Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage IB Breast Cancer AJCC v8, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, Invasive Breast Carcinoma, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8
Conditions
Brief summary
This phase II trial studies how well docetaxel or paclitaxel work in reducing chemotherapy-induced peripheral neuropathy in African American patients with stages I-III breast cancer. Drugs used in chemotherapy, such as docetaxel and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving docetaxel or paclitaxel may work better than other methods in reducing chemotherapy-induced peripheral neuropathy in patients with breast cancer.
Detailed description
PRIMARY OBJECTIVE: I. Prospectively validate a prior germline predictor of paclitaxel-induced peripheral neuropathy (TIPN) using the Common Terminology Criteria for Adverse Events (CTCAE). Specifically, this study will demonstrate that patients with a high-risk TIPN genotype have significantly more grade 2-4 TIPN than patients with a low risk genotype. SECONDARY OBJECTIVES: I. Validate a prior germline predictor of TIPN using the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX) neurotoxicity subscale in Arm A. II. Compare grade 2-4 TIPN based on CTCAE between weekly paclitaxel (Arm A) versus (vs.) every three-week docetaxel (Arm B). III. Prospectively confirm dose reductions due to TIPN are lower for every three-week docetaxel compared with weekly paclitaxel in a prospective cohort of patients of African ancestry. IV. Prospectively confirm dose reductions due to any cause are lower for every three-week docetaxel compared with weekly paclitaxel in a prospective cohort of patients of African ancestry. V. Assess the ability of the high-risk genotype to predict TIPN risk for docetaxel. CORRELATIVE STUDY OBJECTIVES: I. Identify novel markers of TIPN and elucidate the mechanism. II. Whole genome sequencing of germline blood to evaluate for additional predictors of TIPN. III. Create induced pluripotent stem cell (iPSC) derived neurons from patient samples. IIIa. Evaluate whether clinical findings can be mimicked in vitro. IIIb. Evaluate gene expression (ribonucleic acid \[RNA\] sequencing \[seq\]) and the epigenome at baseline versus after exposure in those prone to TIPN versus those not. IV. Create a biorepository of patient derived samples for future translational research. PATIENT REPORTED OUTCOME OBJECTIVES: I. Compare grade 2-4 TIPN (moderate to life threatening) based on Patient Reported Outcomes (PRO)-CTCAE items between weekly paclitaxel (Arm A) vs. every three-week docetaxel (Arm B). II. Prospectively compare FACT/GOG-NTX Health-Related Quality of Life (HRQoL) scores (from the FACT-General \[G\] portion and Patient-Reported Outcomes Measurement Information System \[PROMIS\] Physical Function version \[v.\]2 Short Form \[SF\] 10a, scores between every three-week docetaxel and weekly paclitaxel and between high risk and low risk genotypes (Arm A) in a cohort of African ancestry. III. Compare Chemotherapy-Induced Peripheral Neuropathy (CIPN)-20 sensory neuropathy score between weekly paclitaxel (Arm A) vs. every three-week docetaxel (Arm B). IV. Compare the impact on financial toxicity (Comprehensive Score for Financial Toxicity \[COST\] scores) for every three-week docetaxel compared with weekly paclitaxel. V. Examine associations between social determinants of health (zip code, marital status, education, income & insurance status) and dose reductions and treatment discontinuation. OUTLINE: Patients are assigned to 1 of 2 arms. ARM A: Patients receive paclitaxel intravenously (IV) over 3 hours once weekly. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive trastuzumab and/or pertuzumab per institution routine care per treating physician's discretion. ARM B: Patients receive docetaxel IV over 1 hour once every 3 weeks. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive cyclophosphamide, doxorubicin, trastuzumab, and/or pertuzumab per institution routine care per treating physician's discretion. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Interventions
Given IV
Given IV
Ancillary studies
Ancillary studies
Sponsors
Study design
Eligibility
Inclusion criteria
* Patients must be women with a known stage I-III invasive breast cancer diagnosis * Patients must be capable and willing to provide informed consent * Patients must have plans to receive either neoadjuvant or adjuvant: * Every 3-week docetaxel x 4-6 cycles OR * Weekly paclitaxel x 4 cycles * NOTE: Recommended therapies for various therapy regimens are outlined based on estrogen receptor (ER)/progesterone receptor (PR)/HER2 and nodal status. Where there are options, the treating physician will choose a regimen best fitted for that patient. If the physician does not feel any of the regimens are the best fit for the patient, the patient should not be enrolled. Physicians will also document why a regimen was felt to be inappropriate when an option. Patients who have already started the anthracycline portion of their therapy are eligible assuming they have not yet begun the taxane portion and assuming they will be receiving one of the regimens deemed appropriate for her disease setting * Patients must self-identify their race as black, African American, or of African descent; patients may be of any ethnicity * Patients with a history of other cancers are eligible if they have not received prior taxane or platinum or vinca alkaloid therapy * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Patients of childbearing potential must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
Exclusion criteria
* Patients must not have received prior taxane or prior/concurrent platinum therapy * Patients must not have received neoadjuvant anti-HER2 therapy * Patients must not have pre-existing peripheral neuropathy * Patients must not have a total bilirubin \> upper limit of normal (ULN) (must be obtained within 3 weeks prior to registration) * Patients must not have aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) above 1.5 times the ULN concomitant with alkaline phosphatase above 2.5 times the ULN (must be obtained within 3 weeks prior to registration) * Patients must not be pregnant or lactating * All patients of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy * A patient of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grade 2-4 Taxane-Induced Peripheral Neuropathy (TIPN) by Genotype Risk Group in Arm A | assessed at baseline, an end of each cycle, at 6 months and 1 year post registration | Grade 2-4 TIPN was assessed by treating physician using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who started protocol therapy on arm A (paclitaxel) were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between high-risk vs low-risk genotype groups using Fisher exact test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient-Reported Neuropathy Score Change Between Baseline and End of Treatment by Genotype Risk Group in Patients on Arm A | assessed at baseline and at end of treatment, an average of 3 months | The patient-reported neurotoxicity was assessed using the 11 items about neurotoxicity in the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-Ntx) questionnaire (i.e., FACT/GOG-Ntx additional concerns subscale). The neurotoxicity total score was the sum of the scores for the 11 items, ranging from 0 to 44. Higher values of the FACT/GOG-Ntx neurotoxicity total score indicate less neurotoxicity. The FACT/GOG-Ntx neurotoxicity total score change between the baseline and at end of treatment (negative value indicates worsening symptom, positive value indicates improving symptom) was calculated and compared using two-sample t test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status. |
| Percentage of Participants With Grade 2-4 TIPN Based on CTCAE Between Arm A and Arm B | assessed at baseline, an end of each cycle, at 6 months and 1 year post registration | Grade 2-4 TIPN was assessed by treating physician using CTCAE version 4.0. All patients who started protocol therapy were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between treatment arms using Fisher exact test. |
| Percentage of Participants With Dose Reduction Due to TIPN Between Arm A and Arm B | Dose reduction due to TIPN was assessed at end of each cycle, up to 4 cycles in arm A and 6 cycles in arm B | The percentage of patients with dose reduction due to TIPN was calculated as number of patients with dose reduction due to peripheral neuropathy for any dose of any cycle divided by total number of patients who started protocol therapy. The percentages were calculated along with exact 95% CI based on binomial distribution and were compared between arms using Fisher exact test. |
| Percentage of Participants With Dose Reduction Due to Any Reason Between Arm A and Arm B | Dose reduction due to any reason was assessed at end of each cycle, up to 4 cycles in arm A and 6 cycles in arm B | The percentage of patients with dose reduction due to any reason was calculated as number of patients with any dose reduction for any dose of any cycle, regardless of the reason, divided by total number of patients who started protocol therapy. The percentages were calculated along with exact 95% CI based on binomial distribution and were compared between arms using Fisher exact test. |
| Percentage of Participants With Grade 2-4 TIPN by Genotype Risk Group in Arm B | assessed at baseline, at end of each cycle, at 6 months and 1 year post registration | Grade 2-4 TIPN was assessed by treating physician using CTCAE version 4.0. All patients who started protocol therapy on arm B were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between high-risk vs low-risk genotype groups using Fisher exact test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status. |
Countries
United States
Contacts
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
This study was activated on June 27, 2019, first patient was enrolled on August 9, 2019. Accrual to arm A (paclitaxel) was terminated on June 4, 2021 and accrual to arm B (docetaxel) was terminated on March 31, 2022, after achieving the accrual goal on each arm separately.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Paclitaxel) Patients receive paclitaxel IV over 3 hours once weekly. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive trastuzumab and/or pertuzumab per institution routine care per treating physician's discretion.
Paclitaxel: Given IV | 126 |
| Arm B (Docetaxel) Patients receive docetaxel IV over 1 hour once every 3 weeks. Treatment repeats every 21 days for 4-6 cycles in the absence of disease progression or unacceptable toxicity. Patients may also receive cyclophosphamide, doxorubicin, trastuzumab, and/or pertuzumab per institution routine care per treating physician's discretion.
Docetaxel: Given IV | 123 |
| Total | 249 |
Baseline characteristics
| Characteristic | Arm B (Docetaxel) | Total | Arm A (Paclitaxel) |
|---|---|---|---|
| Age, Continuous | 56 years | 54 years | 53 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 118 Participants | 239 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 123 Participants | 248 Participants | 125 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 123 Participants | 249 Participants | 126 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 126 | 6 / 123 |
| other Total, other adverse events | 121 / 121 | 113 / 118 |
| serious Total, serious adverse events | 46 / 121 | 61 / 118 |
Outcome results
Percentage of Participants With Grade 2-4 Taxane-Induced Peripheral Neuropathy (TIPN) by Genotype Risk Group in Arm A
Grade 2-4 TIPN was assessed by treating physician using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patients who started protocol therapy on arm A (paclitaxel) were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between high-risk vs low-risk genotype groups using Fisher exact test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status.
Time frame: assessed at baseline, an end of each cycle, at 6 months and 1 year post registration
Population: All patients on arm A who received at least one dose of paclitaxel and had genotyping results
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Risk Genotype Group | Percentage of Participants With Grade 2-4 Taxane-Induced Peripheral Neuropathy (TIPN) by Genotype Risk Group in Arm A | 47 percentage of participants |
| Low Risk Genotype Group | Percentage of Participants With Grade 2-4 Taxane-Induced Peripheral Neuropathy (TIPN) by Genotype Risk Group in Arm A | 35 percentage of participants |
Patient-Reported Neuropathy Score Change Between Baseline and End of Treatment by Genotype Risk Group in Patients on Arm A
The patient-reported neurotoxicity was assessed using the 11 items about neurotoxicity in the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT/GOG-Ntx) questionnaire (i.e., FACT/GOG-Ntx additional concerns subscale). The neurotoxicity total score was the sum of the scores for the 11 items, ranging from 0 to 44. Higher values of the FACT/GOG-Ntx neurotoxicity total score indicate less neurotoxicity. The FACT/GOG-Ntx neurotoxicity total score change between the baseline and at end of treatment (negative value indicates worsening symptom, positive value indicates improving symptom) was calculated and compared using two-sample t test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status.
Time frame: assessed at baseline and at end of treatment, an average of 3 months
Population: All patients who started paclitaxel and filled out the FACT/GOG-Ntx questionnaire at both baseline and end of treatment time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Risk Genotype Group | Patient-Reported Neuropathy Score Change Between Baseline and End of Treatment by Genotype Risk Group in Patients on Arm A | -7.3 score on a scale | Standard Deviation 9.1 |
| Low Risk Genotype Group | Patient-Reported Neuropathy Score Change Between Baseline and End of Treatment by Genotype Risk Group in Patients on Arm A | -8.1 score on a scale | Standard Deviation 8.9 |
Percentage of Participants With Dose Reduction Due to Any Reason Between Arm A and Arm B
The percentage of patients with dose reduction due to any reason was calculated as number of patients with any dose reduction for any dose of any cycle, regardless of the reason, divided by total number of patients who started protocol therapy. The percentages were calculated along with exact 95% CI based on binomial distribution and were compared between arms using Fisher exact test.
Time frame: Dose reduction due to any reason was assessed at end of each cycle, up to 4 cycles in arm A and 6 cycles in arm B
Population: All patients who received at least one dose of protocol therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Risk Genotype Group | Percentage of Participants With Dose Reduction Due to Any Reason Between Arm A and Arm B | 39 percentage of participants |
| Low Risk Genotype Group | Percentage of Participants With Dose Reduction Due to Any Reason Between Arm A and Arm B | 25 percentage of participants |
Percentage of Participants With Dose Reduction Due to TIPN Between Arm A and Arm B
The percentage of patients with dose reduction due to TIPN was calculated as number of patients with dose reduction due to peripheral neuropathy for any dose of any cycle divided by total number of patients who started protocol therapy. The percentages were calculated along with exact 95% CI based on binomial distribution and were compared between arms using Fisher exact test.
Time frame: Dose reduction due to TIPN was assessed at end of each cycle, up to 4 cycles in arm A and 6 cycles in arm B
Population: All patients who received at least one dose of protocol therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Risk Genotype Group | Percentage of Participants With Dose Reduction Due to TIPN Between Arm A and Arm B | 28 percentage of participants |
| Low Risk Genotype Group | Percentage of Participants With Dose Reduction Due to TIPN Between Arm A and Arm B | 8 percentage of participants |
Percentage of Participants With Grade 2-4 TIPN Based on CTCAE Between Arm A and Arm B
Grade 2-4 TIPN was assessed by treating physician using CTCAE version 4.0. All patients who started protocol therapy were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between treatment arms using Fisher exact test.
Time frame: assessed at baseline, an end of each cycle, at 6 months and 1 year post registration
Population: All patients who received at least one dose of protocol therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Risk Genotype Group | Percentage of Participants With Grade 2-4 TIPN Based on CTCAE Between Arm A and Arm B | 44 percentage of participants |
| Low Risk Genotype Group | Percentage of Participants With Grade 2-4 TIPN Based on CTCAE Between Arm A and Arm B | 25 percentage of participants |
Percentage of Participants With Grade 2-4 TIPN by Genotype Risk Group in Arm B
Grade 2-4 TIPN was assessed by treating physician using CTCAE version 4.0. All patients who started protocol therapy on arm B were included in the analysis. The percentage of participants with grade 2-4 TIPN was calculated based on binomial distribution and was compared between high-risk vs low-risk genotype groups using Fisher exact test. Genotype risk group (high vs. low) was determined by genotyping. High-risk genotype was defined by FCAMR GG genotype (homozygous wild type) or SBF2 mutated. Low-risk genotype was defined by carriage of at least one variant allele in FCAMR (AG or AA) and SBF2 wild-type status.
Time frame: assessed at baseline, at end of each cycle, at 6 months and 1 year post registration
Population: All patients who received at least one dose of docetaxel and had genotyping results
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Risk Genotype Group | Percentage of Participants With Grade 2-4 TIPN by Genotype Risk Group in Arm B | 28 percentage of participants |
| Low Risk Genotype Group | Percentage of Participants With Grade 2-4 TIPN by Genotype Risk Group in Arm B | 19 percentage of participants |