Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/28/23. Questions regarding updates should be directed to the study team contact.

Subjects

• Clinically or genetically confirmed diagnosis of a neurological, psychiatric, or medical condition of interest.
• Age ≥ 18 years at time of diagnosis.

Controls

• Healthy control participants, either a convenience sample of patient’s friends, acquaintances, or family members; or alternatively, community controls, or control outpatients seen at Mayo Clinic.
• Age ≥ 18 years at time of survey.

Subjects

• Age < 18 years at time of diagnosis.
• Inadequate familiarity with the English language.
• Presence of any medical condition or surgical history that could affect the safety of the subject or interfere with study assessments, safety, or the ability of the subject to complete the evaluation per the judgment of the site principal investigator.

Controls

• Age < 18 years at time of survey.
• Inadequate familiarity with the English language.
• Presence of any medical condition or surgical history that could affect the safety of the subject or interfere with study assessments, safety, or the ability of the subject to complete the evaluation per the judgment of the site principal investigator.
• Personal history of the neurological, psychiatric, or medical conditions being studied.

Eligibility last updated 11/17/21. Questions regarding updates should be directed to the study team contact.

• Male or female.
• Aged 60 to 90 years, inclusive at Visit 1 Screen.
• Clinical diagnosis of normal cognition, subjective cognitive decline, mild cognitive impairment or mild dementia ( CDR® ≤ 1.5).
• Fluent in English or Spanish.

• Contraindications to MRI such as inability to fit inside the MRI scanner, difficulty with close or confined spaces or presence of MRI non-compatible implants such as pacemakers or aneurysm clips.
• History of or current neurologic, psychiatric or medical disease that could confound the results of the study tests and procedures.
• Clinical diagnosis of moderate or severe cognitive impairment or dementia, requiring assistance with basic activities of daily living.

Eligibility last updated 2/17/22.  Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Patients:

• Patient age 18 or above.
• Confirmed diagnosis of fibromyalgia (FM).
• Patient must be able to understand and provide informed consent and HIPAA authorization.
• Able to speak and read English.

Exclusion Criteria
•Patients:

• Patients < 18 years of age.
• Inability to provide informed consent or HIPAA authorization.
• Individuals that decline study participation.
• Patients without a confirmed diagnosis of FM.

Inclusion Criteria
•Clinicians:

• Clinicians providing care to eligible patients at the Fibromyalgia Clinic and division of General Internal Medicine (Mayo Clinic Jacksonville and Rochester).

Exclusion Criteria
•Clinicians:

• Individuals that decline study participation.

Eligibility last updated 10/1/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Subjects must have undergone bronchoscopic lung volume reduction with endobronchial valve(s) placement for treatment of emphysema at Mayo Clinic-Rochester within timeframe of 3/01/2022 to 2/28/2023.
• Subjects must consent to undergoing CT scan of the chest prior to hospital discharge.

• Previous endobronchial valve placement (i.e., undergoing secondary procedure to have additional valves placed or valves upsized).
• Presence of large post-procedure pneumothorax, as defined by > 2 cm of air present between lung margin and chest wall measured at level of the hilum, identified prior to study CT acquisition.

Eligibility last updated 3/1/22. Questions regarding updates should be directed to the study team contact.

• Men and women, ≥ 18 years of age.
• The patients is eligible to undergo WATCHMAN device implant procedure.
• The patient is eligible for short term anticoagulation therapy.
• Ability to tolerate the procedure without the need for general anesthesia as assessed by the treating physician(s).
• Ability to give informed consent for the procedure.
• The patient is able and willing to undergo the procedure under moderate sedation.
• The patient is able and willing to return for required 45-day TEE.

• Patient has contraindication for short term anticoagulation.
• The patient has history of a hypercoagulable state per medical record documentation.
• Pregnancy or planning to get pregnant during the investigation.

Eligibility last updated 9/21/21. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/21/22. Questions regarding updates should be directed to the study team contact.

• Patient is male or female and is 2 months to 24 months of age, inclusive.
• Patient has been diagnosed with IS within 6 weeks prior to Screening. Diagnostic criteria include both clinical spasms and an electroencephalogram (EEG) pattern consistent with hypsarrhythmia or significant abnormality compatible with IS.
  • NOTE: If a video EEG is performed at the clinical site within 48 hours prior to the patient's parent/guardian providing written informed consent, and it meets the criteria, this video EEG may be used as the screening/baseline EEG for the study.
• Patient has normal renal function as defined by an estimated glomerular filtration rate (eGFR).
• > 60 mL/min/1.73 m^2, calculated as eGFR = 0.413 x (height [cm]/ serum creatinine [mg/dL]).
• Patient's legally authodzed representative (i.e., parent or guardian) must provide written informed consent obtained per Institutional Review Board policy and requirements, consistent with the International Council for Harmonisation.
• Patient's parent/guardian is able to understand and willing to comply with study procedures and restrictions.

• Patient has been diagnosed with tuberous sclerosis.
• Patient has acute illness considered clinically significant by the Investigator within 30 days prior to Screening.
• Patient has a diagnosis of recent systemic fungal infection; history of ocular herpes simplex; history of or current peptic ulcer; uncontrolled hypertension or congestive heart failure; or any other condition that would be significantly impacted by the study drug.
• Patient has a preplanned surgery or procedurc(s) that would interfere with the conduct of the study.
• Patient has received any prior treatment for IS.
• Patient has been previously treated with adrenocorticotropic honnonc (ACTH), corticosteroids, or vigabatrin for seizures.
• Patient has been previously treated with a course of corticosteroids for an indication other than seizures within 30 days prior to Screening.
• Patient has a known or suspected allergy to ACTH or vigabatrin or any component of AMZ002 or vigabatrin.
• Patient has used any other investigational drug within 30 days or 5 half-lives prior to the first dose of AMZ002 or vigabatrin (whichever is longer).
• Patient's parent/guardian is unable to provide written informed consent and/or to complete the daily diary.
• Patient has any other disease, condition, or therapy that, in the opinion of the Investigator, might compromise safety or compliance, preclude the patient from successfully completing the study, or interfere with the interpretation of the results.

Eligibility last updated 9/15/21. Questions regarding updates should be directed to the study team contact.

• Participant must be able to understand and provide informed consent and be willing to comply with study procedures and follow up.
• Are at least 18 years of age and not older than 70 years of age at screening.
• Meet the ACR/EULAR Classification Criteria for IgG4-RD.
• Have active disease based at screening on an IgG4-RD RI ≥ 4, with disease manifestations in at least two organ systems.
• May have newly-diagnosed or relapsing disease at screening. Relapsing disease is defined as IgG4-RD that has previously been in remission but is now active again.
• May be on treatment or off treatment at the time of screening. If on treatment, must be willing to discontinue those other treatments before the baseline visit.
• No history of severe allergic reactions to monoclonal antibodies.
• Female participants of childbearing potential must have a negative pregnancy test upon study entry.
• Female participants of childbearing potential and male participants with a partner of childbearing potential must agree to consistently and correctly use FDA approved highly effective methods of birth control, for the entire duration of the study.
• Immunization with one of the FDA authorized or licensed SARS-CoV2 vaccines is required for study entry. Vaccination series must have been completed at least 2 weeks prior to start of study therapy.
• Participants with COVID-19 infections within the preceding three months must have 2 consecutive negative nasal swab PCR tests performed at least 24 hours apart.

• Presence of a condition other than IgG4-RD that (e.g., asthma) is likely to require systemic Glucocorticoids (GC) for disease control during the period of the trial.
• Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin.)
• the following lab values as indicators of hepatic dysfunction:
  • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the upper limit of normal (ULN);
  • Total bilirubin > two times the ULN unless caused by Gilbert’s disease. Gilbert’s disease with total bilirubin > three times ULN;
  • Serum albumin < 2.5 mg/dL.
• Evidence of another uncontrolled condition which, in the judgment of the investigator, could interfere with participation in the trial according to the protocol.
• Active infection requiring hospitalization or treatment with systemic antimicrobial agents within the 30 days prior to randomization.
• Prior use of rituximab or other B cell depleting agents within 9 months of enrollment unless B cells have been demonstrated to have repopulated.
• Use of any investigational agent or biologic and non-biologic DMARDSwithin 5 half-lives of the agent (or 6 months if the half-life is unknown) prior to enrollment.
• Any of the following laboratory tests at the Screening Visit:
  • White blood cell (WBC) count < 3.0 x 10^3/µL;
  • Absolute neutrophil count (ANC) < 1.5 x 10^3/µL;
  • Hemoglobin < 10 g/dL;
  • Platelet count < 75 x 10^9/L;
  • Estimated glomerular filtration rate (eGFR) ≤ 45 ml/minute/1.73m^2.
• The use of supplemental oxygen at baseline.
• Positive Quantiferon gold assay. Indeterminate Quantiferon gold assays must be repeated(with same or other interferon gamma release assay (IGRA) per local policy) and shown to be negative. Alternatively, if the Quantiferon gold assay remains indeterminant, a participant must have a negative PPD. Finally, if the participant has had the Bacille Calmette-Guerin (BCG) vaccine or has some other condition complicating the interpretation of TB testing, consultation with infectious disease specialist must be obtained before receipt of the first investigational infusion.
  • Participants diagnosed with latent TB are eligible but must have received appropriate prophylaxis for 30 days before their first investigational infusion.
• Medical history or serologic evidence at Screening of chronic infections including:
  • Human immunodeficiency virus infection;
  • Hepatitis B as indicated by surface antigen or hepatitis B core antibody positivity;
  • Hepatitis C as indicated by anti-hepatitis C antibody positivity; if a participant is Hepatitis C antibody positive, they will be eligible to participate in the study if he/she is negative for viral load at Screening.
• Live vaccines within 8 weeks of initiating study therapy.
• Participantis pregnant or breastfeeding, or planning a pregnancy while enrolled in the study.
• Substance use disorder, including the recurrent use of alcohol and/or drugs within the past year associated with clinically significant impairment associated with failure to meet major responsibilities at work, school, or home.
• IgG4-RD that is dominated primarily by advanced fibrotic lesions. Specifically, participants whose disease manifestations consist only of:
  • retroperitoneal fibrosis;
  • fibrosing mediatinitis;
  • sclerosing mesenteritis; and
  • Riedel’s thyroiditis. Participants with these disease manifestations can be included; however, only if they have disease in 2 organ systems that is not of an advanced fibrotic nature and otherwise meet the Inclusion and Exclusion Criteria.

Eligibility last updated 8/11/22. Questions regarding updates should be directed to the study team contact.

• Age 18 or older.
• Diagnosis of keratoconus.
• Available baseline corneal topography and pachymetry.
• Amsler-Krumeich keratoconus classification of stage 1 or higher.

• No prior corneal transplantation or INTACTS.
• No prior use of hybrid, corneal or scleral gas permeable lenses.
• Presence of corneal scarring.

Eligibility last updated 9/17/21. Questions regarding updates should be directed to the study team contact.

For patients still alive:

• Enrolled in BEAUTY Study (MC1137) and did not withdraw consent while enrolled on BEAUTY for either specimen collection or long-term follow-up.
• Able to provide written informed consent.
• Willingness to provide mandatory blood specimens for future research on breast cancer at Mayo Clinic.
• Willingness to provide mandatory tissue specimens for future research on breast cancer at Mayo Clinic.
• Willingness to provide consent for use of archived tumor biopsies obtained after enrollment in BEAUTY (Request tissue from prior biopsy of site of recurrence).
• Ability to complete questionnaires by themselves or with assistance.

For patients who have died:

• Enrolled in MC1137 and did not withdraw consent while enrolled on BEAUTY for either specimen collection or long-term follow-up.
• Existence of a family member willing to provide consent for use of archived tumor biopsies obtained after enrollment in BEAUTY.

• Not enrolled in BEAUTY study (MC1137).

Eligibility last updated 6/30/22. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection).
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
  • By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm);
  • By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible);
  • Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen;
    • ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.
  • The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive;
  • The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as: age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to study entry. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.

• Definitive clinical or radiologic evidence of metastatic disease. -pT2
  •pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible).
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible).
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible).
• Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re- excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of less than 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible.
• Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment.
  • Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
• Use of any investigational product within 30 days prior to study entry.

Eligibility last updated 9/20/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Patient has undergone office-based evaluation for hematuria (CT, ultrasound, cystoscopy).

• Patient has known cancer outside of the target cancer 5 years prior to current collection (not including basal cell or squamous cell skin cancers; if patient has not been seen or if information is not available, the patient is eligible).
• Patient has recurrent bladder cancer.
• Patient has ever been previously diagnosed with UTUC (Upper Tract Urothelial Carcinoma) prior to bladder resection.
• Patient has prior diagnosis of bladder cancer for which intravesical immunotherapy (BCG) or chemotherapy (Mitomycin, Valrubicin) was provided.
• Patient has received chemotherapy class drugs for the treatment of cancer in the 5 years prior to current collection.
• Patient has had any prior radiation therapy to the target lesion prior to current collection.
• Patient has had a biopsy to the target organ and/or lesion within 3 days before collection.
• Patient has undergone cystectomy.
• Patient has transurethral instrumentation (placement of urinary catheter) within 7 days prior to urine collection.
• Patient has had a urinary tract infection within 14 days prior to urine collection.
• Patient has chronic indwelling urinary catheter 
• Patient has prior diagnosis of bladder cancer for which prior resection of tumor was performed.

Eligibility last updated 6/29/22. Questions regarding updates should be directed to the study team contact.

• Adults, age ≥ 18 years.
• Any concomitant malignancy being treated with any PD-1 inhibitor (pembrolizumab, nivolumab or cemiplimab) as monotherapy and the presence of inflammatory arthritis defined by:
  • provider documented inflammatory arthritis (meet 2010 EULAR/ACR classification criteria of RA) in one or more large or small joints; and at least one or more of the following:
  • elevated inflammatory markers;
  • supportive imaging and/or supportive synovial fluid analysis.

• Active infection.
• Prior history of the rheumatic disease.
• Any B cell depletion therapy.
• PActive use of high (≥ 30 mg daily) of prednisone or steroid equivalent.
• Clinical features suggestive of non-RA autoimmune rheumatic disease (e.g., lupus, Sjogren’s, psoriatic arthritis, etc.) or axial spondyloarthropathy.

Eligibility last updated 9/21/21. Questions regarding updates should be directed to the study team contact.

• Prior TNFi biologic treatment – Patient has active, moderate-high disease activity RA (CDAI ≥ 10 and HAQ ≥ 0.5) despite the use/experience for ≥ 3 months of a TNFi-biologic OR discontinued the medication(s) due to intolerability or toxicity irrespective of treatment duration prior to the first dose of study drug; AND
• Glucocorticoid and NSAID treatment
  •If receiving glucocorticoids (≤ 10 mg/day of prednisone of equivalent) or NSAIDs, on stable doses for ≥ 2 weeks prior to randomization; AND
• Insurance
  •Insurance plan or patient assistance program allows access to at least 1 drug in each of the two treatment strategies for 1 year trial duration. Participants will be allowed to continue their conventional synthetic DMARD (csDMARD) therapy if they had been using it for ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of study drug. The following csDMARDs are allowed: methotrexate (MTX), sulfasalazine, hydroxychloroquine, and leflunomide (TNFi-biologic and tsDMARD) through insurance plan or a patient assistance program/plan.

• Prior treatment with more than three biologics, defined as TNFi-biologic or non-TNFi biologic.
• Prior treatment with targeted synthetic DMARD.
• Concomitant use of cyclosporine, or azathioprine within 2-months before randomization.
• History of sensitivity to all 4 non-TNF-biologic or a targeted synthetic DMARD.
• Glucocorticoid injection (intravenous, intramuscular, or intraarticular) within 1 month of study entry.
• Live vaccine within 90 days of study entry.
• Acute infection treated with parenteral antibiotics or hospitalization within 1 month or with oral antibiotics within 2 weeks of study entry; or chronic infections requiring long-term antibiotic suppressive therapy.
• History of HIV or opportunistic infections.
• New York Heart Association Class III or IV heart failure.
• Latent TB not treated with anti-mycobacterial medication.
• Untreated Hepatitis B or C infection.
• History of deep venous thrombosis or pulmonary embolism.
• Pregnant or nursing women.
• History of herpes zoster or shingles.

Eligibility last updated 6/1/22. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 7/26/22. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 1/13/23. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 4/17/23. Questions regarding updates should be directed to the study team contact.

• ASA classification I to III, older than or equal to 18 years old.
• All genders.
• Presenting for primary total knee replacement for degenerative joint disease.
• Patient capable of providing their own informed consent.

• Vulnerable study populations including prisoners.
• Patients with a contralateral total knee arthroplasty < 2 years prior to the index procedure.
• Compromised health barring them from proceeding with surgery including acute or chronic kidney injury identified pre-operative.
• Patients unable to provide their own informed consent.
• Pregnancy.
• Patients with documented chronic pain syndromes.
• Patients with a history of prolonged daily opioids (more than 1 month) with an oral morphine equivalent of greater than 5mg/day.
• BMI > 45 kg/m^2.
• Allergies to any component of the study medications, including specific history of type 1 hypersensitivities to any NSAID.
• Patients with impaired cognitive function.
• Major systemic illnesses such as severe renal (estimated glomerular filtration rate less than 50ml/min), coronary artery disease requiring a bypass graft (CABG), other cardiac problems including congestive heart failure (CHF New York Heart Association class III to IV), or severe hepatic disorders defined as current or past diagnosis of acute/subacute liver necrosis, acute hepatic failure, chronic liver disease, liver abscess, hepatic coma, hepatorenal syndrome and other disorders of the liver.

Eligibility last updated 10/12/21. Questions regarding updates should be directed to the study team contact.

• Pathologic findings supporting the clinical impression of anaplastic thyroid  carcinoma. Diagnosis may include consistent with or suggestive of terminology  associated with: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous  carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells present.
• Must have a BRAFV600E mutation-positive tumor, as determined by BRAF V600E  immunohistochemistry on tumor tissue, genetic/molecular testing of tumor, or cell free  (cf)NDA liquid biopsy.
• Have measurable disease based on RECIST 1.1.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN). Total bilirubin ≤ 3 x ULN for  patients with Gilbert's syndrome.
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase  [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])  ≤ 2.5 x ULN, (5 x ULN for patients with concurrent liver metastases).
• Serum creatinine ≤ within 1.5 x ULN.
• Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L.
• Platelets ≥ 100 x 10^9/L.
• Hemoglobin ≥ 9.0 g/dL or 5.6 mmol/L.
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless  participant is receiving anticoagulant therapy as long as PT or activated partial  thromboplastin time (aPTT) is within therapeutic range of intended use of  anticoagulant.
• Subjects must be willing to undergo tumor biopsy prior to and after the run-in with dabrafenib/trametinib (DT), unless in the opinion of the treating physician, a biopsy is not feasible or safe. Subjects must be willing to ultimately undergo surgery if  their tumor becomes surgically resectable. Research subjects retain the right to  refuse any research interventions.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  Evaluation of ECOG is to be performed within 7 days prior to the date of allocation/randomization.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• A male participant must agree to use a contraception of this protocol during the  treatment period and for at least 8 months after the last dose of study treatment and  refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not  breastfeeding, and at least one of the following conditions applies:  
  • Not a woman of childbearing potential (WOCBP); OR
  • A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 months after the last dose of study treatment.

• Significant cardiovascular impairment: history of congestive heart failure greater  than New York Heart Association (NYHA) class II.
• Untreated brain metastases.
• Prior chemotherapy within < 1 week prior to study day 1 or patients who have not  recovered (i.e., ≤ grade 2) from adverse events due to a previously administered  agent, except for patients who have been on dabrafenib/trametinib (DT) according to  the standard run-in outlined in the trial schema.
• Has active autoimmune disease that has required systemic treatment in the past 2 years  (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid  replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• History of human immunodeficiency virus (HIV) or active hepatitis B (chronic or acute)  or hepatitis C infection. Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive  anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. However,  patients with past or resolved hepatitis B virus (HBV) should be monitored for  reactivation by a specialist. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic  acid (RNA).
  • Note: no testing for HIV, hepatitis B and hepatitis C is required unless  mandated by local heath authority.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose  of study drug. Administration of killed vaccines is allowed.
• Has severe hypersensitivity (≥ grade 3) to pembrolizumab and/or any of its excipients.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required  steroids or has current pneumonitis/interstitial lung disease.
• Has known psychiatric or substance abuse disorders that would interfere with  cooperation with the requirements of the trial.
• Females who are breastfeeding or pregnant at screening or baseline (as documented by a positive beta-human chorionic gonadotropin [beta-hCG] (or human chorionic gonadotropin  [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG [or hCG]). A women of childbirth potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to the first infusion will be excluded. If the urine test is  positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• More than 30 days of DT therapy prior to enrollment.
• A known history of retinal vein occlusion (RVO), central serous retinopathy (CSR), uncontrolled glaucoma or ocular hypertension.

Eligibility last updated 9/27/21. Questions regarding updates should be directed to the study team contact.

General Eligibility Criteria:

• Assessment for general eligibility criteria is based on medical records of the site and interview with a candidate patient. Patients must meet ALL general inclusion criteria to participate in the clinical investigation. If ANY general exclusion criteria are met, the patient is excluded from the clinical investigation and cannot be enrolled.
• If any clinical and/or laboratory tests are required for patient screening and are not included in a site’s standard tests, they must be completed after written informed consent is obtained.

• Subject must have at least one of the clinical indications before device implant in adherence with ACC/AHA/HRS/ESC dual chamber pacing guidelines.
• Subject is ≥ 18 years of age or age of legal consent, whichever age is greater.
• Subject has a life expectancy of at least one year.
• Subject is willing to comply with clinical investigation procedures and agrees to return to clinic for all required follow-up visits, tests, and exams.
• Subject has been informed of the nature of the clinical investigation, agrees to its provisions and has provided a signed written informed consent, approved by the IRB/EC.

• Subject is currently participating in another clinical investigation that may confound the results of this study as determined by the Sponsor.
• Subject is pregnant or nursing and those who plan pregnancy during the clinical investigation follow-up period.
• Subject has presence of anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator’s opinion, could confound the assessment of the investigational device and/or implant procedure, limit the subject’s ability to participate in the clinical investigation or to comply with follow-up requirements of the clinical investigation results.
• Subject has a known allergy or hypersensitivity to < 1 mg of dexamethasone sodium phosphate or any blood or tissue contacting material listed in the IFU.
• Subject has an implanted vena cava filter or mechanical tricuspid valve prosthesis.
• Subject has pre-existing, permanent endocardial pacing or defibrillation leads (does not include lead fragments).
• Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device.
• Subject has an implanted leadless cardiac pacemaker (except for an Aveir ventricular LP).
• Subject is implanted with an electrically-active implantable medical device with stimulation capabilities (such as neurological or cardiac stimulators)*.
• Subject is unable to read or write.
  • * NOTE:  Does not apply to a medical device with no known impact to the Aveir Leadless Pacemaker System, including the Aveir Link Module. Patient evaluation and the decision to implant the LP should take into account the presence of other active implantable devices and should include consultation with the Sponsor and/or manufacturer of the co-existing device.

Eligibility last updated 11/18/21. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 5/16/23. Questions regarding updates should be directed to the study team contact.

• Women age ≥ 18 years.
• Eastern Cooperative Oncology Group performance status 0-2 (Karnofsky >60%).
• Patients with metastatic breast cancer.
• HER2 (human epidermal growth factor receptor 2)-positive breast cancer prospectively determined on the primary tumor by a local pathology laboratory and defined as:
  • Immunohistochemistry (IHC) score of 3+ and/or positive by ISH (defined by In Situ Hybridization ratio of ≥ 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies). Both IHC and ISH assays will be performed; however, only one positive result is required for eligibility.
• Estrogen/progesterone receptor positive OR negative disease allowed.
• Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Patients that have failed at least one anti-HER2 therapy in the metastatic setting.
• Patients must have normal organ and marrow function as defined below:
  • absolute neutrophil count ≥ 1,500/mL;
  • platelets ≥ 100,000/mL;
  • total bilirubin ≤ institutional upper limit of normal (ULN);
  • aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 5 ≤ X institutional ULN;
  • creatinine ≤ institutional ULN OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
• Baseline left ventricular ejection fraction (LVEF) ≥ 50% measured by echocardiogram (preferred) or multigated acquisition (MUGA) scans.
• Willing and able to comply with the requirements of the protocol.
• Patient is able to take oral medication.
• Signed informed consent.
• Female patients of childbearing potential must be willing to use one highly effective form of hormonal contraception or two effective forms of nonhormonal contraception.
• Contraception must continue for the duration of study treatment and for 7 months after the last dose of study treatment. The above contraception is not a requirement in the case of any of the following:
  • The patient, or partner of the patient, is surgically sterilized;
  • The female patient is > 45 years of age and is postmenopausal (has not menstruated for at least 12 consecutive months;
  • The patient truly abstains from sexual activity and when this is the preferred option to avoid conception and contraception and/or usual lifestyle of the patient.

• Metastatic breast cancer patients who are HER2 positive and have NOT progressed on at least one prior HER2-targeted therapies for metastatic disease -Patients who have not recovered from CTCAE, v. 4.03 grade 2 or higher toxicities of prior therapy to the point that they would be appropriate for re-dosing will be ineligible for study treatment. Subjects receiving weekly therapy must have a washout period from prior chemotherapy of as least one week. Washout period for chemotherapy administered every 2, 3, or 4 weeks will be 2, 3, and 4 weeks respectively, provided subject has recovered from toxicities of prior therapy such that retreatment is appropriate.
• Patients must be at least two weeks from prior RT.
• Patients must have a one-week washout period from prior hormonal therapy (e.g., testosterone, estrogen, progestin, gonadotropin-releasing hormone antagonist).
• Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and have not been using steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient from study participation regardless of clinical stability. No concurrent anti-cancer treatment of any type.
• Patients with known germline BRCA 1 or BRCA 2 mutations.
• Patient has undergone prior treatment with a known poly(ADP-ribose) polymerase (PARP) inhibitor.
• Prior treatment of a total doxorubicin > 360 mg/m^2 (or equivalent).
• Patient has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is detected).
• Patient has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). -Chronic immunosuppressive therapies including systemic corticosteroids or concurrent short-term use of immunosuppressive therapies is not allowed. Short- term corticosteroid use must be discontinued at least 2 weeks prior to study treatment.
• Patients with known grade 2 or greater allergic reactions attributed to compounds of similar chemical or biological composition to niraparib are ineligible for study enrollment.
• Patients with known grade 2 or greater allergic reactions attributed to compounds of similar chemical or biological composition to herceptin are ineligible for study enrollment.
• Patient is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 7 months after the last dose of study treatment. -History of non-breast malignancies within the 5 years prior to study entry, except for the following:
  • Carcinoma in situ (CIS) of the cervix;
  • CIS of the colon;
  • Melanoma in situ;
  • Basal cell and squamous cell carcinomas of the skin.
• Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease or active infection that requires systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study (including obtaining informed consent).
• Cardiopulmonary dysfunction as defined by any of the following prior to randomization:
  • History of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.0) Grade ≥3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II;
  • Angina pectoris requiring anti-angina medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease -High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz 2] or third degree AV-block]);
  • Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia;
  • Myocardial infarction within 12 months prior to randomization.
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg).
• Evidence of transmural infarction on ECG.
• Heart-rate corrected QT interval (QTc) prolongation > 470 msec at screening.
• Requirement for oxygen therapy.

Eligibility last updated 9/28/21. Questions regarding updates should be directed to the study team contact.

• Aged 18 years of age or older.
• Patients who have had a recent episode of COVID-19 and who present to the Post COVID-19 Clinic at Mayo Clinic Rochester.   
• Access to smartphone (iOS or Android operating systems).
• Ability to complete study questionnaires and provide voice samples using a smartphone application.

• Known history of voice disorder either primary or secondary to neuromuscular or other pathology.
• Cognitively impaired patients.
• Prisoners.
• Non-English speakers.
• Currently on another study assessing depression or quality of life.

Eligibility last updated 2/22/23. Questions regarding updates should be directed to the study team contact.

• Patients must be ≤ 50 years of age at the time of enrollment.
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification are eligible to enroll on the study based upon Stage, Group, and age, as below. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) Classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants.
• ERMS -Stage 4, group IV, ≥ 10 years of age.
• ARMS -Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age.
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study.
• Creatinine clearance or radioisotope glomerular filtration rate (GFR)  7 ≥ 0 mL/min/1.73 m^2; or
• A serum creatinine based on age/gender as follows:
  • Age | Maximum serum creatinine (mg/dL)
  • 1 month to < 6 months | 0.4 mg/dL (male); 0.4 mg/dL (female);
  • 6 months to < 1 year 0.5 mg/dL (male) | 0.5 mg/dL (female);
  • 1 to < 2 years 0.6 mg/dL (male) | 0.6 mg/dL (female);
  • 2 to < 6 years 0.8 mg/dL (male) | 0.8 mg/dL (female);
  • 6 to < 10 years 1 mg/dL (male) | 1 mg/dL (female);
  • 10 to < 13 years; 1.2 mg/dL (male) | 1.2 mg/dL (female);
  • 13 to < 16 years; 1.5 mg/dL (male) | 1.4 mg/dL (female);
  • ≥ 16 years; 1.7 mg/dL (male) | 1.4 mg/dL (female).
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR39 utilizing child length and stature data published by the CDC.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age.
• If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x ULN for age.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Patients with evidence of uncontrolled infection are not eligible.
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed.
• Patients with central nervous system involvement of RMS as defined below:
  • Malignant cells detected in cerebrospinal fluid;
  • Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed);
  • Diffuse leptomeningeal disease;
  • Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment;
  • Note: the following exception:
  • Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation.
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy.
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

Eligibility last updated 9/29/21. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed diagnosis of peripheral T-cell lymphoma (PTCL) with < 10% CD30 expression by immunohistochemistry in the following subtypes (by local review): nodal T-cell lymphoma with T-follicular helper (TFH) phenotype (TFH-PTCL), follicular T-cell lymphoma, PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma.
• Patients will be stratified by presence or absence of TFH phenotype (i.e., diagnosis of AITL, TFH-PTCL, follicular T-cell lymphoma) based on local review of pathology. Determination of TFH phenotype can be defined by expression of two or more of the following markers CD10, BCL6, CXCL13, ICOS, and PD1 by immunohistochemistry.
• Measurable disease as defined by the Lugano criteria.
• No prior systemic therapy for lymphoma (excluding corticosteroids).
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done ≤ 7 days prior to registration is required.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Platelet count ≥ 75,000/mm^3 (≥ 50,000/mm^3 if secondary to bone marrow involvement from lymphoma per investigator assessment; the first 12 patients on each arm of the study must have platelets ≥ 75,000/mm^3 regardless of bone marrow involvement).
• Absolute neutrophil count (ANC) ≥ 1,000/mm^3.
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) ≤ 3.0 x upper limit of normal (ULN) * Except in subjects with documented liver involvement by lymphoma.
• Calculated creatinine clearance ≥ 30 mL/min by Cockcroft-Gault formula.
• Total bilirubin ≤ 2.0 x ULN * Except in cases of Gilbert's Syndrome or documented liver or pancreatic involvement by lymphoma.
• Archival tissue must be available for submission.
• No active viral infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Those who are seropositive (e.g., hepatitis B core antibody [Ab] positive) are permitted if they are negative by polymerase chain reaction (PCR). Those who are seropositive for hepatitis B and are negative for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) by PCR must receive concomitant hepatitis B directed antiviral therapy. Those who have hepatitis C Ab positivity who have completed curative therapy for hepatitis C with negative hepatitis C PCR are eligible.
• Patients with history of HIV are eligible if they have an undetectable viral load for at least 6 months.
• No active uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment).
• Patients with Epstein-Barr virus (EBV) viremia related to their lymphoma are permitted.
• Patients must have documented left ventricular ejection fraction of ≥ 45%.
• No significant active cardiac disease within the previous 6 months including: 
  • New York Heart Association (NYHA) class III or IV congestive heart failure;
  • Unstable angina or angina requiring surgical or medical intervention; and/or
  • Myocardial infarction.

• Patients with expression of CD30 in ≥ 10% of the tumor (based on local immunohistochemistry review) regardless of histology will not be permitted.
• Patients with a diagnosis of other PTCL subtype histologies other than those specified in the inclusion criteria are excluded including large cell transformation of mycosis fungoides.
• Patients known to have HTLV 1/2.
• Patients with known central nervous system involvement.
• No concurrent malignancy requiring active therapy within the last 3 years with the exception of basal cell carcinoma limited to the skin, squamous cell carcinoma limited to the skin, carcinoma in situ of the cervix, breast or localized prostate cancer. Adjuvant hormonal therapy for cancer previously treated for curative intent is permitted.
• No contraindication to any drug in the chemotherapy regimen, including neuropathy ≥ grade 2.
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the study. Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

Eligibility last updated 9/30/21. Questions regarding updates should be directed to the study team contact.

• Age 18 or older.
• Patients with paroxysmal atrial tachyarrhythmias with and without polyuria as a manifestation of their tachyarrhythmia episode.
• Documentation of their paroxysmal atrial tachyarrhythmia episode.

• Patients who are unable to manage the logistics of participating in the study (coming to Saint Mary’s Hospital ot have their blood drawn and urine sample collected during their atrial tachyarrhythmia episode).
• Chronic kidney disease stage 4 or higher.
• Clinical history of heart failure.

Eligibility last updated 10/1/21. Questions regarding updates should be directed to the study team contact.