| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early primary breast cancer, hormone receptor positve or negative, HER2 positive or negative, any nodal status. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early diagnosed breast cancer at first occurence, with hormone receptor over-expressing tumor and any lymph node involvement (from none to any). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006188 |
| E.1.2 | Term | Breast cancer female NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The ADAPT trial aims at personalizing therapy in early breast cancer by integration of dynamic response data into clinical management and at sparing unnecessary therapies without compromising patient outcome.
Primary objective
ADAPT umbrella
• Identification of a responder sub-population with intermediate and high risk, which due to therapy has outcome comparable to HR+/RS ≤ 11 |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives
• Relapse-free and overall survival in corresponding groups
• Overall survival
• Toxicity
• Cost-effectiveness
• distant disease-free survival (DDFS)
• local and regional relapse-free survival (LRFS and RRFS)
Further specific objectives are defined within the sub-protocols. Toxicity and cost efficacy are common endpoints of all sub-protocols. Toxicity and general health economic issues within the whole protocol will be analyzed, when results from the sub-protocols are available.
Additional translational research questions occurring during the trial will be defined in sub-protocols. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Version: 4.8
Date: 27.09.2017
ADAPT Hormone Receptor Positive/HER2 Negative Breast Cancer Sub-trial
Primary objectives
Run-in Phase:
Analysis of reproducibility of each biomarker
Assessment of dropout rate
Assessment of proportions of marker responders vs. non-responders
Central/local pathology
Central/local Ki-67 assessment
Ki-67 change after endocrine induction therapy
Comparison of changes in RS, Ki-67, quantitative ER and proliferation group within the RS
Assessment of distribution of responders/low responders in low (RS≤11), intermediate (RS 12-25) and high-risk (RS≥26) patients with the aim to allow early adjustment of the statistical plan
Identification of other proliferation markers that drop significantly
Run-in phase + main phase
ADAPT HR+/HER2- part I:
Prospective comparison of EFS in patients with intermediate risk by RS (12-25)/response vs. patients with low risk by RS (RS≤11; N0-1); both groups receiving endocrine therapy only
ADAPT HR+/HER2- part II:
Prospective comparison of 5-year EFS of nab-paclitaxel 125mg/m² q1w x 8 versus Paclitaxel 175mg/m² q2w x 4 both followed by conventionally dosed E90C600 x 4 q2w chemotherapy regimens; patients with intermediate risk by RS (12-25)/low response or high risk patients by N0-1/RS ≥26, all N2/3, or Ki-67>40%, >pT1b, and G3 will be treated with chemotherapy
ADAPT Hormone Receptor Positive/HER2 Negative Breast Cancer Sub-trial
Run-in Phase:
Analysis of reproducibility of each biomarker
Assessment of dropout rate
Assessment of proportions of marker responders vs. non-responders
Central/local pathology
Central/local Ki-67 assessment
Ki-67 change after endocrine induction therapy
Comparison of changes in RS, Ki-67, quantitative ER and proliferation group within the RS
Assessment of distribution of responders/low responders in low (RS≤11), intermediate (RS 12-25) and high-risk (RS≥26) patients with the aim to allow early adjustment of the statistical plan
Identification of other proliferation markers that drop significantly
Run-in phase + main phase
ADAPT HR+/HER2- part I:
Prospective comparison of EFS in patients with intermediate risk by RS (12-25)/response vs. patients with low risk by RS (RS≤11; N0-1); both groups receiving endocrine therapy only
ADAPT HR+/HER2- part II:
Prospective comparison of 5-year EFS of nab-paclitaxel 125mg/m² q1w x 8 versus Paclitaxel 175mg/m² q2w x 4 both followed by conventionally dosed E90C600 x 4 q2w chemotherapy regimens; patients with intermediate risk by RS (12-25)/low response or high risk patients by N0-1/RS ≥26, all N2/3, or Ki-67>40%, >pT1b, and G3 will be treated with chemotherapy
ADAPT HER2 Positive/Hormone Receptor Positive Breast Cancer Sub-trial
Primary objectives
Comparison of the pathological complete response rates in patients with HER2+/HR+ breast cancer (HER2+/HR+: HER2+/ER+ and/or PR+) treated by pre-surgical T-DM1 with or without standard endocrine therapy or trastuzumab with endocrine therapy given for a total of 12 weeks
Evaluation of dynamic testing (based on proliferation/apoptosis changes in serial biopsy and/or imaging by ultrasound/breast MRI) after three weeks of treatment as a surrogate parameter for response (pCR (residual cancer burden (RCB) 0-1) or resistance/low response (RCB II-III or progressive disease)
ADAPT Triple Negative (HER2-/HR-) Breast Cancer Sub-trial
Comparison: pCR in nab-paclitaxel/carboplatin vs. nab-paclitaxel/gemcitabine,
Comparison: pCR in responders vs. non-responders.
ADAPT Elderly in HER2 negative Breast Cancer - Sub-trial for Patients beyond 70 years
Primary objectives
Run-in Phase:
Identification of molecular markers correlating with early response/pCR
Feasibility/reproducibility of assessment of these markers
Validation of statistical assumptions (toxicity, pCR)
Run-in phase + main phase
Primary objectives
Comparison of pCR rates in patients with early response and no severe toxicity (Group 1) and in other patients (Group 2). |
|
| E.3 | Principal inclusion criteria |
General Inclusion Criteria:
• Female patients, age at diagnosis 18 years and above (consider ADAPT Elderly for patients at 70 years and above)
• Histologically confirmed unilateral primary invasive carcinoma of the breast
• T1 - T4 (except inflammatory breast cancer)
• All N
• Patients should be candidates for adjuvant chemotherapy according to conventional prognostic factors
• No clinical evidence for distant metastasis (M0)
• Known HR status and HER2 status (local pathology)
• Tumor block available for central pathology review
• Performance Status ECOG <= 1 or KI >= 80%
• Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients
• Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
• The patient must be accessible for treatment and follow-up
Additional Inclusion criteria for patients receiving chemotherapy:
• Laboratory requirements for patients receiving chemotherapy (within 14 days prior to randomization):
o Leucocytes >= 3.5 10^9/L
o Platelets >= 100 10^9/L
o Hemoglobin >= 10 g/dL
o Total bilirubin <= 1 x ULN
o ASAT (SGOT) and ALAT (SGPT) <= 2.5 UNL
o Creatinine <= 175 µmol/L (2 mg/dl)
• LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to randomization)
Additional Inclusion Criteria ADAPT HR+/HER2- Breast Cancer:
In order to be eligible for the participation in the ADAPT HR+/HER2- breast cancer trial, patients who meet the general inclusion/exclusion criteria of the ADAPT trial also have to meet the following additional inclusion criteria:
ER and/or PR positive and HER2 negative
Central pathology available (Grading, Ki-67, RS)* (only in patients with induction treatment)
All patients should be recommended to be treated by adjuvant chemotherapy in the daily routine practice by one of the current guildeines (St. Gallen, AGO Mamma, S3, ESMO) or to be high clinical risk by AdjuvantOnline (breast cancer specific survival of <88%)
o Clinically N+ or cN0 with one of following features: G3, <35 years old, Ki-67 >14%, cT2-4c, If G1 only if clinical tumor size >3 cm
o If Clinical decision is based on AdjuvantOnline patients should derive more than 5% 10-year relapse-free survival benefit by use of chemotherapy (3rd generation anthracycline/taxane-based) additional to standard endocrine therapy (using clinical T and N status)
Additional Inclusion Criteria ADAPT HR+/HER2- Part II
To be eligible for the participation in the ADAPT HR+/HER2- trial part II (neo)adjuvant chemotherapy question) the patients have to meet one of the following inclusion criteria:
More than 3 involved lymph nodes (c/pN2-3)*
N0-1 and RS ≥ 26*
N0-1 and RS 12-25 with Ki-67post > 10%
G3 with Ki-67 ≥40% in tumors >1cm*
To be a candidate for chemotherapy treatment due to high clinical risk irrespective of induction treatment (e.g. by heterogeneous tumor, multifocal tumor etc.)
*with or without prior endocrine “test” treatment
Patients with tumors ≥cT2 and/or cN+ are strongly recommended to be treated by neoadjuvant chemotherapy
Laboratory requirements for patients receiving chemotherapy (within 14 days prior to randomization):
o Leucocytes >= 3.5 x 109/L
o Neutrophils >1.5 x 109/L
o Platelets >= 100 x 109/L
o Hemoglobin >= 10 g/dL
o Total bilirubin <= 1 x ULN
o ASAT (SGOT) and ALAT (SGPT) <= 2.5 x ULN
o AP<5.0 ULN
o Creatinine <= 175 μmol/L (2 mg/dl)
LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to randomization) |
|
| E.4 | Principal exclusion criteria |
General Exclusion Criteria:
• Known hypersensitivity reaction to the compounds or incorporated substances
• Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
• Non-operable breast cancer including inflammatory breast cancer
• Previous or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
• Concurrent treatment with other experimental drugs. Participation in another interventional clinical trial with or without any any investigational not marketed drug within 30 days prior to study entry
• Male breast cancer
• Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
• Breast feeding woman
• Sequential breast cancer
• Reasons indicating risk of poor compliance
• Patients not able to consent
Additional Exclusion Criteria for patients receiving chemotherapy:
• Known polyneuropathy ≥ grade 2
• Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study
• Uncompensated cardiac function
• Inadequate organ function including:
o Leucocytes <= 3.5 x 10^9/l
o Platelets <= 100 x 10^9/l
o Bilirubin above normal limits
o Alkaline phosphatase >= 5 x UNL
o ASAT and/or ALAT associated with AP > 2.5 UNL
Additional Exclusion Criteria ADAPT HR+/HER2-
• Patients with clinical low risk tumors, who are not treated by adjuvant chemotherapy in the daily practice (e.g. cT1, G1, cN0)
Additional Exclusion Criteria ADAPT HR+/HER2- Part II
• Known polyneuropathy ≥ grade 2
• Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study
• Uncompensated cardiac function
• Inadequate organ function including:
o Leucocytes < 3.5 x 109/l
o Neutrophils <1.5 x 109/l
o Platelets < 100 x 109/l
o Bilirubin above normal limits
o Alkaline phosphatase >= 5 x UNL
o ASAT and/or ALAT > 2.5 x UNL |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
As stated in the sub-protocols, primary endpoints for the individual sub-studies are specific to the patient groups considered:
• HR+/HER2-: Five-year EFS
• HR+/HER2+: pCR
• TN: pCR
• HR+/HER2+: pCR
• Elderly: pCR
In addition, for ADAPT umbrella, 5-year EFS will be a primary endpoint for comparisons involving all five substudies: Five-year EFS will be prospectively compared between two groups defined as follows:
• ADAPT Umbrella Test Group comprising
- Patients with intermediate risk (RS 12-25) with early good response (and no chemotherapy);
- Patients with pCR in HR+/HER2+ disease;
- Patients with pCR in HR+/HER2- disease;
- Patients with pCR in TN disease
- Patients with pCR within ELDERLY substudy
• ADAPT Umbrella Control Group comprising
- Low-risk HR+/HER2- (RS< 12, N0-1) patients
ADAPT HR+/HER2- part I:
Primary Endpoint: Prospective comparison of EFS in “intermediate-RS” N0-1 dynamic responders vs. “low-RS” N0-1 patients (RS ≤ 11 AND N0-1)
ADAPT HR+/HER2- part II:
Primary endpoint: Prospective comparison of EFS in nab-paclitaxel vs. paclitaxel based chemotherapy followed by dose dense EC
ADAPT HER2+/HR+:
Primary endpoint of the study:
The study comprises a Run-in phase (n=130) and a Main phase (n=250). The Run-in phase will determine the cut-off for a dynamic test (performed after 3 weeks of therapy) to predict pCR probability in a descriptive manner. During the main phase of the trial, the dynamic test result will define responders and low responders.
• The primary endpoint of the ADAPT HR+/HER2+ study is pCR after 12 weeks of pre-surgical therapy
Assuming a drop-out rate of 5%, an ITT test collective of more than 300 patients is expected. The primary hypotheses are tested in this test collective.
The study will test the hypothesis of higher pCR proportion separately in each of the T-DM1 arms. We expect a 10% rate of pCR in the trastuzumab + endocrine therapy arm. In each T-DM1 arm, 25% pCR is assumed. Assuming total alpha = .05 (one-sided), i.e., alpha =0.025 for each hypothesis, the test has 80% power to detect superiority in each of the T-DM1 containing arms compared to the trastuzumab + endocrine therapy arm.
Interim analysis on correlation between changes in the sequential biopsy and pCR rates in the first 130 patients (Run-In phase) is planned during ongoing recruitment of patients.
ADAPT HER2+/HR-:
The primary endpoint of the study is pCR after 12 weeks of presurgical therapy.
ADAPT TN:
Primary endpoint: The primary endpoint of the study is pCR, defined as no invasive tumor in the breast and lymph nodes
The trial will test two co-primary hypotheses. The family-wise error alpha is controlled for multiple testing at the level 0.05 by an unequal allocation of alpha.
Hypothesis 1 (primary): Proportion achieving pCR is higher in responders (60 % of TN) than in non-responders (about 40 % of TN).
Hypothesis 2 (primary): Proportion achieving pCR is is different in the two arms.
ADAPT Elderly:
The primary endpoint of the ADAPT Elderly trial is pCR. Early response and
toxicity (particularly febrile neutropenia) are stratification criteria. The trial is
designed to test whether therapy switch in patients with either toxicity or
inadequate early response benefit from the addition of taxanes. To this end, a non-inferiority hypothesis for this group (Group 2) compared to responders without toxicity (Group 1) will be tested with respect to
the outcome pCR. Patients in Group 1 receive 4 x MC (2 x MC prior to early-response
assessment, 2 x MC subsequently). Patients in Group 2 receive 2 x MC
followed by Paclitaxel 80 mg/m2 q1w x 6.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Event-free survival (EFS) is defined as the interval from the date of registration to the date of local, regional or metastatic invasive or both invasive/non-invasive relapse or the date of second primary cancer (with the exception of curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix) or death from any cause, whichever occurs first.
pCR: The efficacy parameter pCR is defined at the time of surgery as absence of invasive tumor in the breast and lymph nodes. This will also be measured based on provision of data on size of the residual tumor, proportion of vital cells within invasive carcinoma, number of positive lymph nodes and size of the largest lymph node metastasis and ductal carcinoma in situ.
|
|
| E.5.2 | Secondary end point(s) |
In all sub-studies and for groups within the studies, the following secondary endpoints (defined below) will be prospectively evaluated:
Overall survival
Relapse free survival
Distant disease-free survival
Local and regional relapse-free survival (LRFS and RRFS)
Quality of life
Toxicity
In the ADAPT Umbrella project, these endpoints will be utilized in analyses including
• Translational research/prognostic factor analysis
• Cost-effectiveness analysis
• Comparisons with historical, evidence based outcome estimates (e.g., using Adjuvant Online)
ADAPT HR+/HER2- part II secondary endpoints:
• Interim safety
• pCR rates in the neoadjuvant treatment of dose dense paclitaxel-EC vs. nab-paclitaxel-EC arms
ADAPT HER2+/HR+ secondary endpoints:
• will be analyzed in an exploratory manner
ADAPT TN secondary endpoints:
• The following secondary endpoints (defined below) will be prospectively evaluated:
Overall survival
Relapse free survival
Distant disease-free survival
Local/regional relapse-free survival
Evaluation of proliferation/apoptosis changes as surrogate marker for 5 year EFS.
Relation of survival to study arm.
ADAPT Elderly secondary endpoints:
Comparison of toxicity in the two arms (MC vs MC->pac) allows evaluating whether the presumed higher risk of toxicity in the taxane-containing arm may be outweighed by the higher response rate in poor responders. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
HR+/HER2- run-in: An interim safety analysis is planned after recruitment of 120 patients in both study arms.
In this protocol, time to event (EFS, DDFS, LRFS and OS) will be defined as follows:
• For all analyses related to endocrine-only patients (HR+/HER2-), time-to-event endpoints will start at the date of registration of patients
• For all analysis related to chemotherapy application, time-to-event endpoints will start at the date of registration for the trial
• For all HER2+, HER2+/HR+ and TNBC patients, time will start at the date of the registration for the trial
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Prognosis and prediction of benefit from therapy. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Paclitaxel (HR+/HER2-, Elderly, HER2+/HR-), Trastuzumab (HER2+/HR+), none (HR-/HER2-) |
|
| E.8.2.4 | Number of treatment arms in the trial | 11 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 80 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 11 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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