Sequential Combination Therapy for the Treatment of Patients with De Novo Metastatic Breast Cancer, The SAPPHO Study

Inclusion Criteria

• Participants must have histologically or cytologically confirmed unresectable locally advanced or metastatic invasive breast carcinoma. Patients must have stage IV breast carcinoma at diagnosis (i.e., de novo metastatic) with unequivocal evidence of metastasis on imaging
• Participants must have HER2-positive invasive breast carcinoma defined as 3+ by immunohistochemistry. Fluorescence in situ hybridization (FISH) results will not be considered for eligibility. 3+ must be documented in both breast and metastatic sites of disease with the following exceptions: * HER2 immunohistochemistry (IHC) on a metastatic biopsy of the bone is not required to be HER2+ given potential for false negatives. Documentation of HER2 3+ in the breast would be required to meet eligibility in cases of bone-only metastatic disease. * If a metastatic biopsy is not accessible/feasible or safe, in the opinion of the treating investigator, documented permission must be obtained from the Dana-Farber Cancer Institute (DFCI) Sponsor-Investigator to forgo biopsy of a metastatic site. Formal eligibility exception would not be required in these circumstances. Documentation of HER2 3+ by IHC in the breast would be sufficient to meet eligibility in these cases.
• Any ER and PR expression are permitted but must be known.
• Age >=18 years.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1
• Left ventricular ejection fraction (LVEF) >= 50%, as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 12 weeks prior to first dose of study treatment, or within 12 weeks before starting THP for patients who start metastatic therapy prior to study entry
• Hemoglobin (Hgb) >= 9.0 g/dL (within 28 days prior to registration)
• Absolute neutrophil count >= 1,000 /mm^3 (within 28 days prior to registration)
• Platelets >= 100,000/mm^3 (within 28 days prior to registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (institutional) or direct bilirubin within normal limits in patients with a history of Gilbert's syndrome (within 28 days prior to registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (institutional) or =< 5 x ULN for participants with documented liver metastases (within 28 days prior to registration)
• Serum creatinine =< 1.5 x ULN (institutional) OR calculated glomerular filtration rate (GFR) >= 60mL/min (within 28 days prior to registration)
• Participants with concurrent human immunodeficiency virus (HIV) infection are eligible provided the following criteria are met: * CD4+ T-cell (CD4+) counts > 350 cells/uL * No history of AIDS-defining opportunistic infection within 12 months prior to enrollments * Any medication used in an antiretroviral therapy (ART) regimen must have no known interaction with the agents used in the study treatment regimen
• Participants with active or chronic hepatitis B or C are eligible provided they meet the liver function criteria for Hgb, absolute neutrophil count, platelets, total bilirubin, AST, ALT, and serum creatinine and are not on a medication with a known interaction with the agents used in the study treatment regimen. The following guidance applies: * Patients with chronic hepatitis B virus (HBV) infection with active disease who meet the Food and Drug Administration (FDA) criteria for anti-HBV therapy should be on a suppressive antiviral therapy prior to initiation of cancer therapy * Patients with a history of hepatitis C virus (HCV) infection should have completed curative antiviral treatment. HCV viral load must be below the limit of quantification * Patients who are HCV antibody (Ab) positive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution are eligible
• Participants with brain metastases identified at diagnosis or at time of screening are eligible if the following criteria are met: * Known, untreated brain metastases must undergo definitive local therapy – as determined by treating physician – prior to study entry * Treated brain metastases must be clinically stable since treatment. Restaging brain MRI is not required to deem eligibility if local therapy was given within 28 days from first dose of study treatment. Patients are eligible if time from local therapy and first dose of study treatment is: ** ≥7 days for stereotactic radiosurgery (SRS); ** ≥14 days for whole-brain radiation therapy (WBRT); ** ≥28 days for surgical resection. * Patients who have already started THP prior to study entry and have brain metastasis detected at screening MRI are eligible after completion of definitive local therapy– as determined by treating physician. Systemic treatment can be interrupted as determined by the treating physician and after discussion with the sponsor investigator
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible (i.e., adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer)
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation and for 7 months after completion of study therapy containing trastuzumab or pertuzumab
• Women of childbearing potential must have a negative pregnancy test within 14 days of registration. Childbearing potential is defined as: those who have not been surgically sterilized and/or have had a menstrual period in the past 12 months or who have been on ovarian suppression in the past year
• Ability to understand and the willingness to sign a written informed consent document
• Participants that do not read and understand English are eligible to participate, but will be exempt from the patient-completed questionnaires that are only available in English

Exclusion Criteria

• Prior history of invasive breast carcinoma
• No prior systemic therapy for invasive breast cancer, aside from first-line trastuzumab/pertuzumab/taxane (THP) started prior to enrollment. Participants may have received up to 4 cycles of THP therapy prior to enrollment but must begin treatment on Part B within 3 weeks of last taxane dose. A CT CAP or other appropriate systemic imaging (according to RECIST 1.1 criteria) must have been performed prior to initiation of THP. Participants who were treated with local therapy only, without systemic therapy, will not be excluded from study.
• Treatment with any other investigational agents for this condition
• Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days of study entry or an anticipated need for major surgery during the study
• Extracranial palliative radiotherapy within 7 days prior to enrollment
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to trastuzumab, pertuzumab, paclitaxel, trastuzumab deruxtecan, trastuzumab emtansine, tucatinib
• Participants with a medical history of myocardial infarction within 6 months before enrollment or symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] Class II to IV)
• Subjects must not have any of the following: * Any untreated brain lesion on screening MRI, unless approved by the sponsor investigator * Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent) * Known or concurrent leptomeningeal disease on screening MRI * Poorly controlled (> 1/week) generalized or complex partial seizures
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (Common Terminology Criteria for Adverse Events [CTCAE] grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the sponsor-investigator
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• History of other lung disease, such as: * Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of study enrolment, severe asthma, severe chronic obstructive pulmonary disorder (COPD), restrictive lung disease, pleural effusion etc.); * Any autoimmune, connective tissue or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren’s, sarcoidosis, etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening; * Prior pneumonectomy
• Active or uncontrolled clinically serious infection
• Inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications
• Ongoing ≥ Grade 2 diarrhea of any etiology
• Participants receiving any medications or substances that are inhibitors or inducers of CYP2C8 and/or CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference
• Any of the following due to teratogenic potential of the study drugs: * Pregnant women * Nursing women * Women of childbearing potential who are unwilling to employ adequate contraception * Men who are unwilling to employ adequate contraception
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy * Individuals with the following cancer are eligible regardless of when they were diagnosed and treated: cervical cancer in situ, and non-melanoma cancer of the skin
• Poorly controlled serious mental illness that would hinder the patient's ability to comply with protocol requirements, in the opinion of the treating investigator