Eligibility last updated 6/21/22. Questions regarding updates should be directed to the study team contact.

• Healthy male and female non-smoking participants
• 18 years old or older
• no significant metabolic, cardiovascular or neurologic disease and no contraindications to exercise.  

• Medications that might influence the cardiovascular or respiratory responses to exercise will be excluded (e.g. beta blockers and some other antihypertensives along with anti-asthma drugs). 

All inclusion/exclusion criteria are at the discretion of the principal investigator.

• Willing and able to provide informed consent.
• First degree relatives (age 2.5 – 45 years) of T1D probands.
• Second and third degree relatives (age 2.5 – 20 years) of T1D probands: nieces, nephews, aunts, uncles, grandchildren, cousins, half-siblings.
• Individuals (age 2.5-45 years) who have diabetes-related autoantibodies potentially eligible for clinical trial.

• Have diabetes by 2011 ADA criteria.

• Non-treatment seeking male or females ages 18 to 65 years, inclusive.
• DSM-5 diagnosis of cocaine use disorder in sustained remission as confirmed by the PI’s review of the medical record.
• Are motivated to abstain from cocaine use during the period of the study, as evidenced both by the judgment of the Investigator or designee and by compliance with the requirement to make regular clinic visits.
• In the opinion of the PI, be in good general health as determined by medical and psychiatric history, general clinical examination, vital signs, and laboratory tests.
• Have provided written informed consent. Subjects should be cooperative, willing and able to participate and adhere to the protocol requirements.
• Have hematology, chemistry, kidney and liver function laboratory tests that are within (+/- 10%) of the current Mayo Clinic standardized normal values.
• Show a baseline EKG that demonstrates normal sinus rhythm and conduction without clinically significant abnormalities or arrhythmias.
• Are willing to return to research area for follow-up.

• They show detectable pre-existing immunity to the AAV8 capsid as measured by AAV8 transduction inhibition and AAV8 total antibodies.
• Evidence of HIV or hepatitis of any etiology.
• Creatinine ≥ 1.5 mg/dL.
• Any disease or mental health condition at the physician’s discretion that would prevent the subject from fully complying with the requirements of the study. The physician may exclude subjects with active alcohol abuse, other substance abuse or positive urine toxicology screen for substances of abuse.
• Pregnant &/or lactating. All lactating women will be excluded from study participation. Women of child-bearing potential must have a negative pregnancy test performed at screening visit, agree to use birth control throughout the study period, refrain from getting pregnant within the study period and consent to pregnancy testing throughout the study period. Men must agree to use barrier methods of birth control and refrain from fathering children within the next year.
• Morbid obesity (BM > 40).

• Age ≥ 18 years old.
• Histologically confirmed metastatic adenocarcinoma originating from the colon or the rectum, microsatellite stable.
• Measurable disease as defined by RECIST criteria.
  • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; Disease that is measurable by physical examination only is not eligible.
• Received ≤ 2 lines of prior chemotherapy regimen for mCRC.
  • NOTE: Adjuvant therapy will not be considered a line of therapy for mCRC unless the patient had disease recurrence ≤ 6 months of adjuvant therapy.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• The following laboratory values obtained ≤ 21days prior to registration:
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Hemoglobin ≥ 9 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x ULN (≤5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula below:
  • Cockcroft-Gault Equation:
  • Creatinine clearance for males =     (140
    •age)(weight in kg)
                                                             ( 72)(serum creatinine in mg/dL)
  • Creatinine clearance for females =  (140
    •age)(weight in kg)(0.85)
                                                             ( 72)(serum creatinine in mg/dL).
• Anticipated life expectancy ≥ 6 months.
• Negative 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.
• Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of <1% per year) while enrolled in the study and for 3 months from the last vaccination. An effective form of contraception is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, cervical cap or condom.
• Men must agree to use an effective form of contraception (as defined above), and not donate sperm for 3 months from the last vaccination.
• Willingness to provide mandatory blood and buccal swab specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).  
  • NOTE: During the Active Monitoring Phase of a study.

• Received continuous systemic steroid treatment ≤ 2 weeks prior to registration.
• Colorectal cancer with documented high microsatellite instability (MSI H).
• Pre-existing systemic autoimmune or antibody-mediated diseases or immune deficiency diseases.
• Central nervous system (CNS) metastases.
• Serious, non-healing wounds, ulcers or bone fractures.
• Nephrotic syndrome.
• Arterial thromboembolisms or severe hemorrhages ≤ 6 months before registration (except bleeding tumor before tumor resection surgery).
• Any of the following prior therapies:
  • Major surgery ≤ 12 weeks prior to registration or anticipation of needing such procedure during the study period
  • Radiation therapy ≤ 4 weeks prior to registration
  • Received chronic systemic immune therapy or immunosuppressant medication other than steroids ≤ 6 weeks prior to registration:
  • Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage > once every 28 days;
  • Participants with active malignancy (other than colorectal cancer [CRC]) or a prior malignancy ≤ 12 months prior to registration.
    • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix;
  • Acute or subacute intestinal obstruction or history of chronic intestinal inflammatory diseases;
  • Relevant toxicities of prior therapies must have resolved to ≤Grade 1, except for oxaliplatin-related neuropathy or alopecia;
  • Participant with myocardial infarction ≤ 6 months prior to registration or New York Heart Association Class III or IV, heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system abnormalities;
  • Administration of a live, attenuated vaccine ≤ 4 weeks prior to registration or anticipation of a live attenuated vaccine will be required during the study.
• Participant has or will be participating in any of the following:
  • In another clinical study involving an investigational product (IP) or investigational device ≤ 30 days prior to registration; or
  • Is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study; or
  • Is receiving any other investigational agent which would be considered as a treatment for colorectal cancer.
• Known hypersensitivity to any component of the investigational drug.
• Uncontrolled intercurrent non-cardiac illness including, but not limited to:
• • Ongoing or active infection;
  • Psychiatric illness/social situations;
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy;
  • Any other conditions that would limit compliance with study requirements.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Men and women of childbearing potential who are unwilling to employ adequate contraception as per criteria above.

Eligibility last updated 8/26/21. Questions regarding updates should be directed to the study team contact.

• Patient is 18 years of age or older.
• Patient has a diagnosis of migraine.
• Patient has been newly prescribed fremanezumab, non-fremanezumab CGRP-pathway targeting preventive migraine medications, or non-CGRP-pathway targeting preventive migraine medications.
• Patient has had a blood pressure and heart rate measurement recorded by a healthcare provider within 1 week prior to or on the day of informed consent.

• Patient has been previously treated with CGRP-pathway targeting preventive migraine medications.
• Per prior authorization criteria, patients will not receive approval for treatment with CGRP-pathway preventative migraine medications without prior treatment with non-CGRP medications.

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

• Adult (age ≥ 18 years).
• Known or suspected NAFLD based on:
  • Prior biopsy ≤ 36 months consistent with NAFLD; OR
  • Abnormal ALT (> 30 U/L for men, > 19 U/L for women) without other common causes such as HCV, HBV AND meets criteria within 36 months for ATP III criteria (2005 revision) for metabolic syndrome with any 3 of the 6:
    • Waist circumference (WC) > 102 cm (M) or > 88 cm (F);
    • Fasting glucose ≥ 100 mg g/dL or Rx;
    • TG ≥ 150 mg/dL or Rx;
    • SBP > 130 mmHg;
    • DBP > 85 mm Hg;
    • Reduced HDL-C < 40 mg/dL (M) or < 50 gm/dL (W).
• Able and willing to participate, including maintaining steady-state: diet, physical activity, alcohol use, medications.
• Classifiable into one of the following enrollment categories by FIB-4 (ALT, AST, platelets, date of birth) collected at screening visit if not available already within 3 months prior:
  • Low likelihood of advanced fibrosis: FIB-4 ≤ 1.3 (about one-third of enrolled subjects, minimum 20%, maximum 45%);
  • Intermediate likelihood of advanced fibrosis: 1.3 < FIB-4 < 2.67 (about one-third of enrolled subjects, minimum 20%, maximum 45%);
  • High likelihood of advanced fibrosis: FIB-4 ≥ 2.67: (about one-third of enrolled subjects, minimum 20%, maximum 45%).

• Liver disease other than NAFLD.
• Excess alcohol consumption (≥ 2 units/day for women and ≥ 3 units/day for men).
• Current diagnosis of drug induced liver injury.
• Receiving drug or placebo in treatment trial now or within 30 days.
• Weight loss or gain of ≥ 5 kg in prior 3 months.
• Other factors that in the judgment of the PI might preclude study completion.
• Women who state they are pregnant. Women who state they might be pregnant will be required to undergo a urine pregnancy test within the Screening window with negative results to establish eligibility.
• Patients with active implants such as pacemakers or defibrillators or any other contraindication to MRI or VCTE scanning.

Eligibility last updated 6/10/22. Questions regarding updates should be directed to the study team contact.

• Participants must be 18 years or older.
• Participants must understand and cooperate with requirements of the study in the opinion of the investigators and must be able to provide written informed consent.
• Individuals who had no known COVID-19 exposure (for controls) or had PCR or antibody confirmed COVID-19 who present with neurological symptoms in the months after infection and fit one of the following criteria during the acute phase of the infection:
  • ambulatory with no or mild symptoms;
  • hospitalized but on no oxygen; or
  • hospitalized but on oxygen administered via a nasal cannula, mask or non-invasive ventilation; i.e., individuals with WHO Ordinal Scale40 scores 0-5. 
• English or Spanish speaking (based on self-stated primary language).
• Clear of any contraindications for MRI.

• Patients under 18 years of age.
• Medical conditions likely to interfere with the study, including chronic neurologic conditions, restless leg syndrome, structural abnormalities such as subdural hematoma, intracranial neoplasms, end-stage renal disease, severe chronic obstructive pulmonary disease (COPD) needing oxygen, end-stage liver disease, active psychiatric illness, active drug abuse, stroke unrelated to COVID-19 or heart attack 6 months before study enrollment, active cancer, concurrent illnesses or treatments interfering with cognitive function such as dementia or normal pressure hydrocephalus.
• Individuals who had COVID-19 and required mechanical ventilation.
• Pregnant women.
• Inability to undergo MRI scanning, including but not limited to claustrophobia, unable to remain still in an MRI scanner for more than 30 minutes, presence of paramagnetic substances or pacemakers in body, weight over 300 lbs.
• Inability to adhere to study protocol for whatever reason.

• ≥ 18 years of age, at the time of signing informed consent.
• Histologically or cytologically documented advanced/metastatic or surgically unresectable cholangiocarcinoma who have received at least one line of prior systemic chemotherapy. Patients will be assigned to 1 of 4 cohorts:
  • Cohort A1: FGFR2 fusions who have failed at least one previous treatment with an FGFR inhibitor;
  • Cohort A2: FGFR2 fusions who have previously responded on at least one previous treatment with an FGFR inhibitor;
  • Cohort B: other FGFR alterations, including FGFR2 mutations and FGFR1/3 alterations, including fusions;
  • Cohort C: negative for FGFR alterations (FGFR wild-type).
• At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors.
• Documentation of FGFR gene alteration status.
• ECOG performance status of 0 or 1.
• Adequate organ function confirmed at screening and within 10 days of initiating treatment, as evidenced by:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9 /L;
  • Hemoglobin (Hgb) ≥ 8 g/dl;
  • Platelets (plt) ≥ 75 x 10^9 /L;
  • AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present;
  • Total bilirubin ≤ 1.5 x ULN;
  • Calculated 24-hour clearance ≥ 50 mL/min (Cockcroft Gault formula).
• Negative pregnancy test within 72 hours before starting study treatment in all premenopausal women and women < 12 months after the onset of menopause.
• Must agree to take sufficient contraceptive methods to avoid pregnancy (including male and female participants) during the study and until at least 6 months after ceasing study treatment.
• Able to sign informed consent and comply with the protocol.

• Women who are pregnant or lactating.
• Women of child-bearing potential (WOCBP) who do not use adequate birth control.
• Patients with untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed (e.g. evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases) Note: Patients with treated brain metastases that are off corticosteroids and have been clinically stable for 28 days are eligible for enrollment.
• Patients with a known concurrent malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix or other noninvasive or indolent malignancy that has previously undergone potentially curative therapy.
• Patients with the following mood disorders as judged by the Investigator or a psychiatrist:
  • Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others);
  • ≥ CTCAE grade 3 anxiety.
• Impaired cardiac function or significant diseases, including but not limited to any of the following:
  • LVEF < 45% as determined by MUGA scan or ECHO;
  • Congenital long QT syndrome;
  • QTcF ≥ 480 msec on screening ECG;
  • Unstable angina pectoris ≤ 3 months prior to starting study drug;
  • Acute myocardial infarction ≤ 3 months prior to starting study drug.
• Patients with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic at Screening).
• Patients with:
  • unresolved diarrhea ≥ CTCAE grade 2; or
  • impairment of gastrointestinal (GI) function; or
  • GI disease that may significantly alter the absorption of TT-00420.
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], or active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
• Patients who have received chemotherapy, targeted therapy, or immunotherapy ≤ 5 half-lives or 3 weeks, whichever is shorter, (6 weeks for nitrosourea or mitomycin-C) prior to starting study drug.
• Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.
• Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.
• Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants.
• Patients who are currently receiving treatment with strong CYP3A inhibitors or inducers ≤ 2 weeks prior to starting study drug.
• Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory; patients with well controlled HIV might be enrolled per investigator’s discretion and Sponsor approval).
• Evidence of active infection with Hepatitis B or Hepatitis C that is not adequately controlled. For patients with known prior history of Hepatitis B or Hepatitis C, enrollment may be allowed per investigator’s discretion and Sponsor approval.
• Inability to swallow or tolerate oral medication.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might confound the results of the trial, interfere with the patient’s safe participation and compliance in the trial.

• Women and men between 18 and 85 years of age.
• Chest radiograph or computed tomography (CT) of the thorax within the last 1 year not demonstrating any abnormality considered to be significantly contributing to the refractory chronic cough in the opinion of the Principal Investigator.
• Have a diagnosis of refractory chronic cough or unexplained cough for at least one year.
• Have a score of ≥ 40mm on the Cough Severity VAS at Screening.
• Women of child-bearing potential (defined in supplemental section 1, page 64) must agree to use 2 forms of acceptable birth control and make no donation of eggs from Screening through the end of the 8-week study period. Acceptable birth control methods include established use of oral, injected, or implanted hormonal methods of contraception; intrauterine device (IUD) or intrauterine system (IUS); tubal ligation; or male sterilization. Double-barrier method (diaphragm for female subject and condom for male partner with spermicidal) satisfies the requirement for 2 forms of acceptable birth control. When concordant with the preferred lifestyle of the subject, true and complete abstinence (not periodic abstinence) is acceptable.
• Male subjects and their partners of child-bearing potential must use 2 methods of acceptable birth control, 1 of which must be a barrier method, and make no donation of sperm from Screening until 3 months after the last dose of study drug at the end of 8 weeks.
• Have provided written informed consent.
• Are willing and able to comply with all aspects of the protocol.

• Current smoker (cigarettes, e-cigarettes or marijuana) or former smokers who have smoked within the past 12 months.
• Former smokers with > 20 pack-year history of smoking.
• Ongoing treatment with an ACE-inhibitor that is considered as the potential cause of a subject’s cough or requiring treatment with an ACE-inhibitor during the study or within 12 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
• FEV1/FVC < 60%.
• History of upper or lower respiratory tract infection or recent significant change in pulmonary status within 4 weeks of the Screening/Baseline Visit (Day -14 to Day 0).
• History of opioid use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of opioids for other indications (for example, to treat pain) is permitted.
• History of baclofen use specifically prescribed for chronic cough within 2 weeks of the Screening/Baseline Visit (Day -14 to Day 0). Use of baclofen for other indications (for example, to treat spasticity) is permitted.
• Diagnosis of COPD, bronchiectasis, interstitial lung disease or cystic fibrosis.
• Presence of an untreated or undertreated cause for the patient’s chronic cough (as determined by the treating/referring physician per ACCP guidelines). e.g. uncontrolled asthma, GERD or post-nasal drainage that could potentially explain the patient’s chronic cough.
• Requiring concomitant therapy with prohibited medications (see under ‘prohibited concomitant therapy’ on page 28).
• Treatment with any pharmaceutical or biological investigational therapy (excluding coronavirus disease of 2019 (COVID) vaccination and COVID related monoclonal antibody therapy).
• Participation in another clinical trial that does not allow co-enrollment within 4 weeks prior to the Screening/Baseline Visit (Day -14 to Day 0).
• Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x the upper limit of normal (ULN) during screening.
• Serum creatinine < 30 mL/min, hemodialysis or peritoneal dialysis.
• Advanced liver disease as defined by the presence of cirrhosis and/or signs of portal hypertension.
• History of previous hypersensitivity or intolerance to Duloxetine & Amitriptyline (patients who have previously been on either amitriptyline or duloxetine for chronic cough or other reasons and have tolerated the medication will be offered participation regardless of previous response to therapy).
• Currently pregnant or breastfeeding female subject.
• Presence of any medical condition or disability that the investigators believe could interfere with the assessment of safety or efficacy in this trial or compromise the safety of the subject.
• Planned or anticipated major surgical procedure or other activity that would interfere with the subject’s ability to comply with protocol-mandated assessments (e.g., extended travel) during the subject’s participation in the study.
• Currently taking either another SSRI, SNRI or MAO inhibitor which the patient cannot safely discontinue at least 2 weeks prior to the screening period.

Eligibility last updated 4/15/22. Questions regarding updates should be directed to the study team contact.

Pre-Registration Eligibility Criteria

• Central Pathology Review Submission: This review is mandatory prior to registration to confirm eligibility
• Must have local diagnosis of meningioma (any grade)
• Must have FFPE tumor block OR meningioma tissue slides available for submission to central pathology review and SMO and NF2 testing by a CLIA-certified lab

Registration Eligibility Criteria

• Documentation of Disease
  • Histologically proven intracranial meningioma as documented by central pathology review
  • Presence of SMO or NF2 mutation in tumor sample as documented by central laboratory (SMO W535L, SMO L412F or known missense COSMIC mutations, nonsense mutations, small indels or copy-number loss in NF2)
• Progressive OR residual disease
  • Residual measurable disease immediately after surgery without requirement for progression
  • For Grade I disease, progression pre-operatively needs to be documented, with an increase in size of the measurable primary lesion on imaging by 25% or more (bidirectional area)
    • The change must occur between MRI scans separated by no more than 12 months and will be defined by lesions with clearly defined margins  with a minimum diameter of 10mm in both dimensions
  • Patients with measurable and progressive meningioma who have received radiation are potentially eligible, but need to show evidence of progressive disease after completion of radiation. At least 24 weeks must have elapsed from completion of radiation to registration
  • Measurable disease is defined by a bidimensionally measurable main lesion on magnetic resonance imaging (MRI) or computed tomography (CT) images (MRI preferred) with clearly defined margins
  • Multifocal disease is allowed
• Prior Treatment
  • Prior therapy is allowed but not required
  • No limit on number of prior therapies
  • No chemotherapy, other investigational agents within 28 days of study treatment
  • No other concurrent investigational agents or other meningioma-directed therapy (chemotherapy, radiation) while on study
  • For patients treated with external beam radiation, interstitial brachytherapy or radiosurgery, an interval > 24 weeks must have elapsed from completion of radiation therapy (XRT) to registration
  • Steroid dosing must be stable for at least 4 days
  •  Must be recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity from other agents with exception of alopecia and fatigue
  • No craniotomy within 28 days of registration
• Not pregnant and not nursing
  • A female of childbearing potential is a sexually mature female who
    • Has not undergone a hysterectomy or bilateral oophorectomy
    • Has not been naturally postmenopausal (has not had menses occur at any time) for at least 12 consecutive months
      • Pregnancy monitoring will occur during the duration of the trial
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• Patients with history of neurofibromatosis (NF) may have other stable central nervous system (CNS) tumors (schwannoma, acoustic neuroma or ependymoma) if lesions have been stable for 6 months

Exclusion Criteria

• Metastatic meningiomas as defined by extracranial meningiomas
• History of allergic reactions attributed to compounds of similar or biologic composition to assigned study drug
• Known active hepatitis B or C
• Current Child Pugh Class B or C liver disease
• Uncontrolled gastric ulcer disease (Grade 3 gastric ulcer disease within 28 days of registration)
• Uncontrolled diabetes defined as a known diabetic with hemoglobin A1C (HBA1C) > 7.5 OR fasting glucose > 140
• Uncontrolled hypertension defined as blood pressure (BP) > 140/90
• Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 28 days prior to registration
• Chronic concomitant treatment with strong CYP3A4 inhibitors
  • Patients with NF2 mutation enrolled to GSK2256098 must discontinue the drug for 14 days prior to study registration
• Chronic concomitant treatment with strong CYP3A4 inducers
  • Patients with NF2 mutation enrolled to GSK2256098 must discontinue the drug 14 days prior to the start of study treatment
• Required Initial Laboratory Values
  • Absolute Neutrophil Count (ANC) ≥ 1500/mm^3
  • Platelet Count ≥ 100,000/mm^3
  • Creatinine  ≤ 1.5 mg/dl x upper limit of normal (ULN)
  • Calc. Creatinine Clearance > 45 mL/min
  • Urine protein creatinine ratio (UPC) ≥ 45 mg/mmol,for patients with NF2 mutation
  • Total bilirubin ≤ 1.5 x ULN, Except in case of Gilbert's disease
  • AST/ALT ≤ 2.5 x ULN
  • Fasting triglyceride ≤ 200 mg/dL,for patients with NF2 mutation
  • Fasting cholesterol ≤ 240 mg/dL,for patients with NF2 mutation

• Aged 18-30 years.
• Routinely involved in physical fitness activities.

• Age less than 18 or over 30 years.

• Adults, ≥ 18 years of age.

• Individuals under 18 years of age.
• History of chemotherapy for malignancies.
• Immunosuppressive therapy for autoimmune disease.
• Chronic comorbidities not controlled on medication.
• Acute infectious disease.
• Pregnancy.

Eligibility last updated 4/25/22. 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.

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

Eligibility last updated 12/20/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Phase 1:

• Has Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
• ≥ 1 measurable lesion per RECIST v1.1.
• Has adequate organ function.
• Patients with histologically or cytologically confirmed advanced, metastatic, unresectable solid tumors who have previously received standard systemic therapy or for which treatment is not available, not tolerated or refused.

Inclusion Criteria
•Phase 1B

• Signed informed consent form (ICF) and able to comply with study requirements.
• Age ≥ 18 years (or the legal age of consent) at the time the ICF is signed.
• Histologically or cytologically confirmed tumor types in the following disease cohorts:
  • Cohort 1: stage IV squamous NSCLC;
  • Cohort 2: stage IV non-squamous NSCLC;
  • Cohort 3: stage IV squamous or non-squamous NSCLC with PD-L1 positive;
  • Cohort 4: extensive-stage SCLC; Cohort 5: stage IIIB, IIIC or IV NSCLC;
  • Cohort 6: stage IV ESCC;
  • Cohort 7: stage IV EAC;
  • Cohort 8: recurrent or metastatic HNSCC incurable by local therapies;
  • Cohort 9: stage IV G/GEJ adenocarcinoma.
• ECOG Performance Status ≤ 1.
• Adequate organ function.
• Willing to use highly effective method of birth control.

Exclusion Criteria
•Phase 1:

• Active brain or leptomeningeal metastasis.
• Active autoimmune diseases or history of autoimmune diseases that may relapse.
• With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. (antiviral therapy is permitted for patients with hepatocellular carcinoma).
• Concurrent participation in another therapeutic clinical trial.
• Received prior therapies targeting TIGIT.

Exclusion Criteria
•Phase 1B:

• Patients with any prior therapy for recurrent/metastatic disease.
• Non-squamous NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, and c-ros oncogene 1 (ROS1) fusion.
• Gastric cancer patients with squamous or with positive HER2 expression.
• Prior therapy with any drug specifically targeting T-cell co-stimulation or checkpoint pathways. (anti-PD(L)1 exception for Cohort 5).
• Active leptomeningeal disease or uncontrolled brain metastasis.
• Active autoimmune diseases or history of autoimmune diseases that may relapse.
• With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc. (antiviral therapy is permitted for patients with hepatocellular carcinoma).
• Concurrent participation in another therapeutic clinical study.
  • NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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

• Eligible particiants between the ages of 18 and 90.
• Either a family or personal history of cancer and/or a family or personal history of genetic variants in cancer predisposition genes.
• Participants may also be those who have tested negatively for genetic variants in cancer predisposition genes.

• This project does not involve prisoners or children.

Eligibility last updated 8/16.21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Patients with a WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U with >15% RS (1).
• Prior treatment with lenalidomide, hypomethylating agents, immunosuppressive therapy or investigational agent is allowed as long as patients have not received luspatercept-aamt or sotatercept. If there is prior history of investigational agent, there should be an interval equivalent to at least four elimination half-lives of the agent prior to enrollment.
  • Note: For patients who have received prior lenalidomide, hypomethylating agents, or immunosuppressive therapy, there must be ≥6 weeks since the last dose before luspatercept-aamt treatment is started.
• ECOG Performance Score of 0, 1 or 2.
• Requirement of red blood cell transfusions (≥ 2 units  ≤ 8-weeks prior to registration) OR symptomatic anemia with hemoglobin < 9.5 g/dL OR hematocrit < 30% (as long as there is documentation of adequate iron stores (ferritin  > 50 mg/L)  ≤ 5 weeks prior to registration). Symptomatic anemia is defined as fatigue with or without exertion, shortness of breath with or without exertion, or decrease in exercise tolerance.
• The following laboratory values obtained ≤ 14 days prior to registration:
  • Hemoglobin  <  9.5 g/dL;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula below:
  • Cockcroft-Gault Equation:
  • Creatinine clearance for males =          (140
    •age)(weight in kg)
  •                                                                (72)(serum creatinine in mg/dL);
  • Creatinine clearance for females =       (140
    •age)(weight in kg)(0.85)
  •                                                                (72)(serum creatinine in mg/dL).
• Females of childbearing potential (FCBP) defined as a sexually mature woman who:
  • has achieved menarche at some point;
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) and must:
    • Must have two negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy. A negative pregnancy test must be done ≤ 7 days prior to registration. Patient must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact;
    • Either commit to true abstinence*from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with highly effective, contraception without interruption during the study therapy (including dose interruptions), and for 84 days after discontinuation of study therapy.
• Male participants must:
  • Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 84 days following investigational product discontinuation even if he has undergone a successful vasectomy.
  • * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Willingness to provide mandatory blood specimens for correlative research.

• 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 highly effective contraception.
• Any of the following prior therapies:
  • Surgery ≤ 3 weeks prior to registration;
  • Chemotherapy or other agents ≤ 2 weeks prior to registration.
• Uncontrolled intercurrent non-cardiac illness including, but not limited to:
• • Ongoing or active infection;
  • Uncontrolled hypertension (defined as systolic blood pressure ≥ 140 mmHg or diagnostic blood pressure >=90 mmHg despite use of ≥ 3 anti-hypertensive drugs at optimal doses).
• Psychiatric illness/social situations.
• Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy.
• Clinically significant (symptomatic) anemia either due to nutritional deficiencies or iron, vitamin B12, folate or GI bleeding.
• Any other conditions that would limit compliance with study requirements.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
  • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state (CD4 ≤ 200 x 106/L), are eligible for this trial.
• Receiving any other drug (except hydroxyurea) or investigational agent which would be considered as a treatment for the primary disease, that is, MDS/MPN-RS-T or MDS/MPN-U with RS ≤ 2 weeks prior to registration.
• Other active malignancy ≤ 3 years prior to registration. Patients on hormonal therapy for treated breast or prostate cancer are permitted if they meet other eligibility criteria.
• EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (luteinizing hormone-releasing hormone (LHRH) agonists for prostate cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors) for their cancer.
• History of myocardial infarction, stroke, embolism, deep vein or arterial thrombosis ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.

Eligibility last updated 7/10/23. Questions regarding updates should be directed to the study team contact.

• Male or female, age 21-80 (inclusive) with at least 3 years of life expectancy.
• Subject plans to undergo a one-level Open or Mini-Open TLIF procedure (stabilized with pedicle screws) independent of this research protocol.
• Subject is to be treated with on-label use of an FDA-cleared TLIF cage and pedicle screw system independent of this research protocol.
• The subject has a primary diagnosis of symptomatic lumbar degeneration with or without foraminal or recess stenosis of the lumbar spine at a single level from L1/L2 to L5/S1 confirmed by subject history and radiographic imaging (CT, MRI, X-rays) with no more than a Grade 1 (< 25% translation) spondylolisthesis. Symptomatic lumbar degeneration that may be associated with a co-morbid condition such as:
  • Herniated nucleus pulposus;
  • Scarring/thickening of the ligamentum flavum, annulus fibrosus, or facet joint capsule;
  • Facet joint degeneration/osteophyte formation;
  • Spondylosis (defined by the presence of osteophytes);
  • Disc degeneration and/or annular degeneration; and/or
  • Lumbar stenosis defined by spinal cord or nerve root compression.
• Exhausted conservative treatment (e.g., bed rest, physical therapy, medications, TENS, manipulation, and/or spinal injections) for at least 3 months or has a neurologic emergency.
• Preoperative Oswestry Disability Index score > 40/100 at baseline.
• Psychosocially, mentally and physically able and willing to fully comply with this protocol including adhering to follow-up schedule and requirements and filling out forms.
• Signed informed consent.

• More than one vertebral level requiring treatment.
• revious instrumented surgery (i.e., anterior disc replacement, spinal fusion, interspinous device, etc.) at the index lumbar level or an adjacent level.
• Degenerative or lytic spondylolisthesis greater than Grade 1 (< 25% translation).
• Rotatory scoliosis at the level to be treated.
• Congenital bony and/or spinal cord abnormalities at the level to be treated.
• Subcaudal defect, disrupting the integrity of the pedicle.
• Clinically compromised vertebral bodies at the involved level due to current or past trauma; e.g., by the radiographic appearance of the fracture callus, malunion or nonunion.
• Disrupted anterior longitudinal ligament at the index level.
• Overlying thoracolumbar kyphosis (greater than or equal to 15 degrees) within one level (includes target and adjacent level) of the level to be treated.
• Back pain of unknown etiology without leg pain.
• Severe spondylosis at the level to be treated as characterized by any of the following:
  • Autofusion (solid arthrodesis) determined radiographically (CT);
  • Totally collapsed disc; or
  • Vertebral body that cannot be mobilized.
• Known allergy to cobalt, chromium, molybdenum, nickel, polyethylene, titanium, or vitamin E.
• Unable to undergo a CT scan or other radiograph assessments.
• Osteopenia: All patients will completeThe SCORE/MORES will be utilized to screen if a DEXA scan is indicated. If SCORE/MORES value ≥ 6, then a DEXA scan is required. If DEXA is required, exclusion will be defined as a DEXA bone density measured T score ≤ -1. An existing DEXA is allowed if completed within 6 months of subject screening.
• Has history of any endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget's disease, renal osteodystrophy, Ehler-Danlos syndrome, or osteogenesis imperfecta).
• Insulin-dependent diabetes mellitus.
• Lactating, pregnant or interested in becoming pregnant in the next 3 years.
• Active infection – systemic or local.
• Any medical condition requiring treatment with any drug known to potentially interfere with bone/soft tissue healing or receiving radiation therapy that is expected to continue for the duration of the study.
• Body Mass Index > 40.
• Recurrent history of deep vein thrombosis, symptoms of arterial insufficiency, or thromboembolic disease.
• Systemic disease including Lupus disease, Reiter’s disease, Rheumatoid disease, AIDS, HIV, hepatitis or autoimmune disease that requires immunosuppressive therapy, including biologics, for systemic inflammation.
• Spinal tumor.
• Active malignancy: A patient with a history of any invasive malignancy (except non-melanoma skin cancer), unless he/she has been treated with curative intent and there have been no clinical signs or symptoms of the malignancy for at least 5 years.
• Any degenerative muscular or neurological condition that would interfere with evaluation of outcomes, including but not limited to Parkinson’s disease, amyotrophic lateral sclerosis (ALS), or multiple sclerosis.
• Has chronic or acute renal and/or hepatic impairment and/or failure or prior history of renal and/or hepatic parenchymal disease.
• Has a Waddell Signs of Inorganic Behavior score of 3 or greater.
• In the opinion of the investigator, the subject has a behavioral, cognitive, social or medical problem that may interfere with the assessment of the safety or effectiveness of the device.
• Current or recent history of chemical/alcohol abuse or dependency using standard medical definition of DSM-5 code.
• Currently smoking or using tobacco products, including e-cigarette products (e.g., vaping) (Use within 30 days of screening date is considered ‘current’).
• Currently pursuing or in active spinal litigation for medical negligence, or trauma, or workers compensation.
• Is a prisoner, incarcerated, or has been coerced to participate in the study that could impact the validity of results.
• Is currently participating in an investigational therapy (device and/or pharmaceutical) within 30 days prior to entering the study or such treatment is planned during the 24 months following enrollment into the study.

Eligibility last updated 7/21/22. Questions regarding updates should be directed to the study team contact.

• Age 16-55 years old.
• Medial, lateral, vertical longitutdinal, oblique, or radial meniscal tear.
• Complex tears may be included (investigator discetion) if the patient has one of the tear patterns listed in incluse as the predominant finding.
• No other concomitant procedures unless (one of the following):
  • Chondroplasty;
  • Synovectomy;
  • Loose body removal;
  • “Contralateral” menisectomy (i.e., medial meniscus repair with a lateral menisectomy or lateral meniscus repair with a medial menisectomy) would be permitted for inclusion;
  • Any other procedure that does not include drilling, requires prior approval of the study sponsor for each procedure.

• Patients requiring cartilage restorative or repair procedures (i.e., OCD fixation, micro-fracture repair, or others).
• Patients with meniscus root tears.
• Patients undergoing repair for horizontal cleavage tears.
• Kellgren-Lawrence scale > 2.
• Patients undergoing lateral release.
• Ipsilateral chondral lesion with Outerbridge classification of 3-4.
• Use of prednisone or other steroids, any immunosuppressant, or chemotherapy 1-week before surgery or expected use within six weeks after surgery.
• Cortisone use within the six weeks prior to surgery.
• Utilizing worker’s compensation at the time of screening.
• Any previous ligament surgery on the index limb. Any previous meniscal surgery on the index meniscus.
• Concomitant ligamentous insufficiency.
• Inflammatory rheumatic disease or other rheumatic disease.
• Immune compromised patients (hepatitis, HIV, etc.).
• Any nicotine based products within the three months prior to surgery (including cigarettes, cigars, vaping, nicotaine patch, etc.).
• History of distal femur, proximal tibia, or patellar fracture that was treated operatively.
• Non English-speaking patients.

• Age ≥ 18.
• Blood cancer diagnosis (including B-ALL, multiple myeloma, and lymphoma).
• Receiving a CAR-T product.
• Able to complete a written questionnaire in English either at home or with assistance at an appointment.
• Able to perform a verbal interview either in person or via phone teleconference.

• Severe cognitive deficit of neuropsychiatric condition that would prevent person from being able to provide informed consent or complete survey or interview questions.

Eligibility last updated 6/3/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 8/9/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Clinician:

• All clinicians responsible for caring for eligible patients will be considered for inclusion in the qualitative research. 

Exclusion Criteria
•Clinician:

• If the clinician declines to participate, the patient is still eligible for the study, but qualitative evaluations will be omitted.

Inclusion Criteria
•Patient:

• Participants will be recruited from those identified by a developed electronic health record list of patients with AKI. 
• Included individuals that populate the list are those with stage III AKI (severe) during a hospitalization based on serum creatinine rise or urine output decline from Olmsted County.

Exclusion Criteria
•Patient: 

• Dementia.
• Non-English speaking.
• Expected to be dismissed to a skilled nursing facility or hospice at discharge.
• Expected to need dialysis at discharge.
• Primary Care Transitions Program enrollment.
• Transplant recipients within 100 days of transplant.
• Can only have one time enrollment.  

Eligibility last updated 1/18/22. Questions regarding updates should be directed to the study team contact.

• Mayo Clinic Midwest patient (Rochester or Mayo Clinic Health System [MCHS]) (has a Mayo Clinic number)
• Aged 18 years or older
• Can read and speak in the English language. Based on 2019 data, 97% of our Rochester and MCHS patients speak English. The study will provide all participants with a smoking cessation program delivered through the Mayo Clinic patient portal. Currently, Mayo Clinic’s portal services are not offered in languages other than English.
• Has a Minnesota, Iowa, or Wisconsin address currently or at date of most recent visit.
• Rural resident based on RUCA codes derived from ZIP code of current or last known address.
• Has access to a phone (of any type). Access to a phone is needed to complete the coaching support intervention and to follow-up with participants if there are issues with accessing the patient portal for the smoking cessation intervention.
• Current smoker defined as one or more cigarettes (even a puff) smoked in the past 30 days. This definition allows for enrollment of non-daily and/or “light smokers” enhancing the generalizability. In addition, to enhance the generalizability of our findings, we will enroll participants using other tobacco/nicotine products if cigarette smoking is the primary product used.
• For past 3 months not enrolled in a program or using pharmacotherapy to stop smoking.
• Willing to make a quit attempt.
• Has digital access barriers defined by one or more of the following:
  • based on participant ZIP code from current or last known address geocoded census block group indicates area of poor BB internet coverage;
  • no existing Mayo Clinic patient portal account; or
  • has a Mayo Clinic patient portal account but has not used it in the past 5 years;
  • self-reports having no access to broadband (high speed) internet connection for personal use; and/or
  • self-reports low digital literacy defined with the screening question “How comfortable are you using technology to manage your health care remotely? For example, using patient online services (i.e., patient portal) to schedule appointments, check for test results, or send a message to your provider?” (included: not at all or a little comfortable).

• Anyone not meeting all inclusion criteria will be excluded. 
• Has participated in a behavioral smoking cessation program in the past 3 months.

Eligibility last updated 11/5/21.  Questions regarding updates should be directed to the study team contact.

• Histologically or cytologically confirmed malignant peritoneal mesothelioma for which there has been no prior treatment. Given the indolent nature of well-differentiated papillary mesothelioma and multicystic mesothelioma, patients with these variants are not eligible for participation.
• All slides including performed immunostains from diagnostic tumor tissue together with pathology report for retrospective central pathology review.
• Must have measurable disease per RECIST version (v) 1.1.
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 28 days prior to registration is required.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Required initial laboratory vaues:
  • Leukocytes ≥ 2,500/mm^3;
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal;
  • Total bilirubin ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 3.0 x upper limit of normal (ULN);
  • Urine protein:creatinine (UPC) ratio < 1, or urine protein: ≤ 1+.
• No prior systemic therapy for peritoneal mesothelioma is allowed. No concurrent radiotherapy is allowed.
• No active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
  • Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study;
  • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
  • Rash must cover < 10% of body surface area;
  • Disease is well controlled at baseline and requires only low-potency topical corticosteroids;
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
• No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
• No prior allogeneic stem cell or solid organ transplantation.
• Central nervous system (CNS) metastases must have been treated with local therapy (surgery, radiation, ablation) with systemic steroids tapered to a physiologic dose (10 mg or prednisone equivalent or less).
• Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are allowed.
• No history of inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg).
• No history of hypertensive crisis or hypertensive encephalopathy.
• No clinically significant cardiovascular disease, such as cerebrovascular accidents within 6 months prior to randomization, myocardial infarction within 6 months prior to randomization, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment.
• No clinically significant cardiovascular disease, such as cerebrovascular accidents within 12 months prior to randomization, myocardial infarction within 12 months prior to randomization, unstable angina, New York Heart Association (NYHA) grade II or greater CHF, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment.
• No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to randomization.
• No history of grade ≥ 4 venous thromboembolism.
• No history or evidence upon physical or neurological examination of central nervous system.
• No history of grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood per episode) within 1 month prior to screening.
• No history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation).
• No major surgical procedure or significant traumatic injury within 28 days prior to initiation of study treatment (diagnostic laparoscopy is allowed as part of diagnosing peritoneal mesothelioma).
• No core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment.
• Placement of a vascular access device should be at least 2 days prior to initiation of study treatment.
• No active infection requiring IV antibiotics at the time of initiation of study treatment.
• No history of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to randomization.
• No serious, non-healing wound, active ulcer, or untreated bone fracture.
• No other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer.
• Patients with a creatinine clearance between 45 and 79 mL/min should not use ibuprofen or other nonsteroidal anti-inflammatory drug (NSAIDs) for 2 days before, the day of, and 2 days following pemetrexed administration.
• No treatment with immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
  • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study;
  • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

Eligibility last updated 10/19/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

1. Age between 23 and 80 years, inclusive, at screening.

2. AGHD Diagnosis Criteria

For adult-onset AGHD: documented history of structural hypothalamic-pituitary disease,
hypothalamic-pituitary surgery, cranial irradiation, 1-4 non-GH pituitary hormone
deficiencies, a proven genetic cause of GHD, or traumatic brain injury (TBI).

A. For all countries except Japan: Subjects must satisfy at least one of the following
criteria:

1. Insulin tolerance test: peak GH ≤5 ng/mL

2. Glucagon stimulation test according to body mass index (BMI)

- i. BMI ≤30 kg/m2: peak GH ≤3 ng/mL

- ii. BMI >30 kg/m2: peak GH ≤1 ng/mL

3. Three or four pituitary axis deficiencies (i.e., adrenal, thyroid, gonadal,
and/or vasopressin; not including GH) with IGF-1 SDS ≤ -2.0 at screening

4. Macimorelin test: peak GH ≤2.8 ng/mL

5. Growth hormone releasing hormone (GHRH) + arginine test according to BMI:

- i. BMI <25 kg/m2, peak GH <11 ng/mL

- ii. BMI ≥25-≤30 kg/m2, peak GH <8 ng/mL

- iii. BMI >30 kg/m2, peak GH <4 ng/mL

B. For Japan only: Subjects with AGHD and deficiency of at least one non-GH pituitary
hormones need to satisfy one of the following GH stimulation tests. Subjects with GHD
and evidence of intracranial structure disorder need to satisfy at least 2 of the
following stimulation tests:

1. Insulin tolerance test: peak GH ≤1.8 ng/mL

2. Glucagon test: peak GH ≤1.8 ng/mL

3. Growth Hormone Releasing Peptide-2 (GHRP-2) tolerance test: peak GH ≤9 ng/mL

3. IGF-1 SDS ≤ -1.0 at screening as measured by central laboratory.

4. hGH treatment naïve or no exposure to hGH therapy or GH secretagogue for at least 12
months prior to screening.

5. For subjects on hormone replacement therapies for any hormone deficiencies other than
GH (e.g., adrenal, thyroid, estrogen, testosterone) must be on adequate and stable
doses for ≥6 weeks prior to and throughout screening.

6. For subjects not on glucocorticoid replacement therapy, documentation of adequate
adrenal function at screening defined.

7. For males not on testosterone replacement therapy: morning (6:00
•10:00AM) total
testosterone within normal limits for age.

8. On a stable diet and exercise regime at screening with no intention to modify diet or
exercise pattern during the trial, i.e., no weight reduction program intended during
the trial or within the last 90 days prior to or through screening.

9. No plans to undergo bariatric surgery during the trial.

10. Fundoscopy at screening without signs/symptoms of intracranial hypertension or
diabetic retinopathy above stage 2 / moderate or above or any other retinal disease
contraindicated to growth hormone therapy. For subjects with a diagnosis of diabetes
mellitus at screening, this must be documented with a fundus photograph.

11. Able and willing to provide a written informed consent and authorization for protected
health information (PHI) disclosure in accordance with Good Clinical Practice (GCP).

12. Serum fT4 in the normal range at screening as measured by central laboratory.

Exclusion Criteria

1. Known Prader-Willi Syndrome and/or other genetic diseases that may have an impact on
an endpoint.

2. Diabetes mellitus at screening if any of the following criteria are met:

1. Poorly controlled diabetes, defined as HbA1c >7.5% at screening.

2. Diabetes mellitus (defined as HbA1c ≥6.5% and/or fasting plasma glucose ≥126
mg/dL and/or plasma glucose ≥200 mg/dL two hours after oral glucose tolerance
test) diagnosed <26 weeks prior to screening

3. Change in diabetes regimen (includes dose adjustment) within <90 days prior and
throughout screening

4. Use of any diabetes drugs other than metformin and/or DPP-4 inhibitors for a
cumulative duration of greater than 4 weeks within 12 months prior to screening

5. Diabetes-related complications at screening (i.e., nephropathy as judged by the
investigator, neuropathy requiring pharmacological treatment, retinopathy stage 2
/ moderate and above within 90 days prior to screening or during screening)

3. Active malignant disease or history of malignancy. Exceptions to this exclusion
criterion:

1. Resection of in situ carcinoma of the cervix uteri

2. Complete eradication of squamous cell or basal cell carcinoma of the skin

3. Subjects with GHD attributed to treatment of intracranial malignant tumors or
leukemia, provided that a recurrence-free survival period of at least 5 years
prior to screening is documented in the subject's file (based on a Magnetic
Resonance Imaging (MRI) result for intracranial malignant tumors)

4. Evidence of growth of pituitary adenoma or other benign intracranial tumor within the
last 12 months before screening.

5. Subjects with acromegaly without remission / with documented remission less than 24
months prior to screening.

6. Subjects with Cushing's disease without remission / with documented remission less
than 24 months prior to screening.

7. Subjects with prior cranial irradiation or hypothalamic-pituitary surgery: the
procedure took place less than 12 months prior to screening.

8. eGFR <60 mL/min/1.73m2 determined based on Modification of Diet in Renal Disease
(MDRD) equation.

9. Hepatic transaminases (i.e., AST or ALT) >3 times the upper limit of normal.

10. Heart failure NYHA class 3 or greater (NYHA 1994).

11. QTcF ≥ 451 milliseconds on 12-lead ECG at screening.

12. Poorly controlled hypertension, defined as supine systolic blood pressure >159 mmHg
and/or supine diastolic blood pressure >95 mmHg at screening.

13. Cerebrovascular accident within 5 years prior to screening.

14. Anabolic steroids (other than gonadal steroid replacement therapy) or
oral/intravenous/intramuscular corticosteroids within 90 days prior to or throughout
screening.

15. Currently using or have used within 26 weeks prior to screening any weight-loss or
appetite-suppressive medications.

16. Known history of hypersensitivity and/or idiosyncrasy to any of the test compounds
(somatropin) or excipients employed in this trial.

17. Known history of neutralizing anti-hGH antibodies.

18. Inability to undergo scanning by DXA or a non-interpretable DXA scan at screening.

19. Female who is pregnant, breast-feeding or intends to become pregnant or is of
childbearing potential (i.e., fertile, following menarche and until becoming
post-menopausal unless permanently sterile) and not using adequate contraceptive
methods

20. Male subjects must use a condom, or his female partner of childbearing potential must
use an effective form of contraception as described above, from the beginning of
screening to the last trial visit.

21. Known substance abuse or known (or previous) eating disorders, including anorexia
nervosa, bulimia and severe gastrointestinal disease affecting normal eating (as
judged by the investigator).

22. Any disease or condition that, in the judgement of the investigator, may make the
subject unlikely to comply with the requirements of the trial or any condition that
presents undue risk from the investigational product or procedures.

23. Participation in another interventional clinical trial involving an investigational
compound within 26 weeks prior to screening or in parallel to this trial.

24. Currently using or have used within the last 3 days prior to screening: biotin >0.03
mg/day from supplements

25. Known history of positive results of tests for human immunodeficiency virus (HIV)
antibodies or hepatitis B and/or C (exceptions if vaccinated towards Hepatitis B virus
and Hepatitis C virus).

26. Any of the following: acute critical illness, and complications following open heart
surgery, abdominal surgery, multiple accidental traumas, acute respiratory failure, or
similar conditions within 180 days prior to screening.

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

Eligibility last updated [10/5/22]. Questions regarding updates should be directed to the study team contact.

PRIOR TO STEP 1 REGISTRATION

• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration.
• High-risk disease defined as having at least one or more of the following:
  • PSA > 20 ng/mL prior to starting ADT;
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]);
  • Gleason score of 8-10;
  • Node positive by conventional imaging with a short axis of at least 1.0 cm;
  • Appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 120 days prior to registration;
    • Bone imaging within 120 days prior to registration;
      • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative Na F PET/CT or negative axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed).
  • Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or Na F PET will still be eligible.
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only.
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by > 10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e., N1), but whose nodes do not meet traditional size criteria for positivity (i.e., they measure ≤ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration.
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration).
  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility.
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) within 120 days prior to registration.
    • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible.
    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration).
    • Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration).
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (didanosine [DDI] is not permitted) with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to abiraterone acetate and apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with abiraterone acetate and apalutamide.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients 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 for this trial.
  • Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

PRIOR TO STEP 2 RANDOMIZATION

• Confirmation of Decipher score.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs.
• Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol.

For patients entering the Intensification Cohort ONLY:

• Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization.

For patients entering the Intensification Cohort ONLY:

• Serum potassium ≥ 3.5 mmol/L prior to Step 2 randomization.

PRIOR TO STEP 1 REGISTRATION

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI).
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration.
• Prior radical prostatectomy.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Current use of 5-alpha reductase inhibitor.
  • Note: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible.
• Didanosine (DDI) antiretroviral therapy is not permitted.
• History of any of the following:
  • Seizure disorder;
  • Current severe or unstable angina;
  • New York Heart Association Functional Classification III/IV;
    • Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
  • History of any condition that in the opinion of the investigator, would preclude participation in this study.
• Evidence of any of the following at registration:
  • Active uncontrolled infection requiring IV antibiotics;
  • Baseline moderate and severe hepatic impairment (Child-Pugh class B & C);
  • Inability to swallow oral pills;
  • Any current condition that in the opinion of the investigator, would preclude participation in this study.
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA and testosterone must be obtained prior to the start of any ADT.

PRIOR TO STEP 2 RANDOMIZATION

• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration.

For patients entering the Intensification Cohort ONLY:

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily.

For patients entering the Intensification Cohort ONLY:

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg);
• Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.

Inclusion Criteria:

• Inclusion criteria consists of patients (≥ 18 years old) with predominant spasticity (MAS ≥ 2) in their elbow flexors without a severely fixed joint contracture (≤ 30 degrees of flexion deformity) as a result of an acquired brain injury (cerebrovascular accident, anoxic brain injury, traumatic brain injury).
• Adult patients (≥ 18 years) who are at least 12 months from their neurologic insult without evidence of ongoing neurorecovery will be placed into the muscle-tendon lengthening versus HSN group.  Patients will be randomized to either study group with 16 patients in each cohort.   

• Patients < 18 years of age.
• Patients who are not medically optimized to undergo surgery.
• Patients who cannot participate in the pre-operative electrophysiologic and gait analysis.
• Patients who are on chronic anticoagulation that cannot be held perioperatively.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

• Age 18+.
• Able to give informed consent.
• Newly diagnosed clear-cell renal cell carcinoma.
• Eligible for radical nephrectomy.

• Unable or unwilling to provide informed consent.
• No previous systemic therapy.