today as first line therapy. They were the subject of a meta-analysis which concludes that chemotherapy could be better for response rate, but that the two approaches may be equivalent for overall survival. Indirect comparison of modern chemotherapy and hormone therapy regimen is in favor of an equivalent potential of those two strategies to control disease progression. As a consequence, hormone therapy being less toxic that chemotherapy, this first option is recommended by most expert panels, except in case of rapidly progressive visceral disease (so called visceral crisis ), in which case chemotherapy is recommended. Nevertheless, scientific evidence supporting theses recommendation is of low level, and more research is needed, particularly for patient with extensive visceral disease. - Rationale of the trial hypothesis We make the hypothesis that letrozole/palbociclib combination (i) should be associated with a median progression-free survival of 16 months, much greater that what is expected with chemotherapy or letrozole alone and (ii) should allow better quality of life than chemotherapy. As a consequence, this combination should be superior to a standard chemotherapy regimen in the first line metastatic setting of ER+/HER2-ve MBC, even in case of extensive visceral disease. We plan to restrict the inclusion to patients with soft tissue measurable disease in order (i) to exclude patient with slowly progressive bone only disease for which chemotherapy may not be appropriate and (ii) allow precise evaluation of response rate and time to progression, which is important for a small randomized phase II trial. Bibliographie Barrios C, Sampaio C, Vinholes J and Caponero R: What is the role of chemotherapy in estrogen receptor positive, advanced breast cancer? Ann Oncol 2009; 20: Cardoso F, Costa A, Norton L et al. 1st International consensus guidelines for advanced breast cancer (ABC1). The Breast 2012; 21(3): Cardoso F, Costa A, Norton L et al. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2) Ann Oncol 2014; 1 18 Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol S (14) Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998; 339: Miles DW, Diéras V, Cortés J, Duenne AA, Yi J, O'Shaughnessy J. First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients. Ann Oncol Nov; 24(11): Mouridsen H, Gershanovich M, Sun Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol May 15; 19(10): National Comprehensive Cancer Network: NCCN Guidelines version : Invasive Breast Cancer; Systemic treatment of recurrent or stage IV disease / 14

13 O Shaughnessy J, Diéras V, Glaspy J et al. Comparison of Subgroup Analyses of PFS from Three Phase III Studies of Bevacizumab in Combination with Chemotherapy in Patients with HER2-Negative Metastatic Breast Cancer. Presented at the San Antonio Breast Cancer Symposium, Dec 2009, abst#207 Semiglazov VF, Semiglazov VV, Dashyan GA et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer 2007; 110: Wilklen N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003;CD Finn Lancet Oncol 2015 Turner New Engl J Med / 14

14 H) FLOW CHART 14 / 14