Adaptive Therapy With Capecitabine for Treatment of Metastatic ER Positive, HER2 Negative Breast Cancer

Single Arm Pilot Trial of Adaptive Therapy (AT) With Capecitabine for the Treatment of Metastatic Estrogen Receptor Positive, Hormone Refractory Breast Cancer

This phase II trial evaluates the effect of capecitabine on tumor response using imaging and tumor markers to adjust dose (adaptive therapy) in patients with estrogen receptor (ER) positive, HER2 negative breast cancer that has spread from where it first started to other areas in the body (metastatic). Capecitabine is in a class of medications called antimetabolites. It is taken up by tumor cells and breaks down into fluorouracil, a substance that kills tumor cells. Adaptive therapy with capecitabine based on tumor burden response may slow or stop the growth of tumor cells in patients with metastatic ER positive, HER2 negative breast cancer.

PRIMARY OBJECTIVE:

I. Evaluate the feasibility of adaptive therapy (AT) in hormone receptor positive metastatic breast cancer, defined as the number of patients who can achieve AT modification for 2 or more cycles.

SECONDARY OBJECTIVES:

I. To evaluate time to progression in patients receiving capecitabine AT defined as the interval between treatment start and tumor progression, or death in patients with no evidence of disease progression.

II. Assess overall survival in patients receiving capecitabine as adaptive therapy.

III. Evaluate patient related outcomes by measuring quality of life and global health status of patients on AT using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 questionnaire EORTC QLQ C-30.

IV. Evaluate adverse events secondary to capecitabine using Common Terminology Criteria for Adverse Events (CTCAE) grading system version 5.0.

V. Assess feasibility and accuracy of radiologic 3 dimensional (3D) volumetric approach in measuring target lesions.

EXPLORATORY OBJECTIVES:

I. Assess circulating tumor deoxyribonucleic acid (DNA) (ctDNA) as a low-cost alternative to imaging for measuring tumor burden.

II. Identify gene signatures that could predict response and identify mechanisms of resistance to capecitabine using next generation sequencing technology, including:

IIa. Whole exome DNA sequencing from ctDNA at screening and end of treatment; IIb. Whole transcriptome ribonucleic acid (RNA) sequencing from ctDNA at and at screening and end of treatment.

III. ctDNA quantification is optional at day 1 (D-1).

OUTLINE:

INITIAL STANDARD PHASE: Patients who are capecitabine naive, receive standard dose of capecitabine orally (PO) twice daily (BID) on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients whose disease has responded or remains stable after 2 cycles continue to the Adaptive Phase.

ADAPTIVE PHASE: Patients who have had up to 2 cycles of capecitabine, receive 50% reduced dose of capecitabine PO BID on days 1-14 of each cycle. Patients undergo blood sample collection every cycle and computed tomography (CT) every other cycle for disease response assessment. Patients whose disease burden decreases < 10% on CT or blood begins receiving an additional 50% reduced dose of capecitabine PO BID on days 1-14 of each cycle. Patients whose disease burden is stable on CT or blood continue receiving initial Adaptive Phase dose of capecitabine PO BID on days 1-14 of each cycle. Patients whose disease burden increases > 10% on CT or blood begin receiving a 50% dose increase in capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Additionally, patients undergo blood sample collection, CT or magnetic resonance imaging (MRI), and bone scan if indicated on study.

After completion of study treatment, patients are followed up every 3 months for up to 3 years from time of registration.

Inclusion Criteria:

• PRE-REGISTRATION: Provide written informed consent Note: Pre-registration should occur prior to screening research blood draws being completed
• PRE-REGISTRATION: Provider anticipates the patient will begin on capecitabine within 14 days or has started capecitabine within the past 42 days and has had a maximum of two cycles Note: Pre-registration should occur prior to screening research blood draws being completed

REGISTRATION - INCLUSION CRITERIA

• Age ≥ 18 years

• Histological confirmation of estrogen-receptor positive (ER+), HER2-negative overexpression or amplification negative as per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, metastatic breast cancer

• Measurable disease. Bone only disease allowed if associated with soft tissue component that is measurable by Response Evaluation Criteria is Solid Tumors (RECIST) 1.1 criteria

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

• Hemoglobin ≥ 9.0 g/dL (obtained ≤ 14 days prior to registration), no transfusions allowed ≤ 14 days prior to registration

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 14 days prior to registration)

• Platelet count ≥ 100,000/mm^3 (obtained ≤ 14 days prior to registration)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 14 days prior to registration)

• Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration)

• Negative serum or urine pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Provide written informed consent

• Ability to complete questionnaire(s) by themselves or with assistance

• Willingness to provide mandatory blood specimens for correlative research

• Ability to undergo re-staging CT scans as required by the protocol

  • Note: for patients who have had up to two cycles of capecitabine prior to joining the study, they must have had their initial CT imaging completed within 28 days of their first dose of capecitabine

• Willing to return to enrolling institution at the specified frequency for follow-up (during the active monitoring phase of the study)

• Cohort 2 only: Stable disease, partial or complete response on imaging after beginning capecitabine

Exclusion Criteria:

• Prior chemotherapy or use of antibody drug conjugate in the metastatic setting

  • Note - Cohort 2 only: Patients can have had up to two cycles of capecitabine before joining the study

• Any of the following, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential who are unwilling to employ adequate contraception

• Any of the following prior therapies:

  • Major surgery ≤ 3 weeks prior to registration
  • Radiation therapy ≤ 2 weeks prior to registration

• Evidence of visceral crisis or impending cord compression

• Evidence of uncontrolled brain metastasis requiring whole brain irradiation or intervention

• Uncontrolled intercurrent illness including, but not limited to:

  • ongoing or active infection
  • symptomatic congestive heart failure
  • unstable angina pectoris
  • uncontrolled cardiac arrhythmia
  • chronic oxygen dependence
  • respiratory failure
  • or psychiatric illness/social situations that would limit compliance with study requirements

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy ≤ 3 years prior to registration. EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

• If there is a history of prior malignancy, they must not be receiving other cancer specific treatment. Except for antiestrogen treatment (aromatase inhibitors or selective estrogen modulators) for their cancer are permitted if they meet other eligibility criteria. Denosumab and zoledronic acid, are permitted as established adjunct therapies per guidelines

• History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

• Patients known to have certain homozygous or compound heterozygous dihydropyrimidine dehydrogenase (DPYD) variants that result in complete absence of deoxypyridinoline (DPD) activity. Test results do not need to be available prior to registration

• History of severe hypersensitivity reactions to fluorouracil or capecitabine