Dose-Reduced Docetaxel With Cyclophosphamide for the Treatment of Vulnerable Older Women With Stage I-III HER2 Negative Breast Cancer, the DOROTHY Trial

Study Overview
=================
Brief Summary
-----------------
This phase II trial tests how well dose-reduced docetaxel combined with cyclophosphamide works in treating older women with early stage (stage I-III) HER2 negative breast cancer vulnerable to toxicity. Chemotherapy drugs, such as docetaxel and cyclophosphamide, 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. Docetaxel and cyclophosphamide are commonly used, but is not well tolerated at the standard dose and can affect the way older patients feel physically and emotionally. Giving dose-reduced docetaxel combined with cyclophosphamide may be an effective treatment option and improve quality of life in vulnerable older women with stage I-III HER2 negative breast cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. Compare the relative dose intensity (RDI) of reduced- versus (vs.) standard-dose docetaxel dosing strategies. SECONDARY OBJECTIVE: I. Compare treatment tolerability of reduced- vs. standard-dose docetaxel dosing strategies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive dose-reduced docetaxel intravenously (IV) over 60 minutes and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive standard dose docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days then at least twice yearly for 2 years.

Official Title
-----------------
Dose Reduction of Docetaxel-Based Chemotherapy in Vulnerable Older Women With Early-Stage Breast Cancer (DOROTHY)

Conditions
-----------------
Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, HER2-Negative Breast Carcinoma

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Docetaxel
* Other: Medical Chart Review
* Other: Questionnaire Administration


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to provided informed consent or a legally authorized representative is able to consent on behalf of the patient Willing to answer questionnaires as part of their participation Age: >= 65 years by the time of study registration Cancer and Aging Research Group- Breast Cancer (CARG-BC) score >= 6 Histologically or cytologically confirmed breast cancer(s) that is human epidermal growth factor receptor 2 negative (HER2-negative) per the most recent 2018 American Society of Clinical Oncology College of American Pathologists (ASCO CAP) guidelines relapsed/ refractory disease Estrogen receptor and progesterone receptor immunohistochemistry (IHC) status must be known; any estrogen receptor (ER)/progesterone receptor (PR) status is eligible Non-metastatic, invasive breast cancer (scans are not required to document non-metastatic disease- any staging work-up is up to the treating providers' discretion) Recommended to have either standard dose neoadjuvant docetaxel, cyclophosphamide (TC) chemotherapy or adjuvant TC chemotherapy per their treating provider. Participant may be on immunotherapy concurrently with the protocol regimen at the discretion of the treating physician Any surgery, nodal assessment, radiation, hormonal therapy is left up to the treating provider but should not occur concurrently with study therapy Any patient who received pre-operative hormonal therapy and who is then recommended for neo/adjuvant chemotherapy is eligible, though hormonal therapy should be held during study treatment administration For patients with bilateral or multifocal/multicentric breast cancers, the following criteria must be met to enroll: (1) both cancer are HER2 negative, AND (2) the provider feels the patient will benefit from TC for at least one of the cancers Patients who do not speak or read English are eligible as long as adequate interpreter services are available or the surveys are available in the preferred language (i.e. the Geriatric Assessment [GA] and Patient Reported Outcomes [PRO] surveys are available in many languages) Exclusion Criteria: Participants who have already received any chemotherapy for their current breast cancer Patients with recurrent and/or metastatic disease will be excluded. Prior diagnoses of breast cancers (including ductal carcinoma in situ [DCIS]) are allowed, provided that the treating provider feels that the current cancer most likely represents a new primary breast cancer and not recurrent disease History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide and/or docetaxel Past treatment with the regimen TC for prior breast cancer

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I: (Dose-reduced docetaxel, cyclophosphamide)<br>Patients receive dose-reduced docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Medical Chart Review<br>* Ancillary studies<br>* Other names: Chart Review;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Active Comparator: Arm II: (Standard dose docetaxel, cyclophosphamide)<br>Patients receive standard dose docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Medical Chart Review<br>* Ancillary studies<br>* Other names: Chart Review;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative dose intensity (RDI) | RDI is defined as the ratio of actual dose intensity received to the standard dose intensity, ranging from 0 to 100%. The RDI between the two arms will be compared using T-test, RDI difference and 90% confidence interval. A one-sided p-value < 0.05 will be considered statistically significant. | At completion of 4 cycles, up to 12 weeks (each cycle is every three weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in PRO-CTCAE and clinician-reported toxicities | Treatment related toxicities grade 3 or higher experienced by patients between the 2 arms will be described using NCI-CTCAE version (v) 5.0. Chi-square or Fisher exact test will be used to explore the difference in terms of rate of PRO-CTCAE and clinician reported CTCAE between the 2 arms at the end of chemotherapy. Agreement proportions between PRO-CTCAE and clinician reported CTCAE will be explored and calculated for the 2 arms combined. | At each chemotherapy cycle for 4 cycles and at 3, 6, 12, and 24 months after treatment ends (Each cycle is three weeks). | 
| Patient satisfaction | Patient-reported satisfaction will be measured using the Was It Worth It questionnaire. Data will be scored and summarized according to their scoring manual. Chi-square or Fisher exact test will be used to compare the proportion of patients who consider it worthwhile to undergo treatment, the proportion of patients who would undergo the treatment again, and the proportionof patients who would recommend the treatment to others between the 2 arms. | Up to 3 months after treatment ends | 
| Changes in function and health status | Elements of the Geriatric Assessment (GA) will be used to calculate the deficit accumulation index for each patient on each study arm over time. Trajectories of change in function will be examined. Data will be scored and summarized according to the GA scoring manual. | At baseline and at 3, 6, 12 and 24 months after treatment ends | 
| Incidence of adverse events | Toxicity experienced by patients for each arm at each cycle will be described using NCI CTCAE v 5.0. Hematologic and non-hematologic toxicities will be examined by grade, type and offending agent. | At every 3 weeks up to completion of study treatment | 
| Invasive disease-free survival | Defined as an occurrence of ipsilateral invasive breast cancer recurrence, regional invasive breast cancer recurrence, distant recurrence, death attributable to any cause, contralateral invasive breast cancer and second non-breast invasive cancer. | Up to 2 years | 
| Local recurrences | Local recurrence will be defined as the number of in-breast, chest wall after mastectomy and axillary recurrences. | Up to 3 years | 
| Distant recurrences | Distant recurrence will be defined as the number of recurrences occurring with or without localized recurrence that have occurred distant to the breast. | Up to 2 years | 
| Overall survival | Breast cancer-specific survival and cause of death will also be examined. | From registration to death due to any cause up to 24 months | 
| Progression-free survival | The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works. | From registration to the earliest of progression or death due to any cause up to 24 months | 
| Treatment success | Treatment success is defined as the proportion of patients who receive all 4 planned cycles of chemotherapy without unacceptable toxicity (grade 3-4), hospitalization/death at the end of treatment, and without decline in physical function status. Proportion of treatment success between the 2 arms will be compared using Chi-square test. A one-sided p-value of < 0.05 will be considered statistically significant. | At completion of 4 cycles, up to 12 weeks (Each cycle is three weeks) | 
| Patient-reported symptomatic toxicities | Toxicities will be described using the National Cancer Institute (NCI) Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). Patient reported outcomes will evaluate how well symptoms reported correlate/agree with clinician reported adverse events. | At each chemotherapy cycle for 4 cycles, end of treatment and at 3, 6, 12 and 24 months after treatment ends)(Each cycle is three weeks). |