| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with 1-3 positive Nodes, Hormone Receptor-Positive and Her2-Negative Breast Cancer with recurrence Score (RS) of 25 or Less |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with 1-3 positive Nodes, Hormone Receptor-Positive and Her2-Negative Breast Cancer with recurrence Score (RS) of 25 or Less |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071113 |
| E.1.2 | Term | Node-positive breast cancer |
| 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 |
To determine the effect of chemotherapy in patients with node positive breast cancer who
do not have high Recurrence Scores (RS) by Oncotype DX®. In patients with 1-3 positive
nodes, and hormone receptor (HR)-positive, HER2-negative breast cancer with RS ≤ 25
treated with endocrine therapy we will test whether the difference in disease-free survival
for patients treated with chemotherapy compared to no chemotherapy depends directly
on the magnitude of RS. If benefit depends on the RS score, the trial will determine the
optimal cutpoint for recommending chemotherapy or not. |
|
| E.2.2 | Secondary objectives of the trial |
To compare overall survival (OS), distant disease-free survival (DDFS) and local disease free
interval (LDFI) by receipt of chemotherapy or not and its interaction with RS.
To compare the toxicity across the treatment arms.
To perform other assays or tests (in particular the PAM50 risk of relapse score), as they are developed and validated, that measure potential benefit of chemotherapy and compare them to Oncotype DX®.
To determine the impact of treatment with chemotherapy versus no chemotherapy on patient-reported fatigue and cognitive concerns (secondary HRQL outcomes). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
STEP 1 REGISTRATION (Oncotype DX® Screening):
1. Patients must have a histologically confirmed diagnosis of node positive (1-3 nodes) invasive breast carcinoma with positive estrogen and/or progesterone receptor status, and negative HER-2 status. Estrogen and progesterone receptor positivity must be assessed according to ASCO/CAP guidelines as either ER or PR ≥ 1% positive nuclear staining. HER-2 test result negativity must be assessed as per ASCO/CAP 2013 guidelines using IHC, ISH or both. HER-2 equivocal is not eligible.
2. Patients with multifocal, multicentric and synchronous bilateral breast cancers are allowed. Patients will have undergone axillary staging by sentinel node biopsy or axillary lymph nodes dissection (ALND). Patients must have at least one, but no more than three known positive lymph nodes (pN1a, pN1b or pN1c), see Section 4.0 for definitions. Patients with micrometastases as the only nodal involvement are not eligible. Patients with positive sentinel node are not required to undergo full axillary lymph node dissection. This is at the discretion of the treating physician. Axillary node evaluation is to be performed per the standard of care at each institution.
3. Patients must have had either breast-conserving surgery with planned radiation therapy or total mastectomy (with or without planned postmastectomy radiation). Patients must have clear margins from both invasive breast cancer and DCIS (as per local institutional guidelines). LCIS at the margins is allowed.
4. Registration of patients who have not yet undergone Oncotype DX® screening must occur no later than 56 days after definitive surgery. If the Oncotype DX® Breast Cancer Assay has not been performed, patients must be willing to submit tissue samples for testing to determine the Recurrence Score value. A representative block or unstained sections from the representative block are sent directly to Genomic Health for Oncotype DX® Breast Cancer Assay which will be performed according to the standard commercial process (see Section 15.1).
If the Oncotype DX® Recurrence Score is already known and is 25 or less, the patient must be registered to Step 2 immediately following Step 1 registration. If the Oncotype DX® Recurrence Score is already known and is greater than 25, the patient is ineligible.
5. Patients must be females ≥ 18 years of age. As the Oncotype DX® Recurrence Score has not been validated in men with breast cancer, men are not eligible for this study.
6. Patients must have a complete history and physical examination within 28 days prior to registration.
7. Patients must have a performance status of 0-2 by Zubrod criteria (see Section 10.7).
8. Patients must be able to receive taxane and/or anthracycline based chemotherapy.
9. Patients must not have begun chemotherapy or endocrine therapy for their breast cancer prior to registration.
10.Patients must not require chronic treatment with systemic steroids (inhaled steroids are allowed) or other immunosuppressive agents.
11. Patients must not have received an aromatase inhibitor (AI) or a selective estrogen receptor modulator (SERM) such as tamoxifen or raloxifene within 5 years prior to registration.
12. Patients must not be pregnant or nursing due to the possibility of harm to a fetus or nursing infant from this treatment regimen.
13. No other prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years.
14. The Quality of Life and Economic Substudy is permanently closed to accrual effective 12/1/12.
15. Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
STEP 2 REGISTRATION (Randomization):
16. Recurrence score (RS) by Oncotype DX® must be ≤ 25.
17. Step 2 Registration must take place within 84 days after definitive surgery. Patients must not have begun chemotherapy or endocrine therapy for their breast cancer prior to randomization.
18. Patients randomized to either arm may also co-enroll in Phase III trials that compare local therapies, or compare systemic therapies (such as chemotherapy, if randomized to Arm 1 of S1007)
19. The Quality of Life and Economic Substudy is permanently closed to accrual effective 12/1/12. Patients at U.S. INSTITUTIONS only.
20. All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines. For all patients the appropriate consent form for this registration is the Step 2 Consent Form.
|
|
| E.4 | Principal exclusion criteria |
1. Patients must not have inflammatory breast cancer and must not have metastatic disease.
2. Patients with a prior diagnosis of contralateral DCIS are eligible if they underwent a mastectomy or lumpectomy with whole breast radiation. Prior partial breast irradiation, including brachytherapy, is not allowed. Patients with a prior diagnosis of ipsilateral DCIS or invasive breast cancer who received radiation to that breast are not eligible.
3. Patients must not have begun chemotherapy or endocrine therapy for their breast cancer prior to registration.
4. Patients must not require chronic treatment with systemic steroids (inhaled steroids are allowed) or other immunosuppressive agents.
5. Patients must not have received an aromatase inhibitor (AI) or a selective estrogen receptor modulator (SERM) such as tamoxifen or raloxifene within 5 years prior to registration.
6. Patients must not be pregnant or nursing due to the possibility of harm to a fetus or nursing infant from this treatment regimen. Women of reproductive potential must have agreed to use an effective contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.
7. No other prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years.
8. Step 2 Registration must take place within 84 days after definitive surgery. Patients must not have begun chemotherapy or endocrine therapy for their breast cancer prior to randomization.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY ENDPOINT
DFS: Invasive disease-free survival (DFS) - time from the second registration (randomization) to local, regional, or distant recurrence, new invasive primary, or death due to any cause. The STEEP definition of invasive disease-free survival (IDFS) is used, although it is referred to here by the more common acronym DFS. Survival times are censored at time of last follow-up for individuals who did not have any event meeting the above definition. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The formal study completion date will be five years after the last patient is enrolled to provide sufficient power for analyses. However, individual patients will be followed for a minimum of fifteen years regardless of the date of enrollment.
The first interim analysis would be after 24% of the events have been observed or approximately 6 years after initiation of the study. This would correspond to the end of accrual if accrual is uniform and at the expected level. There would be subsequent annual interim analyses thereafter
with 36%, 50%, 65%, and 82% in years 7-10 with the final analysis in year 11. |
|
| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
OS: Overall survival (OS) - time from the second registration (randomization) to death due to any cause. Survival times are censored at time of last follow-up for individuals who are not known to have died.
DDFS: Distant disease-free survival (DDFS) - time from second registration to distant recurrence, new invasive primary, or death due to any cause. Patients who have local or regional recurrence are continued to be followed for a distant event or death. Survival times are censored at time of last follow-up for individuals who are not known to have died and have not had a distant recurrence or new primary.
LDFI: Local-regional disease-free interval (LDFI) - time from second registration to local/regional recurrence. 3 Patients who have distant recurrence or a new primary or who die without recurrence are censored at time of this event. The analysis of
this endpoint must account for informative censoring using a competing risk framework. Survival times are also censored at time of last follow-up for individuals who are not known to have died and have had a recurrence or new primary.
Toxicity: Toxicities using standard NCI-CTCAE criteria (CTCAE Version 4.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
SECONDARY OUTCOMES ANALYSIS
Analyses for secondary survival outcomes (OS and DDFS) will be analyzed in a similar manner to DFS, though power will be lower than DFS, due to fewer
events. Local disease free interval will use a competing risk framework to accommodate informative censoring due to distant recurrence or death. Analysis of toxicity will be compared between the two arms using logistic regression. |
|
| 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 |
To determine the effect of chemotherapy in patients with node positive breast cancer who
do not have high Recurrence Scores (RS) by Oncotype DX®. |
|
| 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) | No |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 14 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
| All patients will be followed until death or 15 years after randomization, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 19 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 19 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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